FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Boyce, AM Turner, A Watts, L Forestier-Zhang, L Underhill, A Pinedo-Villanueva, R Monsell, F Tessaris, D Burren, C Masi, L Hamdy, N Brandi, ML Chapurlat, R Collins, MT Javaid, MK AF Boyce, A. M. Turner, A. Watts, L. Forestier-Zhang, L. Underhill, A. Pinedo-Villanueva, R. Monsell, F. Tessaris, D. Burren, C. Masi, L. Hamdy, N. Brandi, M. L. Chapurlat, R. Collins, M. T. Javaid, Muhammad Kassim TI Improving patient outcomes in fibrous dysplasia/McCune-Albright syndrome: an international multidisciplinary workshop to inform an international partnership SO ARCHIVES OF OSTEOPOROSIS LA English DT Article DE Fibrous dysplasia; McCune-Albright syndrome; Patient-centered care; Epidemiology ID BONE AB A Summary To develop consensus on improving the management of patients, we convened an international workshop involving patients, clinicians, and researchers. Key findings included the diagnostic delay and variability in subsequent management with agreement to develop an international natural history study. We now invite other stakeholders to join the partnership. Purpose The aim of this study was develop a consensus on how to improve the management of patients with fibrous dysplasia and prioritize areas for research Methods An international workshop was held over 3 days involving patients, clinicians, and researchers. Each day had a combination of formal presentations and facilitated discussions that focused on clinical pathways and research. Results The patient workshop day highlighted the variability of patients' experience in getting a diagnosis, the knowledge of general clinical staff, and understanding long-term outcomes. The research workshop prioritized collaborations that improved understanding of the contemporary natural history of fibrous dysplasia/McCune-Albright syndrome (FD/MAS). The clinical workshop outlined the key issues around diagnostics, assessment of severity, treatment and monitoring of patients. Conclusions In spite of advances in understanding the genetic and molecular underpinnings of fibrous dysplasia/McCune-Albright syndrome, clinical management remains a challenge. From the workshop, a consensus was reached to create an international, multi-stakeholder partnership to advance research and clinical care in FD/MAS. We invite other stakeholders to join the partnership. C1 [Boyce, A. M.; Collins, M. T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. [Boyce, A. M.] Childrens Natl Med Ctr, Bone Hlth Program, Div Orthoped & Sports Med, Washington, DC 20010 USA. [Boyce, A. M.] Childrens Natl Med Ctr, Div Endocrinol & Diabet, Washington, DC 20010 USA. [Turner, A.; Watts, L.; Forestier-Zhang, L.; Pinedo-Villanueva, R.; Javaid, Muhammad Kassim] Univ Oxford, NIHR Musculoskeletal Biomed Res Unit, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Nuffield Orthopaed Ctr, Windmill Rd, Oxford OX3 7LD, England. [Underhill, A.] Chandlers Ford, Eastleigh SO53 1TQ, Hants, England. [Monsell, F.; Burren, C.] Bristol Royal Hosp Children, Paul OGorman Bldg,Upper Maudlin St, Bristol BS2 8BJ, Avon, England. [Tessaris, D.] Univ Turin, Dept Pediat Endocrinol & Diabetol, Regina Margherita Children Hosp, Polonia 94, I-10126 Turin, Italy. [Masi, L.; Brandi, M. L.] Univ Florence, Dept Internal Med, Viale Pieraccini 6, I-50134 Florence, Italy. [Hamdy, N.] Leiden Univ, Med Ctr, Dept Endocrinol & Metab Dis, NL-2333 ZA Leiden, Netherlands. [Chapurlat, R.] Univ Lyon, NSERM UMR 1033, Dept Rheumatol, Hosp Civils Lyon, Lyon, France. RP Javaid, MK (reprint author), Univ Oxford, NIHR Musculoskeletal Biomed Res Unit, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Nuffield Orthopaed Ctr, Windmill Rd, Oxford OX3 7LD, England. EM kassim.javaid@ndorms.ox.ac.uk FU Oxford NIHR Musculoskeletal BRU; NIHR Rare Diseases Translational Research Collaboration; MRC Lifecourse Epidemiology Unit; International Osteoporosis Foundation; ProStrakan FX The workshop was supported by the Oxford NIHR Musculoskeletal BRU, NIHR Rare Diseases Translational Research Collaboration, MRC Lifecourse Epidemiology Unit, and International Osteoporosis Foundation. We are grateful to ProStrakan for providing funding towards the running costs of the workshop. NR 9 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 1862-3522 EI 1862-3514 J9 ARCH OSTEOPOROS JI Arch. Osteoporos. PD DEC PY 2017 VL 12 IS 1 AR 21 DI 10.1007/s11657-016-0271-6 PG 6 WC Endocrinology & Metabolism; Orthopedics SC Endocrinology & Metabolism; Orthopedics GA EP9OW UT WOS:000397703900001 PM 28243882 ER PT J AU Lu, N Huang, P Fan, WP Wang, ZT Liu, YJ Wang, S Zhang, GF Hu, JK Liu, WF Niu, G Leapman, RD Lu, GM Chen, XY AF Lu, Nan Huang, Peng Fan, Wenpei Wang, Zhantong Liu, Yijing Wang, Sheng Zhang, Guofeng Hu, Junkai Liu, Wenfei Niu, Gang Leapman, Richard D. Lu, Guangming Chen, Xiaoyuan TI Tri-stimuli-responsive biodegradable theranostics for mild hyperthermia enhanced chemotherapy SO BIOMATERIALS LA English DT Article DE Tri-stimuli-responsive; Theranostics; Mild hyperthermia; Enhanced chemotherapy; CuS; Periodic mesoporous organosilicas ID COPPER SULFIDE NANOPARTICLES; MESOPOROUS ORGANOSILICA NANOPARTICLES; GUIDED PHOTOTHERMAL THERAPY; DRUG-DELIVERY SYSTEM; IN-VITRO; NANOMEDICINE; FABRICATION; CARCINOMA; ONCOLOGY; RELEASE AB The combination of hyperthermia and chemotherapy is able to greatly enhance the treatment efficacy mainly due to the synergistic interactions between these two treatments. In this study, we propose a new concept of mild hyperthermia enhanced chemotherapy to explore and validate the synergistic mechanism in vitro and in vivo. To do this, a novel kind of biodegradable nanotheranostics based on copper sulfide doped periodic mesoporous organosilica nanoparticles (CuS@PMOs) was constructed via an in situ growth method for light-triggered mild hyperthermia and drug delivery. The as-prepared CuS@PMOs exhibit a high doxorubicin (DOX) loading capacity of 470 mg/g. The DOX release from CuS@PMOs can be precisely controlled by three stimuli, including intracellular glutathione (GSH), acidic environment in tumor cells, and external laser irradiation. Most intriguingly, mild hyperthermia induced by laser-irradiated CuS nanoparticles can dramatically improve the cell uptake of nanotheranostics both in vitro and in vivo, thus significantly enhancing the chemotherapeutic efficacy for complete tumor growth suppression without recurrence. Meanwhile, the fluorescence recovery following the DOX release can be used as an indicator to monitor the chemotherapeutic progress. Published by Elsevier Ltd. C1 [Lu, Nan; Liu, Wenfei; Lu, Guangming] Nanjing Univ, Sch Med, Jinling Hosp, Dept Med Imaging, Nanjing 210002, Jiangsu, Peoples R China. [Huang, Peng; Wang, Sheng] Shenzhen Univ, Sch Biomed Engn, Guangdong Key Lab Biomed Measurements & Ultrasoun, Shenzhen 518060, Guangdong, Peoples R China. [Lu, Guangming] Nanjing Univ, Sch Chem & Chem Engn, State Key Lab Analyt Chem Life Sci, Nanjing 210093, Jiangsu, Peoples R China. [Lu, Nan; Fan, Wenpei; Wang, Zhantong; Liu, Yijing; Wang, Sheng; Niu, Gang; Chen, Xiaoyuan] NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. [Zhang, Guofeng; Leapman, Richard D.] NIBIB, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. [Hu, Junkai] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. RP Huang, P (reprint author), Shenzhen Univ, Sch Biomed Engn, Guangdong Key Lab Biomed Measurements & Ultrasoun, Shenzhen 518060, Guangdong, Peoples R China.; Chen, XY (reprint author), NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA.; Lu, GM (reprint author), Nanjing Univ, Sch Med, Jinling Hosp, Dept Med Imaging, Nanjing 210002, Jiangsu, Peoples R China. EM peng.huang@szu.edu.cn; cjr.luguangming@vip.163.com; shawn.chen@nih.gov FU National Key Basic Research Program of the PRC [2014CB744504, 2014CB744501]; Major International (Regional) Joint Research Program of China [81120108013]; National Natural Science Foundation of China [81201175, 81530054, 81401465, 51573096]; Natural Science Foundation of Jiangsu Province [BK20130863]; National Science Foundation for Postdoctoral Scientists of China [2013T60939, 2012M521934]; National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) FX We greatly appreciate financial support from the National Key Basic Research Program of the PRC (2014CB744504 and 2014CB744501), the Major International (Regional) Joint Research Program of China (81120108013), the National Natural Science Foundation of China (81201175, 81530054, 81401465 and 51573096), the Natural Science Foundation of Jiangsu Province (BK20130863), and the National Science Foundation for Postdoctoral Scientists of China (2013T60939 and 2012M521934). We also acknowledge the support from the Intramural Research Program (IRP), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH). NR 39 TC 0 Z9 0 U1 33 U2 33 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 MAY PY 2017 VL 126 BP 39 EP 48 DI 10.1016/j.biomaterials.2017.02.025 PG 10 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA EP7HH UT WOS:000397548300005 PM 28254692 ER PT J AU Holmes, A AF Holmes, Andrew TI Sex and Orexins: Uncovering a Mechanism Underlying Sex Differences in Stress Susceptibility SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material C1 [Holmes, Andrew] NIH, Lab Behav & Genom Neurosci, NIAAA, 5625 Fishers Lane, Room 2N09, Bethesda, MD 20852 USA. RP Holmes, A (reprint author), NIH, Lab Behav & Genom Neurosci, NIAAA, 5625 Fishers Lane, Room 2N09, Bethesda, MD 20852 USA. EM holmesan@mail.nih.gov FU National Institute on Alcohol Abuse and Alcoholism Intramural Research Program FX This work was supported by the National Institute on Alcohol Abuse and Alcoholism Intramural Research Program. NR 10 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 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2017 VL 81 IS 8 BP 642 EP 644 DI 10.1016/j.biopsych.2017.02.005 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EP3SA UT WOS:000397300800007 PM 28317548 ER PT J AU Zanos, P Moaddel, R Morris, PJ Wainer, IW Albuquerque, EX Thompson, SM Thomas, CJ Zarate, CA Gould, TD AF Zanos, Panos Moaddel, Ruin Morris, Patrick J. Wainer, Irving W. Albuquerque, Edson X. Thompson, Scott M. Thomas, Craig J. Zarate, Carlos A., Jr. Gould, Todd D. TI Reply to: Antidepressant Actions of Ketamine Versus Hydroxynorketamine SO BIOLOGICAL PSYCHIATRY LA English DT Letter ID RESISTANT MAJOR DEPRESSION; D-ASPARTATE ANTAGONIST; ADD-ON TRIAL; DOUBLE-BLIND; SUSTAINED ANTIDEPRESSANT; BIPOLAR DEPRESSION; NMDA ANTAGONISTS; CLINICAL-TRIALS; EFFICACY; METABOLITES C1 [Zanos, Panos; Thompson, Scott M.; Gould, Todd D.] Univ Maryland, Sch Med, Dept Psychiat, Room 934D MSTF,685 W Baltimore St, Baltimore, MD 21201 USA. [Albuquerque, Edson X.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD USA. [Albuquerque, Edson X.; Gould, Todd D.] Univ Maryland, Sch Med, Div Translat Toxicol Pharmacol, Baltimore, MD USA. [Thompson, Scott M.] Univ Maryland, Sch Med, Physiol, Baltimore, MD USA. [Gould, Todd D.] Univ Maryland, Sch Med, Anat & Neurobiol, Baltimore, MD USA. [Albuquerque, Edson X.] Univ Maryland, Sch Med, Med, Baltimore, MD USA. [Moaddel, Ruin] NIA, Biomed Res Ctr, Natl Inst Hlth, Baltimore, MD USA. [Morris, Patrick J.; Thomas, Craig J.] Natl Ctr Adv Translat Sci, Natl Inst Hlth, Div Preclin Innovat, Rockville, MD USA. [Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD USA. [Wainer, Irving W.] Mitchell Woods Pharmaceut, Shelton, CT USA. RP Gould, TD (reprint author), Univ Maryland, Sch Med, Dept Psychiat, Room 934D MSTF,685 W Baltimore St, Baltimore, MD 21201 USA.; Gould, TD (reprint author), Univ Maryland, Sch Med, Dept Psychiat, Room 934D MSTF,685 W Baltimore St, Baltimore, MD 21201 USA. EM gouldlab@me.com OI Morris, Patrick/0000-0003-2380-4178 FU National Institutes of Health [MH107615, MH086828]; National Institute on Aging (RM, IWW); National Institute of Mental Health (CAZ); National Center for Advancing Translational Sciences (CJT); Janssen Pharmaceuticals; Roche Pharmaceuticals FX This work was supported by National Institutes of Health Grant Nos. MH107615 (to TDG) and MH086828 (to SMT), and the National Institute on Aging (RM, IWW), National Institute of Mental Health (CAZ), and National Center for Advancing Translational Sciences (CJT) National Institutes of Health intramural research programs.; TDG has received consulting fees from Janssen Pharmaceuticals and research funding from Janssen Pharmaceuticals and Roche Pharmaceuticals during the preceding 2 years. IWW, RM, and CAZ are listed as co-inventors on a patent for the use of (2R, 6R)-hydroxynorketamine, S-dehydronorketamine, and other stereoisomeric dehydro- and hydroxylated metabolites of (R, S)-ketamine metabolites in the treatment of depression and neuropathic pain. IWW, CAZ, RM, TG, PZ, CT, and PM are listed as co-inventors on a patent application for the use of (2R, 6R)-hydroxynorketamine and (2S, 6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and posttraumatic stress disorders. IWW, CAZ, RM, CT, and PM have assigned their patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. TG and PZ have assigned their patent rights to the University of Maryland Baltimore but will share a percentage of any royalties that may be received by the University of Maryland Baltimore. NR 23 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2017 VL 81 IS 8 BP E69 EP E71 DI 10.1016/j.biopsych.2016.08.039 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EP3SA UT WOS:000397300800004 PM 27817846 ER PT J AU Herrick, JA Legrand, F Gounoue, R Nchinda, G Montavon, C Bopda, J Tchana, SM Ondigui, BE Nguluwe, K Fay, MP Makiya, M Metenou, S Nutman, TB Kamgno, J Klion, AD AF Herrick, Jesica A. Legrand, Fanny Gounoue, Raceline Nchinda, Godwin Montavon, Celine Bopda, Jean Tchana, Steve Mbickmen Ondigui, Bienvenu Etogo Nguluwe, Konrad Fay, Michael P. Makiya, Michelle Metenou, Simon Nutman, Thomas B. Kamgno, Joseph Klion, Amy D. TI Posttreatment Reactions After Single-Dose Diethylcarbamazine or Ivermectin in Subjects With Loa loa Infection SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE Loa loa; ivermectin; diethylcarbamazine; eosinophil; filariasis ID ADVERSE-REACTIONS; LYMPHATIC FILARIASIS; CLINICAL PRESENTATION; HUMAN EOSINOPHILS; ONCHOCERCIASIS; LOIASIS; INTERLEUKIN-5; ENCEPHALITIS; SEVERITY; SERUM AB Background. Severe adverse reactions have been observed in individuals with Loa loa infection treated with either diethylcarbamazine (DEC), the drug of choice for loiasis, or ivermectin (IVM), which is used in mass drug administration programs for control of onchocerciasis and lymphatic filariasis in Africa. In this study, posttreatment clinical and immunologic reactions were compared following single-dose therapy with DEC or IVM to assess whether these reactions have the same underlying pathophysiology. Methods. Twelve patients with loiasis and microfilarial counts < 2000 mf/mL were randomized to receive single-dose DEC (8 mg/kg) or IVM (200 mu g/kg). Clinical and laboratory assessments were performed at 4, 8, 24, 48, and 72 hours and 5, 7, 9, and 14 days posttreatment. Results. Posttreatment adverse events were similar following DEC or IVM, but peaked earlier in subjects who received DEC, consistent with a trend toward more rapid and complete microfilarial clearance in the DEC group. After a transient rise (post-IVM) or fall (post-DEC) in the first 24 hours posttreatment, the eosinophil count rose significantly in both groups, peaking at day 5 in the DEC group and day 9 in the IVM group. Serum interleukin 5 levels and eosinophil activation, as assessed by surface expression of CD69 and serum levels of eosinophil granule proteins, were increased posttreatment in both groups. Conclusions. Despite differences in eosinophil and lymphocyte counts during the first 24 hours posttreatment, the overall pattern of hematologic and immunologic changes suggest that posttreatment reactions following DEC and IVM share a common pathophysiology. C1 [Herrick, Jesica A.; Legrand, Fanny; Makiya, Michelle; Metenou, Simon; Nutman, Thomas B.; Klion, Amy D.] NIAID, Parasit Dis Lab, NIH, Bldg 4,Room B1-28, Bethesda, MD 20892 USA. [Gounoue, Raceline] Univ Yaounde I, Fac Sci, Yaounde, Cameroon. [Nchinda, Godwin] Chantal Biya Int Reference Ctr Res Prevent & Mana, Immunol Lab, Yaounde, Cameroon. [Montavon, Celine] Inst Rech Dev, Montpellier, France. [Bopda, Jean; Tchana, Steve Mbickmen; Kamgno, Joseph] Ctr Res Filariasis & Other Trop Dis, Yaounde, Cameroon. [Ondigui, Bienvenu Etogo] Cent Hosp Yaounde, Yaounde, Cameroon. [Nguluwe, Konrad] Dist Hosp Akonolinga, Akonolinga, Cameroon. [Fay, Michael P.] NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kamgno, Joseph] Univ Yaounde I, Fac Med & Biomed Sci, Yaounde, Cameroon. [Herrick, Jesica A.] Univ Illinois, Div Infect Dis Immunol & Int Med, Chicago, IL USA. RP Klion, AD (reprint author), NIAID, Parasit Dis Lab, NIH, Bldg 4,Room B1-28, Bethesda, MD 20892 USA. EM aklion@nih.gov FU Division of Intramural Research of the National Institute for Allergy; Infectious Diseases, National Institutes of Health FX The work was supported by the Division of Intramural Research of the National Institute for Allergy and Infectious Diseases, National Institutes of Health. NR 25 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD APR 15 PY 2017 VL 64 IS 8 BP 1017 EP 1025 DI 10.1093/cid/cix016 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EQ1DO UT WOS:000397809800004 ER PT J AU Sohn, AH Hazra, R AF Sohn, Annette H. Hazra, Rohan TI Old Problems for New Providers: Managing the Postpediatric HIV Generation SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material DE HIV; adolescents; transition; treatment; resistance ID INFECTED ADOLESCENTS; TRANSITION; OUTCOMES; CHILDREN; CARE C1 [Sohn, Annette H.] TREAT Asia amfAR, 388 Sukhumvit Rd,Ste 2104, Bangkok 10110, Thailand. [Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Sohn, AH (reprint author), TREAT Asia amfAR, 388 Sukhumvit Rd,Ste 2104, Bangkok 10110, Thailand. EM annette.sohn@treata-sia.org NR 11 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD APR 15 PY 2017 VL 64 IS 8 BP 1113 EP 1114 DI 10.1093/cid/cix068 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EQ1DO UT WOS:000397809800017 ER PT J AU Uhde, M Ajamian, M Wormser, GP Marques, AR Alaedini, A AF Uhde, Melanie Ajamian, Mary Wormser, Gary P. Marques, Adriana R. Alaedini, Armin TI Quantitative Versus Qualitative Use of Lyme Enzyme-Linked Immunosorbent Assay Reply SO CLINICAL INFECTIOUS DISEASES LA English DT Letter ID ANTIGENIC VARIATION PROTEIN; BORRELIA-BURGDORFERI; ANTIBODY-RESPONSES; DISEASE; VLSE C1 [Uhde, Melanie; Ajamian, Mary; Alaedini, Armin] Columbia Univ, Dept Med, Med Ctr, 1130 St Nicholas Ave,9th Floor, New York, NY 10032 USA. [Wormser, Gary P.] New York Med Coll, Dept Med, Div Infect Dis, Valhalla, NY 10595 USA. [Marques, Adriana R.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Alaedini, A (reprint author), Columbia Univ, Dept Med, Med Ctr, 1130 St Nicholas Ave,9th Floor, New York, NY 10032 USA. EM aa819@columbia.edu FU National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID) [R56AI093763, U54AI057158]; Global Lyme Alliance; Intramural Research Program of NIAID FX This work was supported by the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID) grants R56AI093763 (A. A.) and U54AI057158 (Northeast Biodefense Center-Lipkin) (A. A.), the Global Lyme Alliance (A. A.), and the Intramural Research Program of NIAID (A. R. M.). NR 9 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD APR 15 PY 2017 VL 64 IS 8 BP 1145 EP 1146 DI 10.1093/cid/cix086 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EQ1DO UT WOS:000397809800028 ER PT J AU Chen, MC Vetrivelan, R Guo, CN Chang, C Fuller, PM Lu, J AF Chen, Michael C. Vetrivelan, Ramalingam Guo, Chun-Ni Chang, Catie Fuller, Patrick M. Lu, Jun TI Ventral medullary control of rapid eye movement sleep and atonia SO EXPERIMENTAL NEUROLOGY LA English DT Article DE REM arousal; GABA; VGAT; DREADD; AAV ID BRAIN-STEM; REM-SLEEP; RETICULAR-FORMATION; ACTIVE SLEEP; TRIGEMINAL MOTONEURONS; GABAERGIC NEURONS; MOTOR ATONIA; CAT; INHIBITION; NUCLEUS AB Discrete populations of neurons at multiple levels of the brainstem control rapid eye movement (REM) sleep and the accompanying loss of postural muscle tone, or atonia. The specific contributions of these brainstem cell populations to REM sleep control remains incompletely understood. Here we show in rats that viral vector-based lesions of the ventromedial medulla at a level rostral to the inferior olive (pSOM) produced violent myoclonic twitches and abnormal electromyographic spikes, but not complete loss of tonic atonia, during REM sleep. Motor tone during non-REM (NREM) sleep was unaffected in these same animals. Acute chemogenetic activation of pSOM neurons in rats robustly and selectively suppressed REM sleep but not NREM sleep. Similar lesions targeting the more rostral ventromedial medulla (RVM) did not affect sleep or atonia, while chemogenetic stimulation of the RVM produced wakefulness and reduced sleep. Finally, selective activation of vesicular GABA transporter (VGAT) pSOM neurons in mice produced complete suppression of REM sleep whereas their loss increased EMG spikes during REM sleep. These results reveal a key contribution of the pSOM and specifically the VGAT+ neurons in this region in REM sleep and motor control. (C) 2017 Elsevier Inc. All rights reserved. C1 [Chen, Michael C.; Vetrivelan, Ramalingam; Fuller, Patrick M.; Lu, Jun] Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Chen, Michael C.; Vetrivelan, Ramalingam; Fuller, Patrick M.; Lu, Jun] Harvard Med Sch, Dept Neurol, Div Sleep Med, Boston, MA 02115 USA. [Chang, Catie] NINDS, Adv Magnet Resonance Imaging Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Guo, Chun-Ni] Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 1, Dept Neurol, Shanghai, Peoples R China. RP Lu, J (reprint author), Ctr Life Sci 717,3 Blackfan Circle, Boston, MA 02115 USA. EM jlu@bidmc.harvard.edu FU Hilda and Preston Davis Foundation; National Institutes of Health [NS088482, NS073613, NS092652, NS062727, NS061841] FX The authors acknowledge the expert technical assistance of Quan Ha and Xi Chen. This work was funded by the Hilda and Preston Davis Foundation (M.C.C.) and National Institutes of Health (NS088482 to RV.; NS073613 and NS092652 to P.M.F; NS062727 and NS061841 to J.L.). NR 33 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 EI 1090-2430 J9 EXP NEUROL JI Exp. Neurol. PD APR PY 2017 VL 290 BP 53 EP 62 DI 10.1016/j.expneurol.2017.01.002 PG 10 WC Neurosciences SC Neurosciences & Neurology GA EM5QR UT WOS:000395368000005 PM 28077261 ER PT J AU Agerbaek, MO Pereira, MA Clausen, TM Pehrson, C Oo, HZ Spliid, C Rich, JR Fung, V Nkrumah, F Neequaye, J Biggar, RJ Reynolds, SJ Tosato, G Pullarkat, ST Ayers, LW Theander, TG Daugaard, M Bhatia, K Nielsen, MA Mbulaiteye, SM Salanti, A AF Agerbaek, Mette O. Pereira, Marina A. Clausen, Thomas M. Pehrson, Caroline Oo, Htoo Zarni Spliid, Charlotte Rich, Jamie R. Fung, Vincent Nkrumah, Francis Neequaye, Janet Biggar, Robert J. Reynolds, Steven J. Tosato, Giovanna Pullarkat, Sheeja T. Ayers, Leona W. Theander, Thor G. Daugaard, Mads Bhatia, Kishor Nielsen, Morten A. Mbulaiteye, Sam M. Salanti, Ali TI Burkitt lymphoma expresses oncofetal chondroitin sulfate without being a reservoir for placental malaria sequestration SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE Burkitt lymphoma; VAR2CSA; cancer; malaria; Plasmodium falciparum; chondroitin sulfate A; CSA; chondroitin sulfate proteoglycan ID FALCIPARUM-INFECTED ERYTHROCYTES; EPSTEIN-BARR-VIRUS; PREGNANCY-ASSOCIATED MALARIA; VARIANT SURFACE-ANTIGENS; PLASMODIUM-FALCIPARUM; PARASITE ADHESION; GENE-EXPRESSION; CELL-LINES; B-CELLS; ANTIBODIES AB Burkitt lymphoma (BL) is a malignant disease, which is frequently found in areas with holoendemic Plasmodium falciparum malaria. We have previously found that the VAR2CSA protein is present on malaria-infected erythrocytes and facilitates a highly specific binding to the placenta. ofCS is absent in other non-malignant tissues and thus VAR2CSA generally facilitates parasite sequestration and accumulation in pregnant women. In this study, we show that the specific receptor for VAR2CSA, the oncofetal chondroitin sulfate ( ofCS), is likewise present in BL tissue and cell lines. We therefore explored whether ofCS in BL could act as anchor site for VAR2CSA-expressing infected erythrocytes. In contrast to the placenta, we found no evidence of in vivo sequestering of infected erythrocytes in the BL tissue. Furthermore, we found VAR2CSA-specific antibody titers in children with endemic BL to be lower than in control children from the same malaria endemic region. The abundant presence of ofCS in BL tissue and the absence of ofCS in non-malignant tissue encouraged us to examine whether recombinant VAR2CSA could be used to target BL. We confirmed the binding of VAR2CSA to BL-derived cells and showed that a VAR2CSA drug conjugate efficiently killed the BL-derived cell lines in vitro. These results identify ofCS as a novel therapeutic BL target and highlight how VAR2CSA could be used as a tool for the discovery of novel approaches for directing BL therapy. C1 [Agerbaek, Mette O.; Pereira, Marina A.; Clausen, Thomas M.; Pehrson, Caroline; Spliid, Charlotte; Nielsen, Morten A.; Salanti, Ali] Univ Copenhagen, Ctr Med Parasitol, Dept Immunol & Microbiol, Copenhagen, Denmark. [Agerbaek, Mette O.; Pereira, Marina A.; Clausen, Thomas M.; Pehrson, Caroline; Spliid, Charlotte; Nielsen, Morten A.; Salanti, Ali] Copenhagen Univ Hosp, Dept Infect Dis, Copenhagen, Denmark. [Clausen, Thomas M.; Oo, Htoo Zarni; Daugaard, Mads] Vancouver Prostate Ctr, Vancouver, BC V6H 3Z6, Canada. [Clausen, Thomas M.; Oo, Htoo Zarni] Univ British Columbia, Dept Urol Sci, Vancouver, BC V6H 3Z6, Canada. [Rich, Jamie R.; Fung, Vincent] Zymeworks Inc, Vancouver, BC V6H 3V9, Canada. [Nkrumah, Francis] Noguchi Mem Inst, Accra, Ghana. [Neequaye, Janet] Korle Bu Univ Teaching Hosp, Dept Child Hlth, Accra, Ghana. [Biggar, Robert J.] Queensland Univ Technol, Inst Hlth & Biotechnol, Brisbane, Qld 4001, Australia. [Reynolds, Steven J.] Natl Inst Hlth, Div Intramural Res, Natl Inst Allergy & Infect Dis, Bethesda, MD USA. [Tosato, Giovanna] Natl Inst Hlth, Cellular Oncol Lab, Natl Canc Inst, Bethesda, MD USA. [Pullarkat, Sheeja T.] Univ Calif Los Angeles, Dept Pathol, Los Angeles, CA USA. [Pullarkat, Sheeja T.] Univ Calif Los Angeles, Lab Med, Los Angeles, CA USA. [Ayers, Leona W.; Mbulaiteye, Sam M.] Ohio State Univ, Dept Pathol, Columbus, OH 43210 USA. [Bhatia, Kishor] Natl Inst Hlth, Div Canc Epidemiol & Genet, Natl Canc Inst, Bethesda, MD USA. RP Salanti, A (reprint author), Univ Copenhagen, Ctr Med Parasitol, Dept Immunol & Microbiol, Copenhagen, Denmark.; Mbulaiteye, SM (reprint author), Natl Inst Hlth, Div Canc Epidemiol & Genet, Natl Canc Inst, Bethesda, MD USA. EM mbulaits@mail.nih.gov; salanti@sund.ku.dk FU Harboe Foundation; European Research Councils under the MalOnco program; Danish Innovation Foundation; EUREKA program; Danish Cancer Society; Intramural Research Program of the Division of Cancer Epidemiology and Genetics; National Cancer Institute; National Institute of Allergy and Infectious Diseases; National Institutes of Health; Department of Health and Human Services [N01-CO-12400, AI-001040] FX Grant sponsor: Harboe Foundation, European Research Councils under the MalOnco program, the Danish Innovation Foundation and the EUREKA program; Grant sponsor: Danish Cancer Society; Grant sponsor: Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, and National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services; Grant numbers: N01-CO-12400, AI-001040 NR 53 TC 0 Z9 0 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD APR PY 2017 VL 140 IS 7 BP 1597 EP 1608 DI 10.1002/ijc.30575 PG 12 WC Oncology SC Oncology GA EM2WT UT WOS:000395177200014 PM 27997697 ER PT J AU Huang, JQ Zagai, U Hallmans, G Nyren, O Engstrand, L Stolzenberg-Solomon, R Duell, EJ Overvad, K Katzke, VA Kaaks, R Jenab, M Park, JY Murillo, R Trichopoulou, A Lagiou, P Bamia, C Bradbury, KE Riboli, E Aune, D Tsilidis, KK Capella, G Agudo, A Krogh, V Palli, D Panico, S Weiderpass, E Tjonneland, A Olsen, A Martinez, B Redondo-Sanchez, D Chirlaque, MD Peeters, PH Regner, S Lindkvist, B Naccarati, A Ardanaz, E Larranaga, N Boutron-Ruault, MC Rebours, V Barre, A Bueno-de-Mesquita, HB Ye, WM AF Huang, Jiaqi Zagai, Ulrika Hallmans, Goran Nyren, Olof Engstrand, Lars Stolzenberg-Solomon, Rachael Duell, Eric J. Overvad, Kim Katzke, Verena A. Kaaks, Rudolf Jenab, Mazda Park, Jin Young Murillo, Raul Trichopoulou, Antonia Lagiou, Pagona Bamia, Christina Bradbury, Kathryn E. Riboli, Elio Aune, Dagfinn Tsilidis, Konstantinos K. Capella, Gabriel Agudo, Antonio Krogh, Vittorio Palli, Domenico Panico, Salvatore Weiderpass, Elisabete Tjonneland, Anne Olsen, Anja Martinez, Begona Redondo-Sanchez, Daniel Chirlaque, Maria-Dolores Peeters, Petra Hm Regner, Sara Lindkvist, Bjorn Naccarati, Alessio Ardanaz, Eva Larranaga, Nerea Boutron-Ruault, Marie-Christine Rebours, Vinciane Barre, Amelie Bueno-de-Mesquita, H. B(as) Ye, Weimin TI Helicobacter pylori infection, chronic corpus atrophic gastritis and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort: A nested case-control study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE H. pylori infection; chronic corpus atrophic gastritis; pancreatic cancer risk; nested case-control study; EPIC cohort ID ABO BLOOD-GROUP; PERNICIOUS-ANEMIA; SEROPOSITIVITY; METAANALYSIS; POPULATION; CAGA; EPIDEMIOLOGY; ASSOCIATION; STATISTICS; NEOPLASIA AB The association between H. pylori infection and pancreatic cancer risk remains controversial. We conducted a nested case-control study with 448 pancreatic cancer cases and their individually matched control subjects, based on the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, to determine whether there was an altered pancreatic cancer risk associated with H. pylori infection and chronic corpus atrophic gastritis. Conditional logistic regression models were applied to calculate odds ratios (ORs) and corresponding 95% confidence intervals (CIs), adjusted for matching factors and other potential confounders. Our results showed that pancreatic cancer risk was neither associated with H. pylori seropositivity (OR = 0.96; 95% CI: 0.70, 1.31) nor CagA seropositivity (OR = 1.07; 95% CI: 0.77, 1.48). We also did not find any excess risk among individuals seropositive for H. pylori but seronegative for CagA, compared with the group seronegative for both antibodies (OR = 0.94; 95% CI: 0.63, 1.38). However, we found that chronic corpus atrophic gastritis was non-significantly associated with an increased pancreatic cancer risk (OR = 1.35; 95% CI: 0.77, 2.37), and although based on small numbers, the excess risk was particularly marked among individuals seronegative for both H. pylori and CagA (OR = 5.66; 95% CI: 1.59, 20.19, p value for interaction < 0.01). Our findings provided evidence supporting the null association between H. pylori infection and pancreatic cancer risk in western European populations. However, the suggested association between chronic corpus atrophic gastritis and pancreatic cancer risk warrants independent verification in future studies, and, if confirmed, further studies on the underlying mechanisms. C1 [Huang, Jiaqi; Zagai, Ulrika; Nyren, Olof; Weiderpass, Elisabete; Ye, Weimin] Karolinska Inst, Dept Med Epidemiol & Biostat, Solna, Sweden. [Hallmans, Goran] Umea Univ, Dept Publ Hlth & Clin Nutr, Umea, Sweden. [Engstrand, Lars] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. [Stolzenberg-Solomon, Rachael] NCI, Metab Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Duell, Eric J.] Catalan Inst Oncol ICO IDIBELL, Unit Nutr & Canc, Canc Epidemiol Res Program, Barcelona, Spain. [Overvad, Kim] Aarhus Univ, Epidemiol Sect, Dept Publ Hlth, Aarhus, Denmark. [Katzke, Verena A.; Kaaks, Rudolf] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Jenab, Mazda; Park, Jin Young; Murillo, Raul] Int Agcy Res Canc, Sect Nutr & Metab, Sect Early Detect & Prevent, Prevent & Implementat Grp, Lyon, France. [Trichopoulou, Antonia; Lagiou, Pagona; Bamia, Christina] Hellen Hlth Fdn, Athens, Greece. [Trichopoulou, Antonia; Lagiou, Pagona; Bamia, Christina] Univ Athens, WHO Collaborating Ctr Nutr & Hlth, Sch Med, Unit Nutr Epidemiol & Nutr Publ Hlth,Dept Hyg Epi, Athens, Greece. [Lagiou, Pagona] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Bradbury, Kathryn E.] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford, England. [Riboli, Elio; Aune, Dagfinn; Tsilidis, Konstantinos K.] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Capella, Gabriel] IDIBELL Catalan Inst Oncol, Translat Res Lab, Barcelona, Spain. [Agudo, Antonio] Catalan Inst Oncol IDIBELL, Canc Epidemiol Res Program, Unit Nutr & Canc, Barcelona, Spain. [Krogh, Vittorio] Fdn IRCCS Ist Nazl Tumori, Epidemiol & Prevent Unit, Milan, Italy. [Palli, Domenico] Canc Res & Prevent Inst ISPO, Canc Risk Factors & Life Style Epidemiol Unit, Florence, Italy. [Panico, Salvatore] Dipartimento Med Clin & Chirurg Federico II, Naples, Italy. [Weiderpass, Elisabete] Arctic Univ Norway, Univ Tromso, Dept Community Med, Tromso, Norway. [Weiderpass, Elisabete] Inst Populat Based Canc Res, Canc Registry Norway, Dept Res, Oslo, Norway. [Weiderpass, Elisabete] Folkhalsan Res Ctr, Genet Epidemiol Grp, Helsinki, Finland. [Tjonneland, Anne; Olsen, Anja] Danish Canc Soc, Res Ctr, Copenhagen, Denmark. [Martinez, Begona; Redondo-Sanchez, Daniel] Inst Invest Biosanitaria Ibs, Andalusian Sch Publ Hlth, Granada, Spain. [Tsilidis, Konstantinos K.] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, Ioannina, Greece. [Chirlaque, Maria-Dolores] IMIB Arrixaca, Reg Hlth Council, Dept Epidemiol, Murcia, Spain. [Redondo-Sanchez, Daniel; Chirlaque, Maria-Dolores; Ardanaz, Eva; Larranaga, Nerea] CIBER Epidemiol & Publ Hlth CIBERESP, Madrid, Spain. [Chirlaque, Maria-Dolores] Univ Murcia, Dept Hlth & Social Sci, Murcia, Spain. [Peeters, Petra Hm] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, Utrecht, Netherlands. [Regner, Sara] Lund Univ, Inst Clin Sci Malmo, Dept Surg, Malmo, Sweden. [Lindkvist, Bjorn] Sahlgrens Univ Hosp, Dept Med, Gothenburg, Sweden. [Naccarati, Alessio] Human Genet Fdn, Mol & Genet Epidemiol Unit, Turin, Italy. [Ardanaz, Eva] Navarra Publ Hlth Inst, Pamplona, Spain. [Ardanaz, Eva] Navarra Inst Hlth Res, IdiSNA, Pamplona, Spain. [Boutron-Ruault, Marie-Christine] Ctr Res Epidemiol & Populat Hlth CESP, Hormones & Womens Hlth Team, INSERM, U1018,Nutr, F-94805 Villejuif, France. [Boutron-Ruault, Marie-Christine] Univ Paris Sud, UMRS 1018, F-94805 Villejuif, France. [Boutron-Ruault, Marie-Christine] Inst Gustave Roussy, F-94805 Villejuif, France. [Rebours, Vinciane] Univ Paris 07, Beaujon Hosp, Dept Gastroenterol & Pancreatol, Clichy, France. [Barre, Amelie] Univ Paris Sud, Le Kremlin Bicetre, France. [Barre, Amelie] CHU Bicetre, Hop Univ Paris Sud, AP HP, Gastroenterol Unit, Le Kremlin Bicetre, France. [Redondo-Sanchez, Daniel] Univ Granada, Hosp Univ Granada, Inst Invest Biosanitaria Ibs, Escuela Andaluza Salud Publ, Granada, Spain. [Bueno-de-Mesquita, H. B(as)] Natl Inst Publ Hlth & Environm RIVM, Dept Determinants Chron Dis DCD, Bilthoven, Netherlands. [Bueno-de-Mesquita, H. B(as)] Univ Med Ctr, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Bueno-de-Mesquita, H. B(as)] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Bueno-de-Mesquita, H. B(as)] Univ Malaya, Fac Med, Dept Social & Prevent Med, Kuala Lumpur, Malaysia. [Ye, Weimin] Umea Univ, Med Biobank, Umea, Sweden. RP Ye, WM (reprint author), Karolinska Inst, Dept Med Epidemiol & Biostat, Box 281, S-17177 Stockholm, Sweden. EM Weimin.ye@ki.se RI Weiderpass, Elisabete/M-4029-2016 OI Weiderpass, Elisabete/0000-0003-2237-0128 FU Karolinska Institutet; European Commission; International Agency for Research on Cancer; Danish Cancer Society; Ligue Contre le Cancer; Institut Gustave Roussy; Mutuelle Generale de l'Education Nationale; Institut National de la Sante et de la Recherche Medicale(INSERM; France); German Cancer Aid; Deutsches German Cancer Research Center (DKFZ); Federal Ministry of Education and Research (Germany); Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy; National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS); Netherlands Cancer Registry (NKR; LK Research Funds; Dutch Prevention Fund; Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund (WCRF); Statistics Netherlands (The Netherlands); Nordic Centre of Excellence programme on Food; Nutrition and Health (Norway); Health Research Fund [PI13/00061]; Regional Governments of Andalucia, Asturias, Basque Country, Murcia [6236]; Navarra; ISCIII RETIC [RD06/0020]; Swedish Cancer Society, Swedish Scientific Council and County Councils of Skane and Vasterbotten (Sweden); Cancer Research UK [14136, C570/A16491]; Medical Research Council [1000143] FX Grant sponsors: Cancerfonden (2013-798) and the Karolinska Institutet (KID; J.H. was partly supported by a scholarship); Grant sponsors: European Commission (DG-SANCO) and the International Agency for Research on Cancer (The coordination of EPIC); Grant sponsor: Danish Cancer Society (Denmark; The National cohorts); Grant sponsors: Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale(INSERM; France); German Cancer Aid, Deutsches German Cancer Research Center (DKFZ) and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund [(FIS), PI13/00061 to Granada], Regional Governments of Andalucia, Asturias, Basque Country, Murcia (no. 6236) and Navarra, ISCIII RETIC (RD06/0020; Spain); Swedish Cancer Society, Swedish Scientific Council and County Councils of Skane and Vasterbotten (Sweden); Cancer Research UK; Grant number: 14136 to EPIC-Norfolk; C570/A16491 to EPIC-Oxford; Grant sponsor: Medical Research Council; Grant number: 1000143 to EPIC-Norfolk; United Kingdom NR 40 TC 0 Z9 0 U1 10 U2 10 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD APR PY 2017 VL 140 IS 8 BP 1727 EP 1735 DI 10.1002/ijc.30590 PG 9 WC Oncology SC Oncology GA EM2YN UT WOS:000395181800002 PM 28032715 ER PT J AU Xi, LF Schiffman, M Ke, Y Hughes, JP Galloway, DA He, ZH Hulbert, A Winer, RL Koutsky, LA Kiviat, NB AF Xi, Long Fu Schiffman, Mark Ke, Yang Hughes, James P. Galloway, Denise A. He, Zhonghu Hulbert, Ayaka Winer, Rachel L. Koutsky, Laura A. Kiviat, Nancy B. TI Type-dependent association between risk of cervical intraepithelial neoplasia and viral load of oncogenic human papillomavirus types other than types 16 and 18 SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE human papillomavirus; viral load; cervical intraepithelial neoplasia; risk association ID TERM NATURAL-HISTORY; CARCINOMA IN-SITU; DNA LOAD; CANCER; LESIONS; WOMEN; INTEGRATION; CLASSIFICATION; INFECTION; HPV16 AB Studies of the clinical relevance of human papillomavirus (HPV) DNA load have focused mainly on HPV16 and HPV18. Data on other oncogenic types are rare. Study subjects were women enrolled in the atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL) triage study who had >= 1 of 11 non-HPV16/18 oncogenic types detected during a 2-year follow-up at 6-month intervals. Viral load measurements were performed on the first type-specific HPV-positive specimens. The association of cervical intraepithelial neoplasia grades 2-3 (CIN2/3) with type-specific HPV DNA load was assessed with discrete-time Cox regression. Overall, the increase in the cumulative risk of CIN2/3 per 1 unit increase in log(10)-transformed viral load was statistically significant for four types within species 9 including HPV31 (adjusted hazard ratio [HRadjusted] = 1.32: 95% confidence interval [CI], 1.14-1.52), HPV35 (HRadjusted = 1.47; 95% CI, 1.23-1.76), HPV52 (HRadjusted = 1.14; 95% CI, 1.01-1.30) and HPV58 (HRadjusted = 1.49; 95% CI, 1.23-1.82). The association was marginally significant for HPV33 (species 9) and HPV45 (species 7) and was not appreciable for other types. The per 1 log(10)-unit increase in viral load of a group of species 9 non-HPV16 oncogenic types was statistically significantly associated with risk of CIN2/3 for women with a cytologic diagnosis of within normal limits, ASC-US, or LSIL at the first HPV-positive visit but not for those with high-grade SIL. Findings suggest that the viral load-associated risk of CIN2/3 is type-dependent, and mainly restricted to the species of HPV types related to HPV16, which shares this association. C1 [Xi, Long Fu; Hulbert, Ayaka; Kiviat, Nancy B.] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98195 USA. [Xi, Long Fu; Winer, Rachel L.; Koutsky, Laura A.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Ke, Yang; He, Zhonghu] Peking Univ, Sch Oncol, Key Lab Carcinogenesis & Translat Res, Beijing, Peoples R China. [Hughes, James P.] Univ Washington, Sch Publ Hlth & Community Med, Dept Biostat, Seattle, WA 98195 USA. [Galloway, Denise A.] Fred Hutchinson Canc Res Ctr, Div Human Biol, 1124 Columbia St, Seattle, WA 98104 USA. RP Xi, LF (reprint author), Univ Washington, Dept Pathol, Harborview Med Ctr, NJB Ste 1187,325 9th Ave, Seattle, WA 98104 USA. EM longfu@u.washington.edu FU National Cancer Institute of the National Institutes of Health [CA133569] FX National Cancer Institute of the National Institutes of Health; Grant number: CA133569. NR 48 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD APR PY 2017 VL 140 IS 8 BP 1747 EP 1756 DI 10.1002/ijc.30594 PG 10 WC Oncology SC Oncology GA EM2YN UT WOS:000395181800004 ER PT J AU Rodriguez, AC Avila, C Herrero, R Hildesheim, A Sherman, ME Burk, RD Morales, J Alfaro, M Guillen, D Trejos, ME Vargas, RM Torres, G Schiffman, M AF Rodriguez, Ana Cecilia Avila, Carlos Herrero, Rolando Hildesheim, Allan Sherman, Mark E. Burk, Robert D. Morales, Jorge Alfaro, Mario Guillen, Diego Trejos, Maria Ethel Vargas, Rosa Maria Torres, Guillermo Schiffman, Mark TI Cervical cancer incidence after screening with HPV, cytology, and visual methods: 18-Year follow-up of the Guanacaste cohort SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE cervical cancer screening; cervical cancer risk 18-years after enrollment into the Guanacaste cohort; screening frequency ID HUMAN-PAPILLOMAVIRUS INFECTION; DEVELOPING-COUNTRIES; INTRAEPITHELIAL NEOPLASIA; LATIN-AMERICA; COSTA-RICA; PREVENTION; CHALLENGES; EFFICACY; VACCINE; PART AB Testing negative for human papillomavirus (HPV) predicts long-term reassurance against invasive cervical cancer (ICC). To provide realistic estimates of effectiveness for new screening programs, we studied ICC risk after a 7-year repeated multimethod screening effort. In 1993-1994, 10,049 women aged 18-97 years were enrolled into a population-based cohort study of cervical HPV in Guanacaste, Costa Rica. Women were screened at different intervals according to enrollment results. Each visit (mean 3.2, 90% attendance) included split-sample conventional, automated, and liquid-based cytology, visual inspection, cervicography, and PCR-based HPV testing. Abnormal screening led to colposcopy and excisional treatment as appropriate during the study. Referral to colposcopy for HPV in the absence of other findings was introduced only at the last visit. Populationbased Costa Rica Cancer Registry linkage identified cohort women diagnosed with ICC in the 18 years following cohort enrollment. The ICC cumulative risk was 0.4% (n = 38); 18 were diagnosed with ICC after study participation. Of these, 9 were missed at the screening step ( negative screening or below the referral threshold, refused screening or colposcopy), 5 attended colposcopy but were not diagnosed as CIN2+, and 4 were treated for CIN2/3 but progressed to ICC nonetheless. Decreasing age-standardized ICC rates for the 1993-2011 period were observed in Guanacaste; cohort women showed additional 31% ICC incidence reduction with apparent downstaging of cancers that occurred. ICC risk following negative HPV testing in the optimal age range 30-50 years was extremely low. Real-life screening effectiveness following introduction is lower than the potential near-complete efficacy predicted by HPV natural history. C1 [Rodriguez, Ana Cecilia] Natl Canc Inst Consultant, San Jose, Costa Rica. [Avila, Carlos; Morales, Jorge; Alfaro, Mario; Guillen, Diego] Fdn INCIENSA, Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. [Herrero, Rolando] Int Agcy Res Canc, Lyon, France. [Hildesheim, Allan; Schiffman, Mark] DHHS, Natl Canc Inst, Natl Inst Hlth, Div Canc Epidemiol & Genet, Rockville, MD USA. [Sherman, Mark E.] DHHS, Natl Canc Inst, Natl Inst Hlth, Canc Prevent Div, Rockville, MD USA. [Burk, Robert D.] Albert Einstein Canc Ctr, Albert Einstein Coll Med, Bronx, NY USA. [Trejos, Maria Ethel; Vargas, Rosa Maria; Torres, Guillermo] Minist Salud, San Jose, Costa Rica. RP Rodriguez, AC (reprint author), Natl Canc Inst Consultant, San Jose, Costa Rica. EM acrodriguez@racsa.co.cr FU National Institutes of Health [N01CP-21081, N01-CP-33061, N01-CP-40542, N01-CP-50535, N01-CP-81023]; intramural program [CA78527]; National Cancer Institute, National Institutes of Health, Department of Health and Human Services; [HHSN261201200474P] FX The authors thank the women who participated in this study and Dr. Rebeca Ocampo from the Guanacaste Project who helped with some data gathering aspects. This work was supported by the National Institutes of Health (N01CP-21081,N01-CP-33061,N01-CP-40542,N01-CP-50535,N01-CP-81023, and intramural program CA78527 to RB) and (HHSN261201200474P). The Guanacaste cohort (design and conduct of the study, sample collection, management, and analysis and interpretation of the data) for the enrollment and follow-up phases were supported by the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 35 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD APR PY 2017 VL 140 IS 8 BP 1926 EP 1934 DI 10.1002/ijc.30614 PG 9 WC Oncology SC Oncology GA EM2YN UT WOS:000395181800024 PM 28120391 ER PT J AU Ueda, K Kawabe, K Lee, L Tachibana, Y Fujimori, N Igarashi, H Oda, Y Jensen, RT Takayanagi, R Ito, T AF Ueda, Keijiro Kawabe, Ken Lee, Lingaku Tachibana, Yuichi Fujimori, Nao Igarashi, Hisato Oda, Yoshinao Jensen, Robert T. Takayanagi, Ryoichi Ito, Tetsuhide TI Diagnostic Performance of 48-Hour Fasting Test and Insulin Surrogates in Patients With Suspected Insulinoma SO PANCREAS LA English DT Article DE insulinoma; diagnosis; fasting test; insulin surrogates; glucagon stimulatory test; beta-hydroxybutyrate ID ISLET-CELL TUMOR; PROLONGED FAST; ENDOGENOUS HYPERINSULINISM; HYPOGLYCEMIC DISORDERS; CLINICAL-PRACTICE; NESIDIOBLASTOSIS; ADULT; MANAGEMENT; GLUCAGON; GLUCOSE AB Objectives: This study aimed to evaluate the usefulness of the 48-hour fasting test and insulin surrogates followed by a glucagon stimulatory test (GST) for the diagnosis of insulinoma. Methods: Thirty-five patients with suspected insulinoma who underwent 48-hour fasting test and GST were retrospectively included in our study: 15 patients with surgically proven insulinomas and 20 patients in whom insulinoma was clinically ruled out. We determined the duration of the fasting test, plasma glucose levels, serum levels of immunoreactive insulin and C-peptide, and insulin surrogates (serum levels of beta-hydroxybutyrate, free fatty acid, and response of plasma glucose to intravenous glucagon [Delta PG]) at the end of the fast. Results: The sensitivity and specificity of the 48-hour fasting test were 100.0% and 80.0%, respectively, for the diagnosis of insulinoma. When the 48-hour fasting test and immunoreactive insulin, C-peptide, or insulin surrogates were combined, the combination with GST showed the best results. The sensitivity, specificity, and accuracy rate were 93.3%, 95.0%, and 94.3%, respectively, with 1 false-negative case and 1 false-positive case occurring. Conclusions: A more accurate and less invasive diagnosis of insulinoma was possible by combining the 48-hour fasting test with the GST, compared with the existing method. C1 [Ueda, Keijiro; Kawabe, Ken; Lee, Lingaku; Tachibana, Yuichi; Igarashi, Hisato; Takayanagi, Ryoichi; Ito, Tetsuhide] Kyushu Univ, Grad Sch Med Sci, Dept Med & Bioregulatory Sci, Fukuoka, Japan. [Fujimori, Nao] Kyushu Med Ctr, Natl Hosp Org, Dept Gastroenterol, Fukuoka, Japan. [Oda, Yoshinao] Kyushu Univ, Grad Sch Med Sci, Dept Anat Pathol, Fukuoka, Japan. [Jensen, Robert T.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Ito, T (reprint author), Kyushu Univ, Grad Sch Med Sci, Dept Med & Bioregulatory Sci, Higashi Ku, 3-1-1 Maidashi, Fukuoka 8128582, Japan. EM itopapa@intmed3.med.kyushu-u.ac.jp NR 26 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 APR PY 2017 VL 46 IS 4 BP 476 EP 481 DI 10.1097/MPA.0000000000000772 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EP9XA UT WOS:000397725100009 PM 28230660 ER PT J AU Averbeck, BB Costa, VD AF Averbeck, Bruno B. Costa, Vincent D. TI Motivational neural circuits underlying reinforcement learning SO NATURE NEUROSCIENCE LA English DT Article ID NUCLEUS-ACCUMBENS CORE; VENTRAL TEGMENTAL AREA; MIDBRAIN DOPAMINE NEURONS; REWARD-SEEKING BEHAVIOR; BASOLATERAL AMYGDALA; PREFRONTAL CORTEX; BASAL GANGLIA; PRIMATE AMYGDALA; AVERSIVE STIMULI; CONDITIONED REINFORCEMENT AB Reinforcement learning (RL) is the behavioral process of learning the values of actions and objects. Most models of RL assume that the dopaminergic prediction error signal drives plasticity in frontal-striatal circuits. The striatum then encodes value representations that drive decision processes. However, the amygdala has also been shown to play an important role in forming Pavlovian stimulus-outcome associations. These Pavlovian associations can drive motivated behavior via the amygdala projections to the ventral striatum or the ventral tegmental area. The amygdala may, therefore, play a central role in RL. Here we compare the contributions of the amygdala and the striatum to RL and show that both the amygdala and striatum learn and represent expected values in RL tasks. Furthermore, value representations in the striatum may be inherited, to some extent, from the amygdala. The striatum may, therefore, play less of a primary role in learning stimulus-outcome associations in RL than previously suggested. C1 [Averbeck, Bruno B.; Costa, Vincent D.] NIMH, Neuropsychol Lab, NIH, Bldg 9, Bethesda, MD 20892 USA. RP Averbeck, BB (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 9, Bethesda, MD 20892 USA. EM bruno.averbeck@nih.gov NR 100 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD APR PY 2017 VL 20 IS 4 BP 505 EP 512 DI 10.1038/nn.4506 PG 8 WC Neurosciences SC Neurosciences & Neurology GA EP7LH UT WOS:000397558800005 PM 28352111 ER PT J AU Morris, VK Salem, ME Nimeiri, H Iqbal, S Singh, P Ciombor, K Polite, B Deming, D Chan, E Wade, JL Xiao, LC Bekaii-Saab, T Vence, L Blando, J Mahvash, A Foo, WC Ohaji, C Pasia, M Bland, G Ohinata, A Rogers, J Mehdizadeh, A Banks, K Lanman, R Wolff, RA Streicher, H Allison, J Sharma, P Eng, C AF Morris, Van K. Salem, Mohamed E. Nimeiri, Halla Iqbal, Syma Singh, Preet Ciombor, Kristen Polite, Blase Deming, Dustin Chan, Emily Wade, James L. Xiao, Lianchun Bekaii-Saab, Tanios Vence, Luis Blando, Jorge Mahvash, Armeen Foo, Wai Chin Ohaji, Chimela Pasia, Manolo Bland, Gail Ohinata, Aki Rogers, Jane Mehdizadeh, Amir Banks, Kimberly Lanman, Richard Wolff, Robert A. Streicher, Howard Allison, James Sharma, Padmanee Eng, Cathy TI Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study SO LANCET ONCOLOGY LA English DT Article ID HUMAN-PAPILLOMAVIRUS TYPE-16; SQUAMOUS-CELL CARCINOMA; CHEMOTHERAPY; COMBINATION; PD-1; E6; CHEMORADIATION; RADIOTHERAPY; CRITERIA; MEMBER AB Background Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy associated with infection by human papillomavirus (HPV). No consensus treatment approach exists for the treatment of metastatic disease. Because intratumoral HPV oncoproteins upregulate immune checkpoint proteins such as PD-1 to evade immune-mediated cytotoxicity, we did a trial of the anti-PD-1 antibody nivolumab for patients with metastatic SCCA. Methods We did this single-arm, multicentre, phase 2 trial at ten academic centres in the USA. We enrolled patients with treatment-refractory metastatic SCCA, who were given nivolumab every 2 weeks (3 mg/kg). The primary endpoint was response according to Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-totreat population. At the time of data cutoff, the study was ongoing, with patients continuing to receive treatment. The study is registered with ClinicalTrials. gov, number NCT02314169. Findings We screened 39 patients, of whom 37 were enrolled and received at least one dose of nivolumab. Among the 37 patients, nine (24% [95% CI 15-33]) had responses. There were two complete responses and seven partial responses. Grade 3 adverse events were anaemia (n= 2), fatigue (n= 1), rash (n= 1), and hypothyroidism (n= 1). No serious adverse events were reported. Interpretation To our knowledge, this is the first completed phase 2 trial of immunotherapy for SCCA. Nivolumab is well tolerated and effective as a monotherapy for patients with metastatic SCCA. Immune checkpoint blockade appears to be a promising approach for patients with this orphan disease. C1 [Morris, Van K.; Xiao, Lianchun; Vence, Luis; Blando, Jorge; Mahvash, Armeen; Foo, Wai Chin; Ohaji, Chimela; Pasia, Manolo; Bland, Gail; Ohinata, Aki; Rogers, Jane; Mehdizadeh, Amir; Wolff, Robert A.; Allison, James; Sharma, Padmanee; Eng, Cathy] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Salem, Mohamed E.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Nimeiri, Halla] Northwestern Univ, Chicago, IL 60611 USA. [Iqbal, Syma] Univ Southern Calif, Los Angeles, CA USA. [Singh, Preet] Washington Univ, St Louis, MO USA. [Ciombor, Kristen; Bekaii-Saab, Tanios] Ohio State Univ, Columbus, OH 43210 USA. [Polite, Blase] Univ Chicago, Chicago, IL 60637 USA. [Deming, Dustin] Univ Wisconsin, Madison, WI USA. [Chan, Emily] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Wade, James L.] Decatur Mem Hosp, Decatur, IL USA. [Banks, Kimberly; Lanman, Richard] Guardant Hlth, Redwood City, CA USA. [Streicher, Howard] NCI, Bethesda, MD 20892 USA. RP Eng, C (reprint author), Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. EM ceng@mdanderson.org FU National Cancer Institute/Cancer Therapy Evaluation Program; HPV and Anal Cancer Foundation; E B Anal Cancer Fund; University of Texas MD Anderson Moon Shots Program FX National Cancer Institute/Cancer Therapy Evaluation Program, the HPV and Anal Cancer Foundation, the E B Anal Cancer Fund, The University of Texas MD Anderson Moon Shots Program, and an anonymous philanthropic donor. NR 36 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 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD APR PY 2017 VL 18 IS 4 BP 446 EP 453 DI 10.1016/S1470-2045(17)30104-3 PG 8 WC Oncology SC Oncology GA EQ0LF UT WOS:000397762000033 PM 28223062 ER PT J AU Mhatre, S Wang, ZM Nagrani, R Badwe, R Chiplunkar, S Mittal, B Yadav, S Zhang, HY Chung, CC Patil, P Chanock, S Dikshit, R Chatterjee, N Rajaraman, P AF Mhatre, Sharayu Wang, Zhaoming Nagrani, Rajini Badwe, Rajendra Chiplunkar, Shubhada Mittal, Balraj Yadav, Saurabh Zhang, Haoyu Chung, Charles C. Patil, Prachi Chanock, Stephen Dikshit, Rajesh Chatterjee, Nilanjan Rajaraman, Preetha TI Common genetic variation and risk of gallbladder cancer in India: a case-control genome-wide association study SO LANCET ONCOLOGY LA English DT Article ID ABCB1 POLYMORPHISMS; GALLSTONE DISEASE; POPULATION; SUSCEPTIBILITY; VARIANTS; CHOLESTASIS; RESISTANCE; SNP AB Background Gallbladder cancer is highly lethal, with notable differences in incidence by geography and ethnic background. The aim of this study was to identify common genetic susceptibility alleles for gallbladder cancer. Methods In this case-control genome-wide association study (GWAS), we did a genome-wide scan of gallbladder cancer cases and hospital visitor controls, both of Indian descent, followed by imputation across the genome. Cases were patients aged 20-80 years with microscopically confirmed primary gallbladder cancer diagnosed or treated at Tata Memorial Hospital, Mumbai, India, and enrolled in the study between Sept 12, 2010, and June 8, 2015. We only included patients who had been diagnosed less than 1 year before the date of enrolment and excluded patients with any other malignancies. We recruited visitor controls aged 20-80 years with no history of cancer visiting all departments or units of Tata Memorial Hospital during the same time period and frequency matched them to cases on the basis of age, sex, and current region of residence. We estimated association using logistic regression, adjusting for age, sex, and five eigenvectors. We recruited samples for a replication cohort from patients visiting Tata Memorial Hospital between Aug 4, 2015, and May 17, 2016, and patients visiting the Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India, between July, 2010, and May, 2015. We used the same inclusion and exclusion criteria for the replication set. We examined three of the most significant single-nucleotide polymorphisms (SNPs) in the replication cohort and did a meta-analysis of the GWAS discovery and replication sets to get combined estimates of association. Findings The discovery cohort comprised 1042 gallbladder cancer cases and 1709 controls and the replication cohort contained 428 gallbladder cancer cases and 420 controls. We observed genome-wide significant associations for several markers in the chromosomal region 7q21.12 harbouring both the ABCB1 and ABCB4 genes, with the most notable SNPs after replication and meta-analysis being rs1558375 (GWAS p= 3.8 x 10(-9); replication p= 0.01; combined p= 2.3 x 10(-10)); rs17209837 (GWAS p= 2.0 x 10(-8); replication p= 0.02; combined p= 2.3 x 10(-9)), and rs4148808 (GWAS p= 2.4 x 10(-8); replication p= 0.008; combined p= 2.7 x 10(-9)). Combined estimates of per-allele trend odds ratios were 1.47 (95% CI 1.30-1.66; p= 2.31 x 10(-9)) for rs1558375, 1.61 (1.38-1.89; p= 2.26 x 10(-9)) for rs17209837, and 1.57 (1.35-1.82; p= 2.71 x 10(-9)) for rs4148808. GWAS heritability analysis suggested that common variants are associated with substantial variation in risk of gallbladder cancer (sibling relative risk 3.15 [95% CI 1.80-5.49]). Interpretation To our knowledge, this study is the first report of common genetic variation conferring gallbladder cancer risk at genome-wide significance. This finding, along with in-silico and biological evidence indicating the potential functional significance of ABCB1 and ABCB4, underlines the likely importance of these hepatobiliary phospholipid transporter genes in the pathology of gallbladder cancer. C1 [Mhatre, Sharayu; Nagrani, Rajini; Dikshit, Rajesh] Tata Mem Hosp, Ctr Canc Epidemiol, Kharghar 410210, Navi Mumbai, India. [Wang, Zhaoming] St Jude Childrens Res Hosp, Dept Computat Biol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Badwe, Rajendra] Tata Mem Hosp, Dept Surg Oncol, Bombay, Maharashtra, India. [Chiplunkar, Shubhada] Tata Mem Hosp, Adv Ctr Treatment Res & Educ Canc, Bombay, Maharashtra, India. [Patil, Prachi] Tata Mem Hosp, Dept Digest Dis & Clin Nutr, Bombay, Maharashtra, India. [Mittal, Balraj; Yadav, Saurabh] Sanjay Gandhi Postgrad Inst Med Sci, Lucknow, Uttar Pradesh, India. [Zhang, Haoyu; Chatterjee, Nilanjan] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Chatterjee, Nilanjan] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Chung, Charles C.] Leidos Biomed Res, Canc Genom Res Lab, Gaithersburg, MD USA. [Chung, Charles C.; Chanock, Stephen; Rajaraman, Preetha] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Rajaraman, Preetha] NCI, Ctr Global Hlth, NIH, Rockville, MD USA. RP Dikshit, R (reprint author), Tata Mem Hosp, Ctr Canc Epidemiol, Kharghar 410210, Navi Mumbai, India. EM dikshitrp@tmc.gov.in OI nagrani, rajini/0000-0002-1708-2319 FU Tata Memorial Centre and Department of Biotechnology FX The Tata Memorial Centre and Department of Biotechnology. NR 34 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 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD APR PY 2017 VL 18 IS 4 BP 535 EP 544 DI 10.1016/S1470-2045(17)30167-5 PG 10 WC Oncology SC Oncology GA EQ0LF UT WOS:000397762000041 PM 28274756 ER PT J AU Leary, AF Quinn, M Fujiwara, K Coleman, RL Kohn, E Sugiyama, T Glasspool, R Ray-Coquard, I Colombo, N Bacon, M Zeimet, A Westermann, A Gomez-Garcia, E Provencher, D Welch, S Small, W Millan, D Okamoto, A Stuart, G Ochiai, K AF Leary, A. F. Quinn, M. Fujiwara, K. Coleman, R. L. Kohn, E. Sugiyama, T. Glasspool, R. Ray-Coquard, I. Colombo, N. Bacon, M. Zeimet, A. Westermann, A. Gomez-Garcia, E. Provencher, D. Welch, S. Small, W. Millan, D. Okamoto, A. Stuart, G. Ochiai, K. CA Fifth Ovarian Canc Consensus Confe TI Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup (GCIG): clinical trial design for rare ovarian tumours SO ANNALS OF ONCOLOGY LA English DT Review DE rare ovarian tumours; clinical trials ID CLEAR-CELL CARCINOMA; GRADE SEROUS CARCINOMA; ADJUVANT CHEMOTHERAPY; SURVEILLANCE POLICY; MULTICENTER TRIAL; ONCOLOGY GROUP; RECURRENT; EXPERIENCE; ADENOCARCINOMA; COMBINATION AB This manuscript reports the consensus statements on designing clinical trials in rare ovarian tumours reached at the fifth Ovarian Cancer Consensus Conference (OCCC) held in Tokyo, November 2015. Three important questions were identified concerning rare ovarian tumours (rare epithelial ovarian cancers (eOC), sex-cord stromal tumours (SCST) and germ cell tumours (GCT)): (i) What are the research and trial issues that are unique to rare ovarian tumours? There is a lack of randomised phase III data defining standards of care which makes it difficult to define control arms, but identifies unmet needs that merit investigation. Internationally agreed upon diagnostic criteria, expert pathological review and translational research are crucial. (ii) What should be investigated in rare eOC, GCT and SCST? Trials dedicated to each rare ovarian tumour should be encouraged. Nonetheless, where the question is relevant, rare eOC can be included in eOC trials but with rigorous stratification. Although there is emerging evidence suggesting that rare eOC have different molecular profiles, trials are needed to define new type-specific standards for each rare eOC (clear cell, low grade serous and mucinous). For GCTs, a priority is reducing toxicities from treatment while maintaining cure rates. Both a robust prognostic scoring system and more effective treatments for de novo poor prognosis and relapsed GCTs are needed. For SCSTs, validated prognostic markers as well as alternatives to the current standard of bleomycin/etoposide/cisplatin (BEP) should be identified. (iii) Are randomised trials feasible? Randomised controlled trials (RCT) should be feasible in any of the rare tumours through international collaboration. Ongoing trials have already demonstrated the feasibility of RCT in rare eOC and SCST. Mucinous OC may be considered for inclusion, stratified, into RCTs of non-gynaecological mucinous tumours, while RCTs in high risk or relapsed GCT may be carried out as a subset of male and/or paediatric germ cell studies. C1 [Leary, A. F.; Ray-Coquard, I.] GINECO, Paris, France. [Quinn, M.] ANZGOG, Melbourne, Vic, Australia. [Fujiwara, K.] GOTIC, Kyoto, Japan. [Coleman, R. L.] G GOC, London, England. [Kohn, E.] NCI, Bethesda, MD 20892 USA. [Sugiyama, T.] JGOG, Tokyo, Japan. [Glasspool, R.; Millan, D.] SGCTG, Glasgow, Lanark, Scotland. [Colombo, N.] MaNGO, Piedmont, Italy. GCIG, Milan, Italy. [Zeimet, A.] AGO AU, Au, Vorarlberg, Austria. [Westermann, A.] DGOG, Amsterdam, Netherlands. [Gomez-Garcia, E.] GICOM, Mexico City, DF, Mexico. [Provencher, D.; Okamoto, A.] CCTG, Kingston, ON, Canada. [Welch, S.] PMHC, Montreal, PQ, Canada. [Small, W.] RTOG, Philadelphia, PA USA. RP Quinn, M (reprint author), Univ Melbourne, Royal Womens Hosp, 20 Flemington Rd, Melbourne, Vic 3052, Australia. EM QuinnM@ramsayhealth.com.au FU Astra Zeneca UK Limited (UK); Bristol-Myers Squibb Company (USA); Clovis Oncology Inc. (USA); Eisai Co., Ltd. (Japan); F. Hoffmann-La Roche Ltd. (Switzerland); Pfizer Inc. (USA); Pharma Mar, S.A. (Spain); TESARO, Inc. (USA); Zeria Pharmaceutical Co., Ltd. (Japan) FX This work was supported by unrestricted grants from Astra Zeneca UK Limited (UK); Bristol-Myers Squibb Company (USA); Clovis Oncology Inc. (USA); Eisai Co., Ltd. (Japan); F. Hoffmann-La Roche Ltd. (Switzerland); Pfizer Inc. (USA); Pharma Mar, S.A. (Spain); TESARO, Inc. (USA); and Zeria Pharmaceutical Co., Ltd. (Japan). The agenda, presentations and statements were entirely developed without involvement of these funding sources. No grant number is applicable. NR 60 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD APR PY 2017 VL 28 IS 4 BP 718 EP 726 DI 10.1093/annonc/mdw662 PG 9 WC Oncology SC Oncology GA EP8JQ UT WOS:000397622100011 ER PT J AU Swain, SM Schneeweiss, A Gianni, L Gao, JJ Stein, A Waldron-Lynch, M Heeson, S Beattie, MS Yoo, B Cortes, J Baselga, J AF Swain, S. M. Schneeweiss, A. Gianni, L. Gao, J. J. Stein, A. Waldron-Lynch, M. Heeson, S. Beattie, M. S. Yoo, B. Cortes, J. Baselga, J. TI Incidence and management of diarrhea in patients with HER2-positive breast cancer treated with pertuzumab SO ANNALS OF ONCOLOGY LA English DT Article DE pertuzumab; diarrhea; breast cancer; docetaxel; HER2; EGFR ID III TRIAL CLEOPATRA; PLUS TRASTUZUMAB; DOCETAXEL; SAFETY; GROWTH AB Background: Pertuzumab disrupts heterodimerization between human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR), HER3, and HER4. Thus, pertuzumab could result in adverse events similar to those observed with EGFR antagonists, such as diarrhea. We report the incidence and severity of diarrhea observed with pertuzumab in the CLEOPATRA, NeoSphere, and TRYPHAENA studies. Patients and methods: Patients (n = 1443) had metastatic [CLEOPATRA (n = 804)] or early-stage breast cancer [NeoSphere (n = 416) and TRYPHAENA (n = 223)]. The incidence and severity of diarrhea were analyzed by treatment received. The incidence of febrile neutropenia concurrent with diarrhea and the effect of pre-existing gastrointestinal comorbidities were also evaluated. Subgroup analyses were carried out using CLEOPATRA data. Results: The incidence of all-grade diarrhea across studies was generally greater for pertuzumab-based treatment, ranging from 28% to 72% (grade 1, 21%-54%; grade 2, 8%-37%; grade 3, 0%-12%; grade 4, 0%). Incidence was highest during the first pertuzumab-containing cycle, decreasing with subsequent cycles. Dose delays or discontinuations due to diarrhea were infrequent, ranging from 0% to 8%. Among pertuzumab-treated patients with diarrhea, 47%-67% received pharmacological intervention, most commonly with loperamide. Overlap between diarrhea and febrile neutropenia was uncommon, ranging from 0% to 11%. No relationship was observed between pre-existing gastrointestinal comorbidities and diarrhea. In CLEOPATRA, patients >= 65 years treated with pertuzumab had a higher incidence of grade 3 diarrhea than patients <65 years (19% versus 8%). All-grade diarrhea occurred at greater frequency among pertuzumab-treated Asian versus white patients with metastatic breast cancer (74% versus 63%); the corresponding rates in the control arm were 53% and 45%, respectively. Conclusions: In both the metastatic and early-stage breast cancer settings, diarrhea was common but manageable for all pertuzumab-containing regimens. Diarrheal episodes were mainly low grade and occurred most often during the first treatment cycle. Diarrheal-related drug delays or discontinuations were uncommon. C1 [Swain, S. M.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, 4000 Reservoir Rd NW 120 Bldg D, Washington, DC 20057 USA. [Schneeweiss, A.] Univ Hosp, Natl Ctr Tumor Dis, Heidelberg, Germany. [Schneeweiss, A.] Univ Heidelberg Hosp, Dept Gynecol & Obstet, Heidelberg, Germany. [Gianni, L.] Hosp San Raffaele, Dept Med Oncol, Milan, Italy. [Gao, J. J.] Natl Canc Inst, Natl Inst Hlth, Med Oncol Serv, Bethesda, MD USA. [Stein, A.; Beattie, M. S.] BioOncol Genentech Inc, San Francisco, CA USA. [Waldron-Lynch, M.; Heeson, S.] Roche Prod Ltd, Clin Dev, Welwyn Garden City, Herts, England. [Yoo, B.] Biostat Genentech Inc, San Francisco, CA USA. [Cortes, J.] Ramon Cajal Univ Hosp, Madrid, Spain. [Cortes, J.] Vall Hebron Inst Oncol, Dept Med Oncol, Barcelona, Spain. [Baselga, J.] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. RP Swain, SM (reprint author), Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, 4000 Reservoir Rd NW 120 Bldg D, Washington, DC 20057 USA. EM sandra.swain@georgetown.edu OI Swain, Sandra/0000-0002-1320-3830 FU Genentech, Inc. FX This work was supported by Genentech, Inc. No grant numbers are applicable. NR 14 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD APR PY 2017 VL 28 IS 4 BP 761 EP 768 DI 10.1093/annonc/mdw695 PG 8 WC Oncology SC Oncology GA EP8JQ UT WOS:000397622100017 ER PT J AU Jonasch, E Hasanov, E Corn, PG Moss, T Shaw, KR Stovall, S Marcott, V Gan, B Bird, S Wang, X Do, KA Altamirano, PF Zurita, AJ Doyle, LA Lara, PN Tannir, NM AF Jonasch, E. Hasanov, E. Corn, P. G. Moss, T. Shaw, K. R. Stovall, S. Marcott, V. Gan, B. Bird, S. Wang, X. Do, K. A. Altamirano, P. F. Zurita, A. J. Doyle, L. A. Lara, P. N., Jr. Tannir, N. M. TI A randomized phase 2 study of MK-2206 versus everolimus in refractory renal cell carcinoma SO ANNALS OF ONCOLOGY LA English DT Article DE renal cell carcinoma; RCC; PI3K pathway; metastatic disease; MK-2206; everolimus ID FACTOR-TARGETED THERAPY; GROWTH; INHIBITOR; PI3K; EXPRESSION; MUTATION; PATHWAY; MTOR; GENE; P53 AB Background: Activation of the phosphoinisitide-3 kinase (PI3K) pathway through mutation and constitutive upregulation has been described in renal cell carcinoma (RCC), making it an attractive target for therapeutic intervention. We performed a randomized phase II study in vascular endothelial growth factor (VEGF) therapy refractory patients to determine whether MK-2206, an allosteric inhibitor of AKT, was more efficacious than the mammalian target of rapamycin inhibitor everolimus. Patients and methods: A total of 43 patients were randomized in a 2:1 distribution, with 29 patients assigned to the MK-2206 arm and 14 to the everolimus arm. Progression-free survival (PFS) was the primary endpoint. Results: The trial was closed at the first futility analysis with an observed PFS of 3.68 months in the MK-2206 arm and 5.98 months in the everolimus arm. Dichotomous response rate profiles were seen in the MK-2206 arm with one complete response and three partial responses in the MK-2206 arm versus none in the everolimus arm. On the other hand, progressive disease was best response in 44.8% of MK2206 versus 14.3% of everolimus-treated patients. MK-2206 induced significantly more rash and pruritis than everolimus, and dose reduction occurred in 37.9% of MK-2206 versus 21.4% of everolimus-treated patients. Genomic analysis revealed that 57.1% of the patients in the PD group had either deleterious TP53 mutations or ATM mutations or deletions. In contrast, none of the patients in the non-PD group had TP53 or ATM defects. No predictive marker for response was observed in this small dataset. Conclusions: Dichotomous outcomes are observed when VEGF therapy refractory patients are treated with MK-2206, and MK2206 does not demonstrate superiority to everolimus. Additionally, mutations in DNA repair genes are associated with early disease progression, indicating that dysregulation of DNA repair is associated with a more aggressive tumor phenotype in RCC. C1 [Jonasch, E.; Hasanov, E.; Corn, P. G.; Moss, T.; Shaw, K. R.; Stovall, S.; Marcott, V.; Gan, B.; Bird, S.; Wang, X.; Do, K. A.; Altamirano, P. F.; Zurita, A. J.; Tannir, N. M.] Univ Texas MD Anderson, Dept Genitourinary Med Oncol, Div Canc Med, 1155 Pressler St, Houston, TX 77030 USA. [Doyle, L. A.] NCI, Bethesda, MD 20892 USA. [Lara, P. N., Jr.] UC Davis Comprehens Canc Ctr, Sacramento, CA USA. RP Jonasch, E (reprint author), Univ Texas MD Anderson, Dept Genitourinary Med Oncol, Div Canc Med, 1155 Pressler St, Houston, TX 77030 USA. EM ejonasch@mdanderson.org FU NIH/NCI [P30CA016672, R01CA190370] FX Supported by the NIH/NCI under award nos. P30CA016672 and R01CA190370, and used the Biostatistics and Bioinformatics core, and the Pathology core. NR 23 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD APR PY 2017 VL 28 IS 4 BP 804 EP 808 DI 10.1093/annonc/mdw676 PG 5 WC Oncology SC Oncology GA EP8JQ UT WOS:000397622100023 ER PT J AU Bang, YJ Giaccone, G Im, SA Oh, DY Bauer, TM Nordstrom, JL Li, H Chichili, GR Moore, PA Hong, S Stewart, SJ Baughman, JE Lechleider, RJ Burris, HA AF Bang, Y. J. Giaccone, G. Im, S. A. Oh, D. Y. Bauer, T. M. Nordstrom, J. L. Li, H. Chichili, G. R. Moore, P. A. Hong, S. Stewart, S. J. Baughman, J. E. Lechleider, R. J. Burris, H. A. TI First-in-human phase 1 study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors SO ANNALS OF ONCOLOGY LA English DT Article DE margetuximab; HER2; solid tumor; breast cancer; gastric cancer ID METASTATIC BREAST-CANCER; RECEPTOR POLYMORPHISMS; ADJUVANT CHEMOTHERAPY; TRASTUZUMAB; PHARMACOKINETICS; PLUS; EFFICACY AB Background: Margetuximab is an anti-HER2 antibody that binds with elevated affinity to both the lower and higher affinity forms of CD16A, an Fc-receptor important for antibody dependent cell-mediated cytotoxicity (ADCC) against tumor cells. A Phase 1 study was initiated to evaluate the toxicity profile, maximum tolerated dose (MTD), pharmacokinetics, and antitumor activity of margetuximab in patients with HER2-overexpressing carcinomas. Patients and methods: Patients with HER2-positive breast or gastric cancer, or other carcinomas that overexpress HER2, for whom no standard therapy was available, were treated with margetuximab by intravenous infusion at doses of 0.1-6.0 mg/kg for 3 of every 4 weeks (Regimen A) or once every 3 weeks (10-18 mg/kg) (Regimen B). Results: Sixty-six patients received margetuximab (34 patients for Regimen A and 32 patients for Regimen B). The MTD was not reached for either regimen. Treatment was well-tolerated, with mostly Grade 1 and 2 toxicities consisting of constitutional symptoms such as pyrexia, nausea, anemia, diarrhea, and fatigue. Among 60 response-evaluable patients, confirmed partial responses and stable disease were observed in 7 (12%) and 30 (50%) patients, respectively; 26 (70%) of these patients had received prior HER2-targeted therapy. Tumor reductions were observed in over half (18/23, 78%) of response-evaluable patients with breast cancer including durable (>30 weeks) responders. Ex vivo analyses of patient peripheral blood mononuclear cell samples confirmed the ability of margetuximab to support enhanced ADCC compared with trastuzumab. Conclusions: Margetuximab was well-tolerated and has promising single-agent activity. Further development efforts of margetuximab as single agent and in combination with other therapeutic agents are ongoing. C1 [Bang, Y. J.; Im, S. A.; Oh, D. Y.] Seoul Natl Univ, Canc Res Inst, Dept Internal Med, Coll Med, Seoul, South Korea. [Giaccone, G.] NCI, Dept Med Oncol, Bethesda, MD 20892 USA. [Bauer, T. M.; Burris, H. A.] Sarah Cannon Res Inst, Dept Drug Dev, Nashville, TN USA. [Bauer, T. M.; Burris, H. A.] Tennessee Oncol, Nashville, TN USA. [Nordstrom, J. L.; Li, H.; Chichili, G. R.; Moore, P. A.; Hong, S.; Stewart, S. J.; Baughman, J. E.; Lechleider, R. J.] MacroGenics Inc, Rockville, MD USA. [Nordstrom, J. L.; Li, H.; Chichili, G. R.; Moore, P. A.; Hong, S.; Stewart, S. J.; Baughman, J. E.; Lechleider, R. J.] MacroGenics Inc, San Francisco, CA USA. RP Bang, YJ (reprint author), Seoul Natl Univ, Coll Med, Dept Internal Med, 101 Daehak Ro, Seoul 03080, South Korea. EM bangyj@snu.ac.kr FU MacroGenics, Inc.; Green Cross Corp. FX This work was supported by MacroGenics, Inc. and Green Cross Corp. No grant numbers applied. NR 20 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD APR PY 2017 VL 28 IS 4 BP 855 EP 861 DI 10.1093/annonc/mdx002 PG 7 WC Oncology SC Oncology GA EP8JQ UT WOS:000397622100031 ER PT J AU Pinal-Fernandez, I Casal-Dominguez, M Carrino, JA Lahouti, AH Basharat, P Albayda, J Paik, JJ Ahlawat, S Danoff, SK Lloyd, TE Mammen, AL Christopher-Stine, L AF Pinal-Fernandez, Iago Casal-Dominguez, Maria Carrino, John A. Lahouti, Arash H. Basharat, Pari Albayda, Jemima Paik, Julie J. Ahlawat, Shivani Danoff, Sonye K. Lloyd, Thomas E. Mammen, Andrew L. Christopher-Stine, Lisa TI Thigh muscle MRI in immune-mediated necrotising myopathy: extensive oedema, early muscle damage and role of anti-SRP autoantibodies as a marker of severity SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID INCLUSION-BODY MYOSITIS; SIGNAL RECOGNITION PARTICLE; INFLAMMATORY MYOPATHIES; DERMATOMYOSITIS; POLYMYOSITIS; ANTIBODIES; DISEASES AB Objectives The aims of this study were to define the pattern of muscle involvement in patients with immune-mediated necrotising myopathy (IMNM) relative to those with other inflammatory myopathies and to compare patients with IMNM with different autoantibodies. Methods All Johns Hopkins Myositis Longitudinal Cohort subjects with a thigh MRI (tMRI) who fulfilled criteria for IMNM, dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM) or clinically amyopathic DM (CADM) were included in the study. Muscles were assessed for intramuscular and fascial oedema, atrophy and fatty replacement. Disease subgroups were compared using univariate and multivariate analyses. Patients with IMNM with anti-signal recognition particle (SRP) autoantibodies were compared with those with IMNM with anti-HMG-CoA reductase (HMGCR) autoantibodies. Results The study included 666 subjects (101 IMNM, 176 PM, 219 DM, 17 CADM and 153 IBM). Compared with DM or PM, IMNM was characterised by a higher proportion of thigh muscles with oedema, atrophy and fatty replacement (p< 0.01). Patients with IMNM with anti-SRP had more atrophy (19%, p=0.003) and fatty replacement (18%, p=0.04) than those with anti-HMGCR. In IMNM, muscle abnormalities were especially common in the lateral rotator and gluteal groups. Fascial involvement was most widespread in DM. Fatty replacement of muscle tissue began early during the course of disease in IMNM and the other groups. An optimal combination of tMRI features had only a 55% positive predictive value for diagnosing IMNM. Conclusions Compared with patients with DM or PM, IMNM is characterised by more widespread muscle involvement. Anti-SRP-positive patients have more severe muscle involvement than anti-HMGCR-positive patients. C1 [Pinal-Fernandez, Iago; Mammen, Andrew L.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Casal-Dominguez, Maria; Carrino, John A.; Lahouti, Arash H.; Basharat, Pari; Albayda, Jemima; Paik, Julie J.; Ahlawat, Shivani; Danoff, Sonye K.; Lloyd, Thomas E.; Mammen, Andrew L.; Christopher-Stine, Lisa] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Pinal-Fernandez, I; Mammen, AL (reprint author), NIAMSD, Muscle Dis Unit, Lab Muscle Stem Cells & Gene Express, NIH, 50 South Dr,Room 1141,Bldg 50,MSC 8024, Bethesda, MD 20892 USA. EM iagopf@yahoo.es; andrew.mammen@nih.gov FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health; Huayi and Siuling Zhang Discovery Fund FX This research was supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. The Myositis Research Database is supported by the Huayi and Siuling Zhang Discovery Fund. NR 22 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD APR PY 2017 VL 76 IS 4 DI 10.1136/annrheumdis-2016-210198 PG 7 WC Rheumatology SC Rheumatology GA EO7FH UT WOS:000396856100011 ER PT J AU Bouhlal, S McBride, CM Trivedi, NS Agurs-Collins, T Persky, S AF Bouhlal, Sofia McBride, Colleen M. Trivedi, Niraj S. Agurs-Collins, Tanya Persky, Susan TI Identifying eating behavior phenotypes and their correlates: A novel direction toward improving weight management interventions SO APPETITE LA English DT Article DE Eating behaviors; Phenotypes; Heatmap; BMI; Self-efficacy ID HEDONIC HUNGER; APPETITE; OBESITY; WOMEN; ADOLESCENTS; SENSITIVITY; HEALTH; SAMPLE; ADULTS; SCALE AB Common reports of over-response to food cues, difficulties with calorie restriction, and difficulty adhering to dietary guidelines suggest that eating behaviors could be interrelated in ways that influence weight management efforts. The feasibility of identifying robust eating phenotypes (showing face, content, and criterion validity) was explored based on well-validated individual eating behavior assessments. Adults (n = 260; mean age 34 years) completed online questionnaires with measurements of nine eating behaviors including: appetite for palatable foods, binge eating, bitter taste sensitivity, disinhibition, food neophobia, pickiness and satiety responsiveness. Discovery-based visualization procedures that have the combined strengths of heatmaps and hierarchical clustering were used to investigate: 1) how eating behaviors cluster, 2) how participants can be grouped within eating behavior clusters, and 3) whether group clustering is associated with body mass index (BMI) and dietary self efficacy levels. Two distinct eating behavior clusters and participant groups that aligned within these clusters were identified: one with higher drive to eat and another with food avoidance behaviors. Participants' BMI (p = 0.0002) and dietary self-efficacy (p < 0.0001) were associated with cluster membership. Eating behavior clusters showed content and criterion validity based on their association with BMI (associated, but not entirely overlapping) and dietary self-efficacy. Identifying eating behavior phenotypes appears viable. These efforts could be expanded and ultimately inform tailored weight management interventions. Published by Elsevier Ltd. C1 [Bouhlal, Sofia; Persky, Susan] NHGRI, Social & Behav Res Branch, NIH, Bldg 31,Room B1B54, Bethesda, MD 20892 USA. [McBride, Colleen M.] Emory Univ, Rollins Sch Publ Hlth, SPH Behav Sci & Hlth Educ, 1518 Clifton Rd NE Mailstop 1518-002-5AA, Atlanta, GA 30322 USA. [Trivedi, Niraj S.] NHGRI, Computat & Stat Genom Branch, NIH, 50 South Dr,Room 5228, Bethesda, MD 20892 USA. [Agurs-Collins, Tanya] NCI, Hlth Behav Res Branch, NIH, Rockville, MD USA. [Bouhlal, Sofia] NIAAA DICBR, Sect Clin Psychoneuroendocrinol & Neuropsychophar, 10 Ctr Dr,10CRC-15330, Bethesda, MD 20892 USA. [Bouhlal, Sofia] NIDA IRP, 10 Ctr Dr,10CRC-15330, Bethesda, MD 20892 USA. RP Persky, S (reprint author), NHGRI, Social & Behav Res Branch, NIH, Bldg 31,Room B1B54, Bethesda, MD 20892 USA. EM sofia.bouhlal@nih.gov; Colleen.marie.mcbride@emory.edu; niraj.trivedi@nih.gov; collinsta@nih.gov; perskys@mail.nih.gov FU Intramural Research Program of the National Human Genome Research Institute [Z01 HG200396-01] FX The authors would like to thank David Kanney and Andy Baxevanis for setting up the study website, Deanna Wilson for assistance with participant follow-up and payments, Christopher Marcum for consults on earlier statistical analyses; Mandy Jawara and Dinora Dominguez for their assistance with the clinical research volunteer database. This work was supported by the Intramural Research Program of the National Human Genome Research Institute [grant number Z01 HG200396-01]. NR 44 TC 0 Z9 0 U1 5 U2 5 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-6663 EI 1095-8304 J9 APPETITE JI Appetite PD APR 1 PY 2017 VL 111 BP 142 EP 150 DI 10.1016/j.appet.2016.12.006 PG 9 WC Behavioral Sciences; Nutrition & Dietetics SC Behavioral Sciences; Nutrition & Dietetics GA EL2UR UT WOS:000394476200017 PM 28043857 ER PT J AU Kadri, SS Swihart, BJ Bonne, SL Hohmann, SF Hennessy, LV Louras, P Evans, HL Rhee, C Suffredini, AF Hooper, DC Follmann, DA Bulger, EM Danner, RL AF Kadri, Sameer S. Swihart, Bruce J. Bonne, Stephanie L. Hohmann, Samuel F. Hennessy, Laura V. Louras, Peter Evans, Heather L. Rhee, Chanu Suffredini, Anthony F. Hooper, David C. Follmann, Dean A. Bulger, Eileen M. Danner, Robert L. TI Impact of Intravenous Immunoglobulin on Survival in Necrotizing Fasciitis With Vasopressor- Dependent Shock: A Propensity Score- Matched Analysis From 130 US Hospitals SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE intravenous immunoglobulin; toxic shock; necrotizing fasciitis ID SOFT-TISSUE INFECTIONS; A STREPTOCOCCAL INFECTIONS; POLYSPECIFIC IMMUNOGLOBULIN; STAPHYLOCOCCUS-AUREUS; THERAPY; MANAGEMENT; DISEASE; SUPERANTIGENS; SURVEILLANCE; PATHOGENESIS AB Background. Shock frequently complicates necrotizing fasciitis (NF) caused by group A Streptococcus (GAS) or Staphylococcus aureus. Intravenous immunoglobulin (IVIG) is sometimes administered for presumptive toxic shock syndrome (TSS), but its frequency of use and efficacy are unclear. Methods. Adult patients with NF and vasopressor-dependent shock undergoing surgical debridement from 2010 to 2014 were identified at 130 US hospitals. IVIG cases were propensity-matched and risk-adjusted. The primary outcome was in-hospital mortality and the secondary outcome was median length of stay (LOS). Results. Of 4127 cases of debrided NF with shock at 121 centers, only 164 patients (4%) at 61 centers received IVIG. IVIG subjects were younger with lower comorbidity indices, but higher illness severity. Clindamycin and vasopressor intensity were higher among IVIG cases, as was coding for TSS and GAS. In-hospital mortality did not differ between matched IVIG and non-IVIG groups (crude mortality, 27.3% vs 23.6%; adjusted odds ratio, 1.00 [95% confidence interval,.55-1.83]; P =.99). Early IVIG (= 2 days) did not alter this effect (P =.99). Among patients coded for TSS, GAS, and/or S. aureus, IVIG use was still unusual (59/868 [6.8%]) and lacked benefit (P =.63). Median LOS was similar between IVIG and non-IVIG groups (26 [ 13-49] vs 26 [11-43]; P =.84). Positive predictive values for identifying true NF and debridement among IVIG cases using our algorithms were 97% and 89%, respectively, based on records review at 4 hospitals. Conclusions. Adjunctive IVIG was administered infrequently in NF with shock and had no apparent impact on mortality or hospital LOS beyond that achieved with debridement and antibiotics. C1 [Kadri, Sameer S.; Suffredini, Anthony F.; Danner, Robert L.] Natl Inst Hlth Clin Ctr, Crit Care Med Dept, 10 Ctr Dr B10,2C145, Bethesda, MD 20892 USA. [Kadri, Sameer S.; Hooper, David C.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA USA. [Swihart, Bruce J.; Follmann, Dean A.] NIAID, Biostat Res Branch, Bethesda, MD USA. [Bonne, Stephanie L.] Barnes Jewish Hosp, Dept Gen Surg, St Louis, MO USA. [Hohmann, Samuel F.] Vizient, Irving, TX USA. [Hohmann, Samuel F.] Rush Univ, Dept Hlth Syst Management, Chicago, IL USA. [Hennessy, Laura V.; Louras, Peter; Evans, Heather L.; Bulger, Eileen M.] Harborview Med Ctr, Dept Surg, Seattle, WA USA. [Rhee, Chanu] Harvard Med Sch, Dept Populat Med, Boston, MA USA. [Rhee, Chanu] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. RP Kadri, SS (reprint author), Natl Inst Hlth Clin Ctr, Crit Care Med Dept, 10 Ctr Dr B10,2C145, Bethesda, MD 20892 USA.; Kadri, SS (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA USA. EM sameer.kadri@nih.gov FU National Institutes of Health Intramural Research Program FX This work was supported by the National Institutes of Health Intramural Research Program. NR 31 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD APR 1 PY 2017 VL 64 IS 7 BP 877 EP 885 DI 10.1093/cid/ciw871 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP5SS UT WOS:000397439600012 PM 28034881 ER PT J AU Bennett, JE AF Bennett, John E. TI Invasive Candidiasis in Very Premature Neonates: Tiny Tots With Big Problems SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material DE candidiasis; neonatal; premature; infants; antifungal ID BIRTH-WEIGHT INFANTS; RISK-FACTORS; EPIDEMIOLOGY; MANAGEMENT; INFECTION; MORTALITY; OUTCOMES; UPDATE C1 [Bennett, John E.] Natl Inst Hlth, Lab Clin Infect Dis, Bethesda, MD 20892 USA. RP Bennett, JE (reprint author), NIH, Clin Ctr room 12C103b, Bethesda, MD USA. EM jbennett@niaid.nih.gov FU Division of Intramural Research at the National Institute of Allergy and Infectious Diseases FX This work was supported by the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases. NR 14 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 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD APR 1 PY 2017 VL 64 IS 7 BP 928 EP 929 DI 10.1093/cid/cix007 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP5SS UT WOS:000397439600019 PM 28362946 ER PT J AU Seddon, JA Makhene, MK Gumbo, T AF Seddon, James A. Makhene, Mamodikoe K. Gumbo, Tawanda TI Old Antibiotics for Tuberculosis Reply SO CLINICAL INFECTIOUS DISEASES LA English DT Letter C1 [Seddon, James A.] Imperial Coll London, Dept Paediat, Ctr Int Child Hlth, Norfolk Pl, London W2 1NY, England. [Makhene, Mamodikoe K.] NIAID, Div Microbiol & Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Gumbo, Tawanda] Baylor Univ, Med Ctr, Baylor Res Inst, Ctr Infect Dis Res & Expt Therapeut, Dallas, TX USA. [Gumbo, Tawanda] Univ Cape Town, Dept Med, Observatory, South Africa. RP Seddon, JA (reprint author), Imperial Coll London, Dept Paediat, Ctr Int Child Hlth, Norfolk Pl, London W2 1NY, England. EM james.seddon@imperial.ac.uk NR 3 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 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD APR 1 PY 2017 VL 64 IS 7 BP 983 EP 984 DI 10.1093/cid/cix038 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP5SS UT WOS:000397439600029 ER PT J AU Shah, R Murthy, V Pacold, M Danielson, K Tanriverdi, K Larson, MG Hanspers, K Pico, A Mick, E Reis, J de Ferranti, S Freinkman, E Levy, D Hoffmann, U Osganian, S Das, S Freedman, JE AF Shah, Ravi Murthy, Venkatesh Pacold, Michael Danielson, Kirsty Tanriverdi, Kahraman Larson, Martin G. Hanspers, Kristina Pico, Alexander Mick, Eric Reis, Jared de Ferranti, Sarah Freinkman, Elizaveta Levy, Daniel Hoffmann, Udo Osganian, Stavroula Das, Saumya Freedman, Jane E. TI Extracellular RNAs Are Associated With Insulin Resistance and Metabolic Phenotypes SO DIABETES CARE LA English DT Article ID NONALCOHOLIC FATTY LIVER; CIRCULATING MICRORNAS; CARDIOVASCULAR-DISEASE; ADIPOSE-TISSUE; OBESITY; SURGERY; PROTEIN; RISK; NETWORKS; MIR-122 AB OBJECTIVE Insulin resistance (IR) is a hallmark of obesity and metabolic disease. Circulating extracellular RNAs (ex-RNAs), stable RNA molecules in plasma, may play a role in IR, though most studies on ex-RNAs in IR are small. We sought to characterize the relationship between ex-RNAs and metabolic phenotypes in a large community-based human cohort. RESEARCH DESIGN AND METHODS We measured circulating plasma ex-RNAs in 2,317 participants without diabetes in the Framingham Heart Study (FHS) Offspring Cohort at cycle 8 and defined associations between ex-RNAs and IR (measured by circulating insulin level). We measured association between candidate ex-RNAs and markers of adiposity. Sensitivity analyses included individuals with diabetes. In a separate cohort of 90 overweight/obese youth, we measured selected ex-RNAs and metabolites. Biology of candidate microRNAs was investigated in silico. RESULTS The mean age of FHS participants was 65.8 years (56% female), with average BMI 27.7 kg/m(2); participants in the youth cohort had a mean age of 15.5 years (60% female), with mean BMI 33.8 kg/m(2). In age-, sex-, and BMI-adjusted models across 391 ex-RNAs in FHS, 18 ex-RNAs were associated with IR (of which 16 were microRNAs). miR-122 was associated with IR and regional adiposity in adults and IR in children (independent of metabolites). Pathway analysis revealed metabolic regulatory roles for miR-122, including regulation of IR pathways (AMPK, target of rapamycin signaling, and mitogen-activated protein kinase). CONCLUSIONS These results provide translational evidence in support of an important role of ex-RNAs as novel circulating factors implicated in IR. C1 [Shah, Ravi; Danielson, Kirsty; Das, Saumya] Massachusetts Gen Hosp, Harvard Med Sch, Dept Med, Boston, MA USA. [Murthy, Venkatesh] Univ Michigan, Dept Med & Radiol, Ann Arbor, MI USA. [Pacold, Michael; de Ferranti, Sarah] MIT, Whitehead Inst, Metabol Core, Boston, MA USA. [Tanriverdi, Kahraman; Mick, Eric; Freedman, Jane E.] Univ Massachusetts, Worcester, MA USA. [Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Hanspers, Kristina; Pico, Alexander] Gladstone Inst, San Francisco, CA USA. [Reis, Jared; Levy, Daniel] NHLBI, Div Cardiovasc, Bethesda, MD USA. [Freinkman, Elizaveta] Boston Childrens Hosp, Dept Med & Cardiol, Prevent Cardiol, Boston, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Osganian, Stavroula] Boston Childrens Hosp, Div Gen Pediat, Boston, MA USA. RP Shah, R (reprint author), Massachusetts Gen Hosp, Harvard Med Sch, Dept Med, Boston, MA USA.; Murthy, V (reprint author), Univ Michigan, Dept Med & Radiol, Ann Arbor, MI USA. EM rvshah@partners.org; vlmurthy@med.umich.edu FU American Heart Association [14FTF19940000]; Harvard Catalyst [UL1-TR-001102]; Thrasher Research Fund; National Institutes of Health [K23-HL-127099, N01-HC-25195]; National Institutes of Health Common Fund Extracellular RNA Communication Consortium [UH3-TR-900921, UH3-TR-000901]; Milton Foundation; New Balance Foundation Obesity Prevention Center at Boston Children's Hospital; Boston Children's Hospital FX This work was supported by the American Heart Association (14FTF19940000 to R.S.), the Harvard Catalyst (UL1-TR-001102), the Thrasher Research Fund (to R.S.), the National Institutes of Health (K23-HL-127099), the National Institutes of Health Common Fund Extracellular RNA Communication Consortium (UH3-TR-900921 to J.E.F. and UH3-TR-000901 to S.D.), the Milton Foundation, New Balance Foundation Obesity Prevention Center at Boston Children's Hospital, and Boston Children's Hospital (for the POOL study to S.O.). The FHS is funded by National Institutes of Health contract N01-HC-25195. NR 38 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2017 VL 40 IS 4 BP 546 EP 553 DI 10.2337/dc16-1354 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EP0UZ UT WOS:000397103500024 PM 28183786 ER PT J AU Rotman, Y Neuschwander-Tetri, BA AF Rotman, Yaron Neuschwander-Tetri, Brent A. TI Liver Fat Accumulation as a Barometer of Insulin Responsiveness Again Points to Adipose Tissue as the Culprit SO HEPATOLOGY LA English DT Editorial Material ID ALANINE AMINOTRANSFERASE LEVELS; TRIGLYCERIDE CONTENT; HEPATIC STEATOSIS; POPULATION; PREVALENCE; RESISTANCE; OBESITY; MEN C1 [Rotman, Yaron] NIDDK, Liver & Energy Metab Unit, Liver Dis Branch, NIH, 10 Ctr Dr, Bethesda, MD 20814 USA. [Neuschwander-Tetri, Brent A.] St Louis Univ, St Louis Univ Sch Med, Div Gastroenterol & Hepatol, St Louis, MO 63103 USA. RP Rotman, Y (reprint author), NIDDK, Liver & Energy Metab Unit, Liver Dis Branch, NIH, 10 Ctr Dr, Bethesda, MD 20814 USA. EM rotmany@niddk.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX Dr. Rotman is funded by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 13 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD APR PY 2017 VL 65 IS 4 BP 1088 EP 1090 DI 10.1002/hep.29094 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EP3SS UT WOS:000397302600002 PM 28152575 ER PT J AU Bonkovsky, HL Kleiner, DE Gu, JZ Odin, JA Russo, MW Navarro, VM Fontana, RJ Ghabril, MS Barnhart, H Hoofnagle, JH AF Bonkovsky, Herbert L. Kleiner, David E. Gu, Jiezhun Odin, Joseph A. Russo, Mark W. Navarro, Victor M. Fontana, Robert J. Ghabril, Marwan S. Barnhart, Huiman Hoofnagle, Jay H. CA US Drug Induced Liver Injury Netwo TI Clinical Presentations and Outcomes of Bile Duct Loss Caused by Drugs and Herbal and Dietary Supplements SO HEPATOLOGY LA English DT Article ID INDUCED LIVER-INJURY; INTRAHEPATIC CHOLESTASIS; PROLONGED CHOLESTASIS; FEATURES; TEMOZOLOMIDE; DUCTOPENIA; ACID AB Bile duct loss during the course of drug-induced liver injury is uncommon, but can be an indication of vanishing bile duct syndrome (VBDS). In this work, we assess the frequency, causes, clinical features, and outcomes of cases of drug-induced liver injury with histologically proven bile duct loss. All cases of drug-induced liver injury enrolled into a prospective database over a 10-year period that had undergone liver biopsies (n = 363) were scored for the presence of bile duct loss and assessed for clinical and laboratory features, causes, and outcomes. Twenty-six of the 363 patients (7%) with drug-, herbal-, or dietary-supplement-associated liver injury had bile duct loss on liver biopsy, which was moderate to severe (< 50% of portal areas with bile ducts) in 14 and mild (50%-75%) in 12. The presenting clinical features of the 26 cases varied, but the most common clinical pattern was a severe cholestatic hepatitis. The implicated agents included amoxicillin/clavulanate (n = 3), temozolomide (n = 3), various herbal products (n = 3), azithromycin (n = 52), and 15 other medications or dietary supplements. Compared to those without, those with bile duct loss were more likely to develop chronic liver injury (94% vs. 47%), which was usually cholestatic and sometimes severe. Five patients died and 2 others underwent liver transplantation for progressive cholestasis despite treatment with corticosteroids and ursodiol. The most predictive factor of poor outcome was the degree of bile duct loss on liver biopsy. Conclusion: Bile duct loss during acute cholestatic hepatitis is an ominous early indicator of possible VBDS, for which at present there are no known means of prevention or therapy. C1 [Bonkovsky, Herbert L.; Kleiner, David E.; Gu, Jiezhun; Odin, Joseph A.; Barnhart, Huiman] Natl Inst Hlth NIH, Bethesda, MD USA. [Odin, Joseph A.; Fontana, Robert J.; Ghabril, Marwan S.] NCI, NIH, Bethesda, MD 20892 USA. [Fontana, Robert J.; Ghabril, Marwan S.] Duke Clin Res Inst, Durham, NC USA. [Fontana, Robert J.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Odin, Joseph A.; Navarro, Victor M.] Carolinas HealthCare Syst, Charlotte, NC USA. [Gu, Jiezhun; Russo, Mark W.; Barnhart, Huiman] Einstein Med Ctr, Philadelphia, PA USA. [Gu, Jiezhun; Ghabril, Marwan S.] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Kleiner, David E.; Gu, Jiezhun; Navarro, Victor M.] Indiana Univ Purdue Univ, Indianapolis, IN 46202 USA. [Bonkovsky, Herbert L.; Kleiner, David E.; Ghabril, Marwan S.] NIDDK, NIH, Bethesda, MD USA. RP Bonkovsky, HL (reprint author), Natl Inst Hlth NIH, Bethesda, MD USA. EM hbonkovsky@me.com FU NIDDK [U01-DK065176, DK065184, DK065193, DK065201, DK065211, DK065238, DK082992, DK083020, DK083023, DK083027, DK100928]; Intramural Division of the National Cancer Institute FX This study was funded as a cooperative agreement with the NIDDK under grant numbers: U01-DK065176, DK065184, DK065193, DK065201, DK065211, DK065238, DK082992, DK083020, DK083023, DK083027, and DK100928. This study was supported, in part, by the Intramural Division of the National Cancer Institute. NR 22 TC 1 Z9 1 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD APR PY 2017 VL 65 IS 4 BP 1267 EP 1277 DI 10.1002/hep.28967 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EP3SS UT WOS:000397302600017 PM 27981596 ER PT J AU Bickhart, DM Rosen, BD Koren, S Sayre, BL Hastie, AR Chan, S Lee, J Lam, ET Liachko, I Sullivan, ST Burton, JN Huson, HJ Nystrom, JC Kelley, CM Hutchison, JL Zhou, Y Sun, J Crisa, A de Leon, FAP Schwartz, JC Hammond, JA Waldbieser, GC Schroeder, SG Liu, GE Dunham, MJ Shendure, J Sonstegard, TS Phillippy, AM Van Tassell, CP Smith, TPL AF Bickhart, Derek M. Rosen, Benjamin D. Koren, Sergey Sayre, Brian L. Hastie, Alex R. Chan, Saki Lee, Joyce Lam, Ernest T. Liachko, Ivan Sullivan, Shawn T. Burton, Joshua N. Huson, Heather J. Nystrom, John C. Kelley, Christy M. Hutchison, Jana L. Zhou, Yang Sun, Jiajie Crisa, Alessandra de Leon, F. Abel Ponce Schwartz, John C. Hammond, John A. Waldbieser, Geoffrey C. Schroeder, Steven G. Liu, George E. Dunham, Maitreya J. Shendure, Jay Sonstegard, Tad S. Phillippy, Adam M. Van Tassell, Curtis P. Smith, Timothy P. L. TI Single-molecule sequencing and chromatin conformation capture enable de novo reference assembly of the domestic goat genome SO NATURE GENETICS LA English DT Article ID RESTRICTION MAPS; CATTLE; CHROMOSOMES; ANNOTATION; EVOLUTION; RECONSTRUCTION; TRANSCRIPTOME; COMPLEXITY; ALIGNMENTS; DROSOPHILA AB The decrease in sequencing cost and increased sophistication of assembly algorithms for short-read platforms has resulted in a sharp increase in the number of species with genome assemblies. However, these assemblies are highly fragmented, with many gaps, ambiguities, and errors, impeding downstream applications. We demonstrate current state of the art for de novo assembly using the domestic goat (Capra hircus) based on long reads for contig formation, short reads for consensus validation, and scaffolding by optical and chromatin interaction mapping. These combined technologies produced what is, to our knowledge, the most continuous de novo mammalian assembly to date, with chromosome-length scaffolds and only 649 gaps. Our assembly represents a similar to 400-fold improvement in continuity due to properly assembled gaps, compared to the previously published C. hircus assembly, and better resolves repetitive structures longer than 1 kb, representing the largest repeat family and immune gene complex yet produced for an individual of a ruminant species. C1 [Bickhart, Derek M.] USDA ARS, Cell Wall Biol & Utilizat Lab, Madison, WI USA. [Rosen, Benjamin D.; Hutchison, Jana L.; Zhou, Yang; Schroeder, Steven G.; Liu, George E.; Van Tassell, Curtis P.] USDA ARS, Anim Genom & Improvement Lab, Beltsville, MD USA. [Koren, Sergey; Phillippy, Adam M.] Natl Human Genome Res Inst, Computat & Stat Genom Branch, Genome Informat Sect, Bethesda, MD USA. [Sayre, Brian L.] Virginia State Univ, Dept Biol, Petersburg, VA USA. [Hastie, Alex R.; Chan, Saki; Lee, Joyce; Lam, Ernest T.] BioNano Genom, San Diego, CA USA. [Liachko, Ivan; Burton, Joshua N.; Dunham, Maitreya J.; Shendure, Jay] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA USA. [Sullivan, Shawn T.] Phase Genom, Seattle, WA USA. [Huson, Heather J.; Nystrom, John C.] Cornell Univ, Dept Anim Sci, Ithaca, NY USA. [Kelley, Christy M.; Smith, Timothy P. L.] USDA ARS, Meat Anim Res Ctr, Clay Ctr, NE USA. [Zhou, Yang] Northwest A&F Univ, Coll Anim Sci & Technol, Shaanxi Key Lab Agr Mol Biol, Yangling, Peoples R China. [Sun, Jiajie] China Agr Univ, Guangzhou, Peoples R China. [Crisa, Alessandra] CREA, Anim Prod Res Ctr, Rome, Italy. [de Leon, F. Abel Ponce] Univ Minnesota, Dept Anim Sci, St Paul, MN USA. [Schwartz, John C.; Hammond, John A.] Pirbright Inst, Livestock Viral Dis Programme, Woking, Surrey, England. [Waldbieser, Geoffrey C.] USDA ARS, Warmwater Aquaculture Res Unit, Stoneville, MS USA. [Shendure, Jay] Howard Hughes Med Inst, Seattle, WA USA. [Sonstegard, Tad S.] Recombinet Inc, St Paul, MN USA. RP Van Tassell, CP (reprint author), USDA ARS, Anim Genom & Improvement Lab, Beltsville, MD USA.; Phillippy, AM (reprint author), Natl Human Genome Res Inst, Computat & Stat Genom Branch, Genome Informat Sect, Bethesda, MD USA.; Smith, TPL (reprint author), USDA ARS, Meat Anim Res Ctr, Clay Ctr, NE USA. EM adam.phillippy@nih.gov; curt.vantassell@ars.usda.gov; tim.smith@ars.usda.gov FU US Agency for International Development Feed the Future program; Norman Borlaug Commemorative Research Initiative; Livestock Improvement Program; Agriculture and Food Research Initiative (AFRI) competitive grant from the USDA National Institute of Food and Agriculture (NIFA) Animal Genome Program [2011-67015-30183, 2015-67015-22970]; USDA CRIS project [8042-31000-104-00, 3040-31320-012-00, 6402-31000-006-00D]; NIH [R01HG006283, P41 GM103533]; UW Commercialization Gap Fund and Commercialization Fellows Program; MN Experiment Station Project [MIN-16-103]; UK Biotechnology and Biological Sciences Research Council Institute Strategic Program on Livestock Viral Diseases award; NIH Intramural Research Program of the National Human Genome Research Institute FX This study used the computational resources of the Biowulf system at the National Institutes of Health (NIH). We thank R. Lee for technical assistance. This project was supported by the US Agency for International Development Feed the Future program, the Norman Borlaug Commemorative Research Initiative, and the Livestock Improvement Program. This work was also supported in part by Agriculture and Food Research Initiative (AFRI) competitive grant 2011-67015-30183 and 2015-67015-22970 from the USDA National Institute of Food and Agriculture (NIFA) Animal Genome Program. D.M.B., B.D.R., S.G.S., and C.P.V.T. were supported by USDA CRIS project number 8042-31000-104-00. C.M.K. and T.P.L.S. were supported by USDA CRIS project number 3040-31320-012-00. G.C.W. was supported by USDA CRIS project number 6402-31000-006-00D. J. Shendure was supported in part by NIH grant R01HG006283. M.J.D. and I.L. were supported in part by NIH grant P41 GM103533. M.J.D. is a Senior Fellow in the Genetic Networks program at the Canadian Institute for Advanced Research and a Rita Allen Foundation Scholar. I.L. is supported by the UW Commercialization Gap Fund and Commercialization Fellows Program. F.A.P.d.L. was supported by MN Experiment Station Project MIN-16-103. J.C.S. and J.A.H. were funded by a UK Biotechnology and Biological Sciences Research Council Institute Strategic Program on Livestock Viral Diseases award to the Pirbright Institute. 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. S.K. and A.M.P. were supported by the NIH Intramural Research Program of the National Human Genome Research Institute. NR 72 TC 1 Z9 1 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD APR PY 2017 VL 49 IS 4 BP 643 EP + DI 10.1038/ng.3802 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA EP8CO UT WOS:000397603700030 PM 28263316 ER PT J AU Cain, DW Cidlowski, JA AF Cain, Derek W. Cidlowski, John A. TI Immune regulation by glucocorticoids SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID PROTEIN-PROTEIN INTERACTION; PERIPHERAL T-CELLS; KAPPA-B-ALPHA; DENDRITIC CELLS; GENE-EXPRESSION; TRANSCRIPTIONAL ACTIVATION; ENDOGENOUS GLUCOCORTICOIDS; CHROMATIN ACCESSIBILITY; TRANSLATIONAL ISOFORMS; INDUCED APOPTOSIS AB Endogenous glucocorticoids are crucial to various physiological processes, including metabolism, development and inflammation. Since 1948, synthetic glucocorticoids have been used to treat various immune-related disorders. The mechanisms that underlie the immunosuppressive properties of these hormones have been intensely scrutinized, and it is widely appreciated that glucocorticoids have pleiotropic effects on the immune system. However, a clear picture of the cellular and molecular basis of glucocorticoid action has remained elusive. In this Review, we distil several decades of intense (and often conflicting) research that defines the interface between the endocrine stress response and the immune system. C1 [Cain, Derek W.; Cidlowski, John A.] NIEHS, Signal Transduct Lab, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 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 Intramural Research Program of the US National Institutes of Health, National Institute of Environmental Health Sciences FX The authors' research of the topic of this Review was supported, in part, by the Intramural Research Program of the US National Institutes of Health, National Institute of Environmental Health Sciences. NR 135 TC 0 Z9 0 U1 4 U2 4 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 APR PY 2017 VL 17 IS 4 BP 233 EP 247 DI 10.1038/nri.2017.1 PG 15 WC Immunology SC Immunology GA EP4YJ UT WOS:000397385600009 PM 28192415 ER PT J AU Croft, M Siegel, RM AF Croft, Michael Siegel, Richard M. TI Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases SO NATURE REVIEWS RHEUMATOLOGY LA English DT Review ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; COLLAGEN-INDUCED ARTHRITIS; TUMOR-NECROSIS-FACTOR; FIBROBLAST-LIKE SYNOVIOCYTES; T-CELL-ACTIVATION; LIGAND 1A TL1A; ALLERGIC LUNG INFLAMMATION; LYMPHOTOXIN-BETA-RECEPTOR; AUTOIMMUNE-DISEASE; SYNOVIAL FIBROBLASTS AB TNF blockers are highly efficacious at dampening inflammation and reducing symptoms in rheumatic diseases such as rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, and also in nonrheumatic syndromes such as inflammatory bowel disease. As TNF belongs to a superfamily of 19 structurally related proteins that have both proinflammatory and anti-inflammatory activity, reagents that disrupt the interaction between proinflammatory TNF family cytokines and their receptors, or agonize the anti-inflammatory receptors, are being considered for the treatment of rheumatic diseases. Biologic agents that block B cell activating factor (BAFF) and receptor activator of nuclear factor-kappa B ligand (RANKL) have been approved for the treatment of systemic lupus erythematosus and osteoporosis, respectively. In this Review, we focus on additional members of the TNF superfamily that could be relevant for the pathogenesis of rheumatic disease, including those that can strongly promote activity of immune cells or increase activity of tissue cells, as well as those that promote death pathways and might limit inflammation. We examine preclinical mouse and human data linking these molecules to the control of damage in the joints, muscle, bone or other tissues, and discuss their potential as targets for future therapy of rheumatic diseases. C1 [Croft, Michael] Univ Calif San Diego, Div Immune Regulat, La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. [Croft, Michael] Univ Calif San Diego, Dept Med, La Jolla, CA 92037 USA. [Siegel, Richard M.] NIAMS, Immunoregulat Sect, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Croft, M (reprint author), Univ Calif San Diego, Div Immune Regulat, La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA.; Croft, M (reprint author), Univ Calif San Diego, Dept Med, La Jolla, CA 92037 USA.; Siegel, RM (reprint author), NIAMS, Immunoregulat Sect, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. EM mick@lji.org; siegelr@mail.nih.gov FU NIH [AI070535, AI103021, AI110929, AI123134]; NIAMS intramural research program FX M.C. is supported by NIH grants AI070535, AI103021, AI110929 and AI123134. R.S. is supported by the NIAMS intramural research program. NR 227 TC 0 Z9 0 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4790 EI 1759-4804 J9 NAT REV RHEUMATOL JI Nat. Rev. Rheumatol. PD APR PY 2017 VL 13 IS 4 BP 217 EP 233 DI 10.1038/nrrheum.2017.22 PG 17 WC Rheumatology SC Rheumatology GA EP3WM UT WOS:000397312400005 PM 28275260 ER PT J AU Schartner, V Romero, NB Donkervoort, S Treves, S Munot, P Pierson, TM Dabaj, I Malfatti, E Zaharieva, IT Zorzato, F Neto, OA Brochier, G Lornage, X Eymard, B Taratuto, AL Bohm, J Gonorazky, H Ramos-Platt, L Feng, L Phadke, R Bharucha-Goebel, DX Sumner, CJ Bui, MT Lacene, E Beuvin, M Labasse, C Dondaine, N Schneider, R Thompson, J Boland, A Deleuze, JF Matthews, E Pakleza, AN Sewry, CA Biancalana, V Quijano-Roy, S Muntoni, F Fardeau, M Bonnemann, CG Laporte, J AF Schartner, Vanessa Romero, Norma B. Donkervoort, Sandra Treves, Susan Munot, Pinki Pierson, Tyler Mark Dabaj, Ivana Malfatti, Edoardo Zaharieva, Irina T. Zorzato, Francesco Neto, Osorio Abath Brochier, Guy Lornage, Xaviere Eymard, Bruno Taratuto, Ana Lia Boehm, Johann Gonorazky, Hernan Ramos-Platt, Leigh Feng, Lucy Phadke, Rahul Bharucha-Goebel, Diana X. Sumner, Charlotte Jane Bui, Mai Thao Lacene, Emmanuelle Beuvin, Maud Labasse, Clemence Dondaine, Nicolas Schneider, Raphael Thompson, Julie Boland, Anne Deleuze, Jean-Francois Matthews, Emma Pakleza, Aleksandra Nadaj Sewry, Caroline A. Biancalana, Valerie Quijano-Roy, Susana Muntoni, Francesco Fardeau, Michel Boennemann, Carsten G. Laporte, Jocelyn TI Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy SO ACTA NEUROPATHOLOGICA LA English DT Article DE DHPR; Congenital myopathy; Excitation-contraction coupling; Triad; Centronuclear myopathy; Core myopathy; Myotubular myopathy ID HYPOKALEMIC PERIODIC PARALYSIS; INTRACELLULAR CALCIUM HOMEOSTASIS; MUSCULAR DYSGENESIS MDG; II-III-LOOP; SKELETAL-MUSCLE; CENTRONUCLEAR MYOPATHY; RELEASE CHANNEL; MUTATIONS; SUBUNIT; GENE AB Muscle contraction upon nerve stimulation relies on excitation-contraction coupling (ECC) to promote the rapid and generalized release of calcium within myofibers. In skeletal muscle, ECC is performed by the direct coupling of a voltage-gated L-type Ca2+ channel (dihydropyridine receptor; DHPR) located on the T-tubule with a Ca2+ release channel (ryanodine receptor; RYR1) on the sarcoplasmic reticulum (SR) component of the triad. Here, we characterize a novel class of congenital myopathy at the morphological, molecular, and functional levels. We describe a cohort of 11 patients from 7 families presenting with perinatal hypotonia, severe axial and generalized weakness. Ophthalmoplegia is present in four patients. The analysis of muscle biopsies demonstrated a characteristic intermyofibrillar network due to SR dilatation, internal nuclei, and areas of myofibrillar disorganization in some samples. Exome sequencing revealed ten recessive or dominant mutations in CACNA1S (Ca(v)1.1), the pore-forming subunit of DHPR in skeletal muscle. Both recessive and dominant mutations correlated with a consistent phenotype, a decrease in protein level, and with a major impairment of Ca2+ release induced by depolarization in cultured myotubes. While dominant CACNA1S mutations were previously linked to malignant hyperthermia susceptibility or hypokalemic periodic paralysis, our findings strengthen the importance of DHPR for perinatal muscle function in human. These data also highlight CACNA1S and ECC as therapeutic targets for the development of treatments that may be facilitated by the previous knowledge accumulated on DHPR. C1 [Schartner, Vanessa; Neto, Osorio Abath; Lornage, Xaviere; Boehm, Johann; Schneider, Raphael; Biancalana, Valerie; Laporte, Jocelyn] Inst Genet & Biol Mol & Cellulaire IGBMC, Rue Laurent Fries,BP 10142, F-67404 1 Illkirch Graffenstaden, France. [Schartner, Vanessa; Lornage, Xaviere; Boehm, Johann; Schneider, Raphael; Biancalana, Valerie; Laporte, Jocelyn] INSERM, F-67404 Illkirch Graffenstaden, France. [Schartner, Vanessa; Lornage, Xaviere; Boehm, Johann; Schneider, Raphael; Biancalana, Valerie; Laporte, Jocelyn] CNRS, F-67404 Illkirch Graffenstaden, France. [Schartner, Vanessa; Lornage, Xaviere; Boehm, Johann; Schneider, Raphael; Biancalana, Valerie; Laporte, Jocelyn] Univ Strasbourg, FMTS, F-67404 Illkirch Graffenstaden, France. [Romero, Norma B.; Malfatti, Edoardo; Brochier, Guy; Bui, Mai Thao; Lacene, Emmanuelle; Beuvin, Maud; Labasse, Clemence; Fardeau, Michel] Univ Paris 06, Univ Sorbonne, GH Pitie Salpetriere,CNRS, Ctr Res Myol,UPMC,INSERM,UMRS974,FRE3617, 47 Blvd l Hop, F-75013 Paris, France. [Romero, Norma B.; Malfatti, Edoardo; Brochier, Guy; Bui, Mai Thao; Lacene, Emmanuelle; Labasse, Clemence; Fardeau, Michel] GHU Pitie Salpetriere, Ctr Ref Pathol Neuromusculaire, Inst Myol, Assistance Publ Hopitaux Paris, Paris, France. [Donkervoort, Sandra; Neto, Osorio Abath; Bharucha-Goebel, Diana X.; Boennemann, Carsten G.] NIH, Natl Inst Neurol Disorders & Stroke, Neuromuscular & Neurogenet Disorders Childhood Se, Neurogenet Branch, Bethesda, MD 20892 USA. [Treves, Susan; Zorzato, Francesco] Univ Basel Hosp, Dept Anesthesia, CH-4031 Basel, Switzerland. [Donkervoort, Sandra; Zorzato, Francesco] Univ Basel Hosp, Dept Biomedizin, CH-4031 Basel, Switzerland. [Munot, Pinki; Zaharieva, Irina T.; Feng, Lucy; Phadke, Rahul; Matthews, Emma; Sewry, Caroline A.; Muntoni, Francesco] UCL Great Ormond St Inst Child Hlth, Dubowitz Neuromuscular Ctr, London WC1N 1EH, England. UCL Great Ormond St Inst Child Hlth, MRC Ctr Neuromuscula Dis, London WC1N 1EH, England. [Pierson, Tyler Mark] Cedars Sinai Med Ctr, Dept Pediat & Neurol, 8700 Beverly Blvd, Los Angeles, CA 90048 USA. [Pierson, Tyler Mark] Board Governors Regenerat Med Inst, Cedars Sinai Med Ctr, 8700 Beverly Blvd, Los Angeles, CA 90048 USA. [Dabaj, Ivana; Quijano-Roy, Susana] Hop Raymond Poincar, Hopitaux Univ Paris Ile France Ouest, AP HP, Serv Pediat, Garches, France. [Dabaj, Ivana; Quijano-Roy, Susana] Ctr Ref Malad Neuromusculaires GNMH, Garches, France. [Dabaj, Ivana; Quijano-Roy, Susana] Reseau Natl Francais Filiere Neuromusculaire FILN, Garches, France. [Eymard, Bruno] Ctr Ref Pathol Neuromusculaire Paris Est, Grp Hosp Pitie Salpetriere, Paris, France. [Taratuto, Ana Lia] Natl Pediat Hosp J P Garrahan, Consultant Neuropathol Dept, Buenos Aires, DF, Argentina. Inst Neurol Res FLENI, Consultant Neuropathol Dept, Buenos Aires, DF, Argentina. [Gonorazky, Hernan] Univ Toronto, Hosp Sick Children, Dept Pediat, Div Neurol, Toronto, ON, Canada. [Ramos-Platt, Leigh] Univ Southern Calif, Childrens Hosp Angeles, Keck Sch Med, Div Neurol, 4650 W Sunset Blvd,Mailstop 34, Los Angeles, CA 90027 USA. [Bharucha-Goebel, Diana X.] Childrens Natl Hlth Syst, Div Neurol, Washington, DC 20010 USA. [Sumner, Charlotte Jane] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Sumner, Charlotte Jane] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Schneider, Raphael; Thompson, Julie] CSTB Complex Syst & Translat Bioinformat, Fac Med, ICube UMR7357, F-67000 Strasbourg, France. [Boland, Anne; Deleuze, Jean-Francois] CEA, Inst Genom, Ctr Natl Genotypage, Evry, France. [Pakleza, Aleksandra Nadaj] CHU Angers, Ctr Ref Malad Neuromusculaires Nantes Anger, Serv Neurol, Angers, France. [Dondaine, Nicolas; Biancalana, Valerie] Nouvel Hop Civil, Fac Med, Lab Diagnost Genet, F-67000 Strasbourg, France. [Quijano-Roy, Susana] Univ Versailles St Quentin, U1179 UVSQ INSERM, Montigny, France. RP Laporte, J (reprint author), Inst Genet & Biol Mol & Cellulaire IGBMC, Rue Laurent Fries,BP 10142, F-67404 1 Illkirch Graffenstaden, France.; Laporte, J (reprint author), INSERM, F-67404 Illkirch Graffenstaden, France.; Laporte, J (reprint author), CNRS, F-67404 Illkirch Graffenstaden, France.; Laporte, J (reprint author), Univ Strasbourg, FMTS, F-67404 Illkirch Graffenstaden, France. EM jocelyn@igbmc.fr FU Institut National de la Sante et de la Recherche Medicale (INSERM), Centre National de la Recherche Scientifique (CNRS), University of Strasbourg; France Genomique National infrastructure; Investissements d'Avenir program [ANR-10-INBS-09]; Fondation Maladies Rares [ANR-10-LABX-0030-INRT, ANR-10-IDEX-0002-02]; Sparks the Children's medical research charity [12KCL 01-MT]; Swiss National Science Foundation [31003A-146198]; Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases; National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust; University College London; Muscular Dystrophy UK FX We thank Isabelle Marty for triadin antibody, John Rendu for RYR1 molecular testing, Anne-Sophie Nicot and Clara Franzini-Armstrong for discussions, Robert Y. Carlier for analysis of MRI images, and Nicola Foulds for clinical discussions. This work was supported by the Institut National de la Sante et de la Recherche Medicale (INSERM), Centre National de la Recherche Scientifique (CNRS), University of Strasbourg, the France Genomique National infrastructure, funded as part of the Investissements d'Avenir program managed by the Agence Nationale pour la Recherche (ANR-10-INBS-09), and by Fondation Maladies Rares within the frame of the "Myocapture" sequencing project, ANR-10-LABX-0030-INRT under the frame program Investissements d'Avenir ANR-10-IDEX-0002-02, Association Francaise contre les Myopathies (AFM-17088), Muscular Dystrophy Association (MDA-186985), Myotubular Trust and Sparks the Children's medical research charity grant No 12KCL 01-MT, and the Swiss National Science Foundation grant No 31003A-146198. T.M.P. was supported by the Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases. F.M. is supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. The Biobank of the MRC Neuromuscular Centre and the support of the Muscular Dystrophy UK to the Dubowitz Neuromuscular Centre are also gratefully acknowledged. NR 41 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 EI 1432-0533 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD APR PY 2017 VL 133 IS 4 BP 517 EP 533 DI 10.1007/s00401-016-1656-8 PG 17 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA EP3XR UT WOS:000397315500002 PM 28012042 ER PT J AU Li, SF Yang, YH Hoffmann, E Tyndale, RF Stein, EA AF Li, Sufang Yang, Yihong Hoffmann, Ewa Tyndale, Rachel F. Stein, Elliot A. TI CYP2A6 Genetic Variation Alters Striatal-Cingulate Circuits, Network Hubs, and Executive Processing in Smokers SO BIOLOGICAL PSYCHIATRY LA English DT Article DE CYP2A6 genotype; Functional connectivity strength; Neuroadaptations; Nicotine; Smoking; Striatal-cingulate-insula circuits ID NICOTINE METABOLITE RATIO; STATE FUNCTIONAL CONNECTIVITY; PLACEBO-CONTROLLED TRIAL; EVENT-RELATED FMRI; SMOKING-CESSATION; PREFRONTAL CORTEX; TRANSDERMAL NICOTINE; CIGARETTE-SMOKING; COCAINE ADDICTION; BRAIN REACTIVITY AB BACKGROUND: Variation in the CYP2A6 gene alters the rate of nicotine metabolic inactivation and is associated with smoking behaviors and cessation success rates. The underlying neurobiological mechanisms of this genetic influence are unknown. METHODS: Intrinsic functional connectivity strength, a whole- brain, data- driven, graph theory- based method, was applied to resting- state functional magnetic resonance imaging data in 66 smokers and 92 nonsmokers. A subset of subjects (n = 23/ 20; smokers/ nonsmokers) performed the monetary incentive delay task, probing reward anticipation, and a go/no-go task, probing response inhibition, on two occasions, in the presence and absence of a nicotine patch. RESULTS: A significant CYP2A6 genotype 3 smoking effect was found in the dorsal anterior cingulate cortex and ventral striatum, such that the normal (vs. slow) genotype individuals showed greater functional connectivity strength among smokers but not nonsmokers. Functional connectivity strength was negatively associated with severity of nicotine dependence in slow metabolizers. Both hubs were biased by inputs from the insula identified from seed-based connectivity. Similar gene 3 environment interactions were seen in ventral striatum during smoking abstinence when subjects performed the monetary incentive delay task and in dorsal anterior cingulate cortex when they performed the go/no-go task; both reductions were " normalized" in smokers (and increased in nonsmokers) after acute nicotine administration. CONCLUSIONS: Because the CYP2A6 effect was seen only in smokers, these data suggest that the rate of nicotine metabolism- and thus the concentration of nicotine presented to the brain over the course of nicotine addiction-shapes brain circuits that, among other functions, compute reward and impulsivity processes. C1 [Li, Sufang; Yang, Yihong; Stein, Elliot A.] Natl Inst Hlth, Natl Inst Drug Abuse Intramural Res Program, Neuroimaging Res Branch, Baltimore, MD USA. [Hoffmann, Ewa; Tyndale, Rachel F.] Univ Toronto, Ctr Addict & Mental Hlth, Campbell Family Mental Hlth Res Inst, Toronto, ON, Canada. [Hoffmann, Ewa; Tyndale, Rachel F.] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON, Canada. [Tyndale, Rachel F.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. RP Stein, EA (reprint author), 251 Bayview Blvd Suite 200, Baltimore, MD 21224 USA. EM estein@mail.nih.gov FU National Institute on Drug Abuse; National Institutes of Health; Pharmacogenomic Research Network [DA020830]; Canadian Institutes for Health Research [TMH109787]; Endowed Chair in Addiction for the Department of Psychiatry; Campbell Family Mental Health Research Institute of the Centre for Addiction and Mental Health and Centre for Addiction and Mental Health Foundation; Canada Foundation for Innovation [20289, 16014]; Ontario Ministry of Research and Innovation FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health (SL, YY, EAS), Pharmacogenomic Research Network Grant No. DA020830 (to EH and RFT), Canadian Institutes for Health Research Grant No. TMH109787 (to EH and RFT), Endowed Chair in Addiction for the Department of Psychiatry, Campbell Family Mental Health Research Institute of the Centre for Addiction and Mental Health and Centre for Addiction and Mental Health Foundation, Canada Foundation for Innovation Grant Nos.20289 and 16014 (to RFT), and the Ontario Ministry of Research and Innovation. NR 66 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 1 PY 2017 VL 81 IS 7 BP 554 EP 563 DI 10.1016/j.biopsych.2016.09.013 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EP3RX UT WOS:000397300500010 PM 27865452 ER PT J AU Schmeichel, BE Herman, MA Roberto, M Koob, GF AF Schmeichel, Brooke E. Herman, Melissa A. Roberto, Marisa Koob, George F. TI Hypocretin Neurotransmission Within the Central Amygdala Mediates Escalated Cocaine Self-administration and Stress-Induced Reinstatement in Rats SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Central amygdala; Cocaine; Drug dependence; Hypocretin/orexin; Intravenous self-administration; Reinstatement ID CORTICOTROPIN-RELEASING-FACTOR; EXTENDED ACCESS; BRAIN STRESS; DRUG INTAKE; OREXIN; ADDICTION; SEEKING; OREXIN/HYPOCRETIN; SYSTEMS; DYSREGULATION AB BACKGROUND: Cocaine addiction is characterized by patterns of compulsive drug-taking, including preoccupation with obtaining cocaine and loss of control over drug intake. The lateral hypothalamic hypocretin/orexin (HCRT) system has been implicated in drug-taking and the reinstatement of drug-seeking. Evidence suggests that HCRT may drive drug-seeking through activation of specific brain regions implicated in stress system dysfunction, including the central amygdala (CeA). The role of HCRT in the persistence of compulsive-like cocaine-taking has yet to be fully elucidated. METHODS: Systemic and intra-CeA microinfusions of the HCRT-receptor 1 antagonist, SB-334867, were administered to rats allowed either short (1 hour; ShA) or long (6 hours; LgA) access to cocaine self-administration. Animals were tested for fixed and progressive ratio responding for cocaine and stress-induced reinstatement of drug-seeking. In addition, using electrophysiological techniques on in vitro slices, we investigated gamma-aminobutyric acidergic (GABAergic) neurotransmission in the medial CeA and the sensitivity of GABAergic synapses to modulation of the HCRT system in ShA or LgA rats. RESULTS: We found systemic administration of SB-334867 (0, 7.5, 15, 30 mg/kg) dose dependently decreased cocaine intake specifically in LgA rats but not in ShA rats. Microinjections of SB-334867 (20 nmol) bilaterally into the CeA significantly reduced cocaine intake in LgA rats. We also observed a significant attenuation of yohimbine-induced reinstatement of cocaine-seeking after intra-CeA SB-334867 (10 nmol) administration. Finally, electrophysiological data indicated enhanced GABAergic neurotransmission within the medial CeA in LgA rats, which was blocked with SB-334867(10 mu mol/L). CONCLUSIONS: These findings suggest that HCRT neurotransmission within the CeA is implicated in compulsive-like cocaine-seeking. C1 [Schmeichel, Brooke E.; Koob, George F.] Natl Inst Drug Abuse, Integrat Neurosci Res Branch, Neurobiol Addict Sect, Baltimore, MD 21224 USA. [Herman, Melissa A.; Roberto, Marisa] Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. [Koob, George F.] Natl Inst Alcohol Abuse & Alcoholism, NIH, Bethesda, MD 20892 USA. RP Schmeichel, BE (reprint author), Natl Inst Drug Abuse, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM brooke.schmeichel@nih.gov FU National Institute on Drug Abuse [DA036355, DA004398]; National Institute of Alcohol Abuse and Alcoholism [AA007456, AA023002, AA006420, AA021491]; Pearson Center for Alcoholism and Addiction Research; Intramural Research Programs of the National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism FX This work was supported by the National Institute on Drug Abuse Grant Nos. DA036355 (to BES) and DA004398 (formerly, GFK); National Institute of Alcohol Abuse and Alcoholism Grant Nos. AA007456 (formerly, GFK), AA023002 (to MAH), AA006420 (to MR), and AA021491 (to MR); and the Pearson Center for Alcoholism and Addiction Research. A portion of this work was also supported by the Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. NR 38 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 1 PY 2017 VL 81 IS 7 BP 606 EP 615 DI 10.1016/j.biopsych.2016.06.010 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EP3RX UT WOS:000397300500015 PM 27567312 ER PT J AU Kwako, LE Momenan, R Litten, RZ Koob, GF Goldman, D AF Kwako, Laura E. Momenan, Reza Litten, Raye Z. Koob, George F. Goldman, David TI Reply to: Neuroclinical Assessment of Addiction Needs to Incorporate Decision-Making Measures and Ecological Validity SO BIOLOGICAL PSYCHIATRY LA English DT Letter C1 [Kwako, Laura E.; Goldman, David] Natl Inst Hlth, Natl Inst Alcohol Abuse & Alcoholism, Off Clin Director, Bethesda, MD USA. [Momenan, Reza] Natl Inst Hlth, Natl Inst Alcohol Abuse & Alcoholism, Sect Brain Electrophysiol & Imaging, Bethesda, MD USA. [Litten, Raye Z.] Natl Inst Hlth, Natl Inst Alcohol Abuse & Alcoholism, Div Medicat Dev, Div Intramural Clin & Biol Res, Bethesda, MD USA. [Koob, George F.] Natl Inst Hlth, Natl Inst Alcohol Abuse & Alcoholism, Off Director, Bethesda, MD USA. [Goldman, David] Natl Inst Hlth, Natl Inst Alcohol Abuse & Alcoholism, Neurogenet Lab, Bethesda, MD USA. RP Kwako, LE (reprint author), Natl Inst Hlth, Natl Inst Alcohol Abuse & Alcoholism, 10 Ctr Dr,1-5340, Bethesda, MD 20892 USA. EM laura.kwako@nih.gov NR 3 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 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 1 PY 2017 VL 81 IS 7 BP E55 EP E55 DI 10.1016/j.biopsych.2016.08.029 PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EP3RX UT WOS:000397300500006 PM 27776735 ER PT J AU Dheda, K Limberis, JD Pietersen, E Phelan, J Esmail, A Lesosky, M Fennelly, KP te Riele, J Mastrapa, B Streicher, EM Dolby, T Abdallah, AM Ben-Rached, F Simpson, J Smith, L Gumbo, T van Helden, P Sirgel, FA McNerney, R Theron, G Pain, A Clark, TG Warren, RM AF Dheda, Keertan Limberis, Jason D. Pietersen, Elize Phelan, Jody Esmail, Aliasgar Lesosky, Maia Fennelly, Kevin P. te Riele, Julian Mastrapa, Barbara Streicher, Elizabeth M. Dolby, Tania Abdallah, Abdallah M. Ben-Rached, Fathia Simpson, John Smith, Liezel Gumbo, Tawanda van Helden, Paul Sirgel, Frederick A. McNerney, Ruth Theron, Grant Pain, Arnab Clark, Taane G. Warren, Robin M. TI Outcomes, infectiousness, and transmission dynamics of patients with extensively drug-resistant tuberculosis and home-discharged patients with programmatically incurable tuberculosis: a prospective cohort study SO LANCET RESPIRATORY MEDICINE LA English DT Article ID MULTIDRUG-RESISTANT; MYCOBACTERIUM-TUBERCULOSIS; PULMONARY TUBERCULOSIS; COUGH AEROSOLS; SOUTH-AFRICA; BEDAQUILINE; DELAMANID; DISEASE; COSTS; CARE AB Background The emergence of programmatically incurable tuberculosis threatens to destabilise control efforts. The aim of this study was to collect prospective patient-level data to inform treatment and containment strategies. Methods In a prospective cohort study, 273 South African patients with extensively drug-resistant tuberculosis, or resistance beyond extensively drug-resistant tuberculosis, were followed up over a period of 6 years. Transmission dynamics, infectiousness, and drug susceptibility were analysed in a subset of patients from the Western Cape using whole-genome sequencing (WGS; n=149), a cough aerosol sampling system (CASS; n=26), and phenotypic testing for 18 drugs (n=179). Findings Between Oct 1, 2008, and Oct 31, 2012, we enrolled and followed up 273 patients for a median of 20.3 months (IQR 9.6-27.8). 203 (74%) had programmatically incurable tuberculosis and unfavourable outcomes (treatment failure, relapse, default, or death despite treatment with a regimen based on capreomycin, aminosalicylic acid, or both). 172 (63%) patients were discharged home, of whom 104 (60%) had an unfavourable outcome. 54 (31%) homedischarged patients had failed treatment, with a median time to death after discharge of 9.9 months (IQR 4.2-17.4). 35 (20%) home-discharged cases were smear-positive at discharge. Using CASS, six (23%) of 26 home-discharged cases with data available expectorated infectious culture-positive cough aerosols in the respirable range (< 5 mu m), and most reported inter-person contact with suboptimal protective mask usage. WGS identified 17 (19%) of the 90 patients (with available sequence data) that were discharged home before the diagnosis of 20 downstream cases of extensively drug-resistant tuberculosis with almost identical sequencing profiles suggestive of community-based transmission (five or fewer single nucleotide polymorphisms different and with identical resistance-encoding mutations for 14 drugs). 11 (55%) of these downstream cases had HIV co-infection and ten (50%) had died by the end of the study. 22 (56%) of 39 isolates in patients discharged home after treatment failure were resistant to eight or more drugs. However, five (16%) of 31 isolates were susceptible to rifabutin and more than 90% were likely to be sensitive to linezolid, bedaquiline, and delamanid. Interpretation More than half of the patients with programmatically incurable tuberculosis were discharged into the community where they remained for an average of 16 months, were at risk of expectorating infectious cough aerosols, and posed a threat of transmission of extensively drug-resistant tuberculosis. Urgent action, including appropriate containment strategies, is needed to address this situation. Access to delamanid, bedaquiline, linezolid, and rifabutin, when appropriate, must be accelerated along with comprehensive drug susceptibility testing. Funding UK Medical Research Council, South African Medical Research Council, South African National Research Foundation, European & Developing Countries Clinical Trials Partnership, Oppenheimer Foundation, Newton Fund, Biotechnology and Biological Sciences Research Council, King Abdullah University of Science & Technology. C1 [Dheda, Keertan; Simpson, John; Smith, Liezel; McNerney, Ruth] Univ Cape Town, Div Pulmonol & UCT Lung Inst, Cape Town, South Africa. [Dheda, Keertan; Simpson, John; Smith, Liezel; McNerney, Ruth] Univ Cape Town, Dept Med, Cape Town, South Africa. [Lesosky, Maia] Univ Cape Town, Div Epidemiol & Biostat, Sch Publ Hlth & Family Med, Cape Town, South Africa. [Fennelly, Kevin P.; McNerney, Ruth] London Sch Hyg Trop Med, Fac Epidemiol & Populat Hlth, London, England. [Fennelly, Kevin P.] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bethesda, MD USA. [te Riele, Julian] Brooklyn Chest Hosp, Cape Town, South Africa. [Abdallah, Abdallah M.] Harry Surtie Hosp, Upington, South Africa. [Smith, Liezel; McNerney, Ruth] Univ Stellenbosch, Fac Med & Hlth Sci, SAMRC Ctr TB Res, Cape Town, South Africa. [te Riele, Julian; McNerney, Ruth] Natl Hlth Lab Serv, Green Point, Cape Town, South Africa. King Abdullah Univ Sci & Technol KAUST, Thuwal, Saudi Arabia. [McNerney, Ruth; Pain, Arnab] Baylor Univ, Med Ctr, Dis Res & Expt Therapeut, Dallas, TX USA. RP Dheda, K (reprint author), Univ Cape Town, Div Pulmonol & UCT Lung Inst, Cape Town, South Africa. EM keertan.dheda@uct.ac.za FU UK Medical Research Council; South African Medical Research Council; South African National Research Foundation; European & Developing Countries Clinical Trials Partnership; Oppenheimer Foundation; Newton Fund; Biotechnology and Biological Sciences Research Council; King Abdullah University of Science Technology FX Funding UK Medical Research Council, South African Medical Research Council, South African National Research Foundation, European & Developing Countries Clinical Trials Partnership, Oppenheimer Foundation, Newton Fund, Biotechnology and Biological Sciences Research Council, King Abdullah University of Science & Technology. NR 46 TC 1 Z9 1 U1 4 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-2600 J9 LANCET RESP MED JI Lancet Resp. Med. PD APR PY 2017 VL 5 IS 4 BP 269 EP 281 DI 10.1016/S2213-2600(16)30433-7 PG 13 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EP3BO UT WOS:000397257700020 PM 28109869 ER PT J AU Kessler, RC Stein, MB Petukhova, MV Bliese, P Bossarte, RM Bromet, EJ Fullerton, CS Gilman, SE Ivany, C Lewandowski-Romps, L Bell, AM Naifeh, JA Nock, MK Reis, BY Rosellini, AJ Sampson, NA Zaslavsky, AM Ursano, RJ AF Kessler, R. C. Stein, M. B. Petukhova, M. V. Bliese, P. Bossarte, R. M. Bromet, E. J. Fullerton, C. S. Gilman, S. E. Ivany, C. Lewandowski-Romps, L. Bell, A. Millikan Naifeh, J. A. Nock, M. K. Reis, B. Y. Rosellini, A. J. Sampson, N. A. Zaslavsky, A. M. Ursano, R. J. CA Army STARRS Collaborators TI Predicting suicides after outpatient mental health visits in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) SO MOLECULAR PSYCHIATRY LA English DT Article ID TRAUMATIC BRAIN-INJURY; US ARMY; SOLDIERS; MILITARY; DEATH; CARE; PREVENTION; DEPRESSION; ATTEMPTORS; DEPLOYMENT AB The 2013 US Veterans Administration/Department of Defense Clinical Practice Guidelines (VA/DoD CPG) require comprehensive suicide risk assessments for VA/DoD patients with mental disorders but provide minimal guidance on how to carry out these assessments. Given that clinician-based assessments are not known to be strong predictors of suicide, we investigated whether a precision medicine model using administrative data after outpatient mental health specialty visits could be developed to predict suicides among outpatients. We focused on male nondeployed Regular US Army soldiers because they account for the vast majority of such suicides. Four machine learning classifiers (naive Bayes, random forests, support vector regression and elastic net penalized regression) were explored. Of the Army suicides in 2004-2009, 41.5% occurred among 12.0% of soldiers seen as outpatient by mental health specialists, with risk especially high within 26 weeks of visits. An elastic net classifier with 10-14 predictors optimized sensitivity (45.6% of suicide deaths occurring after the 15% of visits with highest predicted risk). Good model stability was found for a model using 2004-2007 data to predict 2008-2009 suicides, although stability decreased in a model using 2008-2009 data to predict 2010-2012 suicides. The 5% of visits with highest risk included only 0.1% of soldiers (1047.1 suicides/100 000 person-years in the 5 weeks after the visit). This is a high enough concentration of risk to have implications for targeting preventive interventions. An even better model might be developed in the future by including the enriched information on clinician-evaluated suicide risk mandated by the VA/DoD CPG to be recorded. C1 [Kessler, R. C.; Petukhova, M. V.; Rosellini, A. J.; Sampson, N. A.; Zaslavsky, A. M.] Harvard Med Sch, Dept Hlth Care Policy, Boston, MA USA. [Stein, M. B.] Univ Calif San Diego, Dept Psychiat & Family & Prevent Med, La Jolla, CA USA. [Stein, M. B.] VA San Diego Healthcare Syst, San Diego, CA USA. [Bliese, P.] Univ South Carolina, Darla Moore Sch Business, Columbia, SC USA. [Bossarte, R. M.] Post Deployment Hlth Serv, Dept Vet Affairs, Washington, DC USA. [Bromet, E. J.] Stony Brook Sch Med, Dept Psychiat & Behav Sci, Stony Brook, NY USA. [Fullerton, C. S.; Naifeh, J. A.; Ursano, R. J.] Uniformed Serv Univ Hlth Sci, Sch Med, Ctr Study Traumat Stress, Dept Psychiat, Bethesda, MD USA. [Gilman, S. E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Hlth Behav Branch, Bethesda, MD USA. [Gilman, S. E.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol & Social & Behav Sci, Boston, MA USA. [Ivany, C.] US Army Med Command, Behav Hlth Serv Line, Bethesda, MD USA. [Lewandowski-Romps, L.] Univ Michigan, Inst Social Res, Ann Arbor, MI USA. [Bell, A. Millikan] US Army Publ Hlth Command, Aberdeen Proving Ground, MD USA. [Nock, M. K.] Harvard Univ, Dept Psychol, Cambridge, MA USA. [Reis, B. Y.] Childrens Hosp Boston, Harvard Med Sch, Boston, MA USA. RP Kessler, RC (reprint author), Harvard Med Sch, Dept Hlth Care Policy, Boston, MA 02115 USA. EM Kessler@hcp.med.harvard.edu OI Gilman, Stephen/0000-0002-8331-6419 FU Department of the Army; US Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH) [U01MH087981]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Army STARRS was sponsored by the Department of the Army and funded under cooperative agreement number U01MH087981 with the US Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH). Dr Gilman's participation in this work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. We thank Kenneth L Cox for helpful comments on an earlier version of this paper. Although a draft of this manuscript was submitted to the Army and NIMH for review and comment before submission, this was with the understanding that comments would be no more than advisory. NR 48 TC 1 Z9 1 U1 7 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD APR PY 2017 VL 22 IS 4 BP 544 EP 551 DI 10.1038/mp.2016.110 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA EP0TP UT WOS:000397099900008 PM 27431294 ER PT J AU Eid, M Nguyen, J Brownell, I AF Eid, Mary Nguyen, Jannett Brownell, Isaac TI Seeking Standards for the Detection of Merkel Cell Polyomavirus and its Clinical Significance SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID OROPHARYNGEAL CANCER; CARCINOMA; EXPRESSION; FEATURES; TUMORS AB Merkel cell carcinoma is a rare skin cancer associated with Merkel cell polyomavirus in most cases. Prior studies associating Merkel cell carcinoma viral status with prognosis have inconsistent findings. Moshiri et al. used multimodal virus detection to determine that the 81% of patients with virus-positive Merkel cell carcinoma tumors had earlier stage disease and better outcomes relative to virus-negative cases. C1 [Eid, Mary] NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Nguyen, Jannett; Brownell, Isaac] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Brownell, I (reprint author), Dermatol Branch, 10 Ctr Dr,12N240C, Bethesda, MD 20892 USA. EM isaac.brownell@nih.gov NR 17 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD APR PY 2017 VL 137 IS 4 BP 797 EP 799 DI 10.1016/j.jid.2016.12.024 PG 3 WC Dermatology SC Dermatology GA EO7QE UT WOS:000396884400005 PM 28340681 ER PT J AU Jourdan, T Szanda, G Cinar, R Godlewski, G Holovac, DJ Park, JK Nicoloro, S Shen, Y Liu, J Rosenberg, AZ Liu, Z Czech, MP Kunos, G AF Jourdan, Tony Szanda, Gergo Cinar, Resat Godlewski, Grzegorz Holovac, David J. Park, Joshua K. Nicoloro, Sarah Shen, Yuefei Liu, Jie Rosenberg, Avi Z. Liu, Ziyi Czech, Michael P. Kunos, George TI Developmental Role of Macrophage Cannabinoid-1 Receptor Signaling in Type 2 Diabetes SO DIABETES LA English DT Article ID BETA-CELL DYSFUNCTION; ENDOCANNABINOID SYSTEM; INSULIN-RESISTANCE; ADIPOSE-TISSUE; NLRP3 INFLAMMASOME; LEPTIN RESISTANCE; PANCREATIC-ISLETS; CB1 RECEPTOR; ACTIVATION; OBESITY AB Islet inflammation promotes beta-cell loss and type 2 diabetes (T2D), a process replicated in Zucker Diabetic Fatty (ZDF) rats in which beta-cell loss has been linked to cannabinoid-1 receptor (CB1R)-induced proinflammatory signaling in macrophages infiltrating pancreatic islets. Here, we analyzed CB1R signaling in macrophages and its developmental role in T2D. ZDF rats with global deletion of CB1R are protected from beta-cell loss, hyperglycemia, and nephropathy that are present in ZDF littermates. Adoptive transfer of CB1R-/- bone marrow to ZDF rats also prevents beta-cell loss and hyperglycemia but not nephropathy. ZDF islets contain elevated levels of CB1R, interleukin-1b, tumor necrosis factor-a, the chemokine CCL2, and interferon regulatory factor-5 (IRF5), a marker of inflammatory macrophage polarization. In primary cultured rodent and human macrophages, CB1R activation increased Irf5 expression, whereas knockdown of Irf5 blunted CB1R-induced secretion of inflammatory cytokines without affecting CCL2 expression, which was p38MAPK alpha dependent. Macrophage-specific in vivo knockdown of Irf5 protected ZDF rats from beta-cell loss and hyperglycemia. Thus, IRF5 is a crucial downstream mediator of diabetogenic CB1R signaling in macrophages and a potential therapeutic target. C1 [Jourdan, Tony; Szanda, Gergo; Cinar, Resat; Godlewski, Grzegorz; Holovac, David J.; Park, Joshua K.; Liu, Jie; Liu, Ziyi; Kunos, George] Natl Inst Alcohol Abuse & Alcoholism, Lab Physiol Studies, NIH, Bethesda, MD USA. [Nicoloro, Sarah; Shen, Yuefei; Czech, Michael P.] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA USA. [Rosenberg, Avi Z.] Johns Hopkins Univ, Dept Pathol, Div Renal Pathol, Baltimore, MD USA. [Rosenberg, Avi Z.] NIH, Natl Inst Diabet, Kidney Dis Sect, Bethesda, MD USA. [Rosenberg, Avi Z.] NIH, Digest & Kidney Dis, Bethesda, MD USA. RP Jourdan, T; Szanda, G (reprint author), Natl Inst Alcohol Abuse & Alcoholism, Lab Physiol Studies, NIH, Bethesda, MD USA. EM tony.jourdan@nih.gov; george.kunos@nih.gov FU Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences; NIH [DK-103047]; intramural NIH funds FX G.S. is supported by a Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences. The work from the laboratory of M.P.C. was supported by a grant from the NIH (DK-103047). This study was supported by intramural NIH funds to G.K. NR 45 TC 0 Z9 0 U1 3 U2 3 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 APR PY 2017 VL 66 IS 4 BP 994 EP 1007 DI 10.2337/db16-1199 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EP0ZJ UT WOS:000397114900023 PM 28082458 ER PT J AU Di, X Reynolds, RC Biswal, BB AF Di, Xin Reynolds, Richard C. Biswal, Bharat B. TI Imperfect (De)Convolution May Introduce Spurious Psychophysiological Interactions and How to Avoid It SO HUMAN BRAIN MAPPING LA English DT Article DE mean centering; fMRI; connectivity; psychophysiological interactions ID FUNCTIONAL CONNECTIVITY; HUMAN BRAIN; VISUOSPATIAL ATTENTION; DISCOVERY SCIENCE; FMRI; NETWORKS; CORTEX; FORM; AREA; MRI AB Psychophysiological interaction (PPI) is a widely used regression-based method to study connectivity changes in different experimental conditions. A PPI effect is generated by point-by-point multiplication of a psychological variable (experimental design) and a physiological variable (time series of a seed region). If the psychological variable is non-centered with a constant component, the constant component will add a physiological variable to the PPI term. The physiological component would in theory be accounted for by the physiological main effect in the model. But due to imperfect deconvolution and convolution with hemodynamic response function, the physiological component in PPI may no longer be exactly the same as the physiological main effect. This issue was illustrated by analyzing two block-designed fMRI datasets, one simple visual checkerboard task and a set of different tasks designed to activate different hemispheres. When PPI was calculated with deconvolution but without centering, significant results were usually observed between regions that are known to have baseline functional connectivity. These results could be suppressed by simply centering the psychological variable when calculating the PPI term or adding a deconvolve-reconvolve dversion of the physiological covariate. The PPI results with centering and with deconvolve-reconvolved physiological covariate are consistent with an explicit test for differences in coupling between conditions. It was, therefore, suggested that centering of the psychological variable or the addition of a deconvolve-reconvolved covariate is necessary for PPI analysis. (C) 2017 Wiley Periodicals, Inc. C1 [Di, Xin; Biswal, Bharat B.] New Jersey Inst Technol, Dept Biomed Engn, Newark, NJ 07102 USA. [Reynolds, Richard C.] NIMH, Dept Hlth & Human Serv, Sci & Stat Comp Core, NIH, Bethesda, MD 20892 USA. RP Biswal, BB (reprint author), 607 Fenster Hall, Newark, NJ 07102 USA. EM bbiswal@yahoo.com FU NIH [R01 AG032088, R01 DA038895] FX Contract grant sponsor: NIH; Contract grant numbers: R01 AG032088 and R01 DA038895 NR 32 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD APR PY 2017 VL 38 IS 4 BP 1723 EP 1740 DI 10.1002/hbm.23413 PG 18 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EN5GF UT WOS:000396032900001 PM 28105655 ER PT J AU Mullins, RJ Mustapic, M Goetzl, EJ Kapogiannis, D AF Mullins, Roger J. Mustapic, Maja Goetzl, Edward J. Kapogiannis, Dimitrios TI Exosomal Biomarkers of Brain Insulin Resistance Associated With Regional Atrophy in Alzheimer's Disease SO HUMAN BRAIN MAPPING LA English DT Article DE Alzheimer's disease; insulin resistance; magnetic resonance imaging; exosomes; IRS-1; biomarker ID MIDDLE-AGED ADULTS; MILD COGNITIVE IMPAIRMENT; RECEPTOR SUBSTRATE; SERINE/THREONINE PHOSPHORYLATION; DIAGNOSTIC GUIDELINES; GLUCOSE TRANSPORTERS; NATIONAL INSTITUTE; BLOOD EXOSOMES; MOUSE-BRAIN; RISK AB Brain insulin resistance (IR), which depends on insulin-receptor-substrate-1 (IRS-1) phosphorylation, is characteristic of Alzheimer's disease (AD). Previously, we demonstrated higher pSer(312)-IRS-1 (ineffective insulin signaling) and lower p-panTyr-IRS-1 (effective insulin signaling) in neural origin-enriched plasma exosomes of AD patients vs. controls. Here, we hypothesized that these exosomal biomarkers associate with brain atrophy in AD. We studied 24 subjects with biomarker-supported probable AD (low CSF A beta(42)). Exosomes were isolated from plasma, enriched for neural origin using immunoprecipitation for L1CAM, and measured for pSer(312)- and p-panTyr-IRS-1 phosphotypes. MPRAGE images were segmented by brain tissue type and voxel-based morphometry (VBM) analysis for gray matter against pSer(312)-and p-panTyr-IRS-1 was conducted. Given the regionally variable brain expression of IRS-1, we used the Allen Brain Atlas to make spatial comparisons between VBM results and IRS-1 expression. Brain volume was positively associated with P-panTyr-IRS-1 and negatively associated with pSer(312)-IRS-1 in a strikingly similar regional pattern (bilateral parietal-occipital junction, R middle temporal gyrus). This volumetric association pattern was spatially correlated with Allen Human Brain atlas normal brain IRS-1 expression. Exosomal biomarkers of brain IR are thus associated with atrophy in AD as could be expected by their pathophysiological roles and do so in a pattern that reflects regional IRS-1 expression. Furthermore, neural-origin plasma exosomes may recover molecular signals from specific brain regions. (C) 2017 Wiley Periodicals, Inc. C1 [Mullins, Roger J.; Mustapic, Maja; Kapogiannis, Dimitrios] NIA, Lab Neurosci, Intramural Res Program, NIH, Baltimore, MD USA. [Goetzl, Edward J.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. RP Kapogiannis, D (reprint author), NIA, Lab Neurosci, 3001 S Hanover Str,NM531, Baltimore, MD 21225 USA. EM kapogiannisd@mail.nih.gov OI Mullins, Roger/0000-0002-0561-4402 FU Intramural Research Program of the National Institute on Aging, NIH FX Contract grant sponsor: Intramural Research Program of the National Institute on Aging, NIH. NR 48 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD APR PY 2017 VL 38 IS 4 BP 1933 EP 1940 DI 10.1002/hbm.23494 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EN5GF UT WOS:000396032900015 PM 28105773 ER PT J AU Avery, JA Gotts, SJ Kerr, KL Burrows, K Ingeholm, JE Bodurka, J Martin, A Simmons, WK AF Avery, Jason A. Gotts, Stephen J. Kerr, Kara L. Burrows, Kaiping Ingeholm, John E. Bodurka, Jerzy Martin, Alex Simmons, W. Kyle TI Convergent Gustatory and Viscerosensory Processing in the Human Dorsal Mid-Insula SO HUMAN BRAIN MAPPING LA English DT Article DE interoception; gustation; insular cortex; fMRI; fMRI-adaptation ID FUNCTIONAL CONNECTIVITY; ANOREXIA-NERVOSA; CORTEX; TASTE; BRAIN; NEURONS; BODY; STIMULATION; ACTIVATION; REWARD AB The homeostatic regulation of feeding behavior requires an organism to be able to integrate information from its internal environment, including peripheral visceral signals about the body's current energy needs, with information from its external environment, such as the palatability of energy-rich food stimuli. The insula, which serves as the brain's primary sensory cortex for representing both visceral signals from the body and taste signals from the mouth and tongue, is a likely candidate region in which this integration might occur. However, to date it has been unclear whether information from these two homeostatically critical faculties is merely co-represented in the human insula, or actually integrated there. Recent functional neuroimaging evidence of a common substrate for visceral interoception and taste perception within the human dorsal mid-insula suggests a model whereby a single population of neurons may integrate viscerosensory and gustatory signals. To test this model, we used fMRI-Adaptation to identify whether insula regions that exhibit repetition suppression following repeated interoception trials would then also exhibit adapted responses to subsequent gustatory stimuli. Multiple mid and anterior regions of the insula exhibited adaptation to interoceptive trials specifically, but only the dorsal mid-insula regions exhibited an adapted gustatory response following interoception. The discovery of this gustatory-interoceptive convergence within the neurons of the human insula supports the existence of a heretofore-undocumented neural pathway by which visceral signals from the periphery modulate the activity of brain regions involved in feeding behavior. (C) 2017 Wiley Periodicals, Inc. C1 [Avery, Jason A.; Kerr, Kara L.; Burrows, Kaiping; Bodurka, Jerzy; Simmons, W. Kyle] Laureate Inst Brain Res, 6655 South Yale Ave, Tulsa, OK 74136 USA. [Avery, Jason A.] Univ Tulsa, Dept Biol Sci, Tulsa, OK 74104 USA. [Gotts, Stephen J.; Ingeholm, John E.; Martin, Alex] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Kerr, Kara L.] Univ Tulsa, Dept Psychol, Tulsa, OK 74104 USA. [Simmons, W. Kyle] Univ Tulsa, Sch Community Med, Tulsa, OK 74104 USA. RP Simmons, WK (reprint author), Laureate Inst Brain Res, 6655 South Yale Ave, Tulsa, OK 74136 USA. EM wksimmons@laureateinstitute.org FU Oklahoma Center for the Advancement of Science and Technology [OCAST HR10-141]; NIMH [K01MH096175-01]; NARSAD Young Investigator Award; Laureate Institute for Brain Research; William K. Warren Foundation; University of Tulsa FX Oklahoma Center for the Advancement of Science and Technology; Contract grant number: OCAST HR10-141; Contract grant sponsor: NIMH; Contract grant number: K01MH096175-01; Contract grant sponsor: NARSAD Young Investigator Award (to W.K.S.), Laureate Institute for Brain Research, The William K. Warren Foundation, and the University of Tulsa (to J.A.A.) NR 49 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD APR PY 2017 VL 38 IS 4 BP 2150 EP 2164 DI 10.1002/hbm.23510 PG 15 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EN5GF UT WOS:000396032900030 PM 28070928 ER PT J AU Villarino, AV Kanno, Y O'Shea, JJ AF Villarino, Alejandro V. Kanno, Yuka O'Shea, John J. TI Mechanisms and consequences of Jak-STAT signaling in the immune system SO NATURE IMMUNOLOGY LA English DT Review ID TRANSCRIPTION FACTOR STAT3; GRANULAR LYMPHOCYTIC-LEUKEMIA; ALPHA-CHAIN EXPRESSION; REGULATORY T-CELLS; IFN-GAMMA; INTERFERON-GAMMA; TYROSINE KINASE; DNA-BINDING; PSEUDOKINASE-DOMAIN; GENE-EXPRESSION AB Kinases of the Jak ('Janus kinase') family and transcription factors (TFs) of the STAT ('signal transducer and activator of transcription') family constitute a rapid membrane-to-nucleus signaling module that affects every aspect of the mammalian immune system. Research on this paradigmatic pathway has experienced breakneck growth in the quarter century since its discovery and has yielded a stream of basic and clinical insights that have profoundly influenced modern understanding of human health and disease, exemplified by the bench-to-bedside success of Jak inhibitors ('jakinibs') and pathway-targeting drugs. Here we review recent advances in Jak-STAT biology, focusing on immune cell function, disease etiology and therapeutic intervention, as well as broader principles of gene regulation and signal-dependent TFs. C1 [Villarino, Alejandro V.; Kanno, Yuka; O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP O'Shea, JJ (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. EM john.oshea@nih.gov OI Villarino, Alejandro/0000-0001-8068-2176 FU National Institute of Arthritis, Musculoskeletal and Skin Diseases; US National Institutes of Health FX We thank members of the O'Shea laboratory for discussions about Jak-STAT biology, and C. Hunter and L. Hennighausen for critical reading of this manuscript. Supported by the National Institute of Arthritis, Musculoskeletal and Skin Diseases and the US National Institutes of Health (intramural funding). NR 200 TC 0 Z9 0 U1 14 U2 14 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD APR PY 2017 VL 18 IS 4 BP 374 EP 384 DI 10.1038/ni.3691 PG 11 WC Immunology SC Immunology GA EO6PU UT WOS:000396815800005 PM 28323260 ER PT J AU Choi, S Warzecha, C Zvezdova, E Lee, J Argenty, J Lesourne, R Aravind, L Love, PE AF Choi, Seeyoung Warzecha, Claude Zvezdova, Ekaterina Lee, Jan Argenty, Jeremy Lesourne, Renaud Aravind, L. Love, Paul E. TI THEMIS enhances TCR signaling and enables positive selection by selective inhibition of the phosphatase SHP-1 SO NATURE IMMUNOLOGY LA English DT Article ID T-CELL-RECEPTOR; PROTEIN-TYROSINE PHOSPHATASES; THYMOCYTE DEVELOPMENT; LIGAND DISCRIMINATION; NEGATIVE SELECTION; REDOX REGULATION; ACTIVATION; STIMULATION; SURVIVAL; GENERATION AB THEMIS, a T cell-specific protein with high expression in CD4(+)CD8(+) thymocytes, has a crucial role in positive selection and T cell development. THEMIS lacks defined catalytic domains but contains two tandem repeats of a distinctive module of unknown function (CABIT). Here we found that THEMIS directly regulated the catalytic activity of the tyrosine phosphatase SHP-1. This action was mediated by the CABIT modules, which bound to the phosphatase domain of SHP-1 and promoted or stabilized oxidation of SHP-1's catalytic cysteine residue, which inhibited the tyrosine-phosphatase activity of SHP-1. Deletion of SHP-1 alleviated the developmental block in Themis(-/-) thymocytes. Thus, THEMIS facilitates thymocyte positive selection by enhancing the T cell antigen receptor signaling response to low-affinity ligands. C1 [Choi, Seeyoung; Warzecha, Claude; Zvezdova, Ekaterina; Lee, Jan; Love, Paul E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Hematopoiesis & Lymphocyte Biol, NIH, Bethesda, MD 20892 USA. [Argenty, Jeremy; Lesourne, Renaud] Ctr Physiopathol Toulouse Purpan, Toulouse, France. [Argenty, Jeremy; Lesourne, Renaud] CNRS, INSERM, U1043, U5282, Toulouse, France. [Argenty, Jeremy; Lesourne, Renaud] Univ Paul Sabatier, Univ Toulouse, Toulouse, France. [Aravind, L.] NIH, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. RP Love, PE (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Hematopoiesis & Lymphocyte Biol, NIH, Bethesda, MD 20892 USA. EM lovep@mail.nih.gov RI Lesourne, Renaud/M-1855-2014 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [1ZIAHD001803]; Intramural Research Program of the National Library of Medicine FX We thank M. Muschen (University of California, San Francisco) for Ptpn6flox/flox mice; H. Gu (McGill University) for Grb2fl/fl mice; A. Ullrich (Max-Plank Institute, Germany) for Ptpn6 cDNA; L. Tautz (Sanford-Burnham Medical Research Institute) for Ptpn7 cDNA; J. Chernoff (Fox Chase Cancer Center) for plasmid encoding hemagglutinin-tagged PTPN1; and A. Bhandoola, R. Bosselut, R. Cornall, K. Pfeifer and A. Singer for critical review of the manuscript. Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (1ZIAHD001803 to P.E.L.) and by the Intramural Research Program of the National Library of Medicine (L.A.). NR 49 TC 1 Z9 1 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD APR PY 2017 VL 18 IS 4 BP 433 EP + DI 10.1038/ni.3692 PG 10 WC Immunology SC Immunology GA EO6PU UT WOS:000396815800011 PM 28250424 ER PT J AU Angeletti, D Gibbs, JS Angel, M Kosik, I Hickman, HD Frank, GM Das, SR Wheatley, AK Prabhakaran, M Leggat, DJ McDermott, AB Yewdell, JW AF Angeletti, Davide Gibbs, James S. Angel, Matthew Kosik, Ivan Hickman, Heather D. Frank, Gregory M. Das, Suman R. Wheatley, Adam K. Prabhakaran, Madhu Leggat, David J. McDermott, Adrian B. Yewdell, Jonathan W. TI Defining B cell immunodominance to viruses SO NATURE IMMUNOLOGY LA English DT Article ID ANTIGENIC SIN RESPONSES; ANTIBODY-RESPONSE; INFLUENZA-VIRUSES; MONOCLONAL-ANTIBODIES; IMMUNE-RESPONSE; HEMAGGLUTININ; INFECTION; GENERATION; MEMORY; MICE AB Immunodominance (ID) defines the hierarchical immune response to competing antigens in complex immunogens. Little is known regarding B cell and antibody ID despite its importance in immunity to viruses and other pathogens. We show that B cells and serum antibodies from inbred mice demonstrate a reproducible ID hierarchy to the five major antigenic sites in the influenza A virus hemagglutinin globular domain. The hierarchy changed as the immune response progressed, and it was dependent on antigen formulation and delivery. Passive antibody transfer and sequential infection experiments demonstrated 'original antigenic suppression', a phenomenon in which antibodies suppress memory responses to the priming antigenic site. Our study provides a template for attaining deeper understanding of antibody ID to viruses and other complex immunogens. C1 [Angeletti, Davide; Gibbs, James S.; Angel, Matthew; Kosik, Ivan; Hickman, Heather D.; Frank, Gregory M.; Das, Suman R.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Das, Suman R.] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. [Wheatley, Adam K.; Prabhakaran, Madhu; Leggat, David J.; McDermott, Adrian B.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM jyewdell@mail.nih.gov OI Angeletti, Davide/0000-0002-5256-1972 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases FX We thank the NIAID Comparative Medicine Branch for maintaining the mice used in this study, and P. Palese and F. Krammer (Icahn School of Medicine at Mount Sinai) for the chimeric HA virus construct. Supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (J.W.Y. and A.B.M.). NR 45 TC 1 Z9 1 U1 9 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD APR PY 2017 VL 18 IS 4 BP 456 EP + DI 10.1038/ni.3680 PG 10 WC Immunology SC Immunology GA EO6PU UT WOS:000396815800013 PM 28192417 ER PT J AU Moore, CM Giganti, F Albertsen, P Allen, C Bangma, C Briganti, A Carroll, P Haider, M Kasivisvanathan, V Kirkham, A Klotz, L Ouzzane, A Padhani, AR Panebianco, V Pinto, P Puech, P Rannikko, A Renard-Penna, R Touijer, K Turkbey, B van Poppel, H Valdagni, R Walz, J Schoots, I AF Moore, Caroline M. Giganti, Francesco Albertsen, Peter Allen, Clare Bangma, Chris Briganti, Alberto Carroll, Peter Haider, Masoom Kasivisvanathan, Veeru Kirkham, Alex Klotz, Laurence Ouzzane, Adil Padhani, Anwar R. Panebianco, Valeria Pinto, Peter Puech, Philippe Rannikko, Antti Renard-Penna, Raphaele Touijer, Karim Turkbey, Baris van Poppel, Heinrik Valdagni, Riccardo Walz, Jochen Schoots, Ivo TI Reporting Magnetic Resonance Imaging in Men on Active Surveillance for Prostate Cancer: The PRECISE Recommendations-A Report of a European School of Oncology Task Force SO EUROPEAN UROLOGY LA English DT Article DE Prostate cancer; Prostate MRI; Active surveillance ID FOLLOW-UP; MRI AB Background: Published data on prostate magnetic resonance imaging (MRI) during follow-up of men on active surveillance are lacking. Current guidelines for prostate MRI reporting concentrate on prostate cancer (PCa) detection and staging. A standardised approach to prostate MRI reporting for active surveillance will facilitate the robust collection of evidence in this newly developing area. Objective: To develop preliminary recommendations for reporting of individual MRI studies in men on active surveillance and for researchers reporting the outcomes of cohorts of men having MRI on active surveillance. Design, setting, and participants: The RAND/UCLA Appropriateness Method was used. Experts in urology, radiology, and radiation oncology developed a set of 394 statements relevant to prostate MRI reporting in men on active surveillance for PCa. Each statement was scored for agreement on a 9-point scale by each panellist prior to a panel meeting. Each statement was discussed and rescored at the meeting. Outcome measurements and statistical analysis: Measures of agreement and consensus were calculated for each statement. The most important statements, derived from both group discussion and scores of agreement and consensus, were used to create the Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) checklist and case report form. Results and limitations: Key recommendations include reporting the index lesion size using absolute values at baseline and at each subsequent MRI. Radiologists should assess the likelihood of true change over time (ie, change in size or change in lesion characteristics on one or more sequences) on a 1-5 scale. A checklist of items for reporting a cohort of men on active surveillance was developed. These items were developed based on expert consensus in many areas in which data are lacking, and they are expected to develop and change as evidence is accrued. Conclusions: The PRECISE recommendations are designed to facilitate the development of a robust evidence database for documenting changes in prostateMRI findings over time ofmen on active surveillance. If used, they will facilitate data collection to distinguish-measurement error and natural variability in MRI appearances from true radiologic progression. Patient summary: Few published reports are available on how to use and interpret magnetic resonance imaging for men on active surveillance for prostate cancer. The PRECISE panel recommends that data should be collected in a standardised manner so that natural variation in the appearance and measurement of cancer over time can be distinguished from changes indicating significant tumour progression. (C) 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Moore, Caroline M.; Kasivisvanathan, Veeru] UCL, Div Surg & Intervent Sci, 3rd Floor,Charles Bell House, London W1W7EJ, England. [Moore, Caroline M.; Kasivisvanathan, Veeru] Univ Coll London Hosp Trust, Dept Urol, London, England. [Giganti, Francesco; Allen, Clare; Kirkham, Alex] Univ Coll London Hosp Trust, Dept Radiol, London, England. [Giganti, Francesco] Univ Vita Salute San Raffaele, Dept Radiol, San Raffaele Sci Inst, Milan, Italy. [Giganti, Francesco] Univ Vita Salute San Raffaele, Ctr Expt Imaging, San Raffaele Sci Inst, Milan, Italy. [Albertsen, Peter] Univ Connecticut, Ctr Hlth, Div Urol, Farmington, CT USA. [Bangma, Chris] Erasmus Univ, Med Ctr, Dept Urol, Rotterdam, Netherlands. [Briganti, Alberto] Univ Vita Salute San Raffaele, Dept Urol, San Raffaele Sci Inst, Milan, Italy. [Carroll, Peter] Univ Calif San Francisco, Dept Urol, UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [Haider, Masoom] Univ Toronto, Dept Med Imaging, Sunnybrook Res Inst, Toronto, ON, Canada. [Klotz, Laurence] Univ Toronto, Dept Urol, Sunnybrook Res Inst, Toronto, ON, Canada. [Ouzzane, Adil] Univ Lille, CHU Lille, Dept Urol, Lille, France. [Padhani, Anwar R.] Mt Vernon Hosp, Paul Strickland Scanner Ctr, Northwood, Middx, England. [Panebianco, Valeria] Univ Roma La Sapienza, Dept Radiol Sci Oncol & Pathol, Prostate Unit Diagnost, Rome, Italy. [Pinto, Peter] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Puech, Philippe] Univ Lille, CHU Lille, Dept Radiol, Lille, France. [Rannikko, Antti] Univ Helsinki, Cent Hosp, Dept Urol, Helsinki, Finland. [Renard-Penna, Raphaele] UPMC Paris 06, Pitie Salpetriere Hosp, AP HP, Dept Radiol, Paris, France. [Touijer, Karim] Mem Sloan Kettering Canc Ctr, Dept Surg, Urol Serv, New York, NY 10021 USA. [Turkbey, Baris] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [van Poppel, Heinrik] Univ Hosp KU Leuven, Dept Urol, Leuven, Belgium. [Valdagni, Riccardo] Fdn IRCSS Ist Nazl Tumori, Radiat Oncol, Milan, Italy. [Valdagni, Riccardo] Univ Milan, Diagnost Imaging & Radiotherapy, Milan, Italy. [Walz, Jochen] Inst Paoli Calmettes, Dept Urol, Marseille, France. [Schoots, Ivo] Erasmus MC Univ, Med Ctr, Dept Radiol & Nucl Med, Rotterdam, Netherlands. RP Moore, CM (reprint author), UCL, Div Surg & Intervent Sci, 3rd Floor,Charles Bell House, London W1W7EJ, England. EM caroline.moore@ucl.ac.uk FU Siemens Healthcare GmbH; ProADAMO Foundation; ESO; Siemens Healthcare FX European School of Oncology (ESO), supported by educational grants from Siemens Healthcare GmbH and the ProADAMO Foundation, funded the research. The organisations cited had no role in the data collection or analysis, or in manuscript preparation. The paper was developed by the ESO-PRECISE Task Force, and the initiative was supported by the ESO and through unrestricted educational grants provided by Siemens Healthcare and the ProADAMO Foundation. NR 13 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD APR PY 2017 VL 71 IS 4 BP 648 EP 655 DI 10.1016/j.eururo.2016.06.011 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA EN9RB UT WOS:000396336200033 PM 27349615 ER PT J AU Wang, ZM Dai, JC Hu, N Miao, XP Abnet, CC Yang, M Freedman, ND Chen, JF Burdette, L Zhu, X Chung, CC Ren, CL Dawsey, SM Wang, ML Ding, T Du, JB Gao, YT Zhong, R Giffen, C Pan, WT Koh, WP Dai, NB Liao, LDM Yan, CW Qiao, YL Jiang, Y Shu, XO Chen, JP Wang, CY Ma, HX Su, H Zhang, ZD Wang, LM Wu, C Xiang, YB Hu, ZB Yuan, JM Xie, L Zheng, W Lin, DX Chanock, SJ Shi, YY Goldstein, AM Jin, GF Taylor, PR Shen, HB AF Wang, Zhaoming Dai, Juncheng Hu, Nan Miao, Xiaoping Abnet, Christian C. Yang, Ming Freedman, Neal D. Chen, Jinfei Burdette, Laurie Zhu, Xun Chung, Charles C. Ren, Chuanli Dawsey, Sanford M. Wang, Meilin Ding, Ti Du, Jiangbo Gao, Yu-Tang Zhong, Rong Giffen, Carol Pan, Wenting Koh, Woon-Puay Dai, Ningbing Liao, Linda M. Yan, Caiwang Qiao, You-Lin Jiang, Yue Shu, Xiao-Ou Chen, Jiaping Wang, Chaoyu Ma, Hongxia Su, Hua Zhang, Zhendong Wang, Lemin Wu, Chen Xiang, Yong-Bing Hu, Zhibin Yuan, Jian-Min Xie, Lu Zheng, Wei Lin, Dongxin Chanock, Stephen J. Shi, Yongyong Goldstein, Alisa M. Jin, Guangfu Taylor, Philip R. Shen, Hongbing TI Identification of new susceptibility loci for gastric non-cardia adenocarcinoma: pooled results from two Chinese genome-wide association studies SO GUT LA English DT Article ID GENETIC-VARIATION; CANCER SUSCEPTIBILITY; HELICOBACTER-PYLORI; ESOPHAGEAL; RISK; VARIANTS; 10Q23; MUC1; TRANSCRIPTOME; POPULATION AB Objective Although several genome-wide association studies (GWAS) of non-cardia gastric cancer have been published, more novel association signals could be exploited by combining individual studies together, which will further elucidate the genetic susceptibility of non-cardia gastric cancer. Design We conducted a meta-analysis of two published Chinese GWAS studies (2031 non-cardia gastric cancer cases and 4970 cancer-free controls) and followed by genotyping of additional 3564 cases and 4637 controls in two stages. Results The overall meta-analysis revealed two new association signals. The first was a novel locus at 5q14.3 and marked by rs7712641 (per-allele OR=0.84, 95% CI 0.80 to 0.88; p=1.21x10(-11)). This single-nucleotide polymorphism (SNP) marker maps to the intron of the long non-coding RNA, lnc-POLR3G-4 (XLOC_004464), which we observed has lower expression in non-cardia gastric tumour compared with matched normal tissue (Pwilcoxon signed-rank=7.20x10(-4)). We also identified a new signal at the 1q22 locus, rs80142782 (per-allele OR=0.62; 95% CI 0.56 to 0.69; p=1.71x10(-19)), which was independent of the previously reported SNP at the same locus, rs4072037 (per-allele OR=0.74; 95% CI 0.69 to 0.79; p=6.28x10(-17)). Analysis of the new SNP conditioned on the known SNP showed that the new SNP remained genome-wide significant (P-conditional=3.47x10(-8)). Interestingly, rs80142782 has a minor allele frequency of 0.05 in East Asians but is monomorphic in both European and African populations. Conclusion These findings add new evidence for inherited genetic susceptibility to non-cardia gastric cancer and provide further clues to its aetiology in the Han Chinese population. C1 [Wang, Zhaoming; Hu, Nan; Abnet, Christian C.; Freedman, Neal D.; Burdette, Laurie; Chung, Charles C.; Dawsey, Sanford M.; Liao, Linda M.; Wang, Chaoyu; Su, Hua; Wang, Lemin; Chanock, Stephen J.; Goldstein, Alisa M.; Taylor, Philip R.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Wang, Zhaoming; Burdette, Laurie; Chung, Charles C.] Leidos Biomed Res Inc, Canc Genom Res Lab, Gaithersburg, MD USA. [Wang, Zhaoming; Dai, Juncheng; Zhu, Xun; Ren, Chuanli; Du, Jiangbo; Dai, Ningbing; Yan, Caiwang; Jiang, Yue; Chen, Jiaping; Ma, Hongxia; Hu, Zhibin; Xie, Lu; Jin, Guangfu; Shen, Hongbing] Nanjing Med Univ, Sch Publ Hlth, Collaborat Innovat Ctr Canc Med, Dept Epidemiol & Biostat,Jiangsu Key Lab Canc Bio, Nanjing, Jiangsu, Peoples R China. [Miao, Xiaoping; Zhong, Rong] Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Publ Hlth, Dept Epidemiol & Biostat, Wuhan, Peoples R China. [Miao, Xiaoping; Zhong, Rong] Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Publ Hlth, Minist Educ,Key Lab Environm & Hlth, Wuhan, Peoples R China. [Yang, Ming; Pan, Wenting] Beijing Univ Chem Technol, Coll Life Sci & Technol, Beijing Lab Biomed Mat, State Key Lab Chem Resource Engn, Beijing, Peoples R China. [Chen, Jinfei] Nanjing Med Univ, Nanjing Hosp 1, Dept Oncol, Nanjing, Jiangsu, Peoples R China. [Ren, Chuanli] Yangzhou Univ, Northern Jiangsu Peoples Hosp, Clin Med Testing Lab, Yangzhou, Jiangsu, Peoples R China. [Ren, Chuanli] Yangzhou Univ, Clin Med Coll, Yangzhou, Jiangsu, Peoples R China. [Wang, Meilin; Zhang, Zhendong] Nanjing Med Univ, Sch Publ Hlth, Minist Educ, Dept Genet Toxicol,Key Lab Modern Toxicol, Nanjing, Jiangsu, Peoples R China. [Ding, Ti] Shanxi Canc Hosp, Taiyuan, Shanxi, Peoples R China. [Gao, Yu-Tang; Xiang, Yong-Bing] Shanghai Canc Inst, Shanghai, Peoples R China. [Giffen, Carol] Informat Management Serv Inc, Silver Spring, MD USA. [Koh, Woon-Puay] Natl Univ Singapore, Duke NUS Grad Med Sch Singapore, Singapore, Singapore. [Koh, Woon-Puay] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. [Qiao, You-Lin] Chinese Acad Med Sci, Canc Inst & Hosp, Dept Epidemiol, Beijing, Peoples R China. [Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Wu, Chen; Lin, Dongxin] Chinese Acad Med Sci, Canc Inst & Hosp, Dept Etiol & Carcinogenesis, Beijing, Peoples R China. [Yuan, Jian-Min] Univ Pittsburgh, Inst Canc, Div Canc Control & Populat Sci, Pittsburgh, PA USA. [Yuan, Jian-Min] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Shi, Yongyong] Shanghai Jiao Tong Univ, Bio X Inst, Minist Educ, Key Lab Genet Dev & Neuropsychiatr Disorders, Shanghai, Peoples R China. RP Shen, HB (reprint author), Nanjing Med Univ, Sch Publ Hlth, Collaborat Innovat Ctr Canc Med, Dept Epidemiol & Biostat,Jiangsu Key Lab Canc Bio, Nanjing, Jiangsu, Peoples R China. EM hbshen@njmu.edu.cn RI Abnet, Christian/C-4111-2015; miao, xiaoping/C-4336-2011; OI Abnet, Christian/0000-0002-3008-7843; miao, xiaoping/0000-0002-6818-9722; Qiao, You-Lin/0000-0001-6380-0871 FU National Cancer Institute (NCI); National Institutes of Health; Division of Cancer Epidemiology and Genetics; Center for Cancer Research; National Basic Research Program (973) [2013CB910304]; National Natural Science Foundation of China [81230067, 81573228, 81521004, 81422042, 81373090, 81222038]; Science Foundation for Distinguished Young Scholars in Jiangsu [BK20130042]; Jiangsu Natural Science Foundation [BK2012443, BK2012841]; Jiangsu Province Clinical Science and Technology Projects (Clinical Research Center) [BL2012008]; National Program for Support of Top-notch Young Professionals; Natural Science Foundation of Jiangsu Higher Education Institutions [15KJA330002]; National High-Tech Research and Development Program of China [2015AA020950]; Priority Academic Program for the Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine) FX This work was supported by the Intramural Research Program of the National Cancer Institute (NCI), the National Institutes of Health, the Division of Cancer Epidemiology and Genetics and the Center for Cancer Research. This work was also supported in part by the National Basic Research Program (973) (2013CB910304), Program of National Natural Science Foundation of China (81230067), National Natural Science Foundation of China (81573228, 81521004. 81422042, 81373090); Science Foundation for Distinguished Young Scholars in Jiangsu (BK20130042); Jiangsu Natural Science Foundation (BK2012443, BK2012841); Jiangsu Province Clinical Science and Technology Projects (Clinical Research Center, BL2012008); National Program for Support of Top-notch Young Professionals, National Natural Science Foundation of China (81222038); Key Grant of Natural Science Foundation of Jiangsu Higher Education Institutions (15KJA330002); National High-Tech Research and Development Program of China (2015AA020950) and Priority Academic Program for the Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine). NR 31 TC 3 Z9 3 U1 12 U2 12 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD APR PY 2017 VL 66 IS 4 BP 581 EP 587 DI 10.1136/gutjnl-2015-310612 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EO0WR UT WOS:000396419800005 PM 26701879 ER PT J AU Li, M He, Y Zhou, Z Ramirez, T Gao, YQ Gao, YH Ross, RA Cao, HX Cai, Y Xu, MJ Feng, DC Zhang, P Liangpunsakul, S Gao, B AF Li, Man He, Yong Zhou, Zhou Ramirez, Teresa Gao, Yueqiu Gao, Yanhang Ross, Ruth A. Cao, Haixia Cai, Yan Xu, Mingjiang Feng, Dechun Zhang, Ping Liangpunsakul, Suthat Gao, Bin TI MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the IL-6-p47(phox)-oxidative stress pathway in neutrophils SO GUT LA English DT Article ID NADPH OXIDASES; MACROPHAGE ACTIVATION; DISEASE PATHOGENESIS; HEPATITIS; FIBROSIS; MICE; INFLAMMATION; EXPRESSION; STEATOHEPATITIS; APOPTOSIS AB Objectives Chronic-plus-binge ethanol feeding activates neutrophils and exacerbates liver injury in mice. This study investigates how recent excessive drinking affects peripheral neutrophils and liver injury in alcoholics, and how miR-223, one of the most abundant microRNAs (miRNAs) in neutrophils, modulates neutrophil function and liver injury in ethanol-fed mice. Designs Three hundred alcoholics with (n=140) or without (n=160) recent excessive drinking and 45 healthy controls were enrolled. Mice were fed an ethanol diet for 10 days followed by a single binge of ethanol. Results Compared with healthy controls or alcoholics without recent drinking, alcoholics with recent excessive drinking had higher levels of circulating neutrophils, which correlated with serum levels of alanine transaminase (ALT) and aspartate transaminase (AST). miRNA array analysis revealed that alcoholics had elevated serum miR-223 levels compared with healthy controls. In chronic-plus-binge ethanol feeding mouse model, the levels of miR-223 were increased in both serum and neutrophils. Genetic deletion of the miR-223 gene exacerbated ethanol-induced hepatic injury, neutrophil infiltration, reactive oxygen species (ROS) and upregulated hepatic expression of interleukin (IL)-6 and phagocytic oxidase (phox) p47(phox). Mechanistic studies revealed that miR-223 directly inhibited IL-6 expression and subsequently inhibited p47(phox) expression in neutrophils. Deletion of the p47(phox) gene ameliorated ethanol-induced liver injury and ROS production by neutrophils. Finally, miR-223 expression was downregulated, while IL-6 and p47(phox) expression were upregulated in peripheral blood neutrophils from alcoholics compared with healthy controls. Conclusions miR-223 is an important regulator to block neutrophil infiltration in alcoholic liver disease and could be a novel therapeutic target for the treatment of this malady. C1 [Li, Man; He, Yong; Zhou, Zhou; Ramirez, Teresa; Gao, Yanhang; Cao, Haixia; Cai, Yan; Xu, Mingjiang; Feng, Dechun; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. [Li, Man; Gao, Yueqiu] Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Lab Cellular Immun, Shanghai, Peoples R China. [Ross, Ruth A.; Liangpunsakul, Suthat] Indiana Univ Sch Med, Dept Med, Div Gastroenterol & Hepatol, Indianapolis, IN 46202 USA. [Zhang, Ping] Northeast Ohio Med Univ, Coll Med, Dept Integrat Med Sci, Rootstown, OH USA. [Liangpunsakul, Suthat] Indiana Univ, Dept Biochem & Mol Biol, Indianapolis, IN 46204 USA. [Liangpunsakul, Suthat] Richard L Roudebush Vet Adm Med Ctr, Indianapolis, IN USA. RP Gao, B (reprint author), NIAAA, NIH, 5625 Fishers Lane, Rockville, MD 20852 USA.; Liangpunsakul, S (reprint author), Indiana Univ, Dept Med, Div Gastroenterol & Hepatol, 550 Univ Blvd, Indianapolis, IN 46202 USA. EM sliangpu@iug.edu FU NIAAA, NIH; Veterans Affairs Research and Administration [1I01CX000361-01]; USA Department of Defense [W81XWH-12-1-0497]; Shanghai Municipal Health Bureau [XYQ2013093]; 3-year action plan of development of Traditional Chinese Medicine in Shanghai [ZYSNXD-CC-ZDYJ015] FX This work was supported by the intramural programme of NIAAA, NIH (BG), by the 1I01CX000361-01 from the Veterans Affairs Research and Administration and W81XWH-12-1-0497 from USA Department of Defense (SL). ML was supported by Training Plan of Outstanding Young Medical Talents, Shanghai Municipal Health Bureau (XYQ2013093); YqG was supported by 3-year action plan of development of Traditional Chinese Medicine in Shanghai (ZYSNXD-CC-ZDYJ015). NR 47 TC 2 Z9 2 U1 2 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD APR PY 2017 VL 66 IS 4 BP 705 EP 715 DI 10.1136/gutjnl-2016-311861 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EO0WR UT WOS:000396419800017 PM 27679493 ER PT J AU Serti, E Park, H Keane, M O'Keefe, AC Rivera, E Liang, TJ Ghany, M Rehermann, B AF Serti, Elisavet Park, Heiyoung Keane, Meghan O'Keefe, Ashley C. Rivera, Elenita Liang, T. Jake Ghany, Marc Rehermann, Barbara TI Rapid decrease in hepatitis C viremia by direct acting antivirals improves the natural killer cell response to IFN alpha SO GUT LA English DT Article ID INTERFERON-ALPHA; VIRUS-INFECTION; HCV INFECTION; GENOTYPE 1; NK CELLS; HUMAN HEPATOCYTES; GENE-EXPRESSION; NULL RESPONDERS; THERAPY; DACLATASVIR AB Objective Chronic HCV infection is characterised by innate immune activation with increased interferon-stimulated genes (ISG) expression and by an altered phenotype of interferon-responsive natural killer (NK) cells. Here, we asked whether a rapid reduction in viremia by daclatasvir (DCV) and asunaprevir (ASV) improves the response to pegylated interferon (PegIFN) in patients who had previously failed a standard course of PegIFN/ribavirin (RBV) therapy. Design Twenty-two HCV-infected non-responders to previous PegIFN/RBV therapy were studied for IFN-responsiveness of NK cells during quadruple (QUAD) therapy with DCV, ASV, PegIFN and RBV. A direct comparison of early NK cell responses in PegIFN/RBV therapy and QUAD therapy was performed for seven patients using paired cryopreserved peripheral blood mononuclear cells (PBMC) from both treatment courses. As a validation cohort, nine DCV/ASV-treated patients were studied for their NK cell response to in vitro stimulation with IFN alpha. Results The 24 h virological response to QUAD therapy correlated with an increase in signal transducer and activator of transcription 1 (STAT1), phosphorylated STAT1 (pSTAT1) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) expression in NK cells, and the STAT1/pSTAT1/TRAIL induction was greater during QUAD therapy than during previous PegIFN/RBV therapy. Successful QUAD therapy as well as successful IFN-free DCV/ASV regimen resulted in an improved functional NK cell response (degranulation and TRAIL expression) to in vitro stimulation with IFN alpha. Conclusions IFN-responsiveness can be improved by inhibiting HCV replication and reducing the HCV-induced activation of the innate immune response. This may provide a rationale for clinical trials of a brief period of direct acting antiviral therapy followed by PegIFN/RBV therapy to reduce the overall treatment costs in low-income and middle-income countries. C1 [Serti, Elisavet; Park, Heiyoung; Keane, Meghan; O'Keefe, Ashley C.; Rehermann, Barbara] NIDDK, Immunol Sect, NIH, DHHS, Bethesda, MD 20892 USA. [Serti, Elisavet; Park, Heiyoung; Keane, Meghan; O'Keefe, Ashley C.; Rivera, Elenita; Liang, T. Jake; Ghany, Marc; Rehermann, Barbara] NIDDK, Liver Dis Branch, NIH, DHHS, Bethesda, MD 20892 USA. RP Rehermann, B (reprint author), NIDDK, Immunol Sect, Liver Dis Branch, NIH,DHHS, 10 Ctr Dr,Bldg 10,Rm 9B16, Bethesda, MD 20892 USA. EM Rehermann@nih.gov FU National Institute for Diabetes, Digestive and Kidney Diseases, National Institutes of Health FX This work was supported by the intramural research programme of the National Institute for Diabetes, Digestive and Kidney Diseases, National Institutes of Health Intramural Research Program. NR 37 TC 2 Z9 2 U1 5 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD APR PY 2017 VL 66 IS 4 BP 724 EP 735 DI 10.1136/gutjnl-2015-310033 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EO0WR UT WOS:000396419800019 PM 26733671 ER PT J AU Schwartz, R Schaffer, AA AF Schwartz, Russell Schaffer, Alejandro A. TI The evolution of tumour phylogenetics: principles and practice SO NATURE REVIEWS GENETICS LA English DT Review ID CROSS-SECTIONAL DATA; POTENTIAL THERAPEUTIC TARGETS; MULTIFOCAL PROSTATE-CANCER; IN-SITU HYBRIDIZATION; CELL GENETIC-ANALYSIS; PAIRED EXOME ANALYSIS; COPY NUMBER CHANGES; CLONAL EVOLUTION; BREAST-CANCER; SEQUENCING DATA AB Rapid advances in high-throughput sequencing and a growing realization of the importance of evolutionary theory to cancer genomics have led to a proliferation of phylogenetic studies of tumour progression. These studies have yielded not only new insights but also a plethora of experimental approaches, sometimes reaching conflicting or poorly supported conclusions. Here, we consider this body of work in light of the key computational principles underpinning phylogenetic inference, with the goal of providing practical guidance on the design and analysis of scientifically rigorous tumour phylogeny studies. We survey the range of methods and tools available to the researcher, their key applications, and the various unsolved problems, closing with a perspective on the prospects and broader implications of this field. C1 [Schwartz, Russell] Carnegie Mellon Univ, Dept Biol Sci, Pittsburgh, PA 15217 USA. [Schwartz, Russell] Carnegie Mellon Univ, Computat Biol Dept, Pittsburgh, PA 15217 USA. [Schaffer, Alejandro A.] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Bldg 10, Bethesda, MD 20892 USA. RP Schwartz, R (reprint author), Carnegie Mellon Univ, Dept Biol Sci, Pittsburgh, PA 15217 USA.; Schwartz, R (reprint author), Carnegie Mellon Univ, Computat Biol Dept, Pittsburgh, PA 15217 USA. EM russells@andrew.cmu.edu FU Intramural Research Program of the National Library of Medicine part of the US National Institutes of Health; Pennsylvania Department of Health [4100070287] FX This research was supported in part by the Intramural Research Program of the National Library of Medicine (part of the US National Institutes of Health) and by a grant from the Pennsylvania Department of Health (grant number 4100070287). The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions. NR 191 TC 0 Z9 0 U1 8 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 EI 1471-0064 J9 NAT REV GENET JI Nat. Rev. Genet. PD APR PY 2017 VL 18 IS 4 BP 213 EP 229 DI 10.1038/nrg.2016.170 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA EN9SA UT WOS:000396338700007 PM 28190876 ER PT J AU Noinaj, N Gumbart, JC Buchanan, SK AF Noinaj, Nicholas Gumbart, James C. Buchanan, Susan K. TI The beta-barrel assembly machinery in motion SO NATURE REVIEWS MICROBIOLOGY LA English DT News Item ID OUTER-MEMBRANE PROTEINS; GRAM-NEGATIVE BACTERIA; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; BAM COMPLEX; ESSENTIAL COMPONENT; PERIPLASMIC DOMAIN; LIPOPROTEIN BAMC; YAET COMPLEX AB In Gram-negative bacteria, the biogenesis of beta -barrel outer membrane proteins (OMPs) is mediated by the beta-barrel assembly machinery (BAM) complex. During the past decade, structural and functional studies have collectively contributed to advancing our understanding of the structure and function of the BAM complex; however, the exact mechanism that is involved remains elusive. In this Progress article, we discuss recent structural studies that have revealed that the accessory proteins may regulate essential unprecedented conformational changes in the core component BamA during function. We also detail the mechanistic insights that have been gained from structural data, mutagenesis studies and molecular dynamics simulations, and explore two emerging models for the BAM-mediated biogenesis of OMPs in bacteria. C1 [Noinaj, Nicholas] Purdue Univ, Markey Ctr Struct Biol, Dept Biol Sci, W Lafayette, IN 47907 USA. [Noinaj, Nicholas] Purdue Univ, Purdue Inst Inflammat Immunol & Infect Dis, W Lafayette, IN 47907 USA. [Gumbart, James C.] Georgia Inst Technol, Sch Phys, Atlanta, GA 30332 USA. [Buchanan, Susan K.] NIDDK, Bethesda, MD 20892 USA. RP Noinaj, N (reprint author), Purdue Univ, Markey Ctr Struct Biol, Dept Biol Sci, W Lafayette, IN 47907 USA.; Noinaj, N (reprint author), Purdue Univ, Purdue Inst Inflammat Immunol & Infect Dis, W Lafayette, IN 47907 USA.; Buchanan, SK (reprint author), NIDDK, Bethesda, MD 20892 USA. EM nnoinaj@purdue.edu; skbuchan@helix.nih.gov FU Department of Biological Sciences at Purdue University, Indiana, USA; Showalter Trust Award; US National Institute of Allergy and Infectious Diseases [1K22AI113078-01]; US National Science Foundation [MCB-1452464]; Intramural Research Program of the US National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health FX N.N. is supported by the Department of Biological Sciences at Purdue University, Indiana, USA, a Showalter Trust Award, and by the US National Institute of Allergy and Infectious Diseases (grant 1K22AI113078-01). J.C.G. is supported by a CAREER award from the US National Science Foundation (grant MCB-1452464); S.K.B. is supported by the Intramural Research Program of the US National Institute of Diabetes and Digestive and Kidney Diseases, part of the US National Institutes of Health. NR 73 TC 0 Z9 0 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1740-1526 EI 1740-1534 J9 NAT REV MICROBIOL JI Nat. Rev. Microbiol. PD APR PY 2017 VL 15 IS 4 DI 10.1038/nrmicro.2016.191 PG 8 WC Microbiology SC Microbiology GA EN8AL UT WOS:000396223200002 PM 28216659 ER PT J AU Di Florio, A Putnam, K Altemus, M Apter, G Bergink, V Bilszta, J Brock, R Buist, A Deligiannidis, KM Devouche, E Epperson, CN Guille, C Kim, D Lichtenstein, P Magnusson, PKE Martinez, P Munk-Olsen, T Newport, J Payne, J Penninx, BW O'Hara, M Robertson-Blackmore, E Roza, SJ Sharkey, KM Stuart, S Tiemeier, H Viktorin, A Schmidt, PJ Sullivan, PF Stowe, ZN Wisner, KL Jones, I Rubinow, DR Meltzer-Brody, S AF Di Florio, A. Putnam, K. Altemus, M. Apter, G. Bergink, V. Bilszta, J. Brock, R. Buist, A. Deligiannidis, K. M. Devouche, E. Epperson, C. N. Guille, C. Kim, D. Lichtenstein, P. Magnusson, P. K. E. Martinez, P. Munk-Olsen, T. Newport, J. Payne, J. Penninx, B. W. O'Hara, M. Robertson-Blackmore, E. Roza, S. J. Sharkey, K. M. Stuart, S. Tiemeier, H. Viktorin, A. Schmidt, P. J. Sullivan, P. F. Stowe, Z. N. Wisner, K. L. Jones, I. Rubinow, D. R. Meltzer-Brody, S. CA Postpartum Depression Action TI The impact of education, country, race and ethnicity on the self-report of postpartum depression using the Edinburgh Postnatal Depression Scale SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Culture; Edinburgh Postnatal Depression Scale (EPDS); education; postpartum depression; race. ID MENTAL-ILLNESS; UNITED-STATES; WOMEN; HEALTH; SYMPTOMS; LEAVE; ASSOCIATION; PREVALENCE; VALIDATION; CHILDBIRTH AB Background. Universal screening for postpartum depression is recommended in many countries. Knowledge of whether the disclosure of depressive symptoms in the postpartum period differs across cultures could improve detection and provide new insights into the pathogenesis. Moreover, it is a necessary step to evaluate the universal use of screening instruments in research and clinical practice. In the current study we sought to assess whether the Edinburgh Postnatal Depression Scale (EPDS), the most widely used screening tool for postpartum depression, measures the same underlying construct across cultural groups in a large international dataset. Method. Ordinal regression and measurement invariance were used to explore the association between culture, operationalized as education, ethnicity/race and continent, and endorsement of depressive symptoms using the EPDS on 8209 new mothers from Europe and the USA. Results. Education, but not ethnicity/race, influenced the reporting of postpartum depression [ difference between robust comparative fit indexes (Delta* CFI) < 0.01]. The structure of EPDS responses significantly differed between Europe and the USA (Delta* CFI > 0.01), but not between European countries (Delta* CFI < 0.01). Conclusions. Investigators and clinicians should be aware of the potential differences in expression of phenotype of postpartum depression that women of different educational backgrounds may manifest. The increasing cultural heterogeneity of societies together with the tendency towards globalization requires a culturally sensitive approach to patients, research and policies, that takes into account, beyond rhetoric, the context of a person's experiences and the context in which the research is conducted. C1 [Di Florio, A.; Putnam, K.; Sullivan, P. F.; Rubinow, D. R.; Meltzer-Brody, S.] Univ N Carolina, Dept Psychiat, Campus Box 7160, Chapel Hill, NC 27599 USA. [Di Florio, A.; Jones, I.] Cardiff Univ, Inst Psychol Med & Clin Neurosci, Sch Med, Cardiff, S Glam, Wales. [Altemus, M.] Weill Cornell Med Coll, Dept Psychiat, New York, NY USA. [Apter, G.] Paris Diderot Univ, Erasme Hosp, Paris, France. [Bergink, V.; Roza, S. J.; Tiemeier, H.] Erasmus MC, Dept Psychiat Psychol, Rotterdam, Netherlands. [Bergink, V.; Munk-Olsen, T.] Aarhus Univ, Dept Econ & Business, Natl Ctr Integrated Register Based Res, Aarhus, Denmark. [Bilszta, J.; Buist, A.] Univ Melbourne, Womens Mental Hlth, Melbourne, Vic, Australia. [Brock, R.; O'Hara, M.; Stuart, S.] Univ Iowa, Dept Psychol & Brain Sci, Iowa City, IA USA. [Deligiannidis, K. M.] Hofstra Northwell Sch Med, Dept Psychiat, Glen Oaks, NY USA. [Deligiannidis, K. M.] Hofstra Northwell Sch Med, Dept Obstet & Gynecol, Glen Oaks, NY USA. [Devouche, E.] Paris Descartes Univ, Erasme Hosp, Paris, France. [Epperson, C. N.; Kim, D.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Guille, C.] Med Univ South Carolina, Dept Psychiat, Charleston, SC USA. [Lichtenstein, P.; Viktorin, A.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Martinez, P.; Schmidt, P. J.] NIMH, Behav Endocrinol Branch, NIH, Hlth & Human Serv, Bethesda, MD 20892 USA. [Newport, J.] Univ Miami, Dept Psychiat, Miami, FL USA. [Payne, J.] Johns Hopkins Univ, Dept Psychiat, Baltimore, MD USA. [Penninx, B. W.] Vrije Univ Amsterdam, Dept Psychiat, Med Ctr, Amsterdam, Netherlands. [Robertson-Blackmore, E.] Halifax Hlth, Dept Family Med, Daytona Beach, FL USA. [Sharkey, K. M.] Brown Univ, Rhode Isl Hosp, Dept Psychiat, Alpert Med Sch, Providence, RI 02903 USA. [Stowe, Z. N.] Univ Arkansas Med Sci, Dept Psychiat, Little Rock, AR 72205 USA. [Wisner, K. L.] Northwestern Univ, Feinberg Sch Med, Asher Ctr Study & Treatment Depress Disorders, Chicago, IL 60611 USA. RP Meltzer-Brody, S (reprint author), Univ N Carolina, Dept Psychiat, Campus Box 7160, Chapel Hill, NC 27599 USA. EM meltzerb@med.unc.edu FU European Commission Marie Curie Fellowship [623932]; National Institute of Mental Health (NIMH) [1R01MH10446801, 5K23MH086689, K23 MH07479901A2, 222963, MH50524 NIMH, 5R01MH60335]; NIMH [5R01MH071825, 5R01MH075921, 5-2R01MH057102, ZonMW 10.000.1003, ZIA MH002865-09 BEB, K23 MH097794, P50 MH099910, K23 MH001830, NIDA K24 DA030301, K23MH080290, K23 MH085165]; National Institutes of Health [UL1 TR000161]; Worcester Foundation for Biomedical Research grant; National Alliance for Research on Schizophrenia and Depression; Brain & Behavior Research Foundation; French Ministry of Health (PHRC) [98/001]; Mustela Foundation; Geestkracht program of the Netherlands Organization for Health Research and Development [10-000-1002]; VU University Medical Centre; GGZ Geest; Arkin; Leiden University Medical Centre; GGZ Rivierduinen; University Medical Centre in Groningen, Lentis; GGZ Fries land; GGZ Drenthe; IQ Healthcare; Netherlands Institute for Health Services Research; Netherlands Institute of Mental Health and Addiction; South Carolina Clinical and Translational Research Institute [UL1 TR000062]; Building Interdisciplinary Research Careers in Women's Health [K12 HD055885]; NIH [P50 MH-77928, P50 MH 68036]; National Centre for Mental Health Wales; Swedish Ministry for Higher Education, the Swedish Medical Research Council [K2014-62X14647- 12-51, K2010-61P-21568-01-4]; Swedish Foundation for Strategic Research; Swedish Brain Foundation FX A.D.F. is funded by a European Commission Marie Curie Fellowship (grant number 623932). The National Institute of Mental Health (NIMH) supports T.M.-O., D.R.R., P.F.S. and S.M.-B. (1R01MH10446801). K.M.S. (5K23MH086689), J.P. (K23 MH07479901A2), V.B. (FP7-Health-2007 Project no 222963), M.O. (MH50524 NIMH), K.L.W. (5R01MH60335, NIMH, 5R01MH071825, 5R01MH075921 and 5-2R01MH057102), S.J.R. and H.T. (ZonMW 10.000.1003), and P. J. S. (ZIA MH002865-09 BEB). K. M. D. is supported by the NIMH (K23 MH097794), National Institutes of Health (UL1 TR000161) and a Worcester Foundation for Biomedical Research grant. C.N.E. has been supported by NIMH grants P50 MH099910, K23 MH001830, NIDA K24 DA030301, Pfizer Pharmaceuticals and a young investigator award from the National Alliance for Research on Schizophrenia and Depression. E.R.-B. is supported by the NIMH (K23MH080290) and a young investigator award from the Brain & Behavior Research Foundation; G.A. and E.D. are supported by the French Ministry of Health (PHRC 98/001) and the Mustela Foundation. B.W.P. is supported by the Geestkracht program of the Netherlands Organization for Health Research and Development (10-000-1002) and VU University Medical Centre, GGZ Geest, Arkin, Leiden University Medical Centre, GGZ Rivierduinen, University Medical Centre in Groningen, Lentis, GGZ Fries land, GGZ Drenthe, IQ Healthcare, Netherlands Institute for Health Services Research, and Netherlands Institute of Mental Health and Addiction. C.G. is supported by the South Carolina Clinical and Translational Research Institute (UL1 TR000062) and Building Interdisciplinary Research Careers in Women's Health (K12 HD055885). Z.N. S. is supported by the NIH (P50 MH-77928 and P50 MH 68036). I. J. is supported by the National Centre for Mental Health Wales. P.L., P.K.E.M. and A.V. are supported by the Swedish Ministry for Higher Education, the Swedish Medical Research Council (K2014-62X14647- 12-51 and K2010-61P-21568-01-4), the Swedish Foundation for Strategic Research, the Swedish Brain Foundation and the NIMH (K23 MH085165). NR 47 TC 0 Z9 0 U1 11 U2 11 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 APR PY 2017 VL 47 IS 5 BP 787 EP 799 DI 10.1017/S0033291716002087 PG 13 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA EN9FC UT WOS:000396305100001 PM 27866476 ER PT J AU Liu, M Malone, SM Vaidyanathan, U Keller, MC Abecasis, G Mcgue, M Iacono, WG Vrieze, SI AF Liu, M. Malone, S. M. Vaidyanathan, U. Keller, M. C. Abecasis, G. Mcgue, M. Iacono, W. G. Vrieze, S. I. TI Psychophysiological endophenotypes to characterize mechanisms of known schizophrenia genetic loci SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Endophenotypes; gene-based tests; polygenic risk scores; schizophrenia; single variant association ID GENOME-WIDE ASSOCIATION; ANTISACCADE PERFORMANCE; BIOLOGICAL RELATIVES; HERITABILITY; VARIANTS; ABNORMALITIES; METAANALYSIS; CONSORTIUM; DISORDERS; BIPOLAR AB Background. Endophenotypes are laboratory-based measures hypothesized to lie in the causal chain between genes and clinical disorder, and to serve as a more powerful way to identify genes associated with the disorder. One promise of endophenotypes is that they may assist in elucidating the neurobehavioral mechanisms by which an associated genetic polymorphism affects disorder risk in complex traits. We evaluated this promise by testing the extent to which variants discovered to be associated with schizophrenia through large-scale meta-analysis show associations with psychophysiological endophenotypes. Method. We genome-wide genotyped and imputed 4905 individuals. Of these, 1837 were whole-genome-sequenced at 11x depth. In a community-based sample, we conducted targeted tests of variants within schizophrenia-associated loci, as well as genome-wide polygenic tests of association, with 17 psychophysiological endophenotypes including acoustic startle response and affective startle modulation, antisaccade, multiple frequencies of resting electroencephalogram (EEG), electrodermal activity and P300 event-related potential. Results. Using single variant tests and gene-based tests we found suggestive evidence for an association between contactin 4 (CNTN4) and antisaccade and P300. We were unable to find any other variant or gene within the 108 schizophrenia loci significantly associated with any of our 17 endophenotypes. Polygenic risk scores indexing genetic vulnerability to schizophrenia were not related to any of the psychophysiological endophenotypes after correction for multiple testing. Conclusions. The results indicate significant difficulty in using psychophysiological endophenotypes to characterize the genetically influenced neurobehavioral mechanisms by which risk loci identified in genome-wide association studies affect disorder risk. C1 [Liu, M.; Keller, M. C.; Vrieze, S. I.] Univ Colorado, Inst Behav Genet, 1480 30th St, Boulder, CO 80303 USA. [Liu, M.; Keller, M. C.; Vrieze, S. I.] Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA. [Malone, S. M.; Mcgue, M.; Iacono, W. G.] Univ Minnesota, Dept Psychol, Minneapolis, MN USA. [Vaidyanathan, U.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Abecasis, G.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. RP Vrieze, SI (reprint author), Univ Colorado, Inst Behav Genet, 1480 30th St, Boulder, CO 80303 USA. EM scott.vrieze@colorado.edu FU National Institutes of Health [AA023974, HG008983, DA037904, DA040177, DA041120, DA036216, DA005147, AA009367, DA024417] FX This research was supported through National Institutes of Health grants AA023974, HG008983, DA037904, DA040177, DA041120, DA036216, DA005147, AA009367 and DA024417. NR 46 TC 0 Z9 0 U1 3 U2 3 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 APR PY 2017 VL 47 IS 6 BP 1116 EP 1125 DI 10.1017/S0033291716003184 PG 10 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA EN9FL UT WOS:000396306000012 PM 27995817 ER PT J AU Persoskie, A Nguyen, AB Kaufman, AR Tworek, C AF Persoskie, Alexander Nguyen, Anh B. Kaufman, Annette R. Tworek, Cindy TI Criterion validity of measures of perceived relative harm of e-cigarettes and smokeless tobacco compared to cigarettes SO ADDICTIVE BEHAVIORS LA English DT Article DE Perceived harm; Measures; Validity; Tobacco; Electronic cigarettes; Smokeless tobacco ID RISK PERCEPTIONS; CONSTRUCT-VALIDITY; LIGHT CIGARETTES; UNITED-STATES; HEALTH-RISKS; SMOKING; SMOKERS; AWARENESS; ADULTS; HARMFULNESS AB Beliefs about the relative harmfulness of one product compared to another (perceived relative harm) are central to research and regulation concerning tobacco and nicotine-containing products, but techniques for measuring such beliefs vary widely. We compared the validity of direct and indirect measures of perceived harm of e-cigarettes and smokeless tobacco (SLT) compared to cigarettes. On direct measures, participants explicitly compare the harmfulness of each product. On indirect measures, participants rate the harmfulness of each product separately, and ratings are compared. The U.S. Health Information National Trehds Survey (HINTS-FDA-2015; N = 3738) included direct measures of perceived harm of e-cigarettes and SLT compared to cigarettes. Indirect measures were created by comparing ratings of harm from e-cigarettes, SLT, and cigarettes on 3-point scales. Logistic regressions tested validity by assessing whether direct and indirect measures were associated with criterion variables including: ever-trying e-cigarettes, ever-trying snus, and SLT use status. Compared to the indirect measures, the direct measures of harm were more consistently associated with criterion variables. On direct measures, 26% of adults rated e -cigarettes as less harmful than cigarettes, and 11% rated SLT as less harmful than cigarettes. Direct measures appear to provide valid information about individuals' harm beliefs, which may be used to inform research and tobacco control policy. Further validation research is encouraged. Published by Elsevier Ltd. C1 [Persoskie, Alexander; Nguyen, Anh B.; Tworek, Cindy] US FDA, Off Sci, Ctr Tobacco Prod, Silver Spring, MD USA. [Kaufman, Annette R.] NCI, Tobacco Control Res Branch, Rockville, MD USA. RP Persoskie, A (reprint author), Bldg 71,Room G335,10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM alexander.persoskie@fda.hhs.gov FU U.S. Food and Drug Administration; Center for Tobacco Products; U.S. National Cancer Institute, National Institutes of Health FX Publication of this article was supported by the U.S. Food and Drug Administration, Center for Tobacco Products, and the U.S. National Cancer Institute, National Institutes of Health. No funding was provided specifically for conducting the analysis, drafting the manuscript, or submitting this paper for publication. NR 41 TC 0 Z9 0 U1 6 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 EI 1873-6327 J9 ADDICT BEHAV JI Addict. Behav. PD APR PY 2017 VL 67 BP 100 EP 105 DI 10.1016/j.addbeh.2017.01.001 PG 6 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA EJ1XP UT WOS:000393004200017 PM 28073035 ER PT J AU Bomarito, GF Hochhalter, JD Ruggles, TJ Cannon, AH AF Bomarito, G. F. Hochhalter, J. D. Ruggles, T. J. Cannon, A. H. TI Increasing accuracy and precision of digital image correlation through pattern optimization SO OPTICS AND LASERS IN ENGINEERING LA English DT Article DE Image correlation; Pattern optimization; Pattern quality metrics; 2D full-field measurements ID SPECKLE PATTERNS; QUALITY ASSESSMENT; SYSTEMATIC-ERRORS; INTERPOLATION; GRADIENT; MOTION; NOISE AB The accuracy and precision of digital image correlation (DIC) is based on three primary components: image acquisition, image analysis, and the subject of the image. Focus on the third component, the image subject, has been relatively limited and primarily concerned with comparing pseudo-random surface patterns. In the current work, a strategy is proposed for the creation of optimal DIC patterns. In this strategy, a pattern quality metric is developed as a combination of quality metrics from the literature rather than optimization based on any single one of them. In this way, optimization produces a pattern which balances the benefits of multiple quality metrics. Specifically, sum of square of subset intensity gradients (SSSIG) was found to be the metric most strongly correlated to DIC accuracy and thus is the main component of the newly proposed pattern quality metric. A term related to the secondary auto-correlation peak height is also part of the proposed quality metric which effectively acts as a constraint upon SSSIG ensuring that a regular (e.g., checkerboard-type) pattern is not achieved. The combined pattern quality metric is used to generate a pattern that was on average 11.6% more accurate than a randomly generated pattern in a suite of numerical experiments. Furthermore, physical experiments were performed which confirm that there is indeed improvement of a similar magnitude in DIC measurements for the optimized pattern compared to a random pattern. C1 [Bomarito, G. F.; Hochhalter, J. D.] NASA, Langley Res Ctr, Hampton, VA 23665 USA. [Ruggles, T. J.] NIA, Hampton, VA USA. [Cannon, A. H.] 1900 Engn LLC, Clemson, SC USA. [Cannon, A. H.] Clemson Univ, Dept Chem & Biomol Engn, Clemson, SC USA. RP Bomarito, GF (reprint author), NASA, Langley Res Ctr, Hampton, VA 23665 USA. EM geoffrey.f.bomarito@nasa.gov FU National Aeronautics and Space Administration's Aeronautics Research Mission Directorate through the Digital Twin effort within the Convergent Aeronautics Solutions project FX This work was supported by the National Aeronautics and Space Administration's Aeronautics Research Mission Directorate through the Digital Twin effort within the Convergent Aeronautics Solutions project. NR 34 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0143-8166 EI 1873-0302 J9 OPT LASER ENG JI Opt. Lasers Eng. PD APR PY 2017 VL 91 BP 73 EP 85 DI 10.1016/j.optlaseng.2016.11.005 PG 13 WC Optics SC Optics GA EJ5NF UT WOS:000393264300008 ER PT J AU Sheikhbahaei, S Smith, JC AF Sheikhbahaei, Shahriar Smith, Jeffrey C. TI Breathing to inspire and arouse SO SCIENCE LA English DT Editorial Material ID NEURONS; COMPLEX; SYSTEM; RHYTHM; RATS C1 [Sheikhbahaei, Shahriar; Smith, Jeffrey C.] Natl Inst Neurol Disorders & Stroke, Cellular & Syst Neurobiol Sect, NIH, Bethesda, MD 20892 USA. [Sheikhbahaei, Shahriar] UCL, Dept Neurosci Physiol & Pharmacol, Ctr Cardiovasc & Metab Neurosci, London WC1E 6BT, England. RP Smith, JC (reprint author), Natl Inst Neurol Disorders & Stroke, Cellular & Syst Neurobiol Sect, NIH, Bethesda, MD 20892 USA. EM smithj2@ninds.nih.gov NR 15 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD MAR 31 PY 2017 VL 355 IS 6332 BP 1370 EP 1371 DI 10.1126/science.aan1466 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EQ1DL UT WOS:000397809500018 PM 28360280 ER PT J AU Kamphorst, AO Wieland, A Nasti, T Yang, S Zhang, R Barber, DL Konieczny, BT Daugherty, CZ Koenig, L Yu, K Sica, GL Sharpe, AH Freeman, GJ Blazar, BR Turka, LA Owonikoko, TK Pillai, RN Ramalingam, SS Araki, K Ahmed, R AF Kamphorst, Alice O. Wieland, Andreas Nasti, Tahseen Yang, Shu Zhang, Ruan Barber, Daniel L. Konieczny, Bogumila T. Daugherty, Candace Z. Koenig, Lydia Yu, Ke Sica, Gabriel L. Sharpe, Arlene H. Freeman, Gordon J. Blazar, Bruce R. Turka, Laurence A. Owonikoko, Taofeek K. Pillai, Rathi N. Ramalingam, Suresh S. Araki, Koichi Ahmed, Rafi TI Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent SO SCIENCE LA English DT Article ID CHRONIC VIRAL-INFECTION; RESPONSES; IMMUNITY; CANCER; PD-1; COSTIMULATION; BLOCKADE; EFFECTOR; MEMORY AB Programmed cell death-1 (PD-1)-targeted therapies enhance T cell responses and show efficacy in multiple cancers, but the role of costimulatory molecules in this T cell rescue remains elusive. Here, we demonstrate that the CD28/B7 costimulatory pathway is essential for effective PD-1 therapy during chronic viral infection. Conditional gene deletion showed a cell-intrinsic requirement of CD28 for CD8 T cell proliferation after PD-1 blockade. B7-costimulation was also necessary for effective PD-1 therapy in tumor-bearing mice. In addition, we found that CD8 T cells proliferating in blood after PD-1 therapy of lung cancer patients were predominantly CD28-positive. Taken together, these data demonstrate CD28-costimulation requirement for CD8 T cell rescue and suggest an important role for the CD28/B7 pathway in PD-1 therapy of cancer patients. C1 [Kamphorst, Alice O.; Wieland, Andreas; Nasti, Tahseen; Yang, Shu; Barber, Daniel L.; Konieczny, Bogumila T.; Daugherty, Candace Z.; Araki, Koichi; Ahmed, Rafi] Emory Univ, Sch Med, Emory Vaccine Ctr, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Yang, Shu] Cent S Univ, Xiangya Sch Med, Changsha 410013, Hunan, Peoples R China. [Zhang, Ruan; Turka, Laurence A.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02144 USA. [Zhang, Ruan; Turka, Laurence A.] Harvard Med Sch, Boston, MA 02144 USA. [Barber, Daniel L.] NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. [Koenig, Lydia; Yu, Ke; Owonikoko, Taofeek K.; Pillai, Rathi N.; Ramalingam, Suresh S.] Emory Univ, Sch Med, Winship Canc Inst, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA. [Sica, Gabriel L.] Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA. [Sharpe, Arlene H.] Harvard Med Sch, Dept Microbiol & Immunol, Boston, MA 02115 USA. [Sharpe, Arlene H.] Harvard Med Sch, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA. [Sharpe, Arlene H.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Freeman, Gordon J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Blazar, Bruce R.] Univ Minnesota, Dept Pediat, Div Blood & Marrow Transplantat, Minneapolis, MN 55455 USA. [Yang, Shu] Tianjin Med Univ, Gen Hosp, Dept Neurol, Tianjin 300052, Peoples R China. RP Ahmed, R (reprint author), Emory Univ, Sch Med, Emory Vaccine Ctr, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. EM rahmed@emory.edu OI Nasti, Tahseen/0000-0002-5650-1563 FU Merck [52507]; National Institutes of Health [R01 AI30048, P01 AI080192, P01 AI056299, P01 AI054456, R01 AI089955, R01 CA72669, R01 AI037691] FX This work was supported by Merck preclinical grant 52507 (R.A. and A.O.K.) and the National Institutes of Health grants R01 AI30048 (R.A.), P01 AI080192 (R.A. and G.J.F.), P01 AI056299 (A.H.S., R.A., G.J.F., and B.R.B.), P01 AI054456 (A.H.S.), R01 AI089955 (G.J.F.), R01 CA72669 (B.R.B.), and R01 AI037691 (L.A.T. and R.Z.). The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. We thank M. Ford (Emory University) for reagents and E. Eruslanov (University of Pennsylvania School of Medicine) for experimental advice. R.A., D.L.B., G.J.F., and A.H.S. are inventors on patent numbers US 8552154 B2, US 8652465 B2, and US 9102727 B2, held by Emory University (Atlanta), Dana-Farber Cancer Institute (Boston), Brigham and Women's Hospital (Boston), and Harvard University (Cambridge), which cover the topic of PD-1-directed immunotherapy. G.F. is the inventor on patent numbers US 6,808,710, US 7,101,550, US 7,638,492, US 7,700,301, US 7,432,059, US 7,709,214, US 7,722,868, US 7,635,757, US 7,038,013, US 6,936,704, and US 7,105,328 held by Dana-Farber Cancer Institute, which cover the topic of PD-1-directed immunotherapy. NR 25 TC 2 Z9 2 U1 3 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD MAR 31 PY 2017 VL 355 IS 6332 BP 1423 EP 1427 DI 10.1126/science.aaf0683 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EQ1DL UT WOS:000397809500043 PM 28280249 ER PT J AU Grill, S Ankerst, DP Gail, MH Chatterjee, N Pfeiffer, RM AF Grill, Sonja Ankerst, Donna P. Gail, Mitchell H. Chatterjee, Nilanjan Pfeiffer, Ruth M. TI Comparison of approaches for incorporating new information into existing risk prediction models SO STATISTICS IN MEDICINE LA English DT Article DE calibration; independence Bayes; discrimination; model updating; risk prediction ID PROSTATE-CANCER RISK; LOGISTIC-REGRESSION; LIKELIHOOD RATIOS; PROBABILITY; TOOLS AB We compare the calibration and variability of risk prediction models that were estimated using various approaches for combining information on new predictors, termed markers', with parameter information available for other variables from an earlier model, which was estimated from a large data source. We assess the performance of risk prediction models updated based on likelihood ratio (LR) approaches that incorporate dependence between new and old risk factors as well as approaches that assume independence (naive Bayes' methods). We study the impact of estimating the LR by (i) fitting a single model to cases and non-cases when the distribution of the new markers is in the exponential family or (ii) fitting separate models to cases and non-cases. We also evaluate a new constrained maximum likelihood method. We study updating the risk prediction model when the new data arise from a cohort and extend available methods to accommodate updating when the new data source is a case-control study. To create realistic correlations between predictors, we also based simulations on real data on response to antiviral therapy for hepatitis C. From these studies, we recommend the LR method fit using a single model or constrained maximum likelihood. Copyright (c) 2016 John Wiley & Sons, Ltd. C1 [Grill, Sonja; Ankerst, Donna P.] Tech Univ Munich, Dept Life Sci & Math, Munich, Germany. [Ankerst, Donna P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. [Gail, Mitchell H.; Pfeiffer, Ruth M.] NCI, 9609 Med Ctr Dr,Room 7E142, Bethesda, MD 20892 USA. [Chatterjee, Nilanjan] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. RP Pfeiffer, RM (reprint author), NCI, 9609 Med Ctr Dr,Room 7E142, Bethesda, MD 20892 USA. EM pfeiffer@mail.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases; Technical University Munich Women in Science fund FX We thank Tom O'Brien for helpful comments on the VIRAHEP-C data, and for access to the data, and Yi-Hau Chen for access to the code for the CML method. The VIRAHEP-C study was conducted by the VIRAHEP-C investigators and supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The data and samples from the Virahep-C study reported here were supplied by the National Institute of Diabetes and Digestive and Kidney Diseases Central Repositories. This manuscript was not prepared in collaboration with the Virahep-C study group and does not necessarily reflect the opinions or views of the Virahep-C Trial, the National Institute of Diabetes and Digestive and Kidney Diseases Central Repositories, or the National Institute of Diabetes and Digestive and Kidney Diseases. We thank Regina Riedl for access to R code, the reviewers for helpful suggestions and comments, and the Technical University Munich Women in Science fund for sponsoring portions of this research. NR 20 TC 1 Z9 1 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD MAR 30 PY 2017 VL 36 IS 7 BP 1134 EP 1156 DI 10.1002/sim.7190 PG 23 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA EM5YE UT WOS:000395389100006 PM 27943382 ER PT J AU Pinsky, PF Prorok, PC Kramer, BS AF Pinsky, Paul F. Prorok, Philip C. Kramer, Barnett S. TI Prostate Cancer Screening - A Perspective on the Current State of the Evidence SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID SERVICES TASK-FORCE; PSA TESTING RATES; PLCO TRIAL; FOLLOW-UP; AMERICAN-COLLEGE; RECOMMENDATIONS; ERSPC; LUNG C1 [Pinsky, Paul F.; Prorok, Philip C.; Kramer, Barnett S.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Pinsky, PF (reprint author), NCI, 9609 Med Ctr Dr,Rm 5E108, Bethesda, MD 20892 USA. EM pp4f@nih.gov NR 23 TC 0 Z9 0 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 30 PY 2017 VL 376 IS 13 BP 1285 EP 1289 DI 10.1056/NEJMsb1616281 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA EP8KS UT WOS:000397624900016 PM 28355509 ER PT J AU Afshari, NA Igo, RP Morris, NJ Stambolian, D Sharma, S Pulagam, VL Dunn, S Stamler, JF Truitt, BJ Rimmler, J Kuot, A Croasdale, CR Qin, XJ Burdon, KP Riazuddin, SA Mills, R Klebe, S Minear, MA Zhao, JG Balajonda, E Rosenwasser, GO Baratz, KH Mootha, VV Patel, SV Gregory, SG Bailey-Wilson, JE Price, MO Price, FW Craig, JE Fingert, JH Gottsch, JD Aldave, AJ Klintworth, GK Lass, JH Li, YJ Iyengar, SK AF Afshari, Natalie A. Igo, Robert P., Jr. Morris, Nathan J. Stambolian, Dwight Sharma, Shiwani Pulagam, V. Lakshmi Dunn, Steven Stamler, John F. Truitt, Barbara J. Rimmler, Jacqueline Kuot, Abraham Croasdale, Christopher R. Qin, Xuejun Burdon, Kathryn P. Riazuddin, S. Amer Mills, Richard Klebe, Sonja Minear, Mollie A. Zhao, Jiagang Balajonda, Elmer Rosenwasser, George O. Baratz, Keith H. Mootha, V. Vinod Patel, Sanjay V. Gregory, Simon G. Bailey-Wilson, Joan E. Price, Marianne O. Price, Francis W., Jr. Craig, Jamie E. Fingert, John H. Gottsch, John D. Aldave, Anthony J. Klintworth, Gordon K. Lass, Jonathan H. Li, Yi-Ju Iyengar, Sudha K. TI Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy SO NATURE COMMUNICATIONS LA English DT Article ID CTG18.1 TRINUCLEOTIDE REPEAT; UNITED-STATES; MISSENSE MUTATIONS; TCF4 GENE; DISEASE; PROTEIN; POLYMORPHISMS; EXPANSION; METAANALYSIS; VARIANTS AB The structure of the cornea is vital to its transparency, and dystrophies that disrupt corneal organization are highly heritable. To understand the genetic aetiology of Fuchs endothelial corneal dystrophy (FECD), the most prevalent corneal disorder requiring transplantation, we conducted a genome-wide association study (GWAS) on 1,404 FECD cases and 2,564 controls of European ancestry, followed by replication and meta-analysis, for a total of 2,075 cases and 3,342 controls. We identify three novel loci meeting genome-wide significance (P<5 x 10(-8)): KANK4 rs79742895, LAMC1 rs3768617 and LINC00970/ATP1B1 rs1200114. We also observe an overwhelming effect of the established TCF4 locus. Interestingly, we detect differential sex-specific association at LAMC1, with greater risk in women, and TCF4, with greater risk in men. Combining GWAS results with biological evidence we expand the knowledge of common FECD loci from one to four, and provide a deeper understanding of the underlying pathogenic basis of FECD. C1 [Afshari, Natalie A.; Zhao, Jiagang] Univ Calif San Diego, Shiley Eye Inst, La Jolla, CA 92093 USA. [Igo, Robert P., Jr.; Morris, Nathan J.; Pulagam, V. Lakshmi; Truitt, Barbara J.; Lass, Jonathan H.; Iyengar, Sudha K.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Stambolian, Dwight] Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Sharma, Shiwani; Kuot, Abraham; Burdon, Kathryn P.; Mills, Richard; Klebe, Sonja; Craig, Jamie E.] Flinders Univ S Australia, Flinders Med Ctr, Dept Ophthalmol, Adelaide, SA 5042, Australia. [Dunn, Steven] Michigan Cornea Consultants PC, Southfield, MI 48034 USA. [Stamler, John F.; Fingert, John H.] Univ Iowa, Coll Med, Dept Ophthalmol, Iowa City, IA 52242 USA. [Rimmler, Jacqueline; Qin, Xuejun; Minear, Mollie A.; Gregory, Simon G.; Li, Yi-Ju] Duke Univ, Med Ctr, Duke Mol Physiol Inst, Durham, NC 27701 USA. [Croasdale, Christopher R.] Davis Duehr Dean Clin, Madison, WI 53715 USA. [Burdon, Kathryn P.] Univ Tasmania, Menzies Inst Med Res, Hobart, Tas 7000, Australia. [Riazuddin, S. Amer; Gottsch, John D.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21287 USA. [Klebe, Sonja] Flinders Univ S Australia, Dept Pathol, Flinders Med Ctr, Adelaide, SA 5042, Australia. [Balajonda, Elmer; Klintworth, Gordon K.] Duke Univ, Med Ctr, Duke Univ Eye Ctr, Durham, NC 27710 USA. [Rosenwasser, George O.] Cent Penn Eye Inst, Hershey, PA 17033 USA. [Baratz, Keith H.; Patel, Sanjay V.] Mayo Clin, Dept Ophthalmol, Rochester, MN 55905 USA. [Mootha, V. Vinod] Univ Texas Southwestern Med Ctr Dallas, Dept Ophthalmol, Dallas, TX 75235 USA. [Bailey-Wilson, Joan E.] NHGRI, Computat & Stat Genom Branch, NIH, Baltimore, MD 21224 USA. [Bailey-Wilson, Joan E.] Johns Hopkins Univ, Baltimore, MD 21224 USA. [Price, Marianne O.; Price, Francis W., Jr.] Price Vis Grp, Indianapolis, IN 46260 USA. [Aldave, Anthony J.] Univ Calif Los Angeles, Stein Eye Inst, Los Angeles, CA 90095 USA. [Klintworth, Gordon K.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Lass, Jonathan H.; Iyengar, Sudha K.] Case Western Reserve Univ, Dept Ophthalmol & Visual Sci, Cleveland, OH 44106 USA. [Lass, Jonathan H.; Iyengar, Sudha K.] Univ Hosp Eye Inst, Cleveland, OH 44106 USA. [Li, Yi-Ju] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC 27710 USA. RP Lass, JH; Iyengar, SK (reprint author), Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA.; Li, YJ (reprint author), Duke Univ, Med Ctr, Duke Mol Physiol Inst, Durham, NC 27701 USA.; Lass, JH; Iyengar, SK (reprint author), Case Western Reserve Univ, Dept Ophthalmol & Visual Sci, Cleveland, OH 44106 USA.; Lass, JH; Iyengar, SK (reprint author), Univ Hosp Eye Inst, Cleveland, OH 44106 USA.; Li, YJ (reprint author), Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC 27710 USA. EM Jonathan.Lass@UHhospitals.org; yiju.li@duke.edu; ski@case.edu FU National Eye Institute [R01 EY023196, R01 EY016482, R01 EY016514, R01 EY016835, R21 EY015145, P30 EY11373]; Research to Prevent Blindness; Beulah and Florence Usher Endowment; NHMRC (Australia) Grant [1031362]; Ophthalmic Research Institute of Australia; Flinders Medical Centre Foundation; Ohio Lions Eye Research Foundation; National Human Genome Research Institute, National Institutes of Health (NIH); Centre for Inherited Disease Research [1X01HG006619]; Clinical and Translational Science Collaborative of Cleveland from the National Centre for Advancing Translational Sciences (NCATS) component of the NIH [4UL1TR000439]; NIH Roadmap for Medical Research FX We would like to acknowledge the strong scientific know-how and mentorship provided by Dr Gordon Klintworth, who passed away during the writing of this paper. We are incredibly grateful for the wisdom he imparted. We are also grateful to the patients who provided us with information and samples, and made this study possible. Finally, we would like to show appreciation to the many funding agencies who supported this research, including National Eye Institute Grants R01 EY023196, R01 EY016482, R01 EY016514, R01 EY016835, R21 EY015145 and P30 EY11373; Research to Prevent Blindness; the Beulah and Florence Usher Endowment; NHMRC (Australia) Grant No 1031362; Ophthalmic Research Institute of Australia; Flinders Medical Centre Foundation; the Ohio Lions Eye Research Foundation; and the intramural research program of the National Human Genome Research Institute, National Institutes of Health (NIH). Genotyping was performed by the Centre for Inherited Disease Research under Grant 1X01HG006619. This publication was made possible by the Clinical and Translational Science Collaborative of Cleveland, 4UL1TR000439, from the National Centre for Advancing Translational Sciences (NCATS) component of the NIH and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. This article was prepared while M.A.M. was employed at Duke University; she is currently serving as an American Association for the Advancement of Science (AAAS) Science & Technology Policy Fellow at the NIH. She worked on this article in her personal capacity, and the opinions expressed in this article are her own and do not necessarily reflect the views of the NIH, the Department of Health and Human Services or the United States government. NR 58 TC 0 Z9 0 U1 0 U2 0 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 30 PY 2017 VL 8 AR 14898 DI 10.1038/ncomms14898 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EQ0ZP UT WOS:000397799400001 PM 28358029 ER PT J AU Ksendzovsky, A Pomeraniec, IJ Zaghloul, KA Provencio, JJ Provencio, I AF Ksendzovsky, Alexander Pomeraniec, I. Jonathan Zaghloul, Kareem A. Provencio, J. Javier Provencio, Ignacio TI Clinical implications of the melanopsin-based non-image-forming visual system SO NEUROLOGY LA English DT Article ID RETINAL GANGLION-CELLS; PUPILLARY LIGHT REFLEX; HAMSTER SUPRACHIASMATIC NUCLEUS; CIRCADIAN-RHYTHM; BLIND MICE; ACTION SPECTRUM; NON-CONE; NON-ROD; RESPONSES; PROJECTIONS AB Since the discovery of the non-image-forming visual system, tremendous research efforts have been dedicated to understanding its mechanisms and functional roles. Original functions associated with the melanopsin system include the photoentrainment of circadian sleep-wake cycles and the pupillary light reflex. Recent findings, however, suggest a much broader involvement of this system in an array of physiologic responses to light. This newfound insight into the underlying function of the non-image-forming system has revealed the many connections to human pathology and attendant disease states, including seasonal affective disorder, migraine, glaucoma, inherited mitochondrial optic neuropathy, and sleep dysregulation of aging. In this review, the authors discuss in detail the clinical implications of the melanopsin system. C1 [Ksendzovsky, Alexander; Pomeraniec, I. Jonathan] Univ Virginia, Hlth Sci Ctr, Dept Neurol Surg, Charlottesville, VA 22908 USA. [Provencio, J. Javier] Univ Virginia, Hlth Sci Ctr, Dept Neurol & Neurosci, Charlottesville, VA USA. [Ksendzovsky, Alexander; Zaghloul, Kareem A.] NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Ksendzovsky, Alexander] Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22903 USA. [Provencio, Ignacio] Univ Virginia, Dept Biol, Charlottesville, VA USA. RP Ksendzovsky, A (reprint author), Univ Virginia, Hlth Sci Ctr, Dept Neurol Surg, Charlottesville, VA 22908 USA.; Ksendzovsky, A (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA.; Ksendzovsky, A (reprint author), Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22903 USA. EM alex@virginia.edu NR 60 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAR 28 PY 2017 VL 88 IS 13 BP 1282 EP 1290 DI 10.1212/WNL.0000000000003761 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA EP4XQ UT WOS:000397383600017 PM 28251921 ER PT J AU Huang, KL Li, SQ Mertins, P Cao, S Gunawardena, HP Ruggles, KV Mani, DR Clauser, KR Tanioka, M Usary, J Kavuri, SM Xie, L Yoon, C Qiao, JW Wrobel, J Wyczalkowski, MA Erdmann-Gilmore, P Snider, JE Hoog, J Singh, P Niu, BF Guo, ZF Sun, SQC Sanati, S Kawaler, E Wang, XY Scott, A Ye, K McLellan, MD Wendl, MC Malovannaya, A Held, JM Gillette, MA Fenyo, D Kinsinger, CR Mesri, M Rodriguez, H Davies, SR Perou, CM Ma, C Townsend, RR Chen, X Carr, SA Ellis, MJ Ding, L AF Huang, Kuan-lin Li, Shunqiang Mertins, Philipp Cao, Song Gunawardena, Harsha P. Ruggles, Kelly V. Mani, D. R. Clauser, Karl R. Tanioka, Maki Usary, Jerry Kavuri, Shyam M. Xie, Ling Yoon, Christopher Qiao, Jana W. Wrobel, John Wyczalkowski, Matthew A. Erdmann-Gilmore, Petra Snider, Jacqueline E. Hoog, Jeremy Singh, Purba Niu, Beifung Guo, Zhanfang Sun, Sam Qiancheng Sanati, Souzan Kawaler, Emily Wang, Xuya Scott, Adam Ye, Kai McLellan, Michael D. Wendl, Michael C. Malovannaya, Anna Held, Jason M. Gillette, Michael A. Fenyo, David Kinsinger, Christopher R. Mesri, Mehdi Rodriguez, Henry Davies, Sherri R. Perou, Charles M. Ma, Cynthia Townsend, R. Reid Chen, Xian Carr, Steven A. Ellis, Matthew J. Ding, Li TI Proteogenomic integration reveals therapeutic targets in breast cancer xenografts SO NATURE COMMUNICATIONS LA English DT Article ID TUMOR XENOGRAFTS; INHIBITOR; QUANTIFICATION; MUTATIONS; DISCOVERY; PROTEOMICS; MEDICINE; GENOMICS; PATHWAY; MODELS AB Recent advances in mass spectrometry (MS) have enabled extensive analysis of cancer proteomes. Here, we employed quantitative proteomics to profile protein expression across 24 breast cancer patient-derived xenograft (PDX) models. Integrated proteogenomic analysis shows positive correlation between expression measurements from transcriptomic and proteomic analyses; further, gene expression-based intrinsic subtypes are largely re-capitulated using non-stromal protein markers. Proteogenomic analysis also validates a number of predicted genomic targets in multiple receptor tyrosine kinases. However, several protein/phosphoprotein events such as overexpression of AKT proteins and ARAF, BRAF, HSP90AB1 phosphosites are not readily explainable by genomic analysis, suggesting that druggable translational and/or post-translational regulatory events may be uniquely diagnosed by MS. Drug treatment experiments targeting HER2 and components of the PI3K pathway supported proteogenomic response predictions in seven xenograft models. Our study demonstrates that MS-based proteomics can identify therapeutic targets and highlights the potential of PDX drug response evaluation to annotate MS-based pathway activities. C1 [Huang, Kuan-lin; Li, Shunqiang; Yoon, Christopher; Snider, Jacqueline E.; Guo, Zhanfang; Sun, Sam Qiancheng; Malovannaya, Anna; Ding, Li] Washington Univ, Dept Med, St Louis, MO 63108 USA. [Huang, Kuan-lin; Cao, Song; Yoon, Christopher; Wyczalkowski, Matthew A.; Niu, Beifung; Sun, Sam Qiancheng; Scott, Adam; McLellan, Michael D.; Wendl, Michael C.; Ding, Li] Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA. [Mertins, Philipp; Clauser, Karl R.; Qiao, Jana W.; Gillette, Michael A.; Carr, Steven A.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Gunawardena, Harsha P.; Ruggles, Kelly V.; Chen, Xian] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. [Ruggles, Kelly V.; Kawaler, Emily; Wang, Xuya; Fenyo, David] NYU, Sch Med, 5Center Hlth Informat & Bioinformat, New York, NY 10016 USA. [Tanioka, Maki; Usary, Jerry] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Kavuri, Shyam M.; Singh, Purba; Malovannaya, Anna; Ellis, Matthew J.] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA. [Sanati, Souzan] Washington Univ, Dept Pathol & Immunol, St Louis, MO 63108 USA. [Ye, Kai; Wendl, Michael C.; Ding, Li] Washington Univ, Dept Genet, St Louis, MO 63108 USA. [Wendl, Michael C.] Washington Univ, Dept Math, St Louis, MO 63108 USA. [Malovannaya, Anna] Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Held, Jason M.; Ma, Cynthia; Townsend, R. Reid; Ding, Li] Washington Univ, Siteman Canc Ctr, St Louis, MO 63108 USA. [Held, Jason M.] Washington Univ, Dept Anesthesiol, St Louis, MO 63108 USA. [Kinsinger, Christopher R.; Mesri, Mehdi; Rodriguez, Henry] NCI, NIH, Bethesda, MD 20892 USA. RP Ding, L (reprint author), Washington Univ, Dept Med, St Louis, MO 63108 USA.; Ding, L (reprint author), Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA.; Carr, SA (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.; Ellis, MJ (reprint author), Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA.; Ding, L (reprint author), Washington Univ, Dept Genet, St Louis, MO 63108 USA.; Ding, L (reprint author), Washington Univ, Siteman Canc Ctr, St Louis, MO 63108 USA. EM scarr@broad.mit.edu; matthew.ellis@bcm.edu; lding@genome.wustl.edu OI Fenyo, David/0000-0001-5049-3825; Ruggles, Kelly/0000-0002-0152-0863 FU National Cancer Institute [U24CA160035]; Siteman Cancer Center grant (NCI) [P30 CA091842, U24CA160034, R01CA180006]; National Human Genome Research Institute [U01HG006517]; NCI Breast SPORE program [P50-CA58223-09A1, R01CA195754-01]; Breast Cancer Research Foundation [CCR16380599]; Takeda Pharmaceutical Company Limited; Brown Shoe's foundation; Ministry of Education in Taiwan; Lucille P. Markey Special Emphasis Pathway in Human Pathobiology FX This work was supported by the National Cancer Institute grants U24CA160035 to Reid Townsend/Matthew Ellis/Xian Chen, Siteman Cancer Center grant (NCI P30 CA091842) to Reid Townsend, U24CA160034 to Steven Carr, R01CA180006 to L.D., National Human Genome Research Institute grant U01HG006517 to L.D., the NCI Breast SPORE program (P50-CA58223-09A1), R01CA195754-01, by the Breast Cancer Research Foundation to Charles Perou and Komen CCR award to S.M.K. (CCR16380599). The functional validation experiments were funded by the Takeda Pharmaceutical Company Limited to S.L. The establishment of PDX was funded by the Brown Shoe's foundation to S.L. The authors acknowledge Josh McMichael for the original rendition of Figure 1a and Dr Feng Chen and members of the CPTAC Research Network for helpful discussions. K.-l.H. received fellowship funding in part from the Ministry of Education in Taiwan and the Lucille P. Markey Special Emphasis Pathway in Human Pathobiology. NR 51 TC 0 Z9 0 U1 4 U2 4 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 28 PY 2017 VL 8 AR 14864 DI 10.1038/ncomms14864 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EP7FX UT WOS:000397544300001 PM 28348404 ER PT J AU Nadkarni, GN Galarneau, G Ellis, SB Nadukuru, R Zhang, JL Scott, SA Schurmann, C Li, RL Rasmussen-Torvik, LJ Kho, AN Hayes, MG Pacheco, JA Manolio, TA Chisholm, RL Roden, DM Denny, JC Kenny, EE Bottinger, EP AF Nadkarni, Girish N. Galarneau, Genevieve Ellis, Stephen B. Nadukuru, Rajiv Zhang, Jinglan Scott, Stuart A. Schurmann, Claudia Li, Rongling Rasmussen-Torvik, Laura J. Kho, Abel N. Hayes, M. Geoffrey Pacheco, Jennifer A. Manolio, Teri A. Chisholm, Rex L. Roden, Dan M. Denny, Joshua C. Kenny, Eimear E. Bottinger, Erwin P. TI Apolipoprotein L1 Variants and Blood Pressure Traits in African Americans SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE allele; APOL1; estimated glomerular filtration rate; genetic association studies; kidney disease ID APOL1 GENETIC-VARIANTS; CHRONIC KIDNEY-DISEASE; STAGE RENAL-DISEASE; CARDIOVASCULAR-DISEASE; RISK VARIANTS; FUNCTION DECLINE; HYPERTENSION; ASSOCIATE; NEPHROPATHY; DISPARITIES AB BACKGROUND African Americans (AA) are disproportionately affected by hypertension-related health disparities. Apolipoprotein L1 (APOL1) risk variants are associated with kidney disease in hypertensive AAs. OBJECTIVES This study assessed the APOL1 risk alleles' association with blood pressure traits in AAs. METHODS The discovery cohort included 5,204 AA participants from Mount Sinai's BioMe biobank. Replication cohorts included additional BioMe (n = 1,623), Vanderbilt BioVU (n = 1,809), and Northwestern NUgene (n = 567) AA biobank participants. Single nucleotide polymorphisms determining APOL1 G1 and G2 risk alleles were genotyped in BioMe and imputed in BioVU/NUgene participants. APOL1 risk alleles' association with blood pressure-related traits was tested in the discovery cohort, a meta-analysis of replication cohorts, and a combined meta-analysis under recessive and additive models after adjusting for age, sex, body mass index, and estimated glomerular filtration rate. RESULTS There were 14% to 16% of APOL1 variant allele homozygotes (2 copies of G1/G2) across cohorts. APOL1 risk alleles were associated under an additive model with systolic blood pressure (SBP) and age at diagnosis of hypertension, which was 2 to 5 years younger in the APOL1 variant allele homozygotes (Cox proportional hazards analysis, p value for combined meta-analysis [p(com)] = 1.9 x 10(-5)). APOL1 risk alleles were associated with overall SBP (p(com) = 7.0 x 10(-8)) and diastolic blood pressure (p(com) = 2.8 x 10(-4)). After adjustment for all covariates, those in the 20- to 29-year age range showed an increase in SBP of 0.94 +/- 0.44 mm Hg (p(com) = 0.01) per risk variant copy. APOL1-associated estimated glomerular filtration rate decline was observed starting a decade later in life in the 30- to 39-year age range. CONCLUSIONS APOL1 risk alleles are associated with higher SBP and earlier hypertension diagnoses in young AAs; this relationship appears to follow an additive model. (C) 2017 by the American College of Cardiology Foundation. Published by Elsevier. All rights reserved. C1 [Nadkarni, Girish N.; Galarneau, Genevieve; Ellis, Stephen B.; Nadukuru, Rajiv; Zhang, Jinglan; Scott, Stuart A.; Schurmann, Claudia; Kenny, Eimear E.; Bottinger, Erwin P.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, One Gustave L Levy Pl,Box 1003, New York, NY 10029 USA. [Li, Rongling; Manolio, Teri A.] NHGRI, Div Genom Med, Bethesda, MD 20892 USA. [Rasmussen-Torvik, Laura J.; Kho, Abel N.; Pacheco, Jennifer A.; Chisholm, Rex L.] Northwestern Univ, Feinberg Sch Med, Ctr Genet Med, Chicago, IL 60611 USA. [Hayes, M. Geoffrey] Northwestern Univ, Feinberg Sch Med, Div Endocrinol Metab & Mol Med, Dept Med, Chicago, IL 60611 USA. [Roden, Dan M.; Denny, Joshua C.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Roden, Dan M.; Denny, Joshua C.] Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Nashville, TN USA. RP Bottinger, EP (reprint author), Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, One Gustave L Levy Pl,Box 1003, New York, NY 10029 USA. EM erwin.bottinger@mssm.edu FU National Human Genome Research Institute [U01HG006389, U01HG006382, U01HG006375, U01HG006379, U01HG006380, U01HG006388, U01HG006378, U01HG006385, U01HG004438, U01HG004424]; National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [K23DK107908]; Canadian Institute of Health Research [MFE-140913] FX The BioMe health care delivery cohort at Mount Sinai was established and maintained with a generous gift from the Andrea and Charles Bronfman Philanthropies. The eMERGE Network was initiated and funded by National Human Genome Research Institute through the following grants: U01HG006389 (Essentia Institute of Rural Health, Marshfield Clinic Research Foundation, and Pennsylvania State University), U01HG006382 (Geisinger Clinic), U01HG006375 (Group Health Cooperative/University of Washington), U01HG006379 (Mayo Clinic), U01HG006380 (Icahn School of Medicine at Mount Sinai), U01HG006388 (Northwestern University), U01HG006378 (Vanderbilt University Medical Center), and U01HG006385 (Vanderbilt University Medical Center serving as the Coordinating Center); U01HG004438 (CIDR) and U01HG004424 (the Broad Institute) served as Genotyping Centers. Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Number K23DK107908 (to Dr. Nadkarni). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr. Galarneau is a recipient of a Canadian Institute of Health Research postdoctoral fellowship award (MFE-140913). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Nadkarni and Galarneau contributed equally to this work. Thomas D. Giles, MD, served as the Guest Editor for this article. NR 38 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 28 PY 2017 VL 69 IS 12 BP 1564 EP 1574 DI 10.1016/j.jacc.2017.01.040 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EO5JW UT WOS:000396730200007 PM 28335839 ER PT J AU Winckelmann, A Barton, K Hiener, B Schlub, TE Shao, W Rasmussen, TA Ostergaard, L Sogaard, OS Tolstrup, M Palmer, S AF Winckelmann, Anni Barton, Kirston Hiener, Bonnie Schlub, Timothy E. Shao, Wei Rasmussen, Thomas A. Ostergaard, Lars Sogaard, Ole S. Tolstrup, Martin Palmer, Sarah TI Romidepsin-induced HIV-1 viremia during effective antiretroviral therapy contains identical viral sequences with few deleterious mutations SO AIDS LA English DT Article DE histone deacetylase inhibitor; HIV latency; HIV persistence; HIV reservoirs; latency-reversing agent; romidepsin; single-genome sequencing ID CD4(+) T-CELLS; IN-VIVO; VORINOSTAT AB Objective: To investigate the origin of the HIV-1 viremia induced by the latencyreversing agent romidepsin. Design: Six individuals on suppressive antiretroviral therapy received romidepsin administered intravenously once weekly for 3 consecutive weeks. CD4(+) T cells were obtained at baseline, following the second and third romidepsin infusion, and 10 weeks after the final romidepsin treatment. Plasma samples were collected 24 and 72 h after romidepsin infusions. Methods: Single-genome sequencing of the env and p24-RT region was used to genetically characterize the virus from proviral DNA, the transcribed cell-associated RNA and the plasma RNA pool. Results: In three of six participants with available plasma samples we identified plasma HIV-1 RNA sequences that were identical to DNA and/or cell-associated RNA sequences from peripheral blood CD4(+) T cells. In two participants, plasma RNA sequences contained expansions of identical sequences, corresponding to 62 and 100% of the total sequences, respectively. Plasma HIV-1 RNA had very low amounts of defective viruses compared to cell-associated RNA (odds ratio 20.85, P<0.001) and to DNA ( odds ratio 7.07, P = 0.011) during romidepsin therapy. Conclusions: Romidepsin induced transcription from proviruses in peripheral blood cells, which contributed to viremia in patients on suppressive therapy. The intermingling of these cell-associated HIV-1 RNA with DNA sequences indicates transcription from a diverse range of proviruses, but the expansions of identical viral plasma sequences with few defects indicate that the romidepsin-induced viremia arises from intact proviruses with highly similar or identical genetic backgrounds. Copyright (C) 2017 The Author(s). Published by Wolters Kluwer Health, Inc. C1 [Winckelmann, Anni; Barton, Kirston; Hiener, Bonnie; Palmer, Sarah] Univ Sydney, Westmead Inst Med Res, Ctr Virus Res, Westmead, NSW, Australia. [Winckelmann, Anni; Rasmussen, Thomas A.; Ostergaard, Lars; Sogaard, Ole S.; Tolstrup, Martin] Aarhus Univ Hosp, Dept Infect Dis, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark. [Schlub, Timothy E.] Univ Sydney, Sydney Sch Publ Hlth, Sydney Med Sch, Camperdown, NSW, Australia. [Shao, Wei] Leidos Biomed Res Inc, Adv Biomed Comp Ctr, Frederick Natl Lab Canc Res, Frederick, MD USA. [Shao, Wei] NCI, HIV Dynam & Replicat Program, Frederick, MD 21701 USA. [Ostergaard, Lars; Sogaard, Ole S.; Tolstrup, Martin] Aarhus Univ, Inst Clin Med, Aarhus, Denmark. RP Winckelmann, A (reprint author), Aarhus Univ Hosp, Dept Infect Dis, Palle Juul Jensens Blvd 99, DK-8200 Aarhus N, Denmark. EM anniw@clin.au.dk FU Delaney AIDS Research Enterprise (DARE) [1U19AI096109]; National Health and Medical Research Council (NHMRC) of Australia [APP1061681]; Danish Council for Strategic Research [0603-00521B] FX This work was supported by the Delaney AIDS Research Enterprise (DARE) to Find a Cure 1U19AI096109 and the National Health and Medical Research Council (NHMRC) of Australia (grant APP1061681). The clinical study from which these samples were derived was sponsored by Bionor Pharma.; T.A.R., L.O., M.T. and O.S.S. were supported by a grant from the Danish Council for Strategic Research (grant # 0603-00521B). The funders had no role in data collection and analysis, decision to publish, or preparation of the manuscript. Bionor Pharma contributed to the design of the clinical trial. NR 18 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 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD MAR 27 PY 2017 VL 31 IS 6 BP 771 EP 779 DI 10.1097/QAD.0000000000001400 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EN4UW UT WOS:000396003400005 PM 28272134 ER PT J AU Seremba, E Ssempijja, V Kalibbala, S Gray, RH Wawer, MJ Nalugoda, F Casper, C Phipps, W Ocama, P Serwadda, D Thomas, DL Reynolds, SJ AF Seremba, Emmanuel Ssempijja, Victor Kalibbala, Sarah Gray, Ronald H. Wawer, Maria J. Nalugoda, Fred Casper, Corey Phipps, Warren Ocama, Ponsiano Serwadda, David Thomas, David L. Reynolds, Steven J. TI Hepatitis B incidence and prevention with antiretroviral therapy among HIV-positive individuals in Uganda SO AIDS LA English DT Article DE hepatitis B incidence; HIV-positive adults; Rakai; Uganda ID VIRUS-INFECTION; COHORT; PREVALENCE; MORTALITY; BEHAVIOR; CHILDREN AB Objective: Antiretroviral therapy (ART) may interfere with replication of hepatitis B virus (HBV), raising the hypothesis that HBV infection might be prevented by ART. We investigated the incidence and risk factors associated with HBV among HIV-infected adults in Rakai, Uganda. Methods: We screened stored sera from 944 HIV-infected adults enrolled in the Rakai Community Cohort Study between September 2003 and March 2015 for evidence of HBV exposure. Serum from participants who tested anti-hepatitis B core-negative (497) at baseline were tested over 3-7 consecutive survey rounds for incident HBV. Poisson incidence methods were used to estimate incidence of HBV with 95% confidence intervals (CIs), whereas Cox proportional regression methods were used to estimate hazard ratios (HRs). Results: Thirty-nine HBV infections occurred over 3342 person-years, incidence 1.17/ 100 person-years. HBVincidence was significantly lower with ARTuse: 0.49/100 personyears with ART and 2.3/100 person-years without ART [adjusted HR (aHR) 0.25, 95% CI 0.1-0.5, P<0.001], and with lamivudine (3TC) use: 0.58/100 person-years) with 3TC and 2.25/100 person-years without 3TC (aHR 0.32, 95% CI 0.1-0.7, P = < 0.007). No new HBV infections occurred among those on tenofovir-based ART. HBV incidence also decreased with HIV RNA suppression: 0.6/100 person-years with 400 copies/ml or less and 4.0/100 person-years with more than 400 copies/ml (aHR, 6.4, 95% CI 2.2-19.0, P< 0.001); and with age: 15-29 years versus 40-50 years (aHR 3.2, 95% CI 1.2-9.0); 30-39 years versus 40-50 years (aHR 2.1, 95% CI 0.9-5.3). Conclusion: HBV continues to be acquired in adulthood among HIV-positive Ugandans and HBV incidence is dramatically reduced with HBV-active ART. In addition to widespread vaccination, initiation of ART may prevent HBV acquisition among HIV-positive adults in sub-Saharan Africa. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved. C1 [Seremba, Emmanuel; Ocama, Ponsiano] Makerere Univ, Coll Hlth Sci, Sch Med, Kampala, Uganda. [Ssempijja, Victor] Leidos Biomed Res Inc, Clin Res Directorate, Clin Monitoring Res Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Kalibbala, Sarah; Nalugoda, Fred; Serwadda, David] Rakai Hlth Sci Program, Kalisizo, Uganda. [Gray, Ronald H.; Wawer, Maria J.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Casper, Corey; Phipps, Warren] Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Casper, Corey; Phipps, Warren] Univ Washington, Seattle, WA USA. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Coll Hlth Sci, Kampala, Uganda. [Thomas, David L.; Reynolds, Steven J.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Reynolds, Steven J.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Seremba, E (reprint author), Makerere Univ, Coll Hlth Sci, Kampala, Uganda. EM eseremba@gmail.com FU US National Institute of Health [D43, D43 CA153720-01]; NIH - Fogarty International Center through the Fogarty Global Health Fellowship [R25TW009345]; University of Washington/Fred Hutch Center for AIDS Research (NIH) [P30 AI027757]; Division of Intramural Research; National Institute of Allergy and Infectious Diseases (NIAID) [AI001040]; National Institutes of Health [D43TW010132]; U54 consortium [U54CA190165-02, 2002389678]; NIH from NIAID [UO1 AI11171-01-02, U01AI51171, U01AI075115-01A1, R01 AI47608, R37DA013806, R01 AI114438, R01 AI110324, U01 AI100031, D43 CA 153720]; National Institute of Child Health and Development (NICHD) [HD070769, HD 050180]; Bill and Melinda Gates Foundation [22006]; World Bank FX This study was funded in part by a D43 Grant on HIV-associated malignancies sponsored by the US National Institute of Health (D43 CA153720-01), NIH research training grant R25TW009345 funded by the Fogarty International Center through the Fogarty Global Health Fellowship, and the University of Washington/Fred Hutch Center for AIDS Research (NIH award P30 AI027757). Funding was also obtained from the Division of Intramural Research, the National Institute of Allergy and Infectious Diseases (NIAID) AI001040, National Institutes of Health, D43TW010132, and through the U54 consortium (Federal award number: U54CA190165-02, Sub award No. 2002389678). The RCCS was supported by the following NIH: grants UO1 AI11171-01-02, U01AI51171, U01AI075115-01A1, R01 AI47608, R37DA013806, R01 AI114438, R01 AI110324, U01 AI100031 and D43 CA 153720 from NIAID and grants HD070769 and HD 050180 from the National Institute of Child Health and Development (NICHD), Grant 22006 from The Bill and Melinda Gates Foundation and support from The World Bank. NR 16 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD MAR 27 PY 2017 VL 31 IS 6 BP 781 EP 786 DI 10.1097/QAD.0000000000001399 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EN4UW UT WOS:000396003400006 PM 28099188 ER PT J AU Patel, EU Gianella, S Newell, K Tobian, AAR Kirkpatrick, AR Nalugoda, F Grabowski, MK Gray, RH Serwadda, D Quinn, TC Redd, AD Reynolds, SJ AF Patel, Eshan U. Gianella, Sara Newell, Kevin Tobian, Aaron A. R. Kirkpatrick, Allison R. Nalugoda, Fredrick Grabowski, Mary K. Gray, Ronald H. Serwadda, David Quinn, Thomas C. Redd, Andrew D. Reynolds, Steven J. TI Elevated cytomegalovirus IgG antibody levels are associated with HIV-1 disease progression and immune activation SO AIDS LA English DT Article ID IMMUNOGLOBULIN-G ANTIBODY; ACTIVE ANTIRETROVIRAL THERAPY; PROPENSITY SCORE METHODS; T-CELL DIFFERENTIATION; HOMOSEXUAL-MEN; INFECTED INDIVIDUALS; MONOCYTE ACTIVATION; HUMAN-HERPESVIRUS; GAMBIAN INFANTS; DAILY ACYCLOVIR AB Objective: To assess the association between cytomegalovirus (CMV) IgG antibody levels, HIV disease progression, and immune activation markers. Design: A prospective cohort study was conducted among women enrolled in a trial that was designed to determine the effect of acyclovir on HIV disease progression in Rakai, Uganda. Methods: The primary endpoints were progression to a CD4(+) T-cell count less than 250 cells/mu l, nontraumatic death, or initiation of antiretroviral therapy (ART). CD4(+) T-cell counts, HIV viral load, C-reactive protein (CRP), and soluble CD14 levels were assessed biannually for 24 months. CMV IgG antibodies were measured at baseline among all women and annually among a subset of women who initiated ART. Results: There were 300 HIV/CMV-coinfected participants who contributed a total of 426.4 person-yearswith a median follow-up time of 1.81 years. Comparedwith the lowest CMVIgGtertile groupat baseline, the highestCMVIgGtertilegroupwas associatedwithan increased risk to reach a primary endpoint independent of acyclovir use, age, CD4(+) T-cell count, andHIV viral load at baseline [adjusted hazard ratio = 1.59; (95% CI = 1.05-2.39); P-0.027]. Among pre-ART visits (n-1200), women in the highest baseline CMV IgG tertilehad increasing annual rates of solubleCD14andCRPlevels, whichwas not observed for the lowCMVIgGtertile group. Compared with pre-ART visits, CMVIgGantibody levels were higher post-ART initiation, and concurrent levels remained associated with soluble CD14 and CRP during suppressive ART (n = 88 person-visits). Conclusion: The magnitude of the immune response to CMV was associated with HIV disease progression and immune activation in sub-Saharan Africa. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved. C1 [Patel, Eshan U.; Kirkpatrick, Allison R.; Quinn, Thomas C.; Redd, Andrew D.; Reynolds, Steven J.] NIAID, Div Intramural Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Gianella, Sara] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Newell, Kevin] Res Data & Commun Technol Inc, Garrett Pk, MD USA. [Tobian, Aaron A. R.] Johns Hopkins Sch Med, Dept Pathol, Baltimore, MD USA. [Tobian, Aaron A. R.; Grabowski, Mary K.; Gray, Ronald H.; Quinn, Thomas C.; Reynolds, Steven J.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Tobian, Aaron A. R.; Nalugoda, Fredrick; Grabowski, Mary K.; Gray, Ronald H.; Serwadda, David; Reynolds, Steven J.] Rakai Hlth Sci Program, Kalisizo, Uganda. [Serwadda, David] Makerere Univ, Inst Publ Hlth, Kampala, Uganda. [Quinn, Thomas C.] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA. RP Reynolds, SJ (reprint author), US Embassy, NIAID NIH ICER Program, POB 7007, Kampala, Uganda. EM sjreynolds@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health [AI001040]; National Institutes of Health [AI036214] FX The work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (AI001040), and extramural funding from the National Institutes of Health (AI036214). NR 48 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 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD MAR 27 PY 2017 VL 31 IS 6 BP 807 EP 813 DI 10.1097/QAD.0000000000001412 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EN4UW UT WOS:000396003400009 PM 28121712 ER PT J AU Goedert, JJ AF Goedert, James J. TI The microbiota and HIV: shedding light on dark matters SO AIDS LA English DT Editorial Material DE AIDS; feces; HIV; immune reconstitution; microbiome ID GUT MICROBIOTA; INFECTION; METABOLISM C1 [Goedert, James J.] Natl Inst Hlth, Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. RP Goedert, JJ (reprint author), Natl Inst Hlth, Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. EM goedertj@mail.nih.gov FU Intramural NIH HHS [Z01 CP010150-09] NR 22 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 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD MAR 27 PY 2017 VL 31 IS 6 BP 863 EP 865 DI 10.1097/QAD.0000000000001410 PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EN4UW UT WOS:000396003400015 PM 28272137 ER PT J AU Winkler, CW Myers, LM Woods, TA Carmody, AB Taylor, KG Peterson, KE AF Winkler, Clayton W. Myers, Lara M. Woods, Tyson A. Carmody, Aaron B. Taylor, Katherine G. Peterson, Karin E. TI Lymphocytes have a role in protection, but not in pathogenesis, during La Crosse Virus infection in mice SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Lymphocytes; La Crosse Virus; Brain; Central nervous system; Encephalitis ID CENTRAL-NERVOUS-SYSTEM; CD4(+) T-CELLS; ENCEPHALITIS; RESPONSES; BRAIN; INTERFERON; CLEARANCE; IMMUNOPATHOLOGY; GLYCOPROTEINS; NEUROINVASION AB Background: La Crosse Virus (LACV) is a primary cause of pediatric viral encephalitis in the USA and can result in severe clinical outcomes. Almost all cases of LACV encephalitis occur in children 16 years or younger, indicating an age-related susceptibility. This susceptibility is recapitulated in a mouse model where weanling ( 3 weeks old or younger) mice are susceptible to LACV- induced disease, and adults ( greater than 6 weeks) are resistant. Disease in mice and humans is associated with infiltrating leukocytes to the CNS. However, what cell types are infiltrating into the brain during virus infection and how these cells influence pathogenesis remain unknown. Methods: In the current study, we analyzed lymphocytes recruited to the CNS during LACV- infection in clinical mice, using flow cytometry. We analyzed the contribution of these lymphocytes to LACV pathogenesis in weanling mice using knockout mice or antibody depletion. Additionally, we studied at the potential role of these lymphocytes in preventing LACV neurological disease in resistant adult mice. Results: In susceptible weanling mice, disease was associated with infiltrating lymphocytes in the CNS, including NK cells, CD4 T cells, and CD8 T cells. Surprisingly, depletion of these cells did not impact neurological disease, suggesting these cells do not contribute to virus-mediated damage. In contrast, in disease-resistant adult animals, depletion of both CD4 T cells and CD8 T cells or depletion of B cells increased neurological disease, with higher levels of virus in the brain. Conclusions: Our current results indicate that lymphocytes do not influence neurological disease in young mice, but they have a critical role protecting adult animals from LACV pathogenesis. Although LACV is an acute virus infection, these studies indicate that the innate immune response in adults is not sufficient for protection and that components of the adaptive immune response are necessary to prevent virus from invading the CNS. C1 [Winkler, Clayton W.; Myers, Lara M.; Woods, Tyson A.; Carmody, Aaron B.; Taylor, Katherine G.; Peterson, Karin E.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. RP Peterson, KE (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM petersonka@niaid.nih.gov FU Division of Intramural Research, National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported by the Division of Intramural Research, National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 34 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD MAR 24 PY 2017 VL 14 AR 62 DI 10.1186/s12974-017-0836-3 PG 14 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA EP1OJ UT WOS:000397153900001 PM 28340587 ER PT J AU Li, J Bonkowski, MS Moniot, S Zhang, D Hubbard, BP Ling, AJY Rajman, LA Qin, B Lou, Z Gorbunova, V Aravind, L Steegborn, C Sinclair, DA AF Li, Jun Bonkowski, Michael S. Moniot, Sebastien Zhang, Dapeng Hubbard, Basil P. Ling, Alvin J. Y. Rajman, Luis A. Qin, Bo Lou, Zhenkun Gorbunova, Vera Aravind, L. Steegborn, Clemens Sinclair, David A. TI AGING A conserved NAD(+) binding pocket that regulates protein-protein interactions during aging SO SCIENCE LA English DT Article ID NICOTINAMIDE MONONUCLEOTIDE; DNA-REPAIR; CELL; MECHANISM; SIRTUINS; PATHWAY; DISEASE; SIRT1; DBC1; LIFE AB DNA repair is essential for life, yet its efficiency declines with age for reasons that are unclear. Numerous proteins possess Nudix homology domains (NHDs) that have no known function. We show that NHDs are NAD(+) (oxidized form of nicotinamide adenine dinucleotide) binding domains that regulate protein-protein interactions. The binding of NAD(+) to the NHD domain of DBC1 (deleted in breast cancer 1) prevents it from inhibiting PARP1 [poly(adenosine diphosphate-ribose) polymerase], a critical DNA repair protein. As mice age and NAD(+) concentrations decline, DBC1 is increasingly bound to PARP1, causing DNA damage to accumulate, a process rapidly reversed by restoring the abundance of NAD(+). Thus, NAD(+) directly regulates protein-protein interactions, the modulation of which may protect against cancer, radiation, and aging. C1 [Li, Jun; Bonkowski, Michael S.; Hubbard, Basil P.; Ling, Alvin J. Y.; Rajman, Luis A.; Sinclair, David A.] Harvard Med Sch, Paul F Glenn Ctr Biol Aging, Dept Genet, Boston, MA 02115 USA. [Moniot, Sebastien; Steegborn, Clemens] Univ Bayreuth, Dept Biochem, D-95440 Bayreuth, Germany. [Zhang, Dapeng] Natl Inst Hlth, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Qin, Bo; Lou, Zhenkun] Dept Oncol, Div Oncol Res, Mayo Clin, 200 Ist St SW, Rochester, MN 55905 USA. [Gorbunova, Vera] Div Biol, 434 Hutchinson Hall,River Campus, Rochester, NY 14627 USA. [Sinclair, David A.] Univ New South Wales, Sch Med Sci, Dept Pharmacol, Sydney, NSW 2052, Australia. St Louis Univ, Dept Biol, St Louis, MO 63103 USA. [Hubbard, Basil P.] Univ Alberta, Dept Pharmacol, Edmonton, AB T6G 2H7, Canada. RP Sinclair, DA (reprint author), Harvard Med Sch, Paul F Glenn Ctr Biol Aging, Dept Genet, Boston, MA 02115 USA.; Sinclair, DA (reprint author), Univ New South Wales, Sch Med Sci, Dept Pharmacol, Sydney, NSW 2052, Australia. EM david_sinclair@hms.harvard.edu FU NIA NIH HHS [R37 AG028730] NR 24 TC 0 Z9 0 U1 10 U2 10 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD MAR 24 PY 2017 VL 355 IS 6331 BP 1312 EP + DI 10.1126/science.aad8242 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EP0NB UT WOS:000397082900039 PM 28336669 ER PT J AU Guittard, G Gallardo, DL Li, W Melis, N Lui, JC Kortum, RL Shakarishvili, NG Huh, S Baron, J Weigert, R Kramer, JA Samelson, LE Sommers, CL AF Guittard, Geoffrey Gallardo, Devorah L. Li, Wenmei Melis, Nicolas Lui, Julian C. Kortum, Robert L. Shakarishvili, Nicholas G. Huh, Sunmee Baron, Jeffrey Weigert, Roberto Kramer, Joshua A. Samelson, Lawrence E. Sommers, Connie L. TI Unexpected Cartilage Phenotype in CD4-Cre-Conditional SOS-Deficient Mice SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE SOS; RAS; proliferation; T cell signaling; cartilage homeostasis; chondrocyte dysplasia ID T-CELL DEVELOPMENT; RAS; ACTIVATION; GROWTH; LOCALIZATION; PATHWAY AB RAS signaling is central to many cellular processes and SOS proteins promote RAS activation. To investigate the role of SOS proteins in T cell biology, we crossed Sos1f/ f Sos2-/- mice to CD4-Cre transgenic mice. We previously reported an effect of these mutations on T cell signaling and T cell migration. Unexpectedly, we observed nodules on the joints of greater than 90% of these mutant mice at 5 months of age, especially on the carpal joints. As the mice aged further, some also displayed joint stiffness, hind limb paralysis, and lameness. Histological analysis indicated that the abnormal growth in joints originated from dysplastic chondrocytes. Second harmonic generation imaging of the carpal nodules revealed that nodules were encased by rich collagen fibrous networks. Nodules formed in mice also deficient in RAG2, indicating that conventional T cells, which undergo rearrangement of the T cell antigen receptor, are not required for this phenotype. CD4-Cre expression in a subset of cells, either immune lineage cells (e.g., non-conventional T cells) or non-immune lineage cells (e.g., chondrocytes) likely mediates the dramatic phenotype observed in this study. Disruptions of genes in the RAS signaling pathway are especially likely to cause this phenotype. These results also serve as a cautionary tale to those intending to use CD4-Cre transgenic mice to specifically delete genes in conventional T cells. C1 [Guittard, Geoffrey; Li, Wenmei; Melis, Nicolas; Shakarishvili, Nicholas G.; Huh, Sunmee; Weigert, Roberto; Samelson, Lawrence E.; Sommers, Connie L.] NCI, Cellular & Mol Biol Lab, CCR, NIH, Bldg 37, Bethesda, MD 20892 USA. [Gallardo, Devorah L.; Kramer, Joshua A.] NCI, Lab Anim Sci Program, Leidos Biomed Res, NIH, Bethesda, MD 20892 USA. [Lui, Julian C.; Baron, Jeffrey] NICHD, Sect Growth & Dev, NIH, Bethesda, MD USA. [Kortum, Robert L.] Uniformed Serv Univ Hlth Sci, Dept Pharmacol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. [Guittard, Geoffrey] INSERM, Ctr Rech Cancerol Marseille, Marseille, France. RP Sommers, CL (reprint author), NCI, Cellular & Mol Biol Lab, CCR, NIH, Bldg 37, Bethesda, MD 20892 USA. EM sommersc@mail.nih.gov FU National Cancer Institute Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Cancer Institute Center for Cancer Research. NR 20 TC 0 Z9 0 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD MAR 23 PY 2017 VL 8 AR 343 DI 10.3389/fimmu.2017.00343 PG 8 WC Immunology SC Immunology GA EP1LQ UT WOS:000397146800001 PM 28386265 ER PT J AU Ritter, ML Guo, W Samuels, JF Wang, Y Nestadt, PS Krasnow, J Greenberg, BD Fyer, AJ McCracken, JT Geller, DA Murphy, DL Knowles, JA Grados, MA Riddle, MA Rasmussen, SA McLaughlin, NC Nurmi, EL Askland, KD Cullen, B Piacentini, J Pauls, DL Bienvenu, J Stewart, E Goes, FS Maher, B Pulver, AE Mattheisen, M Qian, J Nestadt, G Shugart, YY AF Ritter, McKenzie L. Guo, Wei Samuels, Jack F. Wang, Ying Nestadt, Paul S. Krasnow, Janice Greenberg, Benjamin D. Fyer, Abby J. McCracken, James T. Geller, Daniel A. Murphy, Dennis L. Knowles, James A. Grados, Marco A. Riddle, Mark A. Rasmussen, Steven A. McLaughlin, Nicole C. Nurmi, Erika L. Askland, Kathleen D. Cullen, Bernadette Piacentini, John Pauls, David L. Bienvenu, Joseph Stewart, Evelyn Goes, Fernando S. Maher, Brion Pulver, Ann E. Mattheisen, Manuel Qian, Ji Nestadt, Gerald Shugart, Yin Yao TI Genome Wide Association Study (GWAS) between Attention Deficit Hyperactivity Disorder (ADHD) and Obsessive Compulsive Disorder (OCD) SO FRONTIERS IN MOLECULAR NEUROSCIENCE LA English DT Article DE ADHD; OCD; GWAS; meta-analysis; polygenic score; protein-protein link analysis; eQTL ID DEFICIT/HYPERACTIVITY DISORDER; PSYCHOMETRIC PROPERTIES; K-SADS; CHILDREN; METAANALYSIS; RELIABILITY; IV; SCHIZOPHRENIA; ADOLESCENTS; COMORBIDITY AB Objective: The aim of this study was to identify any potential genetic overlap between attention deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). We hypothesized that since these disorders share a sub-phenotype, they may share common risk alleles. In this manuscript, we report the overlap found between these two disorders. Methods: A meta-analysis was conducted between ADHD and OCD, and polygenic risk scores (PRS) were calculated for both disorders. In addition, a protein-protein analysis was completed in order to examine the interactions between proteins; p-values for the protein-protein interaction analysis was calculated using permutation. Conclusion: None of the single nucleotide polymorphisms (SNPs) reached genome wide significance and there was little evidence of genetic overlap between ADHD and OCD. C1 [Ritter, McKenzie L.; Guo, Wei; Shugart, Yin Yao] NIMH, Unit Stat Genom, NIH, Bethesda, MD 20892 USA. [Samuels, Jack F.; Wang, Ying; Krasnow, Janice; Grados, Marco A.; Riddle, Mark A.; Cullen, Bernadette; Bienvenu, Joseph; Goes, Fernando S.; Pulver, Ann E.; Nestadt, Gerald] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Nestadt, Paul S.; Maher, Brion] Johns Hopkins Univ, Dept Mental Hlth, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Greenberg, Benjamin D.; Rasmussen, Steven A.; McLaughlin, Nicole C.; Askland, Kathleen D.] Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI USA. [Fyer, Abby J.] Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, New York, NY 10032 USA. [McCracken, James T.; Nurmi, Erika L.; Piacentini, John] Univ Calif Los Angeles, Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90024 USA. [Geller, Daniel A.; Pauls, David L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Geller, Daniel A.; Pauls, David L.] Harvard Med Sch, Boston, MA USA. [Murphy, Dennis L.] NIMH, Clin Sci Lab, Bldg 10, Bethesda, MD 20892 USA. [Knowles, James A.] Univ Southern Calif, Keck Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA USA. [Stewart, Evelyn] Univ British Columbia, Dept Psychiat, Vancouver, BC, Canada. [Mattheisen, Manuel] Aarhus Univ, Dept Biomed, Aarhus, Denmark. [Mattheisen, Manuel] Aarhus Univ, Ctr Integrated Sequencing iSEQ, Aarhus, Denmark. [Mattheisen, Manuel] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Mattheisen, Manuel] Univ Bonn, Dept Genom Math, Bonn, Germany. [Qian, Ji] Fudan Univ, Inst Life Sci, State Key Lab Genet Engn, Shanghai, Peoples R China. RP Shugart, YY (reprint author), NIMH, Unit Stat Genom, NIH, Bethesda, MD 20892 USA.; Nestadt, G (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. EM gnestadt@jhmi.edu; kay1yao@mail.nih.gov FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) [MH002930-06] FX MLR and YYS and WG acknowledge the support of the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) and grant number MH002930-06. The views expressed in this presentation do not necessarily represent the views of the NIMH, NIH, HHS, or the United States Government. NR 49 TC 0 Z9 0 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5099 J9 FRONT MOL NEUROSCI JI Front. Molec. Neurosci. PD MAR 23 PY 2017 VL 10 AR 83 DI 10.3389/fnmol.2017.00083 PG 9 WC Neurosciences SC Neurosciences & Neurology GA EP0NU UT WOS:000397084800001 PM 28386217 ER PT J AU Dunleavy, K AF Dunleavy, Kieron TI Unraveling Castleman: progress in a complex process SO BLOOD LA English DT Editorial Material ID DISEASE C1 [Dunleavy, Kieron] NCI, Bethesda, MD 20892 USA. RP Dunleavy, K (reprint author), NCI, Bethesda, MD 20892 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAR 23 PY 2017 VL 129 IS 12 BP 1570 EP 1570 DI 10.1182/blood-2017-02-764654 PG 1 WC Hematology SC Hematology GA EP3QR UT WOS:000397297300003 PM 28336728 ER PT J AU Fajgenbaum, DC Uldrick, TS Bagg, A Frank, D Wu, D Srkalovic, G Simpson, D Liu, AY Menke, D Chandrakasan, S Lechowicz, MJ Wong, RSM Pierson, S Paessler, M Rossi, JF Ide, M Ruth, J Croglio, M Suarez, A Krymskaya, V Chadburn, A Colleoni, G Nasta, S Jayanthan, R Nabel, CS Casper, C Dispenzieri, A Fossa, A Kelleher, D Kurzrock, R Voorhees, P Dogan, A Yoshizaki, K van Rhee, F Oksenhendler, E Jaffe, ES Elenitoba-Johnson, KSJ Lim, MS AF Fajgenbaum, David C. Uldrick, Thomas S. Bagg, Adam Frank, Dale Wu, David Srkalovic, Gordan Simpson, David Liu, Amy Y. Menke, David Chandrakasan, Shanmuganathan Lechowicz, Mary Jo Wong, Raymond S. M. Pierson, Sheila Paessler, Michele Rossi, Jean-Francois Ide, Makoto Ruth, Jason Croglio, Michael Suarez, Alexander Krymskaya, Vera Chadburn, Amy Colleoni, Gisele Nasta, Sunita Jayanthan, Raj Nabel, Christopher S. Casper, Corey Dispenzieri, Angela Fossa, Alexander Kelleher, Dermot Kurzrock, Razelle Voorhees, Peter Dogan, Ahmet Yoshizaki, Kazuyuki van Rhee, Frits Oksenhendler, Eric Jaffe, Elaine S. Elenitoba-Johnson, Kojo S. J. Lim, Megan S. TI International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease SO BLOOD LA English DT Article ID LYMPH-NODE HYPERPLASIA; LUPUS-ERYTHEMATOSUS PATIENTS; TAFRO SYNDROME; IGG4-RELATED DISEASE; HERPESVIRUS; LESIONS; HIV; INTERLEUKIN-6; SILTUXIMAB; PATHOLOGY AB Human herpesvirus-8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal lymphoproliferation, cytopenias, and multiple organ system dysfunction caused by a cytokine storm often including interleukin-6. iMCD accounts for one third to one half of all cases ofMCDand can occur in individuals of any age. Accurate diagnosis is challenging, because no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders. An international working group comprising 34 pediatric and adult pathology and clinical experts in iMCD and related disorders from 8 countries, including 2 physicians that are also iMCD patients, was convened to establish iMCD diagnostic criteria. The working group reviewed data from 244 cases, met twice, and refined criteria over 15 months (June 2015 to September 2016). The proposed consensus criteria require both Major Criteria (characteristic lymph node histopathology and multicentric lymphadenopathy), at least 2 of 11Minor Criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. Characteristic histopathologic featuresmay include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization, and polytypic plasmacytosis. Laboratory and clinical Minor Criteria include elevatedC-reactive protein or erythrocyte sedimentation rate, anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, renal dysfunction or proteinuria, polyclonal hypergammaglobulinemia, constitutional symptoms, hepatosplenomegaly, effusions or edema, eruptive cherry hemangiomatosis or violaceous papules, and lymphocytic interstitial pneumonitis. iMCD consensus diagnostic criteria will facilitate consistent diagnosis, appropriate treatment, and collaborative research. C1 [Fajgenbaum, David C.; Liu, Amy Y.; Pierson, Sheila; Suarez, Alexander] Univ Pennsylvania, Perelman Sch Med, Div Translat Med & Human Genet, Philadelphia, PA USA. [Uldrick, Thomas S.; Jaffe, Elaine S.] Natl Canc Inst, Natl Inst Hlth, Bethesda, MD USA. [Bagg, Adam; Lim, Megan S.] Univ Pennsylvania, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA USA. [Wu, David] Univ Washington, Dept Lab Med, Seattle, WA USA. [Srkalovic, Gordan] Edward Sparrow Hosp Assoc, Sparrow Canc Ctr, Lansing, MI USA. [Simpson, David] North Shore Hosp, Div Haematol, Auckland, New Zealand. [Menke, David] Mayo Clin, Dept Med, Div Hematol, Rochester, MN USA. [Menke, David] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Chandrakasan, Shanmuganathan; Lechowicz, Mary Jo] Emory Univ Sch Med, Dept Med, Atlanta, GA USA. [Wong, Raymond S. M.] Chinese Univ Hong Kong, Prince Wales Hosp, Sir K Pao Ctr Canc, Hong Kong, Peoples R China. [Wong, Raymond S. M.] Chinese Univ Hong Kong, Dept Med Therapeut, Hong Kong, Peoples R China. [Paessler, Michele] Childrens Hosp Philadelphia, Dept Pathol, Philadelphia, PA USA. [Rossi, Jean-Francois] Hop St Eloi Univ Hosp, Dept Hematol, Montpellier, France. [Ide, Makoto] Takamatsu Red Cross Hosp, Dept Hematol, Takamatsu, Kagawa, Japan. [Ruth, Jason] Dana Farber Canc Inst, Harvard Med Sch, Dept Med Oncol, Boston, MA USA. [Croglio, Michael] SUNY Stony Brook, Sch Med, Stony Brook, NY USA. [Krymskaya, Vera] Univ Penn, Perelman Sch Med, Div Pulm Allergy & Crit Care, Philadelphia, PA USA. [Chadburn, Amy] Weill Cornell Med Coll, Dept Pathol, New York, NY USA. [Colleoni, Gisele] Univ Fed Sao Paulo, Dept Oncol Clin Expt, Sao Paulo, Brazil. [Nasta, Sunita] Univ Pennsylvania, Perelman Sch Med, Div Hematol Oncol, Philadelphia, PA USA. [Jayanthan, Raj] Texas Childrens Hosp, Dept Pediat, Houston, TX USA. [Nabel, Christopher S.] Brigham & Womens Hosp, Dept Med, Boston, MA USA. [Casper, Corey] Fred Hutchinson Canc Ctr, Vaccine & Infect Dis Div, Seattle, WA USA. [Dispenzieri, Angela] Mayo Clin, Div Hematol Oncol, Rochester, MN USA. [Fossa, Alexander] Oslo Univ Hosp, Norwegian Radium Hosp, Dept Oncol, Oslo, Norway. [Kelleher, Dermot] Univ British Columbia, Fac Med, Vancouver, BC, Canada. [Kurzrock, Razelle] UC San Diego Moores Canc Ctr, Ctr Personalized Therapy, La Jolla, CA USA. [Voorhees, Peter] Levine Canc Inst, Dept Hematol Oncol & Blood Disorders, Carolinas HealthCare Syst, Charlotte, NC USA. [Dogan, Ahmet] Mem Sloan Kettering Canc Ctr, Dept Pathol, Lab Med, New York, NY USA. [Yoshizaki, Kazuyuki] Osaka Univ, Inst Sci & Ind Res, Dept Organ Fine Chem, Osaka, Japan. [van Rhee, Frits] Univ Arkansas Med Sci, Myeloma Inst, Little Rock, AR USA. [Oksenhendler, Eric] Hop St Louis, Dept Clin Immunol, Paris, France. RP Fajgenbaum, DC (reprint author), Hosp Univ Penn, 3400 Spruce St,Suite S05094, Philadelphia, PA 19104 USA.; Uldrick, TS; Jaffe, ES (reprint author), Natl Canc Inst, Ctr Canc Res, Bldg 10,Room 3S235, Bethesda, MD USA.; Elenitoba-Johnson, KSJ; Lim, MS (reprint author), Univ Penn, Perelman Sch Med, Dept Pathol, 609 Stellar Chance, Philadelphia, PA 19104 USA. EM megan.lim@uphs.upenn.edu FU CDCN; Penn Orphan Disease Center; Intramural Research Program of the National Institutes of Health FX The authors thank the CDCN and Penn Orphan Disease Center for logistical and funding support and Janssen Pharmaceuticals for providing extensive, deidentified datasets and lymph node slides from clinical trial NCT01024036. All funding from the CDCN and the Penn Orphan Disease Center was provided without fur ther input into the work conduct, results interpretation, and manuscript preparation. The authors also thank Hayley Williamson and Melanie Kier for their assistance with coordinating the meeting and performing preliminary data analyses, Arthur Rubenstein for his guidance, and Noriko Iwaki and Yasuharu Sato for contributing clinical and histopathologic data toward the evidence base for this criteria.; This study was supported, in part, by the Intramural Research Program of the National Institutes of Health. NR 57 TC 2 Z9 2 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAR 23 PY 2017 VL 129 IS 12 BP 1646 EP 1657 DI 10.1182/blood-2016-10-746933 PG 12 WC Hematology SC Hematology GA EP3QR UT WOS:000397297300015 PM 28087540 ER PT J AU Yu, L Tu, MF Cortes, J Xu-Monette, ZY Miranda, RN Zhang, J Orlowski, RZ Neelapu, S Boddu, PC Akosile, MA Uldrick, TS Yarchoan, R Medeiros, LJ Li, Y Fajgenbaum, DC Young, KH AF Yu, Li Tu, Meifeng Cortes, Jorge Xu-Monette, Zijun Y. Miranda, Roberto N. Zhang, Jun Orlowski, Robert Z. Neelapu, Sattva Boddu, Prajwal C. Akosile, Mary A. Uldrick, Thomas S. Yarchoan, Robert Medeiros, L. Jeffrey Li, Yong Fajgenbaum, David C. Young, Ken H. TI Clinical and pathological characteristics of HIV- and HHV-8-negative Castleman disease SO BLOOD LA English DT Article ID MONOCLONAL-ANTIBODY; RECEPTOR ANTIBODY; RITUXIMAB THERAPY; DOUBLE-BLIND; SILTUXIMAB; IMMUNODEFICIENCY; CHEMOTHERAPY; PATHOGENESIS; MANAGEMENT; LYMPHOMA AB Castleman disease (CD) comprises 3 poorly understood lymphoproliferative variants sharing several common histopathological features. Unicentric CD (UCD) is localized to a single region of lymph nodes. Multicentric CD (MCD) manifests with systemic inflammatory symptoms and organ dysfunction due to cytokine dysregulation and involves multiple lymph node regions. Human herpesvirus 8 (HHV-8) causes MCD (HHV8-associated MCD) in immunocompromised individuals, such as HIV-infected patients. However, > 50% of MCD cases are HIV and HHV-8 negative (defined as idiopathic [iMCD]). The clinical and biological behavior of CD remains poorly elucidated. Here, we analyzed the clinicopathologic features of 74 patients (43 with UCD and 31 with iMCD) and therapeutic responseof 96 patients (43 with UC Dand 53 with iMCD) with HIV-/HHV-8-negative CD compared with 51 HIV-/HHV-8-positive patients. Systemic inflammatory symptoms and elevated inflammatory factors were more common in iMCD patients than UCD patients. Abnormal bone marrow features were more frequent in iMCD (77.0%) than UCD (45%); the most frequent was plasmacytosis, which was seen in 3% to 30.4% of marrow cells. In the lymph nodes, higher numbers of CD3(+) lymphocytes (median, 58.88 +/- 20.57) and lower frequency of CD19(+)/CD5(+) (median, 5.8866.52) were observed in iMCD patients compared with UCD patients (median CD3(+) cells, 43.19 +/- 17.37; median CD19(+)/CD5(+) cells, 17.37 +/- 15.80). Complete surgical resection is a better option for patients with UCD. Siltuximab had a greater proportion of complete responses and longer progressionfree survival (PFS) for iMCD than rituximab. Centricity, histopathological type, and anemia significantly impacted PFS. This study reveals that CD represents a heterogeneous group of diseases with differential immunophenotypic profiling and treatment response. C1 [Yu, Li; Xu-Monette, Zijun Y.; Miranda, Roberto N.; Zhang, Jun; Medeiros, L. Jeffrey; Young, Ken H.] Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, 1515 Holcombe Blvd, Houston, TX 77030 USA. [Yu, Li] Nanchang Univ, Affiliate Hosp 2, Dept Hematol, Nanchang, Jiangxi, Peoples R China. [Tu, Meifeng] Peking Univ, Canc Hosp, Dept Lymphoma, Key Lab Carcinogenesis & Translat Res Minist Educ, Beijing, Peoples R China. [Cortes, Jorge; Boddu, Prajwal C.; Akosile, Mary A.] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [Orlowski, Robert Z.; Neelapu, Sattva] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma Myeloma, Houston, TX 77030 USA. [Uldrick, Thomas S.; Yarchoan, Robert] Natl Inst Hlth, Natl Canc Inst, HIV & AIDS Malignancy Branch, Bethesda, MD USA. [Li, Yong] Cleveland Clin, Lerner Res Inst, Dept Canc Biol, Cleveland, OH 44106 USA. [Fajgenbaum, David C.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA USA. [Young, Ken H.] Univ Texas Hlth Sci Ctr, Grad Sch Biomed Sci, Houston, TX USA. RP Young, KH (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM khyoung@mdanderson.org FU National Institutes of Health National Cancer Institute [R01CA138688, R01CA187415, 1RC1CA146299]; Intramural Research Program of the National Institutes of Health National Cancer Institute; Hematology/Oncology Scholarship Award; University of Texas MD Anderson Cancer Center Institutional Research Grant Award; Anderson Lymphoma Specialized Programs of Research Excellence (SPORE) Research Development Program Award; Anderson Myeloma SPORE Research Developmental Program Award; University Cancer Foundation via the Sister Institution Network Fund at The University of Texas MD Anderson Cancer Center; National Institutes of Health, National Cancer Institute [P50CA136411, P50CA142509]; National Institutes of Health, Anderson Cancer Center [CA016672] FX This study is supported by the National Institutes of Health National Cancer Institute (grants R01CA138688, R01CA187415, and 1RC1CA146299) (Y. L. and K. H. Y.) and in part by the Intramural Research Program of the National Institutes of Health National Cancer Institute (T. S. U. and R. Y.). L. Y. and M. T. are the recipients of a Hematology/Oncology Scholarship Award. K. H. Y. is supported by a The University of Texas MD Anderson Cancer Center Institutional Research Grant Award, an Anderson Lymphoma Specialized Programs of Research Excellence (SPORE) Research Development Program Award, an Anderson Myeloma SPORE Research Developmental Program Award, and the University Cancer Foundation via the Sister Institution Network Fund at The University of Texas MD Anderson Cancer Center. The study is also partially supported by the National Institutes of Health, National Cancer Institute grants P50CA136411 and P50CA142509 and an Anderson Cancer Center support grant (CA016672). NR 40 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAR 23 PY 2017 VL 129 IS 12 BP 1658 EP 1668 DI 10.1182/blood-2016-11-748855 PG 11 WC Hematology SC Hematology GA EP3QR UT WOS:000397297300016 PM 28100459 ER PT J AU Nishimura, Y Gautam, R Chun, TW Sadjadpour, R Foulds, KE Shingai, M Klein, F Gazumyan, A Golijanin, J Donaldson, M Donau, OK Plishka, RJ Buckler-White, A Seaman, MS Lifson, JD Koup, RA Fauci, AS Nussenzweig, MC Martin, MA AF Nishimura, Yoshiaki Gautam, Rajeev Chun, Tae-Wook Sadjadpour, Reza Foulds, Kathryn E. Shingai, Masashi Klein, Florian Gazumyan, Anna Golijanin, Jovana Donaldson, Mitzi Donau, Olivia K. Plishka, Ronald J. Buckler-White, Alicia Seaman, Michael S. Lifson, Jeffrey D. Koup, Richard A. . Fauci, Anthony S. Nussenzweig, Michel C. . Martin, Malcolm A. TI Early antibody therapy can induce long-lasting immunity to SHIV SO NATURE LA English DT Article ID BROADLY NEUTRALIZING ANTIBODIES; SIMIAN/HUMAN IMMUNODEFICIENCY VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; PRIMARY HIV-1 INFECTION; CD4(+) T-CELLS; MONOCLONAL-ANTIBODIES; HUMANIZED MICE; RHESUS-MONKEYS; IN-VIVO; MACAQUES AB Highly potent and broadly neutralizing anti-HIV-1 antibodies (bNAbs) have been used to prevent and treat lentivirus infections in humanized mice, macaques, and humans(1-12). In immunotherapy experiments, administration of bNAbs to chronically infected animals transiently suppresses virus replication, which invariably returns to pre-treatment levels and results in progression to clinical disease. Here we show that early administration of bNAbs in a macaque simian/human immunodeficiency virus (SHIV) model is associated with very low levels of persistent viraemia, which leads to the establishment of T-cell immunity and resultant longterm infection control. Animals challenged with SHIVAD8-EO by mucosal or intravenous routes received a single 2-week course of two potent passively transferred bNAbs (3BNC117 and 10-1074 (refs 13, 14)). Viraemia remained undetectable for 56-177 days, depending on bNAb half-life in vivo. Moreover, in the 13 treated monkeys, plasma virus loads subsequently declined to undetectable levels in 6 controller macaques. Four additional animals maintained their counts of T cells carrying the CD4 antigen (CD4+) and very low levels of viraemia persisted for over 2 years. The frequency of cells carrying replication-competent virus was less than 1 per 106 circulating CD4(+) T cells in the six controller macaques. Infusion of a T-cell-depleting anti-CD8 beta monoclonal antibody to the controller animals led to a specific decline in levels of CD8(+) T cells and the rapid reappearance of plasma viraemia. In contrast, macaques treated for 15 weeks with combination anti-retroviral therapy, beginning on day 3 after infection, experienced sustained rebound plasma viraemia when treatment was interrupted. Our results show that passive immunotherapy during acute SHIV infection differs from combination anti-retroviral therapy in that it facilitates the emergence of potent CD8(+) T-cell immunity able to durably suppress virus replication. C1 [Nishimura, Yoshiaki; Gautam, Rajeev; Sadjadpour, Reza; Shingai, Masashi; Donau, Olivia K.; Plishka, Ronald J.; Buckler-White, Alicia; Martin, Malcolm A.] Natl Inst Allergy & Infect Dis, Lab Mol Microbiol, Natl Inst Hlth, Bethesda, MD 20892 USA. [Chun, Tae-Wook; Fauci, Anthony S.] Natl Inst Allergy & Infect Dis, Lab Immunoregulat, Natl Inst Hlth, Bethesda, MD 20892 USA. [Foulds, Kathryn E.; Donaldson, Mitzi; Koup, Richard A. .] Natl Inst Allergy & Infect Dis, Vaccine Res Ctr, Natl Inst Hlth, Bethesda, MD 20892 USA. [Klein, Florian] Univ Cologne, Inst Virol, D-50931 Cologne, Germany. [Klein, Florian] Univ Cologne, CMMC, D-50931 Cologne, Germany. [Gazumyan, Anna; Golijanin, Jovana; Nussenzweig, Michel C. .] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Seaman, Michael S.] Ctr Virol & Vaccine Res, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Lifson, Jeffrey D.] Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Frederick, MD 21702 USA. [Nussenzweig, Michel C. .] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. RP Martin, MA (reprint author), Natl Inst Allergy & Infect Dis, Lab Mol Microbiol, Natl Inst Hlth, Bethesda, MD 20892 USA.; Nussenzweig, MC (reprint author), Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA.; Nussenzweig, MC (reprint author), Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. EM nussen@rockefeller.edu; malm@nih.gov FU National Institutes of Health (NIH) Nonhuman Primate Reagent Resource [HHSN272200900037C, OD10976]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIH); Vaccine Research Center of the National Institute of Allergy and Infectious Diseases (NIH); National Cancer Institute (NIH) [HHSN261200800001E]; Collaboration for AIDS Vaccine Discovery grant [OPP1033115]; NIH Clinical and Translational Science Award (CTSA) program; NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) [1UM1 AI100663-01]; Bill and Melinda Gates Foundation [OPP1092074, OPP1124068]; NIH HIVRAD [P01 AI100148]; Robertson Foundation FX We thank A. Peach and T. Lewis for determining plasma viral RNA loads, and K. Rice, R. Engel, R. Petros, and S. Fong for assisting in the maintenance of animals and performing procedures. We thank R. Fast for technical assistance with ultrasensitive viral load assays, and J. Brenchley for performing FACS analyses. We are indebted to Gilead Sciences for providing tenofovir and emtricitabine. The anti-CD8 mAbs, MT807R1 and CD8b255R1, were obtained from the National Institutes of Health (NIH) Nonhuman Primate Reagent Resource supported by HHSN272200900037C and OD10976. We thank the NIH AIDS Research and Reference Reagent Program for TZM-bl cells. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIH), Vaccine Research Center of the National Institute of Allergy and Infectious Diseases (NIH), and, in part, with federal funds from the National Cancer Institute (NIH) under contract number HHSN261200800001E (J.D.L.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The research was also funded in part by the following grants: Collaboration for AIDS Vaccine Discovery grant OPP1033115 (M.C.N.); NIH Clinical and Translational Science Award (CTSA) program; NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) 1UM1 AI100663-01 (M.C.N.); Bill and Melinda Gates Foundation grants OPP1092074 and OPP1124068 (M.C.N.); NIH HIVRAD P01 AI100148 (M.C.N.); the Robertson Foundation to M.C.N. M.C.N. is a Howard Hughes Medical Institute Investigator. NR 36 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAR 23 PY 2017 VL 543 IS 7646 BP 559 EP + DI 10.1038/nature21435 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EO9OM UT WOS:000397018000053 PM 28289286 ER PT J AU Yamaji, M Jishage, M Meyer, C Suryawanshi, H Evan Yamaji, M Garzia, A Morozov, P Manickavel, S Mcfarland, HL Roeder, RG Hafner, M Tuschl, T AF Yamaji, Masashi Jishage, Miki Meyer, Cindy Suryawanshi, Hemant Evan Der Yamaji, Misaki Garzia, Aitor Morozov, Pavel Manickavel, Sudhir Mcfarland, Hannah L. Roeder, Robert G. Hafner, Markus Tuschl, Thomas TI DND1 maintains germline stem cells via recruitment of the CCR4-NOT complex to target mRNAs SO NATURE LA English DT Article ID STRUCTURAL BASIS; BINDING PROTEIN; TESTICULAR TERATOMAS; TER MUTATION; PAR-CLIP; EMBL-EBI; EXPRESSION; SPECIFICATION; RECOGNITION; MICE AB The vertebrate-conserved RNA-binding protein DND1 is required for the survival of primordial germ cells (PGCs), as well as the suppression of germ cell tumours in mice(1-5). Here we show that in mice DND1 binds a UU(A/U) trinucleotide motif predominantly in the 3' untranslated regions of mRNA, and destabilizes target mRNAs through direct recruitment of the CCR4-NOT deadenylase complex. Transcriptomic analysis reveals that the extent of suppression is dependent on the number of DND1-binding sites. This DND1-dependent mRNA destabilization is required for the survival of mouse PGCs and spermatogonial stem cells by suppressing apoptosis. The spectrum of target RNAs includes positive regulators of apoptosis and inflammation, and modulators of signalling pathways that regulate stem-cell pluripotency, including the TGFa superfamily, all of which are aberrantly elevated in DND1-deficient PGCs. We propose that the induction of the post-transcriptional suppressor DND1 synergizes with concurrent transcriptional changes to ensure precise developmental transitions during cellular differentiation and maintenance of the germ line. C1 [Yamaji, Masashi; Meyer, Cindy; Suryawanshi, Hemant; Yamaji, Misaki; Garzia, Aitor; Morozov, Pavel; Tuschl, Thomas] Rockefeller Univ, Howard Hughes Med Inst, Lab RNA Mol Biol, 1230 York Ave,Box 186, New York, NY 10065 USA. [Jishage, Miki; Roeder, Robert G.] Rockefeller Univ, Lab Biochem & Mol Biol, 1230 York Ave, New York, NY 10065 USA. [Evan Der] Albert Einstein Coll Med, 1300 Morris Pk Ave,Forchheimer Bldg, Bronx, NY 10461 USA. [Manickavel, Sudhir; Mcfarland, Hannah L.; Hafner, Markus] Natl Inst Arthrit & Musculoskeletal & Skin Dis, Lab Muscle Stem Cells & Gene Regulat, 50 South Dr,MSC 8024, Bethesda, MD 20892 USA. RP Tuschl, T (reprint author), Rockefeller Univ, Howard Hughes Med Inst, Lab RNA Mol Biol, 1230 York Ave,Box 186, New York, NY 10065 USA.; Hafner, M (reprint author), Natl Inst Arthrit & Musculoskeletal & Skin Dis, Lab Muscle Stem Cells & Gene Regulat, 50 South Dr,MSC 8024, Bethesda, MD 20892 USA. EM markus.hafner@nih.gov; ttuschl@rockefeller.edu FU Starr Cancer Foundation; Starr Foundation [TRI-SCI 2014-036]; NCI; NCATS/NIH/CTSA; Vilcek Foundation [UL1 TR000043]; DAAD; NIH TRA [R01CA159227]; Intramural Research Program of NIAMS/NIH; JSPS FX The authors acknowledge expert support by the members of the Rockefeller University resource centers (C. Zhao, genomics; H. Molina, proteomics; S. Mazel, flow cytometry; A. North, bio-imaging; R. Norinsky, chimaera assay) and of the NIAMS Genomics Core (G. Gutierrez-Cruz and S. Dell'Orso). We also thank M. Morita (McGill University, Montreal, Canada) for critical discussions on biochemical analysis, K. Hayashi (Kyusyu University, Japan) and Y. Saito (Rockefeller University) for technical guidance regarding PGCLC induction, and N. Mukherjee (Max-Delbruck Centrum for Molecular Medicine, Berlin, Germany) for bioinformatic tools, E. Macosko, M. Goldman, and S. McCarroll for advice to establish DropSeq, and S. Yamada and S. Keeney (Memorial Sloan Kettering Cancer Center, New York) for technical guidance regarding spermatogenic cell sorting. The GST-CNOT constructs were provided by N. Sonenberg (McGill University, Montreal, Canada). pCMV-PP7 and beta-globin-4xPP7-hairpin reporter plasmid were provided by D. R. Larson and M. Palangat (National Cancer Institute/NIH) and J. R. Hogg (National Heart, Lung, and Blood Institute/NIH), respectively. T.T. is an HHMI investigator. The study was supported, in part, by the Starr Cancer Foundation (T. T.), the Starr Foundation (T. T., Ma. Y.: TRI-SCI 2014-036; R. G. R.: TRI-SCI), NCI (R. G. R.), NCATS/NIH/CTSA, the Vilcek Foundation (Ma. Y.; UL1 TR000043), DAAD (C. M.), and NIH TRA (T. T.; R01CA159227). The Intramural Research Program of NIAMS/NIH supports S. M., H.L.M., and M. H. Ma. Y. was a recipient of a JSPS Research Fellowship. NR 56 TC 0 Z9 0 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAR 23 PY 2017 VL 543 IS 7646 BP 568 EP + DI 10.1038/nature21690 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EO9OM UT WOS:000397018000055 PM 28297718 ER PT J AU Aguilar, OA Berry, R Rahim, MMA Reichel, JJ Popovic, B Tanaka, M Fu, ZH Balaji, GR Lau, TNH Tu, MM Kirkham, CL Mahmoud, AB Mesci, A Krmpotic, A Allan, DSJ Makrigiannis, AP Jonjic, S Rossjohn, J Carlyle, JR AF Aguilar, Oscar A. Berry, Richard Rahim, Mir Munir A. Reichel, Johanna J. Popovic, Branka Tanaka, Miho Fu, Zhihui Balaji, Gautham R. Lau, Timothy N. H. Tu, Megan M. Kirkham, Christina L. Mahmoud, Ahmad Bakur Mesci, Aruz Krmpotic, Astrid Allan, David S. J. Makrigiannis, Andrew P. Jonjic, Stipan Rossjohn, Jamie Carlyle, James R. TI A Viral Immunoevasin Controls Innate Immunity by Targeting the Prototypical Natural Killer Cell Receptor Family SO CELL LA English DT Article ID MISSING-SELF-RECOGNITION; MURINE CYTOMEGALOVIRUS-INFECTION; NK GENE-COMPLEX; NKR-P1 RECEPTORS; NK1.1 ANTIGEN; MOUSE; EXPRESSION; REVEALS; PATHOGENS; RESPONSES AB Natural killer (NK) cells play a key role in innate immunity by detecting alterations in self and non-self ligands via paired NK cell receptors (NKRs). Despite identification of numerous NKR-ligand interactions, physiological ligands for the prototypical NK1.1 orphan receptor remain elusive. Here, we identify a viral ligand for the inhibitory and activating NKRP1 (NK1.1) receptors. This murine cytomegalovirus (MCMV)-encoded protein, m12, restrains NK cell effector function by directly engaging the inhibitory NKR-P1B receptor. However, m12 also interacts with the activating NKR-P1A/ C receptors to counterbalance m12 decoy function. Structural analyses reveal that m12 sequesters a large NKR-P1 surface area via a `` polar claw'' mechanism. Polymorphisms in, and ablation of, the viral m12 protein and host NKR-P1B/ C alleles impact NK cell responses in vivo. Thus, we identify the long-sought foreign ligand for this key immunoregulatory NKR family and reveal how it controls the evolutionary balance of immune recognition during host-pathogen interplay. C1 [Aguilar, Oscar A.; Tanaka, Miho; Lau, Timothy N. H.; Kirkham, Christina L.; Mesci, Aruz; Allan, David S. J.; Carlyle, James R.] Univ Toronto, Dept Immunol, Toronto, ON M5S 1A8, Canada. [Aguilar, Oscar A.; Tanaka, Miho; Lau, Timothy N. H.; Kirkham, Christina L.; Mesci, Aruz; Allan, David S. J.; Carlyle, James R.] Sunnybrook Res Inst, Toronto, ON M4N 3M5, Canada. [Berry, Richard; Fu, Zhihui; Balaji, Gautham R.; Rossjohn, Jamie] Monash Univ, Biomed Discovery Inst, Dept Biochem & Mol Biol, Infect & Immun Program, Clayton, Vic 3800, Australia. [Rahim, Mir Munir A.; Tu, Megan M.; Mahmoud, Ahmad Bakur; Makrigiannis, Andrew P.] Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON K1H 8M5, Canada. [Reichel, Johanna J.; Popovic, Branka; Krmpotic, Astrid; Jonjic, Stipan] Univ Rijeka, Dept Histol & Embryol, Fac Med, Rijeka 51000, Croatia. [Berry, Richard; Balaji, Gautham R.] Monash Univ, ARC Ctr Excellence Adv Mol Imaging, Clayton, Vic 3800, Australia. [Rossjohn, Jamie] Cardiff Univ, Inst Infect & Immun, Sch Med, Heath Pk, Cardiff CF14 4XN, S Glam, Wales. [Mahmoud, Ahmad Bakur] Taibah Univ, Coll Appl Med Sci, Madinah Munawwarah 30001, Saudi Arabia. [Rahim, Mir Munir A.; Makrigiannis, Andrew P.] Dalhousie Univ, Dept Microbiol & Immunol, Halifax, NS B3H 4R2, Canada. [Allan, David S. J.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Carlyle, JR (reprint author), Univ Toronto, Dept Immunol, Toronto, ON M5S 1A8, Canada.; Carlyle, JR (reprint author), Sunnybrook Res Inst, Toronto, ON M4N 3M5, Canada.; Rossjohn, J (reprint author), Monash Univ, Biomed Discovery Inst, Dept Biochem & Mol Biol, Infect & Immun Program, Clayton, Vic 3800, Australia.; Makrigiannis, AP (reprint author), Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON K1H 8M5, Canada.; Jonjic, S (reprint author), Univ Rijeka, Dept Histol & Embryol, Fac Med, Rijeka 51000, Croatia.; Rossjohn, J (reprint author), Cardiff Univ, Inst Infect & Immun, Sch Med, Heath Pk, Cardiff CF14 4XN, S Glam, Wales.; Makrigiannis, AP (reprint author), Dalhousie Univ, Dept Microbiol & Immunol, Halifax, NS B3H 4R2, Canada. EM andrew.makrigiannis@dal.ca; stipan.jonjic@medri.uniri.hr; jamie.rossjohn@monash.edu; james.carlyle@utoronto.ca FU Natural Sciences and Engineering Research Council of Canada (NSERC) Post-Graduate Scholarship-Doctoral Award; Canadian Institutes of Health Research (CIHR) Vanier Scholarship; Ontario Graduate Scholarship Award; National Health and Medical Research Council of Australia (NHMRC) Career Development Award [APP1109901]; Australian Research Council Laureate Fellowship [FL160100049]; Croatian Science Foundation [7132]; European Research Council [ERC 322693]; CIHR Operating Grants [86630, 106491]; Ontario Ministry of Research and Innovation [RE07-04-071]; CIHR New Investigator Award; Burroughs Wellcome Fund [1007761] FX We would like to thank Drs. S. Vidal, M.G. Brown, K. Iizuka, W. Yokoyama, and T. Mallevaey for reagents and Y. Amemiya, G. Awong, and G. Knowles for services. We also acknowledge the Monash Macromolecular Crystallization Facility and the staff at the Australian Synchrotron. O.A.A. was supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) Post-Graduate Scholarship-Doctoral Award; A.M. by a Canadian Institutes of Health Research (CIHR) Vanier Scholarship; C.L.K. by an Ontario Graduate Scholarship Award. R.B. is a recipient of a National Health and Medical Research Council of Australia (NHMRC) Career Development Award (APP1109901). J.R. is a recipient of an Australian Research Council Laureate Fellowship (FL160100049). A.K. is supported by the Croatian Science Foundation (Grant #7132). S.J. is supported by an Advanced Grant from the European Research Council (ERC #322693). This work was supported by CIHR Operating Grants (#86630 to A.P.M. and J.R. C.; #106491 to J.R.C.), an Early Researcher Award from the Ontario Ministry of Research and Innovation (#RE07-04-071 to J.R.C.), a CIHR New Investigator Award (to J.R.C.), and an Investigator in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund (#1007761 to J.R.C.). NR 34 TC 0 Z9 0 U1 11 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD MAR 23 PY 2017 VL 169 IS 1 DI 10.1016/j.cell.2017.03.002 PG 28 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EP0PU UT WOS:000397090000008 PM 28340350 ER PT J AU Chowdhury, S Carter, J Rollins, MF Golden, SM Jackson, RN Hoffmann, C Nosaka, L Bondy-Denomy, J Maxwell, KL Davidson, AR Fischer, ER Lander, GC Wiedenheft, B AF Chowdhury, Saikat Carter, Joshua Rollins, MaryClare F. Golden, Sarah M. Jackson, Ryan N. Hoffmann, Connor Nosaka, Lyn'Al Bondy-Denomy, Joseph Maxwell, Karen L. Davidson, Alan R. Fischer, Elizabeth R. Lander, Gabriel C. Wiedenheft, Blake TI Structure Reveals Mechanisms of Viral Suppressors that Intercept a CRISPR RNA-Guided Surveillance Complex SO CELL LA English DT Article ID BACTERIAL IMMUNE-SYSTEM; ESCHERICHIA-COLI; CAS SYSTEMS; ELECTRON-MICROSCOPY; CRYSTAL-STRUCTURE; PSEUDOMONAS-AERUGINOSA; UCSF CHIMERA; CRYO-EM; CASCADE; RECOGNITION AB Genetic conflict between viruses and their hosts drives evolution and genetic innovation. Prokaryotes evolved CRISPR-mediated adaptive immune systems for protection from viral infection, and viruses have evolved diverse anti-CRISPR (Acr) proteins that subvert these immune systems. The adaptive immune system in Pseudomonas aeruginosa (type I-F) relies on a 350 kDa CRISPR RNA (crRNA)-guided surveillance complex (Csy complex) to bind foreign DNA and recruit a trans-acting nuclease for target degradation. Here, we report the cryo-electron microscopy (cryo-EM) structure of the Csy complex bound to two different Acr proteins, AcrF1 and AcrF2, at an average resolution of 3.4 angstrom. The structure explains the molecular mechanism for immune system suppression, and structure-guided mutations show that the Acr proteins bind to residues essential for crRNA-mediated detection of DNA. Collectively, these data provide a snapshot of an ongoing molecular arms race between viral suppressors and the immune system they target. C1 [Chowdhury, Saikat; Nosaka, Lyn'Al; Lander, Gabriel C.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Carter, Joshua; Rollins, MaryClare F.; Golden, Sarah M.; Jackson, Ryan N.; Hoffmann, Connor; Wiedenheft, Blake] Montana State Univ, Dept Microbiol & Immunol, Bozeman, MT 59717 USA. [Bondy-Denomy, Joseph] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94158 USA. [Maxwell, Karen L.; Davidson, Alan R.] Univ Toronto, Dept Biochem, Toronto, ON, Canada. [Davidson, Alan R.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Fischer, Elizabeth R.] NIAID, Res Technol Branch, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Jackson, Ryan N.] Utah State Univ, Dept Chem & Biochem, Logan, UT 84322 USA. RP Lander, GC (reprint author), Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA.; Wiedenheft, B (reprint author), Montana State Univ, Dept Microbiol & Immunol, Bozeman, MT 59717 USA. EM glander@scripps.edu; bwiedenheft@gmail.com FU National Institutes of Health [GM103310, P20GM103500, P30GM110732-03, R01GM110270, R01GM108888, DP2EB020402]; National Science Foundation EPSCoR [EPS-110134]; M.J. Murdock Charitable Trust; Amgen; Montana State University Agricultural Experimental Station; University of California San Francisco Program for Breakthrough in Biomedical Research; NIH Office of the Director Early Independence Award [DP5-OD021344]; Canadian Institutes of Health Research [MOP-130482, MOP-136845]; NIH intramural research program; Sandler Foundation FX We thank Jeff Speir and Anchi Cheng, who aided with early EM data collection and analyses at the National Resource for Automated Molecular Microscopy, which is supported by National Institutes of Health grant (GM103310). We thank Mark A. Herzik, Jr. for advice in model building and C. Martin Lawrence for pointing out the distinct fold of Cas7f. We are grateful to Bill Anderson, TSRI Electron Microscopy facility manager, and Jean-Christophe Ducom at TSRI High Performance Computing for support during EM data collection and processing. Research in the Wiedenheft lab is supported by the National Institutes of Health (P20GM103500, P30GM110732-03, R01GM110270, and R01GM108888), the National Science Foundation EPSCoR (EPS-110134), the M.J. Murdock Charitable Trust, a young investigator award from Amgen, and the Montana State University Agricultural Experimental Station. J.C. is supported by the National Institutes of Health (P20GM103474) through Montana INBRE. R.N.J. is a recipient of the Ruth L. Kirschstein National Research Service Award from the National Institutes of Health (F32 GM108436). G.C.L. is supported as a Searle Scholar, as a Pew Scholar, and by the National Institutes of Health (DP2EB020402). J.B.-D. is supported by the University of California San Francisco Program for Breakthrough in Biomedical Research, funded in part by the Sandler Foundation, and an NIH Office of the Director Early Independence Award (DP5-OD021344). A.R.D. and K.L.M. are supported by the Canadian Institutes of Health Research (MOP-130482 and MOP-136845, respectively). E.R.F. is supported by the NIH intramural research program. NR 62 TC 0 Z9 0 U1 10 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD MAR 23 PY 2017 VL 169 IS 1 DI 10.1016/j.cell.2017.03.012 PG 22 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EP0PU UT WOS:000397090000007 PM 28340349 ER PT J AU Manolio, TA Fowler, DM Starita, LM Haendel, MA MacArthur, DG Biesecker, LG Worthey, E Chisholm, RL Green, ED Jacob, HJ McLeod, HL Roden, D Rodriguez, LL Williams, MS Cooper, GM Cox, NJ Herman, GE Kingsmore, S Lo, C Lutz, C MacRae, CA Nussbaum, RL Ordovas, JM Ramos, EM Robinson, PN Rubinstein, WS Seidman, C Stranger, BE Wang, HY Westerfield, M Bult, C AF Manolio, Teri A. Fowler, Douglas M. Starita, Lea M. Haendel, Melissa A. MacArthur, Daniel G. Biesecker, Leslie G. Worthey, Elizabeth Chisholm, Rex L. Green, Eric D. Jacob, Howard J. McLeod, Howard L. Roden, Dan Rodriguez, Laura Lyman Williams, Marc S. Cooper, Gregory M. Cox, Nancy J. Herman, Gail E. Kingsmore, Stephen Lo, Cecilia Lutz, Cathleen MacRae, Calum A. Nussbaum, Robert L. Ordovas, Jose M. Ramos, Erin M. Robinson, Peter N. Rubinstein, Wendy S. Seidman, Christine Stranger, Barbara E. Wang, Haoyi Westerfield, Monte Bult, Carol TI Bedside Back to Bench: Building Bridges between Basic and Clinical Genomic Research SO CELL LA English DT Editorial Material ID VARIANTS; ASSOCIATION; DISORDERS; GENETICS; DISEASES AB Genome sequencing has revolutionized the diagnosis of genetic diseases. Close collaborations between basic scientists and clinical genomicists are now needed to link genetic variants with disease causation. To facilitate such collaborations, we recommend prioritizing clinically relevant genes for functional studies, developing reference variant- phenotype databases, adopting phenotype description standards, and promoting data sharing. C1 [Manolio, Teri A.; Biesecker, Leslie G.; Green, Eric D.; Rodriguez, Laura Lyman; Ramos, Erin M.] NHGRI, NIH, Bethesda, MD 20892 USA. [Fowler, Douglas M.; Starita, Lea M.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Haendel, Melissa A.] Oregon Hlth & Sci Univ, Dept Med Informat & Clin Epidemiol, Portland, OR 97239 USA. [MacArthur, Daniel G.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [MacArthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Worthey, Elizabeth; Jacob, Howard J.; Cooper, Gregory M.] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. [Chisholm, Rex L.] Northwestern Univ, Feinberg Sch Med, Ctr Genet Med, Chicago, IL 60611 USA. [McLeod, Howard L.] H Lee Moffitt Canc Ctr & Res Inst, DeBartolo Family Personalized Med Inst, Tampa, FL 33612 USA. [Roden, Dan] Vanderbilt Univ, Med Ctr, Dept Med Pharmacol & Biomed Informat, Nashville, TN 37203 USA. [Williams, Marc S.] Geisinger Hlth Syst, Genom Med Inst, Danville, PA 17822 USA. [Cox, Nancy J.] Vanderbilt Univ, Med Ctr, Div Med Genet, Nashville, TN 37203 USA. [Herman, Gail E.] Nationwide Childrens Hosp, Res Inst, Inst Genom Med, Columbus, OH 43205 USA. [Kingsmore, Stephen] Rady Childrens Inst Genom Med, San Diego, CA 92123 USA. [Lo, Cecilia] Univ Pittsburgh, Sch Med, Dept Dev Biol, Pittsburgh, PA 1526 USA. [Lutz, Cathleen] Jackson Lab Mammalian Genet, Rare & Orphan Dis Ctr, Bar Harbor, ME 04609 USA. [MacRae, Calum A.] Brigham & Womens Hosp, Network Med & Genet, Div Cardiovasc Med, Boston, MA 02115 USA. [Nussbaum, Robert L.] Invitae Genet Informat & Testing Co, San Francisco, CA 94107 USA. [Ordovas, Jose M.] Tufts Univ, JM USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Robinson, Peter N.] Jackson Lab Genom Med, Farmington, CT 06032 USA. [Rubinstein, Wendy S.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Seidman, Christine] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Seidman, Christine] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Seidman, Christine] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Stranger, Barbara E.] Univ Chicago, Ctr Data Intens Sci, Inst Genom & Syst Biol, Dept Med,Sect Genet Med, Chicago, IL 60637 USA. [Wang, Haoyi; Bult, Carol] Jackson Lab Mammalian Genet, Bar Harbor, ME 04609 USA. [Westerfield, Monte] Univ Oregon, Dept Biol, Portland, OR 97403 USA. RP Manolio, TA (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM manolio@nih.gov FU NIH HHS [R24 OD011883] NR 15 TC 0 Z9 0 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD MAR 23 PY 2017 VL 169 IS 1 DI 10.1016/j.cell.2017.03.005 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EP0PU UT WOS:000397090000003 PM 28340351 ER PT J AU Moutsopoulos, NM Zerbe, CS Wild, T Dutzan, N Brenchley, L DiPasquale, G Uzel, G Axelrod, KC Lisco, A Notarangelo, LD Hajishengallis, G Notarangelo, LD Holland, SM AF Moutsopoulos, Niki M. Zerbe, Christa S. Wild, Teresa Dutzan, Nicolas Brenchley, Laurie DiPasquale, Giovanni Uzel, Gulbu Axelrod, Karen C. Lisco, Andrea Notarangelo, Lucia D. Hajishengallis, George Notarangelo, Luigi D. Holland, Steven M. TI Interleukin-12 and Interleukin-23 Blockade in Leukocyte Adhesion Deficiency Type 1 SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PYODERMA-GANGRENOSUM; DOUBLE-BLIND; USTEKINUMAB; THERAPY; GRANULOPOIESIS; NEUTROPHILS; INHIBITION; EFFICACY; ANTIBODY; DISEASE AB A patient with leukocyte adhesion deficiency type 1 (LAD1) had severe periodontitis and an intractable, deep, nonhealing sacral wound. We had previously found a dominant interleukin-23-interleukin-17 signature at inflamed sites in humans with LAD1 and in mouse models of the disorder. Blockade of this pathway in mouse models has resulted in resolution of the immunopathologic condition. We treated our patient with ustekinumab, an antibody that binds the p40 subunit of interleukin-23 and interleukin-12 and thereby blocks the activity of these cytokines, inhibiting interleukin-23-dependent production of interleukin-17. After 1 year of therapy, our patient had resolution of his inflammatory lesions without serious infections or adverse reactions. Inhibition of interleukin-23 and interleukin-17 may have a role in the management of LAD1. C1 [Moutsopoulos, Niki M.; Wild, Teresa; Dutzan, Nicolas; Brenchley, Laurie; DiPasquale, Giovanni] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Zerbe, Christa S.; Uzel, Gulbu; Holland, Steven M.] NIH, Lab Clin Infect Dis, Bldg 10, Bethesda, MD 20892 USA. [Axelrod, Karen C.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Axelrod, Karen C.] NIH, Wound Ostomy Care Nursing Serv, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Notarangelo, Lucia D.] Spedali Civili Brescia, Childrens Hosp, Pediat Oncohematol & Bone Marrow Transplantat Uni, Brescia, Italy. [Hajishengallis, George] Univ Penn, Dept Microbiol, Sch Dent Med, Philadelphia, PA 19104 USA. [Notarangelo, Lucia D.] Boston Childrens Hosp, Div Immunol, Boston, MA USA. [Notarangelo, Lucia D.] Harvard Med Sch, Boston, MA USA. RP Holland, SM (reprint author), NIH, Bldg 10-11N248 MSC 1960, Bethesda, MD 20892 USA. EM smh@nih.gov FU Intramural Programs of the National Institute of Allergy and Infectious Diseases; National Institute of Dental and Craniofacial Research; U.S. Public Health Service [DE024153] FX Supported by the Intramural Programs of the National Institute of Allergy and Infectious Diseases, the National Institute of Dental and Craniofacial Research, and the U.S. Public Health Service (grant DE024153 to Dr. Hajishengallis). NR 14 TC 1 Z9 1 U1 2 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 23 PY 2017 VL 376 IS 12 BP 1141 EP 1146 DI 10.1056/NEJMoa1612197 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA EO9NB UT WOS:000397014300010 PM 28328326 ER PT J AU Gross, A Bishop, R Widemann, BC AF Gross, Andrea Bishop, Rachel Widemann, Brigitte C. TI Selumetinib in Plexiform Neurofibromas REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Gross, Andrea] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Bishop, Rachel] NEI, Bethesda, MD 20892 USA. [Widemann, Brigitte C.] NCI, Bethesda, MD 20892 USA. RP Widemann, BC (reprint author), NCI, Bethesda, MD 20892 USA. EM widemanb@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 23 PY 2017 VL 376 IS 12 BP 1195 EP 1195 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA EO9NB UT WOS:000397014300030 PM 28328340 ER PT J AU Herbomel, G Hatte, G Roul, J Padilla-Parra, S Tassan, JP Tramier, M AF Herbomel, Gaetan Hatte, Guillaume Roul, Julien Padilla-Parra, Sergi Tassan, Jean-Pierre Tramier, Marc TI Actomyosin-generated tension on cadherin is similar between dividing and non-dividing epithelial cells in early Xenopus laevis embryos SO SCIENTIFIC REPORTS LA English DT Article ID ADHERENS JUNCTIONS; MECHANICAL TENSION; ALPHA-CATENIN; CYTOKINESIS; ADHESION; TISSUE; MECHANOTRANSDUCTION; DYNAMICS; DIVISION; FORCES AB Epithelia represent a unique situation where polarized cells must maintain sufficiently strong cell-cell contacts to guarantee the epithelial integrity indispensable for barrier functions. Nevertheless, epithelia must also keep sufficient plasticity which is crucial during development and morphogenesis. Adherens junctions and mechanical forces produced by the actomyosin cytoskeleton are major players for epithelial integrity maintenance and plasticity regulations. To understand how the epithelium is able to meet such a challenge, it is indispensable to determine how cellular junctions and mechanical forces acting at adherens junctions are regulated. Here, we investigate the tensile forces acting on adherens junctions via cadherin during cell division in the Xenopus embryos epithelium. Using the recently developed E-cadherin FRET tension sensor and a fastFLIM prototype microscope, we were able to measure mechanical forces applied on cadherin at cell-cell junctions. We have shown that the Xenopus epithelium is under tension, approximately 3 pN which remains stable, indicating that tensile forces acting on cadherin at the adherens junction are at equilibrium. Unexpectedly, mechanical tension across cadherin was similar between dividing and non- dividing epithelial cells. C1 [Herbomel, Gaetan; Hatte, Guillaume; Roul, Julien; Padilla-Parra, Sergi; Tassan, Jean-Pierre; Tramier, Marc] CNRS, UMR 6290, Rennes, France. [Herbomel, Gaetan; Hatte, Guillaume; Roul, Julien; Padilla-Parra, Sergi; Tassan, Jean-Pierre; Tramier, Marc] Univ Rennes 1, Inst Genet & Dev Rennes, 2 Av Pr Leon Bernard, F-35043 Rennes, France. [Tramier, Marc] Univ Rennes 1, Microscopy Rennes Imaging Ctr, Biosit, Rennes, France. [Herbomel, Gaetan] Natl Inst Hlth, Dept Hlth & Human Serv, Sect Biol Chem, NIDCR, Bethesda, MD 20892 USA. [Roul, Julien] CNRS, LAAS, Toulouse, France. [Padilla-Parra, Sergi] Univ Oxford, Div Struct Biol, Henry Wellcome Bldg Genomic Med, Oxford OX3 7BN, England. RP Tassan, JP; Tramier, M (reprint author), CNRS, UMR 6290, Rennes, France.; Tassan, JP; Tramier, M (reprint author), Univ Rennes 1, Inst Genet & Dev Rennes, 2 Av Pr Leon Bernard, F-35043 Rennes, France.; Tramier, M (reprint author), Univ Rennes 1, Microscopy Rennes Imaging Ctr, Biosit, Rennes, France. EM jean-pierre.tassan@univ-rennes1.fr; marc.tramier@univ-rennes1.fr FU Agence Nationale pour la Recherche (ANR): KinBioFRET program [ANR-11-BSV5-0023]; IBiSA; Region Bretagne and Rennes Metropole; CNRS; MENESR; Ligue Nationale contre le Cancer FX This work was mainly carried out at the Microscopy Rennes Imaging Centre (MRic) imaging facilities. We thank Dr. S. Dutertre and Dr. C. Chevalier for their constant effort to provide the microscopes at their best performance. We also acknowledge Dr. S. Huet and Dr. R. Leborgne for advice and comments during the execution of this project, Dr. Y. Le Cunff for helpful discussion with statistical analysis and Dr. G. Bertolin for critical reading of the manuscript. We thank Dr. N. Borghi (Institut Jacques Monod, Paris, France) and Dr. BM. Gumbiner (University of Washington, Seattle, USA) for plasmid constructs and Dr. P. McCrea (University of Texas, Houston, USA) for antibodies. This research was supported by the Agence Nationale pour la Recherche (ANR): KinBioFRET program (ANR-11-BSV5-0023) to MT and JPT. The development of the fast FLIM prototype was funded by IBiSA, Region Bretagne and Rennes Metropole. Research in the MT and JPT groups are further supported by CNRS and UR1. G. Hatte was supported by the MENESR and partly by a grant from the Ligue Nationale contre le Cancer. NR 35 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 22 PY 2017 VL 7 AR 45058 DI 10.1038/srep45058 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EO9CZ UT WOS:000396988100001 PM 28327558 ER PT J AU Matsui, A Alvarez, VA AF Matsui, Aya Alvarez, Veronica A. TI Undercover Power of Endocannabinoids: Postsynaptic Ion-Channel Modulator SO NEURON LA English DT Editorial Material ID PURKINJE-CELLS; ANANDAMIDE; INHIBITION; SYNAPSES AB In this issue of Neuron, Gantz and Bean (2017) show that the endocannabinoid 2-arachidonoyl glycerol (2-AG) can directly alter the properties of native ion-channel Kv4.3 and accelerate the pacemaker activity of rodent dopamine neurons. These findings are one of the first demonstrations of postsynaptic, cell-autonomous actions of endocannabinoids in the mammalian brain. C1 [Matsui, Aya; Alvarez, Veronica A.] Natl Inst Hlth, Natl Inst Alcohol Abuse & Alcoholism, Lab Neurobiol Compuls Behaviors, Bethesda, MD 20892 USA. RP Alvarez, VA (reprint author), Natl Inst Hlth, Natl Inst Alcohol Abuse & Alcoholism, Lab Neurobiol Compuls Behaviors, Bethesda, MD 20892 USA. EM alvarezva@mail.nih.gov NR 12 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD MAR 22 PY 2017 VL 93 IS 6 BP 1243 EP 1244 DI 10.1016/j.neuron.2017.03.014 PG 3 WC Neurosciences SC Neurosciences & Neurology GA EO9DT UT WOS:000396990100003 PM 28334600 ER PT J AU Gantz, SC Bean, BP AF Gantz, Stephanie C. Bean, Bruce P. TI Cell-Autonomous Excitation of Midbrain Dopamine Neurons by Endocannabinoid-Dependent Lipid Signaling SO NEURON LA English DT Article ID VENTRAL TEGMENTAL AREA; CB1 CANNABINOID RECEPTOR; MOSSY FIBER BOUTONS; A-TYPE; POTASSIUM CHANNELS; ENDOGENOUS CANNABINOIDS; SUBSTANTIA-NIGRA; ARACHIDONIC-ACID; K+ CHANNELS; NEOCORTICAL INTERNEURONS AB The major endocannabinoid in the mammalian brain is the bioactive lipid 2-arachidonoylglycerol (2-AG). The best-known effects of 2-AG are mediated by G-protein-coupled cannabinoid receptors. In principle, 2-AG could modify neuronal excitability by acting directly on ion channels, but such mechanisms are poorly understood. Using a preparation of dissociated mouse midbrain dopamine neurons to isolate effects on intrinsic excitability, we found that 100 nM 2-AG accelerated pacemaking and steepened the frequency-current relationship for burst-like firing. In voltage-clamp experiments, 2-AG reduced A-type potassium current (IA) through a cannabinoid receptor-independent mechanism mimicked by arachidonic acid, which has no activity on cannabinoid receptors. Activation of orexin, neurotensin, and metabotropic glutamate G(q/11)-linked receptors mimicked the effects of exogenous 2-AG and their actions were prevented by inhibiting the 2-AG-synthesizing enzyme diacylglycerol lipase alpha. The results show that 2-AG and related lipid signaling molecules can directly tune neuronal excitability in a cell-autonomous manner by modulating I-A. C1 [Gantz, Stephanie C.; Bean, Bruce P.] Harvard Med Sch, Dept Neurobiol, Boston, MA 02115 USA. [Gantz, Stephanie C.] Natl Inst Drug Abuse, Synapt Plast Sect, Intramural Res Program, Baltimore, MD 21224 USA. RP Gantz, SC; Bean, BP (reprint author), Harvard Med Sch, Dept Neurobiol, Boston, MA 02115 USA.; Gantz, SC (reprint author), Natl Inst Drug Abuse, Synapt Plast Sect, Intramural Res Program, Baltimore, MD 21224 USA. EM stephanie.gantz@nih.gov; bruce_bean@hms.harvard.edu FU NINDS [R01NS036855] FX This work was supported by NINDS R01NS036855. NR 85 TC 1 Z9 1 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD MAR 22 PY 2017 VL 93 IS 6 BP 1375 EP + DI 10.1016/j.neuron.2017.02.025 PG 15 WC Neurosciences SC Neurosciences & Neurology GA EO9DT UT WOS:000396990100014 PM 28262417 ER PT J AU Nguyen, TH Park, MD Otto, M AF Nguyen, Thuan H. Park, Matthew D. Otto, Michael TI Host Response to Staphylococcus epidermidis Colonization and Infections SO FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY LA English DT Review DE Coagulase-negative staphylococci; Staphylococcus epidermidis; innate immunity; host defense; sepsis; biofilms; biofilm-associated infection ID COAGULASE-NEGATIVE STAPHYLOCOCCI; BIOFILM FORMATION; ATOPIC-DERMATITIS; OXIDATIVE-BURST; IMMUNE-SYSTEM; ECZEMA FRIEND; HUMAN SKIN; CELLS; PHAGOCYTOSIS; COMPLEMENT AB The majority of research in the Staphylococcus field has been dedicated to the understanding of Staphylococcus aureus infections. In contrast, there is limited information on infections by coagulase-negative Staphylococci (CoNS) and how the host responds to them. S. epidermidis, a member of the coagulase-negative Staphylococci, is an important commensal organism of the human skin and mucous membranes; and there is emerging evidence of its benefit for human health in fighting off harmful microorganisms. However, S. epidermidis can cause opportunistic infections, which include particularly biofilm-associated infections on indwelling medical devices. These often can disseminate into the bloodstream; and in fact, S. epidermidis is the most frequent cause of nosocomial sepsis. The increasing use of medical implants and the dramatic shift in the patient demographic population in recent years have contributed significantly to the rise of S. epidermidis infections. Furthermore, treatment has been complicated by the emergence of antibiotic-resistant strains. Today, S. epidermidis is a major nosocomial pathogen posing significant medical and economic burdens. In this review, we present the current understanding of mechanisms of host defense against the prototypical CoNS species S. epidermidis as a commensal of the skin and mucous membranes, and during biofilm-associated infection and sepsis. C1 [Nguyen, Thuan H.; Park, Matthew D.; Otto, Michael] Natl Inst Hlth, Natl Inst Allergy & Infect Dis, Bacteriol Lab, Pathogen Mol Genet Sect, Bethesda, MD 20892 USA. RP Otto, M (reprint author), Natl Inst Hlth, Natl Inst Allergy & Infect Dis, Bacteriol Lab, Pathogen Mol Genet Sect, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID); U.S. National Institutes of Health (NIH) [ZIA AI001080] FX This study was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH), project number ZIA AI001080. NR 52 TC 0 Z9 0 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2235-2988 J9 FRONT CELL INFECT MI JI Front. Cell. Infect. Microbiol. PD MAR 21 PY 2017 VL 7 AR 90 DI 10.3389/fcimb.2017.00090 PG 7 WC Immunology; Microbiology SC Immunology; Microbiology GA EO8IB UT WOS:000396931400003 PM 28377905 ER PT J AU Gulley, JL Berzofsky, JA Butler, MO Cesano, A Fox, BA Gnjatic, S Janetzki, S Kalavar, S Karanikas, V Khleif, SN Kirsch, I Lee, PP Maccalli, C Maecker, H Schlom, J Seliger, B Siebert, J Stroncek, DF Thurin, M Yuan, JD Butterfield, LH AF Gulley, James L. Berzofsky, Jay A. Butler, Marcus O. Cesano, Alessandra Fox, Bernard A. Gnjatic, Sacha Janetzki, Sylvia Kalavar, Shyam Karanikas, Vaios Khleif, Samir N. Kirsch, Ilan Lee, Peter P. Maccalli, Cristina Maecker, Holden Schlom, Jeffrey Seliger, Barbara Siebert, Janet Stroncek, David F. Thurin, Magdalena Yuan, Jianda Butterfield, Lisa H. TI Immunotherapy biomarkers 2016: overcoming the barriers SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Article DE Biomarkers; Immunotherapy; Immune monitoring; High throughput; Baseline measures; Tumor microenvironment ID MONITORING TECHNOLOGY PRIMER; T-CELL RESPONSES; ADVANCED MELANOMA PATIENTS; CHIMERIC ANTIGEN RECEPTOR; PD-1 BLOCKADE; LUNG-CANCER; IMMUNE CONTEXTURE; PERIPHERAL-BLOOD; PREDICT RESPONSE; DRUG DEVELOPMENT AB This report summarizes the symposium, 'Immunotherapy Biomarkers 2016: Overcoming the Barriers', which was held on April 1, 2016 at the National Institutes of Health in Bethesda, Maryland. The symposium, cosponsored by the Society for Immunotherapy of Cancer (SITC) and the National Cancer Institute (NCI), focused on emerging immunotherapy biomarkers, new technologies, current hurdles to further progress, and recommendations for advancing the field of biomarker development. C1 [Gulley, James L.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, 10 Ctr Dr,13 N240, Bethesda, MD 20892 USA. [Berzofsky, Jay A.] Ctr Canc Res, Vaccine Branch, 41 Medlars Dr,Bldg 41 Rm D702D, Bethesda, MD 20892 USA. [Butler, Marcus O.] Princess Margaret Canc Ctr, Ontario Canc Inst, RM 9-622,610 Univ Ave, Toronto, ON, Canada. [Cesano, Alessandra] NanoString Inc, 500 Fairview Ave North, Seattle, WA 98109 USA. [Fox, Bernard A.] Providence Canc Ctr, Earle A Chiles Res Inst, 4805 NE Glisan St, Portland, OR 97213 USA. [Gnjatic, Sacha] Icahn Sch Med Mt Sinai, Dept Hematol Oncol, Tisch Canc Inst, S5-105,1470 Madison Ave,Box 1128, New York, NY 10029 USA. [Janetzki, Sylvia] ZellNet Consulting Inc, 555 North Ave, Ft Lee, NJ 07024 USA. [Kalavar, Shyam] US FDA, Ctr Devices & Radiol Hlth, 1401 Rockville Pike, Rockville, MD 20852 USA. [Karanikas, Vaios] Roche Innovat Ctr Zurich, Wagistr 18, Schlieren, Switzerland. [Khleif, Samir N.] Augusta Univ, Georgia Canc Ctr, 1120 15th St,CN-2101A, Augusta, GA 30912 USA. [Kirsch, Ilan] Adapt Biotechnol Inc, 1551 Eastlake Ave E, Seattle, WA 98102 USA. [Lee, Peter P.] City Hope Natl Med Ctr, Dept Immunooncol, 1500 East Duarte Rd, Duarte, CA 91010 USA. [Maccalli, Cristina] Sidra Med & Res Ctr, Dept Translat Med, Doha, Qatar. [Maecker, Holden] Stanford Univ, Med Ctr, 299 Campus Dr, Stanford, CA 94303 USA. [Schlom, Jeffrey] NCI, NIH, 10 Ctr Dr,Bldg 10,Room 8B09, Bethesda, MD 20892 USA. [Seliger, Barbara] Martin Luther Univ Halle Wittenberg, Inst Med Immunol, Magdeburger Str 2, Halle, Germany. [Siebert, Janet] CytoAnalytics, 3500 South Alb St, Cherry Hills Village, CO 80113 USA. [Stroncek, David F.] NIH, Dept Transfus Med, 10 Ctr Dr,Bldg 10,Room 3C720, Bethesda, MD 20892 USA. [Thurin, Magdalena] NCI, Canc Diag Program, DCTD, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Yuan, Jianda] Merck Res Labs, Early Clin Oncol Dev, Rahway, NJ 07065 USA. [Butterfield, Lisa H.] Univ Pittsburgh, Inst Canc, Dept Med Surg & Immunol, 5117 Ctr Ave, Pittsburgh, PA 15213 USA. RP Butterfield, LH (reprint author), Univ Pittsburgh, Inst Canc, Dept Med Surg & Immunol, 5117 Ctr Ave, Pittsburgh, PA 15213 USA. EM butterfieldl@upmc.edu NR 75 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-1426 J9 J IMMUNOTHER CANCER JI J. Immunother. Cancer PD MAR 21 PY 2017 VL 5 AR 29 DI 10.1186/s40425-017-0225-6 PG 10 WC Oncology SC Oncology GA EO8CT UT WOS:000396917300002 ER PT J AU Hege, KM Bergsland, EK Fisher, GA Nemunaitis, JJ Warren, RS McArthur, JG Lin, AA Schlom, J June, CH Sherwin, SA AF Hege, Kristen M. Bergsland, Emily K. Fisher, George A. Nemunaitis, John J. Warren, Robert S. McArthur, James G. Lin, Andy A. Schlom, Jeffrey June, Carl H. Sherwin, Stephen A. TI Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Article ID T-CELLS; IN-VIVO; ANTIBODY CC49; INFILTRATING LYMPHOCYTES; CARCINOEMBRYONIC ANTIGEN; ADOPTIVE IMMUNOTHERAPY; MONOCLONAL-ANTIBODIES; METASTATIC MELANOMA; ANTITUMOR-ACTIVITY; GLYCOPROTEIN-72 AB Background: T cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s. Methods: Patients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-alpha) was given with each CART72 infusion to upregulate expression of TAG-72. Results: Fourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (<= 14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had (111)Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed. Conclusion: These findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity. C1 [Hege, Kristen M.; McArthur, James G.; Lin, Andy A.; Sherwin, Stephen A.] Cell Genesys Inc, Foster City, CA 94404 USA. [Hege, Kristen M.] Celgene Corp, San Francisco, CA 94158 USA. [Hege, Kristen M.; Bergsland, Emily K.; Warren, Robert S.; Sherwin, Stephen A.] Stanford Univ, Stanford, CA 94305 USA. [Nemunaitis, John J.] Mary Crowley Canc Ctr, Dallas, TX USA. [Schlom, Jeffrey] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, Bethesda, MD 20892 USA. [June, Carl H.] Univ Penn, Philadelphia, PA 19104 USA. RP Hege, KM (reprint author), Cell Genesys Inc, Foster City, CA 94404 USA.; Hege, KM (reprint author), Celgene Corp, San Francisco, CA 94158 USA.; Hege, KM (reprint author), Stanford Univ, Stanford, CA 94305 USA. EM khege@celgene.com FU Cell Genesys; Aventis Pharmaceuticals FX The CC-9701 and CC-9702 clinical trials were sponsored and funded by Cell Genesys in partnership with Aventis Pharmaceuticals. NR 43 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-1426 J9 J IMMUNOTHER CANCER JI J. Immunother. Cancer PD MAR 21 PY 2017 VL 5 AR 22 DI 10.1186/s40425-017-0222-9 PG 14 WC Oncology SC Oncology GA EO8CL UT WOS:000396916400002 PM 28344808 ER PT J AU Stroncek, DF Butterfield, LH Cannarile, MA Dhodapkar, MV Greten, TF Grivel, JC Kaufman, DR Kong, HH Korangy, F Lee, PP Marincola, F Rutella, S Siebert, JC Trinchieri, G Seliger, B AF Stroncek, David F. Butterfield, Lisa H. Cannarile, Michael A. Dhodapkar, Madhav V. Greten, Tim F. Grivel, Jean Charles Kaufman, David R. Kong, Heidi H. Korangy, Firouzeh Lee, Peter P. Marincola, Francesco Rutella, Sergio Siebert, Janet C. Trinchieri, Giorgio Seliger, Barbara TI Systematic evaluation of immune regulation and modulation SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Review DE Immune biomarkers; Systematic monitoring; Immune regulation; High-throughput ID TUMOR-INFILTRATING LYMPHOCYTES; CHIMERIC-ANTIGEN-RECEPTOR; CD8(+) T-CELLS; METASTATIC MELANOMA PATIENTS; MISMATCH-REPAIR DEFICIENCY; CYTOKINE RELEASE SYNDROME; EXPANDED ACCESS PROGRAM; ACUTE MYELOID-LEUKEMIA; BREAST-CANCER PATIENTS; ADOPTIVE TRANSFER AB Cancer immunotherapies are showing promising clinical results in a variety of malignancies. Monitoring the immune as well as the tumor response following these therapies has led to significant advancements in the field. Moreover, the identification and assessment of both predictive and prognostic biomarkers has become a key component to advancing these therapies. Thus, it is critical to develop systematic approaches to monitor the immune response and to interpret the data obtained from these assays. In order to address these issues and make recommendations to the field, the Society for Immunotherapy of Cancer reconvened the Immune Biomarkers Task Force. As a part of this Task Force, Working Group 3 (WG3) consisting of multidisciplinary experts from industry, academia, and government focused on the systematic assessment of immune regulation and modulation. In this review, the tumor microenvironment, microbiome, bone marrow, and adoptively transferred T cells will be used as examples to discuss the type and timing of sample collection. In addition, potential types of measurements, assays, and analyses will be discussed for each sample. Specifically, these recommendations will focus on the unique collection and assay requirements for the analysis of various samples as well as the high-throughput assays to evaluate potential biomarkers. C1 [Stroncek, David F.] NIH, Dept Transfus Med, 10 Ctr Dr,Bldg 10,Room 3C720, Bethesda, MD 20892 USA. [Butterfield, Lisa H.] Univ Pittsburgh, Inst Canc, Dept Med Surg & Immunol, 5117 Ctr Ave, Pittsburgh, PA 15213 USA. [Cannarile, Michael A.] Roche Innovat Ctr Munich, Roche Pharmaceut Res & Early Dev, Nonnenwald 2, D-82377 Penzberg, Germany. [Dhodapkar, Madhav V.] Yale Univ, Dept Hematol & Immunobiol, 333 Cedar St,Box 208021, New Haven, CT 06510 USA. [Greten, Tim F.; Korangy, Firouzeh] NCI, GI Malignancy Sect, Thorac & GI Oncol Branch, Ctr Canc Res,NIH, Bldg 10 Room 12 N226,9000 Rockville, Bethesda, MD 20892 USA. [Grivel, Jean Charles; Marincola, Francesco] Sidra Med & Res Ctr, Div Translat Med, POB 26999Al Luqta St, Doha, Qatar. [Kaufman, David R.] Merck Res Labs, POB 1000UG 3CD28, N Wales, PA 19454 USA. [Kong, Heidi H.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10,MSC 1908, Bethesda, MD 20892 USA. [Lee, Peter P.] City Hope Natl Med Ctr, Dept Immunooncol, 1500 East Duarte Rd, Duarte, CA 91010 USA. [Rutella, Sergio] Nottingham Trent Univ, John van Geest Canc Res Ctr, Clifton Campus, Nottingham NG11 8NS, England. [Siebert, Janet C.] CytoAnalytics, 3500 South Alb St, Cherry Hills Village, CO 80113 USA. [Trinchieri, Giorgio] NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Bldg 37 Room 4146, Bethesda, MD 20892 USA. [Seliger, Barbara] Martin Luther Univ Halle Wittenberg, Inst Med Immunol, Magdeburger Str 2, Halle, Germany. RP Stroncek, DF (reprint author), NIH, Dept Transfus Med, 10 Ctr Dr,Bldg 10,Room 3C720, Bethesda, MD 20892 USA. EM dstroncek@cc.nih.gov NR 222 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-1426 J9 J IMMUNOTHER CANCER JI J. Immunother. Cancer PD MAR 21 PY 2017 VL 5 AR 21 DI 10.1186/s40425-017-0223-8 PG 23 WC Oncology SC Oncology GA EO8CL UT WOS:000396916400001 PM 28331613 ER PT J AU Kim, HS Yeom, YS Nguyen, TT Choi, C Han, MC Lee, JK Kim, CH Zankl, M Petoussi-Henss, N Bolch, WE Lee, C Qiu, R Eckerman, K Chung, BS AF Kim, Han Sung Yeom, Yeon Soo Thang Tat Nguyen Choi, Chansoo Han, Min Cheol Lee, Jai Ki Kim, Chan Hyeong Zankl, Maria Petoussi-Henss, Nina Bolch, Wesley E. Lee, Choonsik Qiu, Rui Eckerman, Keith Chung, Beom Sun TI Inclusion of thin target and source regions in alimentary and respiratory tract systems of mesh-type ICRP adult reference phantoms SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE specific absorbed fraction; alimentary tract system; respiratory tract system; ICRP reference phantom; mesh phantom; Monte Carlo ID SIMULATION; CONVERSION AB It is not feasible to define very small or complex organs and tissues in the current voxel-type adult reference computational phantoms of the International Commission on Radiological Protection (ICRP), which limit dose coefficients for weakly penetrating radiations. To address the problem, the ICRP is converting the voxel-type reference phantoms into mesh-type phantoms. In the present study, as a part of the conversion project, the micrometer-thick target and source regions in the alimentary and respiratory tract systems as described in ICRP Publications 100 and 66 were included in the mesh-type ICRP reference adult male and female phantoms. In addition, realistic lung airway models were simulated to represent the bronchial (BB) and bronchiolar (bb) regions. The electron specific absorbed fraction (SAF) values for the alimentary and respiratory tract systems were then calculated and compared with the values calculated with the stylized models of ICRP Publications 100 and 66. The comparisons show generally good agreement for the oral cavity, oesophagus, and BB, whereas for the stomach, small intestine, large intestine, extrathoracic region, and bb, there are some differences (e.g. up to similar to 9 times in the large intestine). The difference is mainly due to anatomical difference in these organs between the realistic mesh-type phantoms and the simplified stylized models. The new alimentary and respiratory tract models in the meshtype ICRP reference phantoms preserve the topology and dimensions of the voxel-type ICRP phantoms and provide more reliable SAF values than the simplified models adopted in previous ICRP Publications. C1 [Kim, Han Sung; Yeom, Yeon Soo; Thang Tat Nguyen; Choi, Chansoo; Han, Min Cheol; Lee, Jai Ki; Kim, Chan Hyeong] Hanyang Univ, Dept Nucl Engn, Seoul, South Korea. [Zankl, Maria; Petoussi-Henss, Nina] Deutsch Forschungszentrum Gesundheit & Umwelt Gmb, Helmholtz Zentrum Munchen, Res Unit Med Radiat Phys & Diagnost, Neuherberg, Germany. [Bolch, Wesley E.] Univ Florida, J Crayton Pruitt Family Dept Biomed Engn, Gainesville, FL USA. [Lee, Choonsik] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Qiu, Rui] Tsinghua Univ, Dept Engn Phys, Beijing, Peoples R China. [Eckerman, Keith] Oak Ridge Natl Lab, Oak Ridge, TN USA. [Chung, Beom Sun] Ajou Univ, Sch Med, Dept Anat, Suwon, South Korea. RP Kim, CH (reprint author), Hanyang Univ, Dept Nucl Engn, Seoul, South Korea. EM chkim@hanyang.ac.kr FU Nuclear Safety and Security Commission (NSSC) through the Korea Foundation of Nuclear Safety (KOFONS); Ministry of Science, ICT and Future Planning through the National Research Foundation of Korea [1403012, 2016R1D1A1A09916337]; ETRI R&D Program - Government of Korea [15ZC1810] FX This project was supported by the Nuclear Safety and Security Commission (NSSC) through the Korea Foundation of Nuclear Safety (KOFONS) and also by the Ministry of Science, ICT and Future Planning through the National Research Foundation of Korea (Project No.: 1403012, 2016R1D1A1A09916337). This work was also supported by ETRI R&D Program (Development of particle beam range verification technology based on prompt gamma-ray measurements, 15ZC1810) funded by the Government of Korea. NR 26 TC 0 Z9 0 U1 0 U2 0 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD MAR 21 PY 2017 VL 62 IS 6 BP 2132 EP 2152 DI 10.1088/1361-6560/aa5b72 PG 21 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA EN3VD UT WOS:000395935100006 ER PT J AU Krupovic, M Koonin, EV AF Krupovic, Mart Koonin, Eugene V. TI Multiple origins of viral capsid proteins from cellular ancestors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE virus evolution; capsid proteins; nucleocapsids; origin of viruses; primordial replicons ID STRANDED-DNA VIRUSES; CRYSTAL-STRUCTURE; MATRIX PROTEIN; NUCLEOPROTEIN REVEALS; PROVIDES INSIGHT; STRUCTURAL BASIS; BUILDING-BLOCK; GIANT VIRUSES; CORE PROTEIN; RNA VIRUSES AB Viruses are the most abundant biological entities on earth and show remarkable diversity of genome sequences, replication and expression strategies, and virion structures. Evolutionary genomics of viruses revealed many unexpected connections but the general scenario(s) for the evolution of the virosphere remains a matter of intense debate among proponents of the cellular regression, escaped genes, and primordial virus world hypotheses. A comprehensive sequence and structure analysis of major virion proteins indicates that they evolved on about 20 independent occasions, and in some of these cases likely ancestors are identifiable among the proteins of cellular organisms. Virus genomes typically consist of distinct structural and replication modules that recombine frequently and can have different evolutionary trajectories. The present analysis suggests that, although the replication modules of at least some classes of viruses might descend from primordial selfish genetic elements, bona fide viruses evolved on multiple, independent occasions throughout the course of evolution by the recruitment of diverse host proteins that became major virion components. C1 [Krupovic, Mart] Inst Pasteur, Dept Microbiol, Unite Biol Mol Gene Chez Extremophiles, F-75015 Paris, France. [Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Krupovic, M (reprint author), Inst Pasteur, Dept Microbiol, Unite Biol Mol Gene Chez Extremophiles, F-75015 Paris, France.; Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM krupovic@pasteur.fr; koonin@ncbi.nlm.nih.gov NR 111 TC 0 Z9 0 U1 5 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 21 PY 2017 VL 114 IS 12 BP E2401 EP E2410 DI 10.1073/pnas.1621061114 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EO7TS UT WOS:000396893600019 PM 28265094 ER PT J AU Rao, MP Al-Khatib, SM Pokorney, SD She, LL Romanov, A Nicolau, JC Lee, KL Carson, P Selzman, CH Stepinska, J Cleland, JGF Tungsubutra, W Desvigne-Nickens, PM Sueta, CA Siepe, M Lang, I Feldman, AM Yii, M Rouleau, JL Velazquez, EJ AF Rao, Meena P. Al-Khatib, Sana M. Pokorney, Sean D. She, Lilin Romanov, Alexander Nicolau, Jose C. Lee, Kerry L. Carson, Peter Selzman, Craig H. Stepinska, Janina Cleland, John G. F. Tungsubutra, Wiwun Desvigne-Nickens, Patrice M. Sueta, Carla A. Siepe, Matthias Lang, Irene Feldman, Arthur M. Yii, Michael Rouleau, Jean L. Velazquez, Eric J. CA STICH Trial Investigators TI Sudden Cardiac Death in Patients With Ischemic Heart Failure Undergoing Coronary Artery Bypass Grafting Results From the STICH Randomized Clinical Trial (Surgical Treatment for Ischemic Heart Failure) SO CIRCULATION LA English DT Article DE coronary artery bypass; death, sudden, cardiac; heart failure ID IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR; HIGH-RISK; VENTRICULAR RECONSTRUCTION; EJECTION FRACTION; SURGERY; REVASCULARIZATION; CARDIOMYOPATHY; ASSOCIATION; PREVENTION; THERAPY AB BACKGROUND: The risk of sudden cardiac death (SCD) in patients with heart failure after coronary artery bypass graft surgery (CABG) has not been examined in a contemporary clinical trial of surgical revascularization. This analysis describes the incidence, timing, and clinical predictors of SCD after CABG. METHODS: Patients enrolled in the STICH trial (Surgical Treatment of Ischemic Heart Failure) who underwent CABG with or without surgical ventricular reconstruction were included. We excluded patients with prior implantable cardioverter-defibrillator and those randomized only to medical therapy. The primary outcome was SCD as adjudicated by a blinded committee. A Cox model was used to examine and identify predictors of SCD. The Fine and Gray method was used to estimate the incidence of SCD accounting for the competing risk of other deaths. RESULTS: Over a median follow-up of 46 months, 113 of 1411 patients who received CABG without (n =934) or with (n =477) surgical ventricular reconstruction had SCD; 311 died of other causes. The mean left ventricular ejection fraction at enrollment was 28 +/- 9%. The 5-year cumulative incidence of SCD was 8.5%. Patients who had SCD and those who did not die were younger and had fewer comorbid conditions than did those who died of causes other than SCD. In the first 30 days after CABG, SCD (n=5) accounted for 7% of all deaths. The numerically greatest monthly rate of SCD was in the 31-to 90-day time period. In a multivariable analysis including baseline demographics, risk factors, coronary anatomy, and left ventricular function, end-systolic volume index and B-type natriuretic peptide were most strongly associated with SCD. CONCLUSIONS: The monthly risk of SCD shortly after CABG among patients with a low left ventricular ejection fraction is highest between the first and third months, suggesting that risk stratification for SCD should occur early in the postoperative period, particularly in patients with increased preoperative end-systolic volume index or B-type natriuretic peptide. C1 [Rao, Meena P.; Al-Khatib, Sana M.; Pokorney, Sean D.; She, Lilin; Lee, Kerry L.; Velazquez, Eric J.] Duke Clin Res Inst, POB 17969, Durham, NC 27715 USA. [Lee, Kerry L.] Duke Univ, Sch Med, Dept Biostat & Bioinformat, Durham, NC USA. [Al-Khatib, Sana M.; Velazquez, Eric J.] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Romanov, Alexander] State Res Inst Circulat Pathol, Novosibirsk, Russia. [Nicolau, Jose C.] Univ Sao Paulo, Sch Med, Inst Heart, Sao Paulo, Brazil. [Carson, Peter] Washington DC Vet Affairs Med Ctr, Washington, DC USA. [Selzman, Craig H.] Univ Utah, Div Cardiothorac Surg, Salt Lake City, UT USA. [Stepinska, Janina] Inst Cardiol, Warsaw, Poland. [Cleland, John G. F.] Imperial Coll, Natl Heart & Lung Inst, Royal Brompton Hosp, London, England. [Cleland, John G. F.] Imperial Coll, Natl Heart & Lung Inst, Harefield Hosp, London, England. [Tungsubutra, Wiwun] Mahidol Univ, Siriraj Hosp, Bangkok, Thailand. [Desvigne-Nickens, Patrice M.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. [Sueta, Carla A.] Univ N Carolina, Chapel Hill, NC USA. [Siepe, Matthias] Univ Heart Ctr Freiburg Bad Krozingen, Bad Krozingen, Germany. [Lang, Irene] Med Univ Vienna, Vienna, Austria. [Feldman, Arthur M.] Temple Univ, Dept Med, Philadelphia, PA 19122 USA. [Yii, Michael] Univ Melbourne, St Vincents Hosp, Fitzroy, Vic, Australia. [Rouleau, Jean L.] Univ Montreal, Dept Med, Montreal Heart Inst, Quebec City, PQ, Canada. RP Velazquez, EJ (reprint author), Duke Clin Res Inst, POB 17969, Durham, NC 27715 USA. EM velazquez@duke.edu FU National Heart, Lung, and Blood Institute/National Institutes of Health [U01-HL69015, U01-HL69013, R01-HL10583] FX This work was supported by grants U01-HL69015, U01-HL69013, and R01-HL10583 from the National Heart, Lung, and Blood Institute/National Institutes of Health. The views expressed in this article do not necessarily reflect those of the National Heart, Lung, and Blood Institute or the National Institutes of Health. NR 21 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 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 21 PY 2017 VL 135 IS 12 BP 1136 EP 1144 DI 10.1161/CIRCULATIONAHA.116.026075 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EO5LA UT WOS:000396733400018 PM 28154006 ER PT J AU Dufouil, C Beiser, A McLure, LA Wolf, PA Tzourio, C Howard, VJ Westwood, AJ Himali, JJ Sullivan, L Aparicio, HJ Kelly-Hayes, M Ritchie, K Kase, CS Pikula, A Romero, JR D'Agostino, RB Samieri, C Vasan, RS Chene, G Howard, G Seshadri, S AF Dufouil, Carole Beiser, Alexa McLure, Leslie A. Wolf, Philip A. Tzourio, Christophe Howard, Virginia J. Westwood, Andrew J. Himali, Jayandra J. Sullivan, Lisa Aparicio, Hugo J. Kelly-Hayes, Margaret Ritchie, Karen Kase, Carlos S. Pikula, Aleksandra Romero, Jose R. D'Agostino, Ralph B. Samieri, Cecilia Vasan, Ramachandran S. Chene, Genevieve Howard, George Seshadri, Sudha TI Revised Framingham Stroke Risk Profile to Reflect Temporal Trends SO CIRCULATION LA English DT Article DE cerebrovascular disorders; cohort studies; epidemiology; primary prevention; statistics [publication type] ID ATRIAL-FIBRILLATION; RACIAL-DIFFERENCES; PREDICTION MODELS; SURVIVAL ANALYSIS; ISCHEMIC-STROKE; LIFETIME RISK; POPULATION; COHORT; PREVALENCE; MORTALITY AB BACKGROUND: Age-adjusted stroke incidence has decreased over the past 50 years, likely as a result of changes in the prevalence and impact of various stroke risk factors. An updated version of the Framingham Stroke Risk Profile (FSRP) might better predict current risks in the FHS (Framingham Heart Study) and other cohorts. We compared the accuracy of the standard (old) and of a revised (new) version of the FSRP in predicting the risk of all-stroke and ischemic stroke and validated this new FSRP in 2 external cohorts, the 3C (3 Cities) and REGARDS (Reasons for Geographic and Racial Differences in Stroke) studies. METHODS: We computed the old FSRP as originally described and a new model that used the most recent epoch-specific risk factor prevalence and hazard ratios for individuals >= 55 years of age and for the subsample >= 65 years of age (to match the age range in REGARDS and 3C studies, respectively) and compared the efficacy of these models in predicting 5-and 10-year stroke risks. RESULTS: The new FSRP was a better predictor of current stroke risks in all 3 samples than the old FSRP (calibration.2 of new/old FSRP: in men: 64.0/12.1, 59.4/30.6, and 20.7/12.5; in women: 42.5/4.1, 115.4/90.3, and 9.8/6.5 in FHS, REGARDS, and 3C, respectively). In the REGARDS, the new FSRP was a better predictor among whites compared with blacks. CONCLUSIONS: A more contemporaneous, new FSRP better predicts current risks in 3 large community samples and could serve as the basis for examining geographic and racial differences in stroke risk and the incremental diagnostic utility of novel stroke risk factors. C1 [Beiser, Alexa; Wolf, Philip A.; Himali, Jayandra J.; Aparicio, Hugo J.; Kelly-Hayes, Margaret; Kase, Carlos S.; Pikula, Aleksandra; Romero, Jose R.; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, 72 E Concord St,B-602, Boston, MA 02118 USA. [Dufouil, Carole; Tzourio, Christophe; Samieri, Cecilia; Chene, Genevieve] Univ Bordeaux, INSERM, Bordeaux Populat Hlth Res Ctr, UMR 1219, Bordeaux, France. [Dufouil, Carole; Samieri, Cecilia; Chene, Genevieve] Univ Bordeaux, ISPED, Bordeaux, France. [Dufouil, Carole; Tzourio, Christophe; Chene, Genevieve] CHU Bordeaux, Pole Sante Publ, Bordeaux, France. [Beiser, Alexa; Sullivan, Lisa] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [D'Agostino, Ralph B.] Boston Univ, Dept Math, Boston, MA 02215 USA. [Beiser, Alexa; Wolf, Philip A.; Westwood, Andrew J.; Himali, Jayandra J.; Aparicio, Hugo J.; Kelly-Hayes, Margaret; Kase, Carlos S.; Pikula, Aleksandra; Romero, Jose R.; D'Agostino, Ralph B.; Vasan, Ramachandran S.; Seshadri, Sudha] NHLBI, Framingham Heart Study, Framingham, MA USA. [McLure, Leslie A.] Drexel Univ, Dept Biostat, Sch Publ Hlth, Philadelphia, PA 19104 USA. [Howard, Virginia J.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Howard, George] Univ Alabama Birmingham, Dept Biostat, Sch Publ Hlth, Birmingham, AL 35294 USA. [Ritchie, Karen] Univ Montpellier, INSERM, Unit 1061, Montpellier, France. RP Seshadri, S (reprint author), Boston Univ, Sch Med, Dept Neurol, 72 E Concord St,B-602, Boston, MA 02118 USA. EM suseshad@bu.edu RI Tzourio, christophe/B-4015-2009 OI Tzourio, christophe/0000-0002-6517-2984 FU National Institute of Neurological Disorders and Stroke [5R01-NS017950]; National Heart, Lung, and Blood Institute's Framingham Heart Study (National Institutes of Health/National Heart, Lung, and Blood Institute) [N01-HC-25195, HH-SN268201500001I]; National Institute of Neurological Diseases and Stroke, National Institutes of Health [U01 NS041588]; Department of Health and Human Services; American Reinvestment and Recovery Act Supplement; Institut National de la Sante et de la Recherche Medicale; Victor Segalen-Bordeaux II University; Fondation Plan Alzheimer; Sanofi-Synthelabo Co; Fondation pour la Recherche Medicale; Caisse Nationale Maladie des Travailleurs Salaries; Direction Generale de la Sante; Haute Autorite de la Sante; Institut National de Prevention et d'Education pour la Sante; Conseils Regionaux of Bourgogne; Fondation de France; Ministry of Research-Institut National de la Sante et de la Recherche Medicale Program "Cohortes et collections de donnees biologiques"; Mutuelle Generale de l'Education Nationale; Institut de la Longevite; Conseil Geneal de la Cote d'or FX This work was supported by grants from the National Institute of Neurological Disorders and Stroke (5R01-NS017950) and the National Heart, Lung, and Blood Institute's Framingham Heart Study (National Institutes of Health/National Heart, Lung, and Blood Institute contracts N01-HC-25195 and HH-SN268201500001I). The REGARDS (Reasons for Geographic and Racial Differences in Stroke) project is supported by cooperative agreement U01 NS041588 from the National Institute of Neurological Diseases and Stroke, National Institutes of Health, and Department of Health and Human Services and an American Reinvestment and Recovery Act Supplement. The 3C (3 Cities) project is supported by Institut National de la Sante et de la Recherche Medicale, Victor Segalen-Bordeaux II University, Fondation Plan Alzheimer, the Sanofi-Synthelabo Co, Fondation pour la Recherche Medicale, Caisse Nationale Maladie des Travailleurs Salaries, Direction Generale de la Sante, Haute Autorite de la Sante, Institut National de Prevention et d'Education pour la Sante, Conseils Regionaux of Bourgogne, Fondation de France, Ministry of Research-Institut National de la Sante et de la Recherche Medicale Program "Cohortes et collections de donnees biologiques," Mutuelle Generale de l'Education Nationale, Institut de la Longevite, and Conseil Geneal de la Cote d'or. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. NR 42 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 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 21 PY 2017 VL 135 IS 12 BP 1145 EP 1159 DI 10.1161/CIRCULATIONAHA.115.021275 PG 15 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EO5LA UT WOS:000396733400019 PM 28159800 ER PT J AU Woimo, TT Yimer, WK Bati, T Gesesew, HA AF Woimo, Tadele Teshome Yimer, Wondwossen Kassahun Bati, Temesgen Gesesew, Hailay Abrha TI The prevalence and factors associated for anti-tuberculosis treatment non-adherence among pulmonary tuberculosis patients in public health care facilities in South Ethiopia: a cross-sectional study SO BMC PUBLIC HEALTH LA English DT Article DE Prevalence; anti-tuberculosis; non-adherence; cross-sectional survey; mixed method; qualitative method; Ethiopia ID CHINA; ADHERENCE AB Background: Evidence exists pointing out how non-adherence to treatment remains a major hurdle to efficient tuberculosis control in developing countries. Many tuberculosis (Tb) patients do not complete their six-month course of anti-tuberculosis medications and are not aware of the importance of sputum re-examinations, thereby putting themselves at risk of developing multidrug-resistant and extensively drug-resistant forms of tuberculosis and relapse. However, there is a dearth of publications about non-adherence towards anti-Tb medication in these settings. We assessed the prevalence of and associated factors for anti-Tb treatment non-adherence in public health care facilities of South Ethiopia. Methods: This was a cross-sectional survey using both quantitative and qualitative methods. The quantitative study was conducted among 261 Tb patients from 17 health centers and one general hospital. The qualitative aspect included an in-depth interview of 14 key informants. For quantitative data, the analysis of descriptive statistics, bivariate and multiple logistic regression was carried out, while thematic framework analysis was applied for the qualitative data. Results: The prevalence of non-adherence towards anti-Tb treatment was 24.5%. Multiple logistic regression analysis demonstrated that poor knowledge towards tuberculosis and its treatment (AOR = 4.6, 95% CI: 1.4-15.6), cost of medication other than Tb (AOR = 4.7, 95% CI: 1.7-13.4), having of health information at every visit (AOR = 3, 95% CI: 1.1-8.4) and distance of DOTS center from individual home (AOR = 5.7, 95% CI: 1.9-16.8) showed statistically significant association with non-adherence towards anti-tuberculosis treatment. Qualitative study also revealed that distance, lack of awareness about importance of treatment completion and cost of transportation were the major barriers for adherence. Conclusions: A quarter of Tb patients interrupted their treatment due to knowledge, availability and accessibility of DOTS service. We recommend creating awareness about anti-Tb treatment, and decentralization of drug pick-ups to the lowest level of health institutions. C1 [Woimo, Tadele Teshome] Dawro Dist Hlth Off, Dept Infect Dis, Dawro, Ethiopia. [Yimer, Wondwossen Kassahun] US Dept HHS, Biostat & Bioinformat Branch, NICHD, New York, NY USA. [Bati, Temesgen] Wolaita Sodao Univ, Dept Publ Hlth, Sodo, Ethiopia. [Gesesew, Hailay Abrha] Jimma Univ, Dept Epidemiol, Coll Hlth Sci, Jimma, Ethiopia. [Gesesew, Hailay Abrha] Flinders Univ S Australia, Fac Med Nursing & Hlth Sci, Discipline Publ Hlth, Adelaide, SA, Australia. RP Gesesew, HA (reprint author), Jimma Univ, Dept Epidemiol, Coll Hlth Sci, Jimma, Ethiopia.; Gesesew, HA (reprint author), Flinders Univ S Australia, Fac Med Nursing & Hlth Sci, Discipline Publ Hlth, Adelaide, SA, Australia. EM hailushepi@gmail.com FU Jimma University; Dawro Zone FX This research was funded by Jimma University and Dawro Zone, and was received by Tadele Teshome. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD MAR 20 PY 2017 VL 17 AR 269 DI 10.1186/s12889-017-4188-9 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EO4RH UT WOS:000396681500001 PM 28320351 ER PT J AU Gurnev, PA Roark, TC Petrache, HI Sodt, AJ Bezrukov, SM AF Gurnev, Philip A. Roark, Torri C. Petrache, Horia I. Sodt, Alexander J. Bezrukov, Sergey M. TI Cation-Selective Channel Regulated by Anions According to Their Hofmeister Ranking SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE interface phenomena; ion channels; ion specificity; membranes; nanopores ID PHOSPHOLIPID SURFACE-CHARGE; GRAMICIDIN CHANNEL; ELECTROLYTE-SOLUTIONS; BILAYER DEFORMATIONS; AQUEOUS-SOLUTIONS; LIPID-BILAYERS; ION OCCUPANCY; MEMBRANES; CONDUCTANCE; KINETICS AB Specificity of small ions, the Hofmeister ranking, is long-known and has many applications including medicine. Yet it evades consistent theoretical description. Here we study the effect of Hofmeister anions on gramicidin A channels in lipid membranes. Counterintuitively, we find that conductance of this perfectly cation-selective channel increases about twofold in the H2PO4- < Cl- approximate to Br- approximate to NO3- < ClO4- < SCN- series. Channel dissociation kinetics show even stronger dependence, with the dwell time increasing about 20-fold. While the conductance can be quantitatively explained by the changes in membrane surface potential due to exclusion of kosmotropes from (or accumulation of chaotropes at) the surface, the kinetics proved to be more difficult to treat. We estimate the effects of changes in the energetics at the bilayer surfaces on the channel dwell time, concluding that the change would have to be greater than typically observed for the Hofmeister effect outside the context of the lipid bilayer. C1 [Gurnev, Philip A.; Roark, Torri C.; Sodt, Alexander J.; Bezrukov, Sergey M.] NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bldg 9,Rm 1 N-124B, Bethesda, MD 20892 USA. [Roark, Torri C.; Petrache, Horia I.] Indiana Univ Purdue Univ, Dept Phys, Indianapolis, IN 46202 USA. RP Bezrukov, SM (reprint author), NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bldg 9,Rm 1 N-124B, Bethesda, MD 20892 USA. EM bezrukos@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH FX This work was supported by intramural funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. NR 37 TC 0 Z9 0 U1 1 U2 1 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 20 PY 2017 VL 56 IS 13 BP 3506 EP 3509 DI 10.1002/ange.201611335 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA EP4GR UT WOS:000397339400009 PM 28198582 ER PT J AU Li, MJ Tse, LA Chan, WC Kwok, CH Leung, SL Wu, C Yu, WC Lee, PMY Tsang, KH Law, SH Vermeulen, R Gu, FY Caporaso, NE Yu, ITS Wang, F Yang, XHR AF Li, Mengjie Tse, Lap Ah Chan, Wing-cheong Kwok, Chi-hei Leung, Siu-lan Wu, Cherry Yu, Wai-cho Lee, Priscilla Ming-yi Tsang, Koon-ho Law, Sze-hong Vermeulen, Roel Gu, Fangyi Caporaso, Neil E. Yu, Ignatius Tak-sun Wang, Feng Yang, Xiaohong Rose TI Nighttime eating and breast cancer among Chinese women in Hong Kong SO BREAST CANCER RESEARCH LA English DT Article DE Nighttime eating behavior; Dietary factors; Breast cancer ID FOOD-FREQUENCY QUESTIONNAIRES; SLEEP DURATION; CIRCADIAN CLOCK; CALORIC-INTAKE; OBESE WOMEN; WEIGHT-GAIN; SHIFT WORK; AGED MEN; RISK; COHORT AB Background: A novel line of research suggests that eating at nighttime may have several metabolic consequences that are highly relevant to breast cancer. We investigated the association between nighttime eating habits after 10 p.m. and breast cancer in Hong Kong women. Methods: A hospital-based case-control study was conducted during 2012-2015. A total of 922 patients with incident breast cancer (cases) and 913 hospital controls were recruited and interviewed using a standard questionnaire including information on eating behavior during both daytime and nighttime. We collected the timing, duration, types and frequencies of food intake of eating at nighttime. Odds ratios (ORs) for the risk of breast cancer in relation to nighttime eating-related variables were calculated by unconditional multivariable logistic regression. Results: Eating at night after 10 pm was significantly associated with breast cancer with an adjusted OR of 1.50 (95% confidence interval (CI) 1.06-2.12, P = 0.02), and the associations were stronger in women who had the longest duration of nighttime eating (>= 20 years) (adjusted OR = 2.28 (95% CI 1.13-4.61, P = 0.02) and who ate late (midnight to 2 a.m.) (adjusted OR = 2.73, 95% CI 1.01-6.99, P = 0.04). Interestingly, nighttime eating was only associated with breast cancer among women who consumed staple foods (OR = 2.16, 95% CI 1.42-3.29, P < 0.001) but not those who ate vegetables or fruits as nighttime meals. The significant association between nighttime eating and breast cancer was observed among women with body mass index (BMI) <25 (OR = 2.29, 95% CI 1.48-3.52, P < 0.001) but not among women with BMI >= 25. Conclusions: Results from this study suggest a possible association between nighttime eating behavior and breast cancer. These findings need to be confirmed by independent large studies. C1 [Li, Mengjie; Tse, Lap Ah; Lee, Priscilla Ming-yi; Yu, Ignatius Tak-sun; Wang, Feng] Chinese Univ Hong Kong, JC Sch Publ Hlth & Primary Care, Hong Kong, Hong Kong, Peoples R China. [Chan, Wing-cheong] North Dist Hosp, Dept Surg, Hong Kong, Hong Kong, Peoples R China. [Kwok, Chi-hei] Princess Margaret Hosp, Dept Oncol, Hong Kong, Hong Kong, Peoples R China. [Leung, Siu-lan] Pamela Youde Nethersole Eastern Hosp, Dept Surg, Hong Kong, Hong Kong, Peoples R China. [Wu, Cherry] North Dist Hosp, Dept Pathol, Hong Kong, Hong Kong, Peoples R China. [Yu, Wai-cho] Princess Margaret Hosp, Dept Med, Hong Kong, Hong Kong, Peoples R China. [Tsang, Koon-ho] Yan Chai Hosp, Dept Pathol, Hong Kong, Hong Kong, Peoples R China. [Law, Sze-hong] Yan Chai Hosp, Dept Surg, Hong Kong, Hong Kong, Peoples R China. [Vermeulen, Roel] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. [Gu, Fangyi; Caporaso, Neil E.; Yang, Xiaohong Rose] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Tse, LA (reprint author), Chinese Univ Hong Kong, JC Sch Publ Hlth & Primary Care, Hong Kong, Hong Kong, Peoples R China. EM shelly@cuhk.edu.hk FU Research Grants Council of Hong Kong [474811] FX This work was supported by the Research Grants Council of Hong Kong (grant number 474811). NR 50 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X EI 1465-5411 J9 BREAST CANCER RES JI Breast Cancer Res. PD MAR 17 PY 2017 VL 19 AR 31 DI 10.1186/s13058-017-0821-x PG 9 WC Oncology SC Oncology GA EO8EX UT WOS:000396923000001 PM 28302140 ER PT J AU Pan, YC Liu, HL Wang, YR Kang, XZ 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 Pan, Yongchu Liu, Hongliang Wang, Yanru Kang, Xiaozheng 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 TI Associations between genetic variants in mRNA splicing-related genes and risk of lung cancer: a pathway-based analysis from published GWASs SO SCIENTIFIC REPORTS LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; CHINESE POPULATION; COLON-CANCER; IDENTIFIES 2; ADENOCARCINOMA; MACHINERY; MUTATIONS; JAPANESE; SMOKING AB mRNA splicing is an important mechanism to regulate mRNA expression. Abnormal regulation of this process may lead to lung cancer. Here, we investigated the associations of 11,966 single-nucleotide polymorphisms (SNPs) in 206 mRNA splicing-related genes with lung cancer risk by using the summary data from six published genome-wide association studies (GWASs) of Transdisciplinary Research in Cancer of the Lung (TRICL) (12,160 cases and 16,838 controls) and another two lung cancer GWASs of Harvard University (984 cases and 970 controls) and deCODE (1,319 cases and 26,380 controls). We found that a total of 12 significant SNPs with false discovery rate (FDR) <= 0.05 were mapped to one novel gene PRPF6 and two previously reported genes (DHX16 and LSM2) that were also confirmed in this study. The six novel SNPs in PRPF6 were in high linkage disequilibrium and associated with PRPF6 mRNA expression in lymphoblastoid cells from 373 Europeans in the 1000 Genomes Project. Taken together, our studies shed new light on the role of mRNA splicing genes in the development of lung cancer. C1 [Pan, Yongchu; Liu, Hongliang; Wang, Yanru; Kang, Xiaozheng; Liu, Zhensheng; Owzar, Kouros; Wei, Qingyi] Duke Univ, Med Ctr, Duke Canc Inst, Durham, NC 27708 USA. [Pan, Yongchu] Nanjing Med Univ, Affiliated Hosp Stomatol, Nanjing, Jiangsu, Peoples R China. [Pan, Yongchu; Liu, Hongliang; Wang, Yanru; Kang, Xiaozheng; Liu, Zhensheng; Wei, Qingyi] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Owzar, Kouros] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC USA. [Han, Younghun] Dartmouth Coll, Geisel Sch Med, Dept Biomed Data Sci, 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 Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Hung, Rayjean J.; Brhane, Yonathan] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [McLaughlin, John] Publ Hlth Ontario, Toronto, ON, Canada. [Brennan, Paul] Int Agcy Res Canc, Genet Epidemiol Grp, Lyon, France. [Bickeboeller, Heike; Rosenberger, Albert] Georg August Univ Gottingen, Dept Genet Epidemiol, Univ Med Ctr, Gottingen, Germany. [Houlston, Richard S.] Inst Canc Res, Div Genet & Epidemiol, London, England. [Caporaso, Neil; Landi, Maria Teresa] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD USA. [Heinrich, Joachim] Helmholtz Ctr Munich, German Res Ctr Environm Hlth, Inst Epidemiol 1, Neuherberg, Germany. [Risch, Angela] Salzburg Univ, Dept Mol Biol, 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, Durham, NC 27708 USA.; Wei, QY (reprint author), Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. EM qingyi.wei@duke.edu FU Duke Cancer Institute, P30 Cancer Center Support Grant [NIH CA014236]; Duke Cancer Institute, Duke University Medical Center; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University; Transdisciplinary Research in Cancer of the Lung (TRICL), Genetic Associations and Mechanisms in Oncology (GAME-ON) Network [U19-CA148127]; Canadian Cancer Society Research Institute [020214]; Ontario Institute of Cancer; Cancer Research UK [C1298/A8780, C1298/A8362]; NCRN; HEAL; Sanofi-Aventis; NIH [5R01CA055769, 5R01CA127219, 5R01CA133996, 5R01CA121197, U19CA148127, P50 CA70907, R01CA121197, R01CA127219, U19 CA148127, R01 CA55769, K07CA160753]; Roy Castle Lung Cancer Foundation, UK; Deutsche Krebshilfe [70-2919]; Helmholtz-DAAD fellowship [A/07/97379]; GSF - German Federal Ministry of Education, Science, Research and Technology; State of Bavaria; National Genome Research Network (NGFN); DFG [BI576/2-1, BI 576/2-2]; Helmholtzgemeinschaft (HGF); Federal office for Radiation Protection [BfS: STSch4454]; Institute National du Cancer, France; European Community (Integrated Project DNA repair) [LSHG-CT-2005-512113]; Norwegian Cancer Association; European Regional Development Fund; State Budget of the Czech Republic (RECAMO) [CZ.1.05/2.1.00/03.0101]; US National Cancer Institute, NIH [R01 CA111703, UO1 CA63673]; Fred Hutchinson Cancer Research Center; US National Cancer Institute [R01 CA092039]; FP7 grant [REGPOT245536]; Estonian Government [SF0180142s08]; EU RDF; University of Tartu [SP1GVARENG]; IARC; Intramural Research Program of NIH, NCI, Division of Cancer Epidemiology and Genetics; US Public Health Service from the NCI [N01-CN-45165, N01-RC-45035, N01-RC-37004]; American Cancer Society; NIH Genes, Environment and Health Initiative (GEI) [HG-06-033-NCI-01, RO1HL091172-01, U01HG004438, NIH HHSN268200782096C, U01 HG004446]; NCI [NO1-CN-25514, NO1-CN-25522, NO1-CN-25515, NO1-CN-25512, NO1-CN-25513, NO1-CN-25516, NO1-CN-25511, NO1-CN-25524, NO1-CN-25518, NO1-CN-75022, NO1-CN-25476, NO1-CN-25404]; CPRIT grant [RP100443]; CIDR [HHSN268200782096C]; NIH (National Cancer Institute) [CA092824, CA090578, CA074386]; GENADDICT [LSHMCT-2004-005166]; National Institutes of Health [R01-DA017932] FX The authors thank the investigators and participants of all TRICL-ILCCO studies (i.e., ICR, MDACC, IARC, NCI, Toronto, GLC, Harvard and deCODE) for their important contributions. As Duke Cancer Institute members, QW and KO acknowledge support from the Duke Cancer Institute as part of the P30 Cancer Center Support Grant (Grant ID: NIH CA014236). QW was also supported by a start-up fund from Duke Cancer Institute, Duke University Medical Center. Yongchu Pan was sponsored by Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University. TRICL: This work was supported by the Transdisciplinary Research in Cancer of the Lung (TRICL) Study, U19-CA148127 on behalf of the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network. The Toronto study was supported by Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to RH The ICR study was supported by Cancer Research UK (C1298/A8780 and C1298/A8362-Bobby Moore Fund for Cancer Research UK) and NCRN, HEAL and Sanofi-Aventis. Additional funding was obtained from NIH grants (5R01CA055769, 5R01CA127219, 5R01CA133996, and 5R01CA121197). The Liverpool Lung Project (LLP) was supported by The Roy Castle Lung Cancer Foundation, UK. The ICR and LLP studies made use of genotyping data from the Wellcome Trust Case Control Consortium 2 (WTCCC2); a full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Sample collection for the Heidelberg lung cancer study was in part supported by a grant (70-2919) from the Deutsche Krebshilfe. The work was additionally supported by a Helmholtz-DAAD fellowship (A/07/97379 to MNT) and by the NIH (U19CA148127). The KORA Surveys were financed by the GSF, which is funded by the German Federal Ministry of Education, Science, Research and Technology and the State of Bavaria. The Lung Cancer in the Young study (LUCY) was funded in part by the National Genome Research Network (NGFN), the DFG (BI576/2-1; BI 576/2-2), the Helmholtzgemeinschaft (HGF) and the Federal office for Radiation Protection (BfS: STSch4454). Genotyping was performed in the Genome Analysis Center (GAC) of the Helmholtz Zentrum Muenchen. Support for the Central Europe, HUNT2/Tromso and CARET genome-wide studies was provided by Institute National du Cancer, France. Support for the HUNT2/Tromso genome-wide study was also provided by the European Community (Integrated Project DNA repair, LSHG-CT-2005-512113), the Norwegian Cancer Association and the Functional Genomics Programme of Research Council of Norway. Support for the Central Europe study, Czech Republic, was also provided by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101). Support for the CARET genome-wide study was also provided by grants from the US National Cancer Institute, NIH (R01 CA111703 and UO1 CA63673), and by funds from the Fred Hutchinson Cancer Research Center. Additional funding for study coordination, genotyping of replication studies and statistical analysis was provided by the US National Cancer Institute (R01 CA092039). The lung cancer GWAS from Estonia was partly supported by a FP7 grant (REGPOT245536), by the Estonian Government (SF0180142s08), by EU RDF in the frame of Centre of Excellence in Genomics and Estoinian Research Infrastructure's Roadmap and by University of Tartu (SP1GVARENG). The work reported in this paper was partly undertaken during the tenure of a Postdoctoral Fellowship from the IARC (for MNT).; The Environment and Genetics in Lung Cancer Etiology (EAGLE), the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC), and the Prostate, Lung, Colon, Ovary Screening Trial (PLCO) studies and the genotyping of ATBC, the Cancer Prevention Study II Nutrition Cohort (CPS-II) and part of PLCO were supported by the Intramural Research Program of NIH, NCI, Division of Cancer Epidemiology and Genetics. ATBC was also supported by US Public Health Service contracts (N01-CN-45165, N01-RC-45035 and N01-RC-37004) from the NCI. PLCO was also supported by individual contracts from the NCI to the University of Colorado Denver (NO1-CN-25514), Georgetown University (NO1-CN-25522), Pacific Health Research Institute (NO1-CN-25515), Henry Ford Health System (NO1-CN-25512), University of Minnesota (NO1-CN-25513), Washington University (NO1-CN-25516), University of Pittsburgh (NO1-CN-25511), University of Utah (NO1-CN-25524), Marshfield Clinic Research Foundation (NO1-CN-25518), University of Alabama at Birmingham (NO1-CN-75022, Westat, Inc. NO1-CN-25476), University of California, Los Angeles (NO1-CN-25404). The Cancer Prevention Study II Nutrition Cohort was supported by the American Cancer Society. The NIH Genes, Environment and Health Initiative (GEI) partly funded DNA extraction and statistical analyses (HG-06-033-NCI-01 and RO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C) and study coordination at the GENEVA Coordination Center (U01 HG004446) for EAGLE and part of PLCO studies. Funding for the MD Anderson Cancer Study was provided by NIH grants (P50 CA70907, R01CA121197, R01CA127219, U19 CA148127, R01 CA55769, and K07CA160753) and CPRIT grant (RP100443). Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is funded through a federal contract from the NIH to The Johns Hopkins University (HHSN268200782096C). The Harvard Lung Cancer Study was supported by the NIH (National Cancer Institute) grants CA092824, CA090578, and CA074386. deCODE: The project was funded in part by GENADDICT: LSHMCT-2004-005166), the National Institutes of Health (R01-DA017932). NR 38 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 17 PY 2017 VL 7 AR 44634 DI 10.1038/srep44634 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EO9IE UT WOS:000397001600001 PM 28304396 ER PT J AU Desimmie, BA Smith, JL Matsuo, H Hu, WS Pathak, VK AF Desimmie, Belete A. Smith, Jessica L. Matsuo, Hiroshi Hu, Wei-Shau Pathak, Vinay K. TI Identification of a tripartite interaction between the N-terminus of HIV-1 Vif and CBF beta that is critical for Vif function SO RETROVIROLOGY LA English DT Article DE APOBEC3G; CBF beta; HIV-1; Proteasomal degradation; Vif; Restriction factor ID BINDING-FACTOR-BETA; E3 LIGASE COMPLEX; VIRUS TYPE-1 VIF; APOBEC3 PROTEINS; CULLIN 5; TRANSCRIPTION; DETERMINANTS; DEGRADATION; INFECTION; CELLS AB Background: HIV-1 Vif interacts with the cellular core-binding factor beta (CBF beta) and counteracts the protective roles of certain human APOBEC3 (A3) proteins by targeting them for proteasomal degradation. Previous studies have identified some amino acids important for Vif-CBF beta interactions, and recently a co-crystal structure of a pentameric complex of HIV-1 Vif, CBF beta, Cul5, EloB, and EloC was resolved. However, a comprehensive analysis of Vif-CBF beta interactions that are important for Vif function has not been performed. Results: Here, we carried out double-alanine scanning mutagenesis of the first 60 amino acids of Vif and determined their effects on interaction with CBF beta and their ability to induce A3G degradation as well as rescue HIV-1 replication in the presence of A3G. We found that multiple Vif residues are involved in the extensive N-terminal Vif-CBF beta interaction and that the (5)WQVMIVW(11) region of Vif is the major determinant. A minimum of three alanine substitutions are required to completely abrogate the Vif-CBF beta interaction and Vif's ability to rescue HIV-1 infectivity in the presence of A3G. Mutational analysis of CBF beta revealed that F68 and I55 residues are important and participate in a tripartite hydrophobic interaction with W5 of Vif to maintain a stable and functional Vif-CBF beta complex. We also determined that CBF beta amino acids (73)WQGEQR(78), which are not resolved in the structure of the pentameric complex, are not involved in interaction with HIV-1 Vif. Conclusions: Our results provide detailed insight into the Vif-CBF beta interactions that are critical for Vif function and may contribute to the rational design of HIV-1 inhibitors that block Vif-mediated degradation of A3 proteins. C1 [Desimmie, Belete A.; Smith, Jessica L.; Pathak, Vinay K.] NCI, Viral Mutat Sect, HIV Dynam & Replicat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Matsuo, Hiroshi] Leidos Biomed Res Inc, Frederick Natl Lab, Basic Res Lab, Frederick, MD USA. [Hu, Wei-Shau] NCI, Viral Recombinat Sect, HIV Dynam & Replicat Program, Ctr Canc Res, Frederick, MD 21701 USA. RP Pathak, VK (reprint author), NCI, Viral Mutat Sect, HIV Dynam & Replicat Program, Ctr Canc Res, Frederick, MD 21702 USA. EM vinay.pathak@nih.gov FU NIH FX 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 U. S. Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 32 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD MAR 17 PY 2017 VL 14 AR 19 DI 10.1186/s12977-017-0346-5 PG 13 WC Virology SC Virology GA EO4PY UT WOS:000396678000001 PM 28302150 ER PT J AU Li, S Alvarez, RV Sharan, R Landsman, D Ovcharenko, I AF Li, Shan Alvarez, Roberto Vera Sharan, Roded Landsman, David Ovcharenko, Ivan TI Quantifying deleterious effects of regulatory variants SO NUCLEIC ACIDS RESEARCH LA English DT Article ID GENOME-WIDE ASSOCIATION; OPEN-ACCESS DATABASE; B-CELL DEVELOPMENT; TRANSCRIPTION FACTORS; NONCODING VARIANTS; GENETIC-VARIATION; DISEASE; DNA; PERIODONTITIS; EXPRESSION AB The majority of genome-wide association study (GWAS) risk variants reside in non-coding DNA sequences. Understanding how these sequence modifications lead to transcriptional alterations and cellto- cell variability can help unraveling genotypephenotype relationships. Here, we describe a computational method, dubbed CAPE, which calculates the likelihood of a genetic variant deactivating enhancers by disrupting the binding of transcription factors (TFs) in a given cellular context. CAPE learns sequence signatures associated with putative enhancers originating from large-scale sequencing experiments (such as ChIP-seq or DNase-seq) and models the change in enhancer signature upon a single nucleotide substitution. CAPE accurately identifies causative cis-regulatory variation including expression quantitative trait loci (eQTLs) and DNase I sensitivity quantitative trait loci (dsQTLs) in a tissuespecific manner with precision superior to several currently available methods. The presented method can be trained on any tissue-specific dataset of enhancers and known functional variants and applied to prioritize disease-associated variants in the corresponding tissue. C1 [Li, Shan; Alvarez, Roberto Vera; Landsman, David; Ovcharenko, Ivan] NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, Bethesda, MD 20892 USA. [Sharan, Roded] Tel Aviv Univ, Sch Comp Sci, IL-69978 Tel Aviv, Israel. RP Ovcharenko, I (reprint author), NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, Bethesda, MD 20892 USA. EM ovcharen@nih.gov FU Intramural Research Program of the National Institutes of Health; National Library of Medicine FX Intramural Research Program of the National Institutes of Health; National Library of Medicine. Funding for open access charge: Intramural Research Program of the National Institutes of Health; National Library of Medicine. NR 48 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR 17 PY 2017 VL 45 IS 5 BP 2307 EP 2317 DI 10.1093/nar/gkw1263 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EP3MO UT WOS:000397286600016 ER PT J AU Wang, L Rishishwar, L Marino-Ramirez, L Jordan, IK AF Wang, Lu Rishishwar, Lavanya Marino-Ramirez, Leonardo Jordan, I. King TI Human population-specific gene expression and transcriptional network modification with polymorphic transposable elements SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HUMAN GENOME; ENDOGENOUS RETROVIRUSES; REGULATORY SEQUENCES; SVA ELEMENTS; EVOLUTION; DISEASE; FAMILY; LOCI; RETROTRANSPOSONS; RETROPOSON AB Transposable element (TE) derived sequences are known to contribute to the regulation of the human genome. The majority of known TE-derived regulatory sequences correspond to relatively ancient insertions, which are fixed across human populations. The extent to which human genetic variation caused by recent TE activity leads to regulatory polymorphisms among populations has yet to be thoroughly explored. In this study, we searched for associations between polymorphic TE (polyTE) loci and human gene expression levels using an expression quantitative trait loci (eQTL) approach. We compared locusspecific polyTE insertion genotypes to B cell gene expression levels among 445 individuals from 5 human populations. Numerous human polyTE loci correspond to both cis and trans eQTL, and their regulatory effects are directly related to cell type-specific function in the immune system. PolyTE loci are associated with differences in expression between European and African population groups, and a single polyTE loci is indirectly associated with the expression of numerous genes via the regulation of the B cell-specific transcription factor PAX5. The polyTEgene expression associations we found indicate that human TE genetic variation can have important phenotypic consequences. Our results reveal that TEeQTL are involved in population-specific gene regulation as well as transcriptional network modification. C1 [Wang, Lu; Rishishwar, Lavanya; Jordan, I. King] Georgia Inst Technol, Sch Biol, Atlanta, GA 30332 USA. [Rishishwar, Lavanya; Jordan, I. King] Appl Bioinformat Lab, Atlanta, GA 30332 USA. [Rishishwar, Lavanya; Marino-Ramirez, Leonardo; Jordan, I. King] PanAmer Bioinformat Inst, Cali 170002, Valle Del Cauca, Colombia. [Rishishwar, Lavanya; Jordan, I. King] BIOS Ctr Bioinformat & Biol Computac, Manizales 170002, Caldas, Colombia. [Marino-Ramirez, Leonardo] NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Jordan, I. King] 950 Atlantic Dr, Atlanta, GA 30332 USA. RP Jordan, IK (reprint author), Georgia Inst Technol, Sch Biol, Atlanta, GA 30332 USA.; Jordan, IK (reprint author), Appl Bioinformat Lab, Atlanta, GA 30332 USA.; Jordan, IK (reprint author), PanAmer Bioinformat Inst, Cali 170002, Valle Del Cauca, Colombia.; Jordan, IK (reprint author), BIOS Ctr Bioinformat & Biol Computac, Manizales 170002, Caldas, Colombia. EM king.jordan@biology.gatech.edu OI Rishishwar, Lavanya/0000-0002-2055-9392 FU Georgia Institute of Technology Bioinformatics Graduate Program, IHRC-Georgia Tech Applied Bioinformatics Laboratory (ABiL); BIOS Centro de Bioinformatica y Biologia Computacional; Intramural Research Program of the National Institutes of Heatlh (NIH), National Library of Medicine (NLM), National Center for Biotechnology Information (NCBI) FX Georgia Institute of Technology Bioinformatics Graduate Program, IHRC-Georgia Tech Applied Bioinformatics Laboratory (ABiL); BIOS Centro de Bioinformatica y Biologia Computacional; Intramural Research Program of the National Institutes of Heatlh (NIH), National Library of Medicine (NLM), National Center for Biotechnology Information (NCBI). Funding for open access charge: Departmental funds. NR 51 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR 17 PY 2017 VL 45 IS 5 BP 2318 EP 2328 DI 10.1093/nar/gkw1286 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EP3MO UT WOS:000397286600017 ER PT J AU Wang, YT Khan, A Marks, AB Smith, OK Giri, S Lin, YC Creager, R MacAlpine, DM Prasanth, KV Aladjem, MI Prasanth, SG AF Wang, Yating Khan, Abid Marks, Anna B. Smith, Owen K. Giri, Sumanprava Lin, Yo-Chuen Creager, Rachel MacAlpine, David M. Prasanth, Kannanganattu V. Aladjem, Mirit I. Prasanth, Supriya G. TI Temporal association of ORCA/LRWD1 to late-firing origins during G1 dictates heterochromatin replication and organization SO NUCLEIC ACIDS RESEARCH LA English DT Article ID EUKARYOTIC DNA-REPLICATION; RECOGNITION COMPLEX; SACCHAROMYCES-CEREVISIAE; BINDING-SITES; ORC BINDING; GENOME; INITIATION; METHYLATION; CHROMATIN; ACTIVATION AB DNA replication requires the recruitment of a prereplication complex facilitated by Origin Recognition Complex (ORC) onto the chromatin during G1 phase of the cell cycle. The ORC-associated protein (ORCA/LRWD1) stabilizes ORC on chromatin. Here, we evaluated the genome- wide distribution of ORCA using ChIP- seq during specific time points of G1. ORCA binding sites on the G1 chromatin are dynamic and temporally regulated. ORCA association to specific genomic sites decreases as the cells progressed towards S- phase. The majority of the ORCA- bound sites represent replication origins that also associate with the repressive chromatin marks H3K9me3 and methylated- CpGs, consistent with ORCA- bound origins initiating DNA replication late in S- phase. Further, ORCA directly associates with the repressive marks and interacts with the enzymes that catalyze these marks. Regions that associate with both ORCA and H3K9me3, exhibit diminished H3K9methylation in ORCA- depleted cells, suggesting a role for ORCA in recruiting the H3K9me3 mark at certain genomic loci. Similarly, DNA methylation is altered at ORCA- occupied sites in cells lacking ORCA. Furthermore, repressive chromatinmarks influence ORCA's binding on chromatin. We propose that ORCA coordinates with the histone and DNA methylationmachinery to establish a repressive chromatin environment at a subset of origins, which primes them for late replication. C1 [Wang, Yating; Khan, Abid; Giri, Sumanprava; Lin, Yo-Chuen; Prasanth, Kannanganattu V.; Prasanth, Supriya G.] Univ Illinois, Dept Cell & Dev Biol, 601S Goodwin Ave, Urbana, IL 61801 USA. [Marks, Anna B.; Smith, Owen K.; Aladjem, Mirit I.] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Creager, Rachel; MacAlpine, David M.] Duke Univ, Sch Med, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. RP Prasanth, SG (reprint author), Univ Illinois, Dept Cell & Dev Biol, 601S Goodwin Ave, Urbana, IL 61801 USA.; Aladjem, MI (reprint author), NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM aladjemm@mail.nih.gov; supriyap@illinois.edu FU NSF-CMMB-IGERT; F31 [NIH fellowship] [CA180616]; NIH [1RO1GM088252, 1RO1GM099669]; NSF [1243372]; National Institutes of Health [1ZIABC010411-16] FX NSF-CMMB-IGERT and F31 [CA180616 NIH fellowship to S.G.]; NIH [1RO1GM088252 award to K.V.P.]; NSF career [1243372]; NIH [1RO1GM099669 awards to S.G. P.];CCR, National Cancer Institute, National Institutes of Health [1ZIABC010411-16 to M.I.A.]. NR 54 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR 17 PY 2017 VL 45 IS 5 BP 2490 EP 2502 DI 10.1093/nar/gkw1211 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EP3MO UT WOS:000397286600029 ER PT J AU Ahmad, M Shen, WP Li, W Xue, YT Zou, SG Xu, DY Wang, WD AF Ahmad, Muzammil Shen, Weiping Li, Wen Xue, Yutong Zou, Sige Xu, Dongyi Wang, Weidong TI Topoisomerase 3 beta is the major topoisomerase for mRNAs and linked to neurodevelopment and mental dysfunction SO NUCLEIC ACIDS RESEARCH LA English DT Article ID FRAGILE-X-SYNDROME; DNA TOPOISOMERASES; BINDING PROTEINS; III-BETA; SCHIZOPHRENIA; TOP3-BETA; FMRP; PERSPECTIVE; AUTISM; ROLES AB Human cells contain five topoisomerases in the nucleus and cytoplasm, but which one is the major topoisomerase for mRNAs is unclear. To date, Top3 beta is the only known topoisomerase that possesses RNA topoisomerase activity, binds mRNA translation machinery and interacts with an RNA-binding protein, FMRP, to promote synapse formation; and Top3 beta gene deletion has been linked to schizophrenia. Here, we show that Top3 beta is also the most abundant mRNA-binding topoisomerase in cells. Top3 beta, but not other topoisomerases, contains a distinctive RNA-binding domain; and deletion of this domain diminishes the amount of Top3 beta that associates with mRNAs, indicating that Top3 beta is specifically targeted to mRNAs by its RNA binding domain. Moreover, Top3 beta mutants lacking either its RNA-binding domain or catalytic residue fail to promote synapse formation, suggesting that Top3 beta requires both its mRNA-binding and catalytic activity to facilitate neurodevelopment. Notably, Top3 beta proteins bearing point mutations from schizophrenia and autism individuals are defective in association with FMRP; whereas one of the mutants is also deficient in binding mRNAs, catalyzing RNA topoisomerase reaction, and promoting synapse formation. Our data suggest that Top3 beta is the major topoisomerase for mRNAs, and requires both RNA binding and catalytic activity to promote neurodevelopment and prevent mental dysfunction. C1 [Ahmad, Muzammil; Shen, Weiping; Xue, Yutong; Wang, Weidong] Natl Inst Hlth, Genome Instabil & Chromatin Remodeling Sect, 251 Bayview Blvd, Baltimore, MD 21224 USA. [Li, Wen; Xu, Dongyi] Peking Univ, Sch Life Sci, State Key Lab Prot & Plant Gene Res, Beijing 100871, Peoples R China. [Zou, Sige] Natl Inst Hlth, Natl Inst Aging, Translat Gerontol Branch, 251 Bayview Blvd, Baltimore, MD 21224 USA. RP Wang, WD (reprint author), Natl Inst Hlth, Genome Instabil & Chromatin Remodeling Sect, 251 Bayview Blvd, Baltimore, MD 21224 USA.; Xu, DY (reprint author), Peking Univ, Sch Life Sci, State Key Lab Prot & Plant Gene Res, Beijing 100871, Peoples R China. EM dongyixu@pku.edu.cn; wangw@grc.nia.nih.gov FU National Institutes of Health [Z01 AG00065708]; National Basic Research Program of China [2013CB911002]; National Natural Science Foundation of China [31271435] FX Intramural Research Program of the National Institute on Aging, National Institutes of Health [Z01 AG00065708 in part]; National Basic Research Program of China [2013CB911002]; National Natural Science Foundation of China [31271435]. Funding for open access charge: National Institute on Aging, NIH [Z01 AG000657-08]. NR 30 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR 17 PY 2017 VL 45 IS 5 BP 2704 EP 2713 DI 10.1093/nar/gkw1293 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EP3MO UT WOS:000397286600044 ER PT J AU Perera, L Freudenthal, BD Beard, WA Pedersen, LG Wilson, SH AF Perera, Lalith Freudenthal, Bret D. Beard, William A. Pedersen, Lee G. Wilson, Samuel H. TI Revealing the role of the product metal in DNA polymerase beta catalysis SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ACTIVE-SITE; NUCLEOTIDE INSERTION; ESCHERICHIA-COLI; MECHANISM; COMPLEXES; BINDING; IONS AB DNA polymerases catalyze a metal-dependent nucleotidyl transferase reaction during extension of a DNA strand using the complementary strand as a template. The reaction has long been considered to require two magnesium ions. Recently, a third active site magnesium ion was identified in some DNA polymerase product crystallographic structures, but its role is not known. Using quantum mechanical/molecular mechanical calculations of polymerase beta, we find that a third magnesium ion positioned near the newly identified product metal site does not alter the activation barrier for the chemical reaction indicating that it does not have a role in the forward reaction. This is consistent with time-lapse crystallographic structures following insertion of S-p-dCTP alpha S. Although sulfur substitution deters product metal binding, this has only a minimal effect on the rate of the forward reaction. Surprisingly, monovalent sodium or ammonium ions, positioned in the product metal site, lowered the activation barrier. These calculations highlight the impact that an active site water network can have on the energetics of the forward reaction and how metals or enzyme side chains may interact with the network to modulate the reaction barrier. These results also are discussed in the context of earlier findings indicating that magnesium at the product metal position blocks the reverse pyrophosphorolysis reaction. C1 [Perera, Lalith; Beard, William A.; Pedersen, Lee G.; Wilson, Samuel H.] Natl Inst Environm Hlth Sci, Natl Inst Hlth, Genome Integr & Struct Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. [Freudenthal, Bret D.] Univ Kansas, Med Ctr, Dept Biochem & Mol Biol, 3901 Rainbow Blvd,1080 HLSIC,Mailstop 3030, Kansas City, KS 66160 USA. [Pedersen, Lee G.] Univ N Carolina, Dept Chem, POB 3290, Chapel Hill, NC 27517 USA. RP Perera, L (reprint author), Natl Inst Environm Hlth Sci, Natl Inst Hlth, Genome Integr & Struct Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM pereral2@niehs.nih.gov FU Intramural Research Program of the US National Institutes of Health [Z01-ES043010, Z01-ES050158, Z01-ES050159]; US National Institute of Environmental Health Sciences; US National Institutes of Health [U19CA105010] FX Research Project [Z01-ES043010 to L. P., Z01-ES050158 and Z01-ES050159 to S. H. W] in the Intramural Research Program of the US National Institutes of Health, US National Institute of Environmental Health Sciences and in association with the US National Institutes of Health Grant [U19CA105010]. Funding for open access charge: Intramural Research Program of the US National Institutes of Health, US National Institute of Environmental Health Sciences. NR 29 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR 17 PY 2017 VL 45 IS 5 BP 2736 EP 2745 DI 10.1093/nar/gkw1363 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EP3MO UT WOS:000397286600047 ER PT J AU Zhang, J Gonzalez, LE Hall, TMT AF Zhang, Jun Gonzalez, Lauren E. Hall, Traci M. Tanaka TI Structural analysis reveals the flexible C-terminus of Nop15 undergoes rearrangement to recognize a pre-ribosomal RNA folding intermediate SO NUCLEIC ACIDS RESEARCH LA English DT Article ID CRYSTAL-STRUCTURE; SACCHAROMYCES-CEREVISIAE; SECONDARY STRUCTURE; PROTEIN REVEALS; HNRNP-F; YEAST; MOTIF; CORE; RRM; NMR AB The RNA recognition motif (RRM) is the most abundant RNA-binding domain in eukaryotes, and it plays versatile roles in RNA metabolism. Despite its abundance, diversity of RRM structure and function is generated by variations on a conserved core. Yeast Nop15 is an RRM protein that is essential for large ribosomal subunit biogenesis. We determined a 2.0 A crystal structure of Nop15 that reveals a C-terminal alpha-helical region obscures its canonical RNA-binding surface. Small-angle X-ray scattering, NMR and RNA-binding analyses further reveal that the C-terminal residues of Nop15 are highly flexible, but essential for tight RNA binding. Moreover, comparison with a recently reported cryo-electron microscopy structure indicates that dramatic rearrangement of the C-terminal region of Nop15 in the pre-ribosome exposes the RNA-binding surface to recognize the base of its stem-loop target RNA and extends a newly formed alpha helix to the distal loop where it forms protein interactions. C1 [Zhang, Jun; Gonzalez, Lauren E.; Hall, Traci M. Tanaka] NIEHS, Epigenet & Stem Cell Biol Lab, NIH, POB 12233,MD F3-05, Res Triangle Pk, NC 27709 USA. RP Hall, TMT (reprint author), NIEHS, Epigenet & Stem Cell Biol Lab, NIH, POB 12233,MD F3-05, Res Triangle Pk, NC 27709 USA. EM hall4@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences; US Department of Energy [W-31-109-Eng-38]; Advanced Light Source (ALS); DOE Office of Biological and Environmental Research; National Institute of Health project MINOS [R01GM105404]; National Institutes of Health Intramural Research Program FX This work was supported by the Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences; The Advanced Photon Source used for this study is supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under contract no. W-31-109-Eng-38; SAXSwork was conducted at the Advanced Light Source (ALS), a national user facility operated by Lawrence Berkeley National Laboratory on behalf of the Department of Energy, Office of Basic Energy Sciences, through the Integrated Diffraction Analysis Technologies (IDAT) program, supported by DOE Office of Biological and Environmental Research, and additional support comes fromthe National Institute of Health project MINOS [R01GM105404]. Funding for open access charge: National Institutes of Health Intramural Research Program. NR 38 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR 17 PY 2017 VL 45 IS 5 BP 2829 EP 2837 DI 10.1093/nar/gkw961 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EP3MO UT WOS:000397286600054 ER PT J AU Popuri, V Hsu, J Khadka, P Horvath, K Liu, Y Croteau, DL Bohr, VA AF Popuri, Venkateswarlu Hsu, Joseph Khadka, Prabhat Horvath, Kent Liu, Yie Croteau, Deborah L. Bohr, Vilhelm A. TI Human RECQL1 participates in telomere maintenance (vol 42, pg 5671, 2014) SO NUCLEIC ACIDS RESEARCH LA English DT Correction C1 [Popuri, Venkateswarlu; Hsu, Joseph; Khadka, Prabhat; Horvath, Kent; Liu, Yie; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM vbohr@nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR 17 PY 2017 VL 45 IS 5 BP 2935 EP 2935 DI 10.1093/nar/gkw1217 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EP3MO UT WOS:000397286600063 ER PT J AU Kaltman, JR Burns, KM Pearson, GD AF Kaltman, Jonathan R. Burns, Kristin M. Pearson, Gail D. TI Perspective on Congenital Heart Disease Research SO CIRCULATION RESEARCH LA English DT Article DE cardiologists; cardiopulmonary bypass; congenital heart disease; congenital heart surgery; heart failure; pulmonary artery ID INSTITUTE WORKING GROUP; CLINICAL-RESEARCH; NATIONAL HEART; TRIAL; LUNG AB Congenital heart disease (CHD) is the most common birth defect and a leading cause of morbidity and mortality in patients with congenital malformations. The past 7 decades have witnessed dramatic advances in the medical, catheter, and surgical management of these patients. Clinical research has been a driving force to improve our understanding of the pathophysiology of disease and to refine therapy. Here, we identify some of the themes that have characterized the research process in the past and that have propelled the field to its present state. We discuss current research-related challenges and speculate about what trends may define the future of CHD research. C1 [Kaltman, Jonathan R.; Burns, Kristin M.; Pearson, Gail D.] NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr, Bethesda, MD 20187 USA. RP Kaltman, JR (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr, Bethesda, MD 20187 USA. EM kaltmanj@nhlbi.nih.gov NR 11 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD MAR 17 PY 2017 VL 120 IS 6 BP 898 EP 900 DI 10.1161/CIRCRESAHA.116.310334 PG 3 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA EP4DL UT WOS:000397330700002 PM 28302736 ER PT J AU Bramlet, M Olivieri, L Farooqi, K Ripley, B Coakley, M AF Bramlet, Matthew Olivieri, Laura Farooqi, Kanwal Ripley, Beth Coakley, Meghan TI Impact of Three-Dimensional Printing on the Study and Treatment of Congenital Heart Disease SO CIRCULATION RESEARCH LA English DT Article DE 3D printing; cardiac models; congenital heart disease; database; peer review; segmentation ID SIMULATION; MODELS AB Three-dimensional (3D) printing technology allows for the translation of a 2-dimensional medical imaging study into a physical replica of a patient's individual anatomy. 3D printed models can facilitate a deeper understanding of complex patient anatomy and can aid in presurgical decision-making.(1) Although there are 3D printing case reports in almost every subspecialty of medicine to date, the rate of adoption in the field of congenital heart disease (CHD) is particularly advanced.(2,3) This is due, in no small part, to the fact that the heart is a hollow organ, which makes it a perfect substrate for 3D printing. More importantly, medical decision-making in CHD is informed by assessment of the anatomic morphology of the heart because cardiac pathology is a direct manifestation of the underlying 3D structure. C1 [Bramlet, Matthew] Univ Illinois, Coll Med, Pediat Cardiol, 1306 N Berkeley Ave, Peoria, IL 61603 USA. [Bramlet, Matthew] Jump Trading Simulat & Educ Ctr, Adv Imaging & Modeling Initiat, 1306 N Berkeley Ave, Peoria, IL 61603 USA. [Olivieri, Laura] Childrens Natl Med Ctr, Div Cardiol, Washington, DC USA. [Farooqi, Kanwal] Univ Med & Dent New Jersey, Dept Pediat, Rutgers Div Pediat Cardiol, Newark, NJ USA. [Farooqi, Kanwal] Icahn Sch Med Mt Sinai, Dept Pediat, Div Pediat Cardiol, New York, NY USA. [Ripley, Beth] VA Puget Sound Hlth Care Syst, Radiol, Seattle, WA USA. [Ripley, Beth] Univ Washington, Sch Med, Seattle, WA USA. [Coakley, Meghan] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD USA. RP Bramlet, M (reprint author), Univ Illinois, Coll Med, Pediat Cardiol, 1306 N Berkeley Ave, Peoria, IL 61603 USA.; Bramlet, M (reprint author), Jump Trading Simulat & Educ Ctr, Adv Imaging & Modeling Initiat, 1306 N Berkeley Ave, Peoria, IL 61603 USA. EM Matthew.T.Bramlet@osfhealthcare.org FU National Institutes of Allergy and Infectious Diseases [GS35F0373X]; US Department of Health and Human Services through HHS Ignite program; US Department of Health and Human Services through HHS Ventures program FX The National Institutes of Health (NIH) 3D Print Exchange is operated by the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Resources are provided in part through BCBB Support Services Contract [GS35F0373X], funded by the National Institutes of Allergy and Infectious Diseases. Initial funding for the 3D Print Exchange was supplemented by the US Department of Health and Human Services through the HHS Ignite and HHS Ventures programs. NR 16 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 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD MAR 17 PY 2017 VL 120 IS 6 BP 904 EP 907 DI 10.1161/CIRCRESAHA.116.310546 PG 4 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA EP4DL UT WOS:000397330700004 PM 28302738 ER PT J AU Jandl, C Liu, SM Canete, PF Warren, J Hughes, WE Vogelzang, A Webster, K Craig, ME Uzel, G Dent, A Stepensky, P Keller, B Warnatz, K Sprent, J King, C AF Jandl, Christoph Liu, Sue M. Canete, Pablo F. Warren, Joanna Hughes, William E. Vogelzang, Alexis Webster, Kylie Craig, Maria E. Uzel, Gulbu Dent, Alexander Stepensky, Polina Keller, Barbel Warnatz, Klaus Sprent, Jonathan King, Cecile TI IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2 SO NATURE COMMUNICATIONS LA English DT Article ID GERMINAL CENTER REACTION; CHRONIC VIRAL-INFECTION; HELPER-CELLS; PRIMARY IMMUNODEFICIENCY; B-CELLS; RECEPTOR; DIFFERENTIATION; INTERLEUKIN-21; EXPRESSION; GENERATION AB T follicular regulatory (Tfr) cells control the magnitude and specificity of the germinal centre reaction, but how regulation is contained to ensure generation of high-affinity antibody is unknown. Here we show that this balance is maintained by the reciprocal influence of interleukin (IL)-2 and IL-21. The number of IL-2-dependent FoxP3(+) regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). In mice, IL-21: IL-21R interactions influence the phenotype of T follicular cells, reducing the expression of CXCR4 and inhibiting the expansion of Tfr cells after T-cell-dependent immunization. The negative effect of IL-21 on Tfr cells in mice is cell intrinsic and associated with decreased expression of the high affinity IL-2 receptor (CD25). Bcl-6, expressed in abundance in Tfr cells, inhibits CD25 expression and IL-21-mediated inhibition of CD25 is Bcl-6 dependent. These findings identify a mechanism by which IL-21 reinforces humoral immunity by restricting Tfr cell proliferation. C1 [Jandl, Christoph; Liu, Sue M.; Warren, Joanna; Hughes, William E.; Vogelzang, Alexis; Webster, Kylie; Sprent, Jonathan; King, Cecile] Garvan Inst Med Res, Dept Immunol, 384 Victoria St, Darlinghurst, NSW 2010, Australia. [Jandl, Christoph; Liu, Sue M.; Webster, Kylie; Sprent, Jonathan; King, Cecile] Univ NSW, Dept Med, St Vincents Clin Sch, Sydney, NSW 2010, Australia. [Canete, Pablo F.] Australian Natl Univ, John Curtin Sch Med Res, Div Immunol & Genet, Canberra, ACT 2601, Australia. [Craig, Maria E.] Childrens Hosp Westmead, Inst Endocrinol & Diabet, Westmead, NSW 2145, Australia. [Craig, Maria E.] Univ New South Wales, Sch Womens & Childrens Hlth, High St, Sydney, NSW 2031, Australia. [Uzel, Gulbu] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Dent, Alexander] Indiana Univ Sch Med, Dept Microbiol & Immunol, 635 Barnhill Dr,MS 420, Indianapolis, IN 46202 USA. [Stepensky, Polina] Hadassah Hebrew Univ Hosp, Pediat Hematol Oncol & Bone Marrow Transplantat, POB 12000, IL-91120 Jerusalem, Israel. [Keller, Barbel; Warnatz, Klaus] Univ Med Ctr, Ctr Chron Immunodeficiency CCI, Breisacher Str 117, D-79106 Freiburg, Germany. [Keller, Barbel; Warnatz, Klaus] Univ Freiburg, Breisacher Str 117, D-79106 Freiburg, Germany. RP King, C (reprint author), Garvan Inst Med Res, Dept Immunol, 384 Victoria St, Darlinghurst, NSW 2010, Australia.; King, C (reprint author), Univ NSW, Dept Med, St Vincents Clin Sch, Sydney, NSW 2010, Australia. EM c.king@garvan.org.au OI Jandl, Christoph/0000-0002-6975-6004 FU Diabetes Australia Research Trust; National Health and Medical Research Council FX We thank Drs Cindy Ma and Stuart Tangye for their help with human samples. This work was supported by grants from the Diabetes Australia Research Trust and the National Health and Medical Research Council. NR 70 TC 0 Z9 0 U1 2 U2 2 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 17 PY 2017 VL 8 AR 14647 DI 10.1038/ncomms14647 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EO0QB UT WOS:000396401900001 PM 28303891 ER PT J AU Huang, D Ovcharenko, I AF Huang, Di Ovcharenko, Ivan TI Epigenetic and genetic alterations and their influence on gene regulation in chronic lymphocytic leukemia SO BMC GENOMICS LA English DT Article DE DNA methylation; Regulatory elements; Genetic mutation; Transcription factor binding site; Genomewide association study ID MYELOID-LEUKEMIA; DNA METHYLATION; PROMOTER HYPERMETHYLATION; HUMAN CANCERS; HYPOMETHYLATION; SEQUENCE; CELLS; IDENTIFICATION; TRANSCRIPTION; DISRUPTION AB Background: To understand the changes of gene regulation in carcinogenesis, we explored signals of DNA methylation -a stable epigenetic mark of gene regulatory elements - and designed a computational model to profile loss and gain of regulatory elements (REs) during carcinogenesis. We also utilized sequencing data to analyze the allele frequency of single nucleotide polymorphisms (SNPs) and detected the cancer-associated SNPs, i. e., the SNPs displaying the significant allele frequency difference between cancer and normal samples. Results: After applying this model to chronic lymphocytic leukemia (CLL) data, we identified REs differentially activated (dREs) between normal and CLL cells, consisting of 6,802 dREs gained and 4,606 dREs lost in CLL. The identified regulatory perturbations coincide with changes in the expression of target genes. In particular, the genes encoding DNA methyltransferases harbor multiple lost-in-cancer dREs and zero gained-in-cancer dREs, indicating that the damaged regulation of these genes might be one of the key causes of tumor formation. dREs display a significantly elevated density of the genome-wide association study (GWAS) SNPs associated with CLL and CLLrelated traits. We observed that most of dRE GWAS SNPs associated with CLL and CLL-related traits (83%) display a significant haplotype association among the identified cancer-associated alleles and the risk alleles that have been reported in GWAS. Also dREs are enriched for the binding sites of the well-established B-cell and CLL transcription factors (TFs) NF-kB, AP2, P53, E2F1, PAX5, and SP1. We also identified CLL-associated SNPs and demonstrated that the mutations at these SNPs change the binding sites of key TFs much more frequently than expected. Conclusions: Through exploring sequencing data measuring DNA methylation, we identified the epigenetic alterations (more specifically, DNA methylation) and genetic mutations along non-coding genomic regions CLL, and demonstrated that these changes play a critical role in carcinogenesis through damaging the regulation of key genes and alternating the binding of key TFs in B and CLL cells. C1 [Huang, Di; Ovcharenko, Ivan] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Ovcharenko, I (reprint author), NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. EM ovcharen@nih.gov FU Intramural Research Program of the National Institutes of Health, National Library of Medicine FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 50 TC 0 Z9 0 U1 1 U2 1 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 16 PY 2017 VL 18 AR 236 DI 10.1186/s12864-017-3617-6 PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA EO5UV UT WOS:000396759300003 PM 28302063 ER PT J AU Stroncek, DF Lee, DW Ren, JQ Sabatino, M Highfill, S Khuu, H Shah, NN Kaplan, RN Fry, TJ Mackall, CL AF Stroncek, David F. Lee, Daniel W. Ren, Jiaqiang Sabatino, Marianna Highfill, Steven Khuu, Hanh Shah, Nirali N. Kaplan, Rosandra N. Fry, Terry J. Mackall, Crystal L. TI Elutriated lymphocytes for manufacturing chimeric antigen receptor T cells SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Chimeric antigen receptor T cells; Cancer immunotherapy; Cellular therapy; T cells; Elutriation; Myeloid derived suppressor cells; Peripheral blood mononuclear cells ID MULTIPLE-MYELOMA; REMISSIONS; MALIGNANCIES; LEUKEMIA; CD19 AB Background: Clinical trials of Chimeric Antigen Receptor (CAR) T cells manufactured from autologous peripheral blood mononuclear cell (PBMC) concentrates for the treatment of hematologic malignancies have been promising, but CAR T cell yields have been variable. This variability is due in part to the contamination of the PBMC concentrates with monocytes and granulocytes. Methods: Counter-flow elutriation allows for the closed system separation of lymphocytes from monocytes and granulocytes. We investigated the use of PBMC concentrates enriched for lymphocytes using elutriation for manufacturing 8 CD19- and 5 GD2-CAR T cell products. Results: When compared to PBMC concentrates, lymphocyte-enriched elutriation fractions contained greater proportions of CD3+ and CD56+ cells and reduced proportions of CD14+ and CD15+ cells. All 13 CAR T cell products manufactured using the elutriated lymphocytes yielded sufficient quantities of transduced CAR T cells to meet clinical dose criteria. The GD2-CAR T cell products contained significantly more T cells and transduced T cells than the CD19CAR T cell products. A comparison of the yields of CAR T cells produced from elutriated lymphocytes with the yields of CAR T cells previous produced from cells isolated from PBMC concentrates by anti-CD3/CD28 bead selection or by anti-CD3/CD28 bead selection plus plastic adherence found that greater quantities of GD2-CAR T cells were produced from elutriated lymphocytes, but not CD19-CAR T cells. Conclusions: Enrichment of PBMC concentrates for lymphocytes using elutriation increased the quantity of GD2CAR T cells produced. These results provide further evidence that CAR T cell expansion is inhibited by monocytes and granulocytes. C1 [Stroncek, David F.; Ren, Jiaqiang; Sabatino, Marianna; Highfill, Steven; Khuu, Hanh] NIH, NIH Clin Ctr, Dept Transfus Med, Cell Proc Sect, 10 Ctr Drive MSC-1184,Bldg 10,Room 3C720, Bethesda, MD 20892 USA. [Shah, Nirali N.; Kaplan, Rosandra N.; Fry, Terry J.] NIH, Natl Canc Ctr, Ctr Canc Res, Pediat Oncol Branch, Bethesda, MD USA. [Lee, Daniel W.] Univ Virginia, Dept Pediat, Div Pediatr Hematol, Charlottesville, VA USA. [Mackall, Crystal L.] Stanford Univ, Parker Inst Canc Immunotherapy, Stanford, CA USA. RP Stroncek, DF (reprint author), NIH, NIH Clin Ctr, Dept Transfus Med, Cell Proc Sect, 10 Ctr Drive MSC-1184,Bldg 10,Room 3C720, Bethesda, MD 20892 USA. EM dstroncek@cc.nih.gov FU Intramural Research Program of the NIH, Clinical Center; Intramural Research Program of the NIH, National Cancer Institute FX This research was supported by the Intramural Research Program of the NIH, Clinical Center and National Cancer Institute. NR 16 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD MAR 16 PY 2017 VL 15 AR 59 DI 10.1186/s12967-017-1160-5 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EO8MA UT WOS:000396942100001 PM 28298232 ER PT J AU Soltero, EG Konopken, YP Olson, ML Keller, CS Castro, FG Williams, AN Patrick, DL Ayers, S Hu, HH Sandoval, M Pimentel, J Knowler, WC Frick, KD Shaibi, GQ AF Soltero, Erica G. Konopken, Yolanda P. Olson, Micah L. Keller, Colleen S. Castro, Felipe G. Williams, Allison N. Patrick, Donald L. Ayers, Stephanie Hu, Houchun H. Sandoval, Matthew Pimentel, Janiel Knowler, William C. Frick, Kevin D. Shaibi, Gabriel Q. TI Preventing diabetes in obese Latino youth with prediabetes: a study protocol for a randomized controlled trial SO BMC PUBLIC HEALTH LA English DT Article DE Adolescents; Latino; Obesity; Diabetes prevention; Intervention; Disparities ID ORAL GLUCOSE-TOLERANCE; QUALITY-OF-LIFE; INSULIN SENSITIVITY INDEXES; BETA-CELL FUNCTION; BODY-MASS INDEX; PHYSICAL-ACTIVITY; STYLE INTERVENTION; CHILDHOOD OBESITY; US ADOLESCENTS; UNITED-STATES AB Background: Obese Latino adolescents are disproportionately impacted by insulin resistance and type 2 diabetes. Prediabetes is an intermediate stage in the pathogenesis of type 2 diabetes and represents a critical opportunity for intervention. However, to date, no diabetes prevention studies have been conducted in obese Latino youth with prediabetes, a highly vulnerable and underserved group. Therefore, we propose a randomized-controlled trial to test the short-term (6-month) and long-term (12-month) efficacy of a culturally-grounded, lifestyle intervention, as compared to usual care, for improving glucose tolerance and reducing diabetes risk in 120 obese Latino adolescents with prediabetes. Methods: Participants will be randomized to a lifestyle intervention or usual care group. Participants in the intervention group will attend weekly nutrition and wellness sessions and physical activity sessions twice a week for six months, followed by three months of booster sessions. The overall approach of the intervention is framed within a multilevel Ecodevelopmental model that leverages community, family, peer, and individual factors during the critical transition period of adolescence. The intervention is also guided by Social Cognitive Theory and employs key behavioral modification strategies to enhance self-efficacy and foster social support for making and sustaining healthy behavior changes. We will test intervention effects on quality of life, explore the potential mediating effects of changes in body composition, total, regional, and organ fat on improving glucose tolerance and increasing insulin sensitivity, and estimate the initial incremental cost effectiveness of the intervention as compared with usual care for improving glucose tolerance. Discussion: The proposed trial builds upon extant collaborations of a transdisciplinary team of investigators working in concert with local community agencies to address critical gaps in how diabetes prevention interventions for obese Latino youth are developed, implemented and evaluated. This innovative approach is an essential step in the development of scalable, cost-effective, solution oriented programs to prevent type 2 diabetes in this and other populations of high-risk youth. C1 [Soltero, Erica G.; Olson, Micah L.; Keller, Colleen S.; Castro, Felipe G.; Williams, Allison N.; Shaibi, Gabriel Q.] Arizona State Univ, Coll Nursing & Hlth Innovat, Ctr Hlth Promot & Dis Prevent, 500 N 3rd St, Phoenix, AZ 85013 USA. [Olson, Micah L.; Pimentel, Janiel; Shaibi, Gabriel Q.] Phoenix Childrens Hosp, Div Endocrinol & Diabet, 1919 East Thomas Rd, Phoenix, AZ 85016 USA. [Konopken, Yolanda P.] Virginia G Piper St Vincent Paul Med & Dent Clin, Family Wellness Program, 1730 E Monroe St, Phoenix, AZ 85034 USA. [Williams, Allison N.; Ayers, Stephanie; Shaibi, Gabriel Q.] Arizona State Univ, Southwest Interdisciplinary Res Ctr, 411 N Cent Ave,Suite 720, Phoenix, AZ 85004 USA. [Patrick, Donald L.] Univ Washington, Sch Publ Hlth & Commun Med, Dept Hlth Serv, Seattle Qual Life Grp, Seattle, WA 98195 USA. [Hu, Houchun H.] Phoenix Childrens Hosp, Dept Radiol, 1919 East Thomas Rd, Phoenix, AZ 85016 USA. [Sandoval, Matthew] Valley Sun YMCA, 350 N 1st Ave, Phoenix, AZ 85003 USA. [Knowler, William C.] NIH, Natl Inst Diabet & Digest & Kidney Dis, Diabet Epidemiol & Clin Res Sect, 4212 North 16th St, Phoenix, AZ 85016 USA. [Frick, Kevin D.] Johns Hopkins Carey Business Sch, 100 Int Dr, Baltimore, MD 21202 USA. RP Shaibi, GQ (reprint author), Arizona State Univ, Coll Nursing & Hlth Innovat, Ctr Hlth Promot & Dis Prevent, 500 N 3rd St, Phoenix, AZ 85013 USA.; Shaibi, GQ (reprint author), Phoenix Childrens Hosp, Div Endocrinol & Diabet, 1919 East Thomas Rd, Phoenix, AZ 85016 USA. EM Gabriel.Shaibi@asu.edu FU National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease [R01DK10757901] FX This project is supported by a grant from the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease (R01DK10757901). NR 93 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD MAR 16 PY 2017 VL 17 AR 261 DI 10.1186/s12889-017-4174-2 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EO4QX UT WOS:000396680500002 PM 28302101 ER PT J AU Valent, P Akin, C Metcalfe, DD AF Valent, Peter Akin, Cem Metcalfe, Dean D. TI Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts SO BLOOD LA English DT Review ID ADVANCED SYSTEMIC MASTOCYTOSIS; NEOPLASTIC MAST-CELLS; CURRENT TREATMENT OPTIONS; KINASE INHIBITOR PKC412; C-KIT MUTATION; OF-THE-ART; THERAPEUTIC TARGET; RESPONSE CRITERIA; GEMTUZUMAB OZOGAMICIN; URTICARIA PIGMENTOSA AB Over the past few years, substantial advances have been made in understanding the pathogenesis, evolution, and complexity of mast cell neoplasms. New diagnostic and prognostic parameters and novel therapeutic targets with demonstrable clinical impact have been identified. Several of these new markers, molecular targets, and therapeutic approaches have been validated and translated into clinical practice. At the same time, the classification of mastocytosis and related diagnostic criteria have been refined and updated by the consensus group and the World Health Organization (WHO). As a result, more specific therapies tailored toward prognostic subgroups of patients have been developed. Emerging treatment concepts use drugs directed against KIT and other relevant targets in neoplastic mast cells and will hopefully receive recognition by health authorities in the near future. This article provides an overview of recent developments in the field, with emphasis on the updated WHO classification, refined criteria, additional prognostic parameters, and novel therapeutic approaches. Based on these emerging concepts, the prognosis, quality of life, and survival of patients with advanced mastocytosis are expected to improve in the coming years. C1 [Valent, Peter] Med Univ Vienna, Dept Med 1, Div Hematol & Hemostaseol, Waehringer Guertel 18-20, Vienna, Austria. [Valent, Peter] Med Univ Vienna, Dept Med 1, Ludwig Boltzmann Cluster Oncol, Vienna, Austria. [Akin, Cem] Harvard Med Sch, Brigham & Womens Hosp, Div Allergy & Immunol, Dept Med, Boston, MA USA. [Metcalfe, Dean D.] NIAID, Mast Cell Biol Sect, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Valent, P (reprint author), Med Univ Vienna, Dept Med 1, Div Hematol & Hemostaseol, Waehringer Guertel 18-20, Vienna, Austria.; Valent, P (reprint author), Med Univ Vienna, Ludwig Boltzmann Cluster Oncol, Waehringer Guertel 18-20, A-1090 Vienna, Austria. EM peter.valent@meduniwien.ac.at FU Austrian Science Fund [F4701-B20, F4704-B20]; Division of Intramural Research; National Institute of Allergy and Infectious Diseases; National Institutes of Health FX This study was supported by the Austrian Science Fund (F4701-B20 and F4704-B20) (P.V.) and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (D.D.M.). NR 103 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAR 16 PY 2017 VL 129 IS 11 BP 1420 EP 1427 DI 10.1182/blood-2016-09-731893 PG 8 WC Hematology SC Hematology GA EP3PR UT WOS:000397294700010 PM 28031180 ER PT J AU Koelle, SJ Espinoza, DA Wu, C Xu, J Lu, R Li, B Donahue, RE Dunbar, CE AF Koelle, Samson J. Espinoza, Diego A. Wu, Chuanfeng Xu, Jason Lu, Rong Li, Brian Donahue, Robert E. Dunbar, Cynthia E. TI Quantitative stability of hematopoietic stem and progenitor cell clonal output in rhesus macaques receiving transplants SO BLOOD LA English DT Article ID IN-VIVO; NONHUMAN-PRIMATES; DYNAMICS; TRACKING; MOUSE; IDENTIFICATION; INTEGRATION; REVEALS; RECONSTITUTION; HETEROGENEITY AB Autologous transplantation of hematopoietic stem and progenitor cells lentivirally labeled with unique oligonucleotide barcodes flanked by sequencing primer targets enables quantitative assessment of the self-renewal and differentiation patterns of these cells in a myeloablative rhesus macaque model. Compared with other approaches to clonal tracking, this approach is highly quantitative and reproducible. We documented stable multipotent long-term hematopoietic clonal output of monocytes, granulocytes, B cells, and T cells from a polyclonal pool of hematopoietic stem and progenitor cells in 4 macaques observed for up to 49 months posttransplantation. A broad range of clonal behaviors characterized by contribution level and biases toward certain cell types were extremely stable over time. Correlations between granulocyte and monocyte clonalities were greatest, followed by correlations between these cell types and B cells. We also detected quantitative expansion of T cell-biased clones consistent with an adaptive immuneresponse. In contrast to recent data from a nonquantitative murine model, there waslittle evidence for clonal succession after initial hematopoietic reconstitution. These findings have important implications for human hematopoiesis, given the similarities between macaque and human physiologies. C1 [Koelle, Samson J.; Espinoza, Diego A.; Wu, Chuanfeng; Li, Brian; Donahue, Robert E.; Dunbar, Cynthia E.] Natl Heart & Blood Inst, Natl Lung & Blood Inst, Natl Inst Hlth, Hematol Branch, Bethesda, MD 20892 USA. [Koelle, Samson J.; Xu, Jason] Univ Washington, Dept Stat, Seattle, WA 98195 USA. [Koelle, Samson J.] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA. [Lu, Rong] Univ Southern Calif, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA USA. RP Dunbar, CE (reprint author), Natl Heart & Blood Inst, Natl Lung & Blood Inst, Natl Inst Hlth, Hematol Branch, Bethesda, MD 20892 USA. EM dunbarc@nhlbi.nih.gov FU intramural research program of the NIH [NHLBIK99-HL11304]; NHLBI; California Institute for Regenerative Medicine [TG2-01159] FX This research was supported by the intramural research program of the NIH, NHLBI and the following grants: NIH, NHLBIK99-HL11304 (R.L.) and California Institute for Regenerative Medicine TG2-01159 (R.L.). NR 48 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAR 16 PY 2017 VL 129 IS 11 BP 1448 EP 1457 DI 10.1182/blood-2016-07-728691 PG 10 WC Hematology SC Hematology GA EP3PR UT WOS:000397294700013 PM 28087539 ER PT J AU Ahn, IE Underbayev, C Albitar, A Herman, SEM Tian, X Maric, I Arthur, DC Wake, L Pittaluga, S Yuan, CM Stetler-Stevenson, M Soto, S Valdez, J Nierman, P Lotter, J Xi, L Raffeld, M Farooqui, M Albitar, M Wiestner, A AF Ahn, Inhye E. Underbayev, Chingiz Albitar, Adam Herman, Sarah E. M. Tian, Xin Maric, Irina Arthur, Diane C. Wake, Laura Pittaluga, Stefania Yuan, Constance M. Stetler-Stevenson, Maryalice Soto, Susan Valdez, Janet Nierman, Pia Lotter, Jennifer Xi, Liqiang Raffeld, Mark Farooqui, Mohammed Albitar, Maher Wiestner, Adrian TI Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia SO BLOOD LA English DT Article ID TYROSINE KINASE INHIBITOR; PHASE-II; TUMOR PROLIFERATION; INITIAL THERAPY; OPEN-LABEL; IN-VIVO; CLL; TRIAL; MUTATIONS; LYMPHOMA AB Disease progression in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib has been attributed to histologic transformation or acquired mutations in BTK and PLCG2. The rate of resistance and clonal composition of PD are incompletely characterized. We report on CLL patients treated with single-agent ibrutinib on an investigator-initiated phase 2 trial. With median follow-up of 34 months, 15 of 84 evaluable patients (17.9%) progressed. Relapsed/refractory disease at study entry, TP53 aberration, advanced Rai stage, and high beta-2 microglobulin were independently associated with inferior progression-free survival (P<.05 for all tests). Histologic transformation occurred in 5 patients (6.0%) and was limited to the first 15 months on ibrutinib. In contrast, progression due to CLL in 10 patients (11.9%) occurred later, diagnosed at a median 38 months on study. At progression, mutations in BTK (Cys481) and/or PLCG2 (within the autoinhibitory domain) were found in 9 patients (10.7%), in 8 of 10 patients with progressive CLL, and in 1 patient with prolymphocytic transformation. Applying highsensitivity testing (detection limit similar to 1 in 1000 cells) to stored samples, we detected mutations up to 15 months before manifestation of clinical progression (range, 2.9-15.4 months). In 5 patients (6.0%), multiple subclones carrying different mutations arose independently, leading to subclonal heterogeneity of resistant disease. For a seamless transition to alternative targeted agents, patients progressing with CLL were continued on ibrutinib for up to 3 months, with 19.8 months median survival from the time of progression. C1 [Ahn, Inhye E.] Med Oncol Serv, Natl Canc Inst, Bethesda, MD 20892 USA. [Underbayev, Chingiz; Herman, Sarah E. M.; Soto, Susan; Valdez, Janet; Nierman, Pia; Lotter, Jennifer; Farooqui, Mohammed; Wiestner, Adrian] Natl Heart & Blood Inst, Natl Lung & Blood Inst, Hematol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Albitar, Adam; Albitar, Maher] NeoGen Labs, Irvine, CA USA. [Tian, Xin] Off Biostat Res, Natl Heart & Blood Inst, Natl Lung & Blood Inst, Bethesda, MD USA. [Maric, Irina] Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. [Arthur, Diane C.; Wake, Laura; Pittaluga, Stefania; Yuan, Constance M.; Stetler-Stevenson, Maryalice; Xi, Liqiang; Raffeld, Mark] Pathol Lab, Natl Canc Inst, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Ahn, IE (reprint author), Med Oncol Serv, Natl Canc Inst, Bethesda, MD 20892 USA.; Underbayev, C (reprint author), Natl Heart & Blood Inst, Natl Lung & Blood Inst, Hematol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. EM wiestnera@mail.nih.gov FU Intramural Research Program of the National Institutes of Health National Heart, Lung, and Blood Institute; National Cancer Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health National Heart, Lung, and Blood Institute and National Cancer Institute. NR 42 TC 1 Z9 1 U1 3 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAR 16 PY 2017 VL 129 IS 11 BP 1469 EP 1479 DI 10.1182/blood-2016-06-719294 PG 11 WC Hematology SC Hematology GA EP3PR UT WOS:000397294700015 PM 28049639 ER PT J AU Burk, RD Chen, ZG Saller, C Tarvin, K Carvalho, AL Scapulatempo-Neto, C Silveira, HC Fregnani, JH Creighton, CJ Anderson, ML Castro, P Wang, SS Yau, C Benz, C Robertson, AG Mungall, K Lim, L Bowlby, R Sadeghi, S Brooks, D Sipahimalani, P Mar, R Ally, A Clarke, A Mungall, AJ Tam, A Lee, D Chuah, E Schein, JE Tse, K Kasaian, K Ma, Y Marra, MA Mayo, M Balasundaram, M Thiessen, N Dhalla, N Carlsen, R Moore, RA Holt, RA Jones, SJM Wong, TN Pantazi, A Parfenov, M Kucherlapati, R Hadjipanayis, A Seidman, J Kucherlapati, M Ren, XJ Xu, AW Yang, LX Park, PJ Lee, S Rabeno, B Huelsenbeck-Dill, L Borowsky, M Cadungog, M Iacocca, M Petrelli, N Swanson, P Ojesina, AI Le, X Sandusky, G Adebamowo, SN Akeredolu, T Adebamowo, C Reynolds, SM Shmulevich, I Shelton, C Crain, D Mallery, D Curley, E Gardner, J Penny, R Morris, S Shelton, T Liu, J Lolla, L Chudamani, S Wu, Y Birrer, M McLellan, MD Bailey, MH Miller, CA Wyczalkowski, MA Fulton, RS Fronick, CC Lu, C Mardis, ER Appelbaum, EL Schmidt, HK Fulton, LA Cordes, MG Li, TD Ding, L Wilson, RK Rader, JS Behmaram, B Uyar, D Bradley, W Wrangle, J Pastore, A Levine, DA Dao, F Gao, JJ Schultz, N Sander, C Ladanyi, M Einstein, M Teeter, R Benz, S Wentzensen, N Felau, I Zenklusen, JC Bodelon, C Demchok, JA Yang, LM Sheth, M Ferguson, ML Tarnuzzer, R Yang, HN Schiffman, M Zhang, JS Wang, ZN Davidsen, T Olaniyan, O Hutter, CM Sofia, HJ Gordenin, DA Chan, K Roberts, SA Klimczak, LJ Van Waes, C Chen, Z Saleh, AD Cheng, H Parfitt, J Bartlett, J Albert, M Arnaout, A Sekhon, H Gilbert, S Peto, M Myers, J Harr, J Eckman, J Bergsten, J Tucker, K Zach, LA Karlan, BY Lester, J Orsulic, S Sun, Q Naresh, R Pihl, T Wan, YH Zaren, H Sapp, J Miller, J Drwiega, P Ojesina, AI Murray, BA Zhang, HL Cherniack, AD Sougnez, C Pedamallu, CS Lichtenstein, L Meyerson, M Noble, MS Heiman, DI Voet, D Getz, G Saksena, G Kim, J Shih, J Cho, J Lawrence, MS Gehlenborg, N Lin, P Beroukhim, R Frazer, S Gabriel, SB Schumacher, SE Leraas, KM Lichtenberg, TM Zmuda, E Bowen, J Frick, J Gastier-Foster, JM Wise, L Gerken, M Ramirez, NC Danilova, L Cope, L Baylin, SB Salvesen, HB Vellano, CP Ju, ZL Diao, LX Zhao, H Chong, ZC Ryan, MC Martinez-Ledesma, E Verhaak, RG Byers, LA Yuan, Y Chen, K Ling, SY Mills, GB Lu, YL Akbani, R Seth, S Liang, H Wang, J Han, L Weinstein, JN Bristow, CA Zhang, W Mahadeshwar, HS Sun, HD Tang, JB Zhang, JH Song, XZ Protopopov, A Shaw, KRM Chin, L Olabode, O Ojesina, AI DiSaia, P Radenbaugh, A Haussler, D Zhu, JC Stuart, J Chalise, P Koestler, D Fridley, BL Godwin, AK Madan, R Ciriello, G Martinez, C Higgins, K Bocklage, T Auman, JT Perou, CM Tan, DH Parker, JS Hoadley, KA Wilkerson, MD Mieczkowski, PA Skelly, T Veluvolu, U Hayes, DN Rathmell, WK Hoyle, AP Simons, JV Wu, JY Mose, LE Soloway, MG Balu, S Meng, SW Jefferys, SR Bodenheimer, T Shi, Y Roach, J Thorne, LB Boice, L Huang, M Jones, CD Zuna, R Walker, J Gunderson, C Snowbarger, C Brown, D Moxley, K Moore, K Andrade, K Landrum, L Mannel, R McMeekin, S Johnson, S Nelson, T Elishaev, E Dhir, R Edwards, R Bhargava, R Tiezzi, DG Andrade, JM Noushmehr, H Carlotti, CG Tirapelli, DPD Weisenberger, DJ Van Den Berg, DJ Maglinte, DT Bootwalla, MS Lai, PH Triche, T Swisher, EM Agnew, KJ Shelley, CS Laird, PW Schwarz, J Grigsby, P Mutch, D AF Burk, Robert D. Chen, Zigui Saller, Charles Tarvin, Katherine Carvalho, Andre L. Scapulatempo-Neto, Cristovam Silveira, Henrique C. Fregnani, Jose H. Creighton, Chad J. Anderson, Matthew L. Castro, Patricia Wang, Sophia S. Yau, Christina Benz, Christopher Robertson, A. Gordon Mungall, Karen Lim, Lynette Bowlby, Reanne Sadeghi, Sara Brooks, Denise Sipahimalani, Payal Mar, Richard Ally, Adrian Clarke, Amanda Mungall, Andrew J. Tam, Angela Lee, Darlene Chuah, Eric Schein, Jacqueline E. Tse, Kane Kasaian, Katayoon Ma, Yussanne Marra, Marco A. Mayo, Michael Balasundaram, Miruna Thiessen, Nina Dhalla, Noreen Carlsen, Rebecca Moore, Richard A. Holt, Robert A. Jones, Steven J. M. Wong, Tina Pantazi, Angeliki Parfenov, Michael Kucherlapati, Raju Hadjipanayis, Angela Seidman, Jonathan Kucherlapati, Melanie Ren, Xiaojia Xu, Andrew W. Yang, Lixing Park, Peter J. Lee, Semin Rabeno, Brenda Huelsenbeck-Dill, Lori Borowsky, Mark Cadungog, Mark Iacocca, Mary Petrelli, Nicholas Swanson, Patricia Ojesina, Akinyemi I. Le, Xuan Sandusky, George Adebamowo, Sally N. Akeredolu, Teniola Adebamowo, Clement Reynolds, Sheila M. Shmulevich, Ilya Shelton, Candace Crain, Daniel Mallery, David Curley, Erin Gardner, Johanna Penny, Robert Morris, Scott Shelton, Troy Liu, Jia Lolla, Laxmi Chudamani, Sudha Wu, Ye Birrer, Michael McLellan, Michael D. Bailey, Matthew H. Miller, Christopher A. Wyczalkowski, Matthew A. Fulton, Robert S. Fronick, Catrina C. Lu, Charles Mardis, Elaine R. Appelbaum, Elizabeth L. Schmidt, Heather K. Fulton, Lucinda A. Cordes, Matthew G. Li, Tiandao Ding, Li Wilson, Richard K. Rader, Janet S. Behmaram, Behnaz Uyar, Denise Bradley, William Wrangle, John Pastore, Alessandro Levine, Douglas A. Dao, Fanny Gao, Jianjiong Schultz, Nikolaus Sander, Chris Ladanyi, Marc Einstein, Mark Teeter, Randall Benz, Stephen Wentzensen, Nicolas Felau, Ina Zenklusen, Jean C. Bodelon, Clara Demchok, John A. Yang, Liming Sheth, Margi Ferguson, Martin L. Tarnuzzer, Roy Yang, Hannah Schiffman, Mark Zhang, Jiashan Wang, Zhining Davidsen, Tanja Olaniyan, Olayinka Hutter, Carolyn M. Sofia, Heidi J. Gordenin, Dmitry A. Chan, Kin Roberts, Steven A. Klimczak, Leszek J. Van Waes, Carter Chen, Zhong Saleh, Anthony D. Cheng, Hui Parfitt, Jeremy Bartlett, John Albert, Monique Arnaout, Angel Sekhon, Harman Gilbert, Sebastien Peto, Myron Myers, Jerome Harr, Jodi Eckman, John Bergsten, Julie Tucker, Kelinda Zach, Leigh Anne Karlan, Beth Y. Lester, Jenny Orsulic, Sandra Sun, Qiang Naresh, Rashi Pihl, Todd Wan, Yunhu Zaren, Howard Sapp, Jennifer Miller, Judy Drwiega, Paul Ojesina, Akinyemi I. Murray, Bradley A. Zhang, Hailei Cherniack, Andrew D. Sougnez, Carrie Pedamallu, Chandra Sekhar Lichtenstein, Lee Meyerson, Matthew Noble, Michael S. Heiman, David I. Voet, Doug Getz, Gad Saksena, Gordon Kim, Jaegil Shih, Juliann Cho, Juok Lawrence, Michael S. Gehlenborg, Nils Lin, Pei Beroukhim, Rameen Frazer, Scott Gabriel, Stacey B. Schumacher, Steven E. Leraas, Kristen M. Lichtenberg, Tara M. Zmuda, Erik Bowen, Jay Frick, Jessica Gastier-Foster, Julie M. Wise, Lisa Gerken, Mark Ramirez, Nilsa C. Danilova, Ludmila Cope, Leslie Baylin, Stephen B. Salvesen, Helga B. Vellano, Christopher P. Ju, Zhenlin Diao, Lixia Zhao, Hao Chong, Zechen Ryan, Michael C. Martinez-Ledesma, Emmanuel Verhaak, Roeland G. Byers, Lauren Averett Yuan, Yuan Chen, Ken Ling, Shiyun Mills, Gordon B. Lu, Yiling Akbani, Rehan Seth, Sahil Liang, Han Wang, Jing Han, Leng Weinstein, John N. Bristow, Christopher A. Zhang, Wei Mahadeshwar, Harshad S. Sun, Huandong Tang, Jiabin Zhang, Jianhua Song, Xingzhi Protopopov, Alexei Shaw, Kenna R. Mills Chin, Lynda Olabode, Oluwole Ojesina, Akinyemi I. DiSaia, Philip Radenbaugh, Amie Haussler, David Zhu, Jingchun Stuart, Josh Chalise, Prabhakar Koestler, Devin Fridley, Brooke L. Godwin, Andrew K. Madan, Rashna Ciriello, Giovanni Martinez, Cathleen Higgins, Kelly Bocklage, Therese Auman, J. Todd Perou, Charles M. Tan, Donghui Parker, Joel S. Hoadley, Katherine A. Wilkerson, Matthew D. Mieczkowski, Piotr A. Skelly, Tara Veluvolu, Umadevi Hayes, D. Neil Rathmell, W. Kimryn Hoyle, Alan P. Simons, Janae V. Wu, Junyuan Mose, Lisle E. Soloway, Matthew G. Balu, Saianand Meng, Shaowu Jefferys, Stuart R. Bodenheimer, Tom Shi, Yan Roach, Jeffrey Thorne, Leigh B. Boice, Lori Huang, Mei Jones, Corbin D. Zuna, Rosemary Walker, Joan Gunderson, Camille Snowbarger, Carie Brown, David Moxley, Katherine Moore, Kathleen Andrade, Kelsi Landrum, Lisa Mannel, Robert McMeekin, Scott Johnson, Starla Nelson, Tina Elishaev, Esther Dhir, Rajiv Edwards, Robert Bhargava, Rohit Tiezzi, Daniel G. Andrade, Jurandyr M. Noushmehr, Houtan Carlotti, Carlos Gilberto, Jr. Tirapelli, Daniela Pretti da Cunha Weisenberger, Daniel J. Van Den Berg, David J. Maglinte, Dennis T. Bootwalla, Moiz S. Lai, Phillip H. Triche, Timothy, Jr. Swisher, Elizabeth M. Agnew, Kathy J. Shelley, Carl Simon Laird, Peter W. Schwarz, Julie Grigsby, Perry Mutch, David CA Canc Genome Atlas Res Network TI Integrated genomic and molecular characterization of cervical cance SO NATURE LA English DT Article ID TO-MESENCHYMAL TRANSITION; RNA-SEQ; TRANSCRIPTION FACTORS; DNA METHYLATION; BREAST-CANCER; 14-3-3-SIGMA; RESISTANCE; EXPRESSION; SIGNATURE; ACCURATE C1 [Burk, Robert D.; Chen, Zigui] Albert Einstein Coll Med, Bronx, NY 10461 USA. [Saller, Charles; Tarvin, Katherine] Analyt Biol Serv Inc, Wilmington, DE 19801 USA. [Carvalho, Andre L.; Scapulatempo-Neto, Cristovam; Silveira, Henrique C.; Fregnani, Jose H.] Barretos Canc Hosp, Barretos, SP, Brazil. [Wang, Sophia S.] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA. [Yau, Christina; Benz, Christopher] Buck Inst Res Aging, Novato, CA 94945 USA. [Robertson, A. Gordon; Mungall, Karen; Lim, Lynette; Bowlby, Reanne; Sadeghi, Sara; Brooks, Denise; Sipahimalani, Payal; Mar, Richard; Ally, Adrian; Clarke, Amanda; Mungall, Andrew J.; Tam, Angela; Lee, Darlene; Chuah, Eric; Schein, Jacqueline E.; Tse, Kane; Kasaian, Katayoon; Ma, Yussanne; Marra, Marco A.; Mayo, Michael; Balasundaram, Miruna; Thiessen, Nina; Dhalla, Noreen; Carlsen, Rebecca; Moore, Richard A.; Holt, Robert A.; Jones, Steven J. M.; Wong, Tina] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada. [Pantazi, Angeliki; Parfenov, Michael; Kucherlapati, Raju; Hadjipanayis, Angela; Seidman, Jonathan; Kucherlapati, Melanie; Ren, Xiaojia; Xu, Andrew W.; Yang, Lixing; Park, Peter J.; Lee, Semin] Harvard Med Sch, Boston, MA 02115 USA. [Rabeno, Brenda; Huelsenbeck-Dill, Lori; Borowsky, Mark; Cadungog, Mark; Iacocca, Mary; Petrelli, Nicholas; Swanson, Patricia] Christiana Care Hlth Serv Inc, Helen F Graham Canc Ctr, Newark, DE 19713 USA. [Rabeno, Brenda; Huelsenbeck-Dill, Lori; Borowsky, Mark; Cadungog, Mark; Iacocca, Mary; Petrelli, Nicholas; Swanson, Patricia] Christiana Care Hlth Serv Inc, Res Inst, Newark, DE 19713 USA. [Ojesina, Akinyemi I.] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. [Ojesina, Akinyemi I.; Murray, Bradley A.; Zhang, Hailei; Cherniack, Andrew D.; Sougnez, Carrie; Pedamallu, Chandra Sekhar; Lichtenstein, Lee; Meyerson, Matthew; Noble, Michael S.; Heiman, David I.; Voet, Doug; Getz, Gad; Saksena, Gordon; Kim, Jaegil; Shih, Juliann; Cho, Juok; Lawrence, Michael S.; Gehlenborg, Nils; Lin, Pei; Beroukhim, Rameen; Frazer, Scott; Gabriel, Stacey B.; Schumacher, Steven E.; Protopopov, Alexei] Eli & Edythe L Broad Inst Massachusetts Inst Tech, Cambridge, MA 02142 USA. [Ojesina, Akinyemi I.] Univ Alabama Birmingham, Birmingham, AL 35294 USA. [Le, Xuan] ILSbio LLC, Chestertown, MD 21620 USA. [Sandusky, George] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Adebamowo, Sally N.; Akeredolu, Teniola; Adebamowo, Clement] Inst Human Virol, Abuja, Nigeria. [Reynolds, Sheila M.; Shmulevich, Ilya] Inst Syst Biol, Seattle, WA 98109 USA. [Shelton, Candace; Crain, Daniel; Mallery, David; Curley, Erin; Gardner, Johanna; Penny, Robert; Morris, Scott; Shelton, Troy] Int Genom Consortium, Phoenix, AZ 85004 USA. [Liu, Jia; Lolla, Laxmi; Chudamani, Sudha; Wu, Ye] Leidos Biomed, Rockville, MD 20850 USA. [Birrer, Michael] Massachusetts Gen Hosp, Boston, MA 02114 USA. [McLellan, Michael D.; Bailey, Matthew H.; Miller, Christopher A.; Wyczalkowski, Matthew A.; Fulton, Robert S.; Fronick, Catrina C.; Lu, Charles; Mardis, Elaine R.; Appelbaum, Elizabeth L.; Schmidt, Heather K.; Fulton, Lucinda A.; Cordes, Matthew G.; Li, Tiandao; Ding, Li; Wilson, Richard K.] Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA. [Rader, Janet S.; Behmaram, Behnaz; Uyar, Denise; Bradley, William] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Wrangle, John] Med Univ South Carolina, Charleston, SC 29425 USA. [Pastore, Alessandro; Levine, Douglas A.; Dao, Fanny; Gao, Jianjiong; Schultz, Nikolaus; Sander, Chris; Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Einstein, Mark; Teeter, Randall] Montefiore Med Ctr, Bronx, NY 10461 USA. [Benz, Stephen] NantOmics, Santa Cruz, CA 95060 USA. [Wentzensen, Nicolas; Felau, Ina; Zenklusen, Jean C.; Bodelon, Clara; Demchok, John A.; Yang, Liming; Sheth, Margi; Ferguson, Martin L.; Tarnuzzer, Roy; Yang, Hannah; Schiffman, Mark; Zhang, Jiashan; Wang, Zhining; Davidsen, Tanja] NCI, Bethesda, MD 20892 USA. [Olaniyan, Olayinka] Natl Hosp, Abuja, Nigeria. [Hutter, Carolyn M.; Sofia, Heidi J.] NHGRI, Bethesda, MD 20892 USA. [Gordenin, Dmitry A.; Chan, Kin; Roberts, Steven A.; Klimczak, Leszek J.] NIEHS, POB 12233, Durham, NC 27709 USA. [Van Waes, Carter; Chen, Zhong; Saleh, Anthony D.; Cheng, Hui] NIDCD, Bethesda, MD 20892 USA. [Parfitt, Jeremy] London Hlth Sci Ctr, Ontario Tumour Bank, London, ON N6A 5A5, Canada. [Bartlett, John; Albert, Monique] Ontario Inst Canc Res, Ontario Tumour Bank, Toronto, ON M5G 0A3, Canada. [Arnaout, Angel; Sekhon, Harman; Gilbert, Sebastien] Ottawa Hosp, Ontario Tumour Bank, Ottawa, ON K1H 8L6, Canada. [Peto, Myron] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Myers, Jerome; Harr, Jodi; Eckman, John; Bergsten, Julie; Tucker, Kelinda; Zach, Leigh Anne] Penrose St Francis Hlth Serv, Colorado Springs, CO 80906 USA. [Karlan, Beth Y.; Lester, Jenny; Orsulic, Sandra] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Sun, Qiang; Naresh, Rashi; Pihl, Todd; Wan, Yunhu] SRA Int, Fairfax, VA 22033 USA. [Zaren, Howard; Sapp, Jennifer; Miller, Judy; Drwiega, Paul] St Josephs Candler Hlth Syst, Savannah, GA 31406 USA. [Leraas, Kristen M.; Lichtenberg, Tara M.; Zmuda, Erik; Bowen, Jay; Frick, Jessica; Gastier-Foster, Julie M.; Wise, Lisa; Gerken, Mark; Ramirez, Nilsa C.] Nationwide Childrens Hosp, Res Inst, Columbus, OH 43205 USA. [Danilova, Ludmila; Cope, Leslie; Baylin, Stephen B.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA. [Salvesen, Helga B.] Univ Bergen, Bergen, Norway. [Vellano, Christopher P.; Ju, Zhenlin; Diao, Lixia; Zhao, Hao; Chong, Zechen; Ryan, Michael C.; Martinez-Ledesma, Emmanuel; Verhaak, Roeland G.; Byers, Lauren Averett; Yuan, Yuan; Chen, Ken; Ling, Shiyun; Mills, Gordon B.; Lu, Yiling; Akbani, Rehan; Seth, Sahil; Liang, Han; Wang, Jing; Han, Leng; Weinstein, John N.; Bristow, Christopher A.; Zhang, Wei; Mahadeshwar, Harshad S.; Sun, Huandong; Tang, Jiabin; Zhang, Jianhua; Song, Xingzhi; Protopopov, Alexei; Shaw, Kenna R. Mills; Chin, Lynda] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Olabode, Oluwole] Univ Abuja, Teaching Hosp, Gwagwalada, Abuja, Nigeria. [DiSaia, Philip] Univ Calif Irvine, Orange, CA 92668 USA. [Radenbaugh, Amie; Haussler, David; Zhu, Jingchun; Stuart, Josh] Univ Calif Santa Cruz, Santa Cruz, CA 95064 USA. [Chalise, Prabhakar; Koestler, Devin; Fridley, Brooke L.; Godwin, Andrew K.; Madan, Rashna] Univ Kansas, Med Ctr, Kansas City, KS 66160 USA. [Ciriello, Giovanni] Univ Lausanne, Lausanne, Switzerland. [Martinez, Cathleen; Higgins, Kelly; Bocklage, Therese] Univ New Mexico, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Auman, J. Todd; Perou, Charles M.; Tan, Donghui; Parker, Joel S.; Hoadley, Katherine A.; Wilkerson, Matthew D.; Mieczkowski, Piotr A.; Skelly, Tara; Veluvolu, Umadevi; Hayes, D. Neil; Rathmell, W. Kimryn; Hoyle, Alan P.; Simons, Janae V.; Wu, Junyuan; Mose, Lisle E.; Soloway, Matthew G.; Balu, Saianand; Meng, Shaowu; Jefferys, Stuart R.; Bodenheimer, Tom; Shi, Yan; Roach, Jeffrey; Thorne, Leigh B.; Boice, Lori; Huang, Mei; Jones, Corbin D.] Univ N Carolina, Chapel Hill, NC 27599 USA. [Zuna, Rosemary; Walker, Joan; Gunderson, Camille; Snowbarger, Carie; Brown, David; Moxley, Katherine; Moore, Kathleen; Andrade, Kelsi; Landrum, Lisa; Mannel, Robert; McMeekin, Scott; Johnson, Starla; Nelson, Tina] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK 73104 USA. [Elishaev, Esther; Dhir, Rajiv; Edwards, Robert; Bhargava, Rohit] Univ Pittsburgh, Pittsburgh, PA 15213 USA. [Tiezzi, Daniel G.; Andrade, Jurandyr M.; Noushmehr, Houtan; Carlotti, Carlos Gilberto, Jr.; Tirapelli, Daniela Pretti da Cunha] Univ Sao Paulo, Ribeirao Preto Med Sch, BR-14049900 Ribeirao Preto, SP, Brazil. [Weisenberger, Daniel J.; Van Den Berg, David J.; Maglinte, Dennis T.; Bootwalla, Moiz S.; Lai, Phillip H.; Triche, Timothy, Jr.] Univ Southern Calif, Los Angeles, CA 90033 USA. [Swisher, Elizabeth M.; Agnew, Kathy J.] Univ Washington, Seattle, WA 98109 USA. [Shelley, Carl Simon] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI 53705 USA. [Laird, Peter W.] Van Andel Res Inst, Grand Rapids, MI 49503 USA. [Schwarz, Julie; Grigsby, Perry; Mutch, David] Washington Univ, St Louis, MO 63110 USA. RP Ojesina, AI (reprint author), HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA.; Ojesina, AI (reprint author), Eli & Edythe L Broad Inst Massachusetts Inst Tech, Cambridge, MA 02142 USA.; Ojesina, AI (reprint author), Univ Alabama Birmingham, Birmingham, AL 35294 USA.; Rader, JS (reprint author), Med Coll Wisconsin, Milwaukee, WI 53226 USA.; Rader, JS (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI 53705 USA. EM ojesina@uab.edu; jrader@mcw.edu; wentzenn@mail.nih.gov; vellcp2@gmail.com NR 67 TC 0 Z9 0 U1 7 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAR 16 PY 2017 VL 543 IS 7645 BP 378 EP + PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN9RN UT WOS:000396337400042 ER PT J AU Doci, CL Mikelis, CM Callejas-Valera, JL Hansen, KK Molinolo, AA Inoue, A Offermanns, S Gutkind, JS AF Doci, Colleen L. Mikelis, Constantinos M. Callejas-Valera, Juan Luis Hansen, Karina K. Molinolo, Alfredo A. Inoue, Asuka Offermanns, Stefan Gutkind, J. Silvio TI Epidermal loss of Gag confers a migratory and differentiation defect in keratinocytes SO PLOS ONE LA English DT Article ID PROTEIN-COUPLED RECEPTORS; GROWTH-FACTOR-BETA; UVEAL MELANOMA; ANAPHYLACTIC SHOCK; MICE; SKIN; EXPRESSION; WOUNDS; TRANSACTIVATION; ACTIVATION AB G-protein coupled receptors (GPCRs), which activate heterotrimeric G proteins, are an essential class of transmembrane receptors that are responsible for a myriad of signaling events in normal and pathologic conditions. Two members of the G protein family, Gaq and Ga-11, activate one of the main GPCR pathways and function as oncogenes by integrating mitogen-stimulated signaling cascades that are active under malignant conditions. Recently, it has been shown that targeted deletion of Ga-11 and Gaq from endothelial cells impairs the Rho -mediated formation of focal adherens junctions, suggesting that Gai vg signaling may also play a significant role in cytoskeletal-mediated cellular responses in epithelial cells. Indeed, combined deletion of Ga-11 and Gaq confers a significant migratory defect in keratinocytes that delays cutaneous wound healing in an in vivo setting. This delay can be attributed to a defect during the reepithelialization phase due to significantly attenuated migratory capacity of Gaq-null keratinocytes under combined Ga-11 deficiency. In fact, cells lacking Gaivg demonstrate a severely reduced ability to respond to mitogenic and migratory signals in the microenvironment, leading to inappropriate and premature terminal differentiation. These results suggest that Gaivg signaling pathways may be critical for integrating mitogenic signals and cytoskeletal function to achieve normal physiological responses. Emergence of a malignant phenotype may therefore arise from both under- and overexpression of Gai vg signaling, implicating its upstream regulation as a potential therapeutic target in a host of pathologic conditions. C1 [Doci, Colleen L.] Marian Univ Indianapolis, Coll Arts & Sci, Indianapolis, IN 46222 USA. [Mikelis, Constantinos M.] Texas Tech Univ, Hlth Sci Ctr, Sch Pharm, Dept Biomed Sci, Amarillo, TX USA. [Callejas-Valera, Juan Luis; Gutkind, J. Silvio] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. [Callejas-Valera, Juan Luis; Gutkind, J. Silvio] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Hansen, Karina K.] NIDCD, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Molinolo, Alfredo A.] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA. [Inoue, Asuka] Tohoku Univ, Grad Sch Pharmaceut Sci, Sendai, Miyagi, Japan. [Inoue, Asuka] Japan Sci & Technol Agcy JST, PRESTO, Kawaguchi, Saitama, Japan. [Offermanns, Stefan] Max Planck Inst Heart & Lung Res, Dept Pharmacol, Bad Nauheim, Germany. RP Doci, CL (reprint author), Marian Univ Indianapolis, Coll Arts & Sci, Indianapolis, IN 46222 USA. EM cdoci@marian.edu FU Intramural Research Program of the National Institute of Dental and Craniofacial Research; Marian University Indianapolis; PRESTO, Japan Science and Technology Agency [13408007]; JST, PRESTO [13408007] FX This research was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, and in part by Marian University Indianapolis. AI received Grant #13408007 from PRESTO, Japan Science and Technology Agency. This does not alter our adherence to PLOS ONE policies on sharing data and materials.; This research was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, and in part by Marian University Indianapolis. A.I. was funded by JST, PRESTO Grant #13408007. NR 43 TC 0 Z9 0 U1 0 U2 0 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 16 PY 2017 VL 12 IS 3 AR e0173692 DI 10.1371/journal.pone.0173692 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN9KE UT WOS:000396318300062 PM 28301547 ER PT J AU Eranki, A Farr, N Partanen, A Sharma, KV Chen, H Rossi, CT Kothapalli, SVVN Oetgen, M Kim, A Negussie, AH Woods, D Wood, BJ Kim, PCW Yarmolenko, PS AF Eranki, Avinash Farr, Navid Partanen, Ari Sharma, Karun V. Chen, Hong Rossi, Christopher T. Kothapalli, Satya V. V. N. Oetgen, Matthew Kim, AeRang Negussie, Ayele H. Woods, David Wood, Bradford J. Kim, Peter C. W. Yarmolenko, Pavel S. TI Boiling histotripsy lesion characterization on a clinical magnetic resonance imaging-guided high intensity focused ultrasound system SO PLOS ONE LA English DT Article ID PERCUTANEOUS RADIOFREQUENCY ABLATION; LOCALIZED PROSTATE-CANCER; LIVER-TUMORS; HEPATOCELLULAR-CARCINOMA; TISSUE FRACTIONATION; MICROWAVE ABLATION; MILD HYPERTHERMIA; ETHANOL INJECTION; THERMAL ABLATION; LASER-ABLATION AB Purpose High intensity focused ultrasound (HIFU) is a non-invasive therapeutic technique that can thermally ablate tumors. Boiling histotripsy (BH) is a HIFU approach that can emulsify tissue in a few milliseconds. Lesion volume and temperature effects for different BH sonication parameters are currently not well characterized. In this work, lesion volume, temperature distribution, and area of lethal thermal dose were characterized for varying BH sonication parameters in tissue-mimicking phantoms (TMP) and demonstrated in ex vivo tissues. Methods The following BH sonication parameters were varied using a clinical MR-HIFU system (Sonalleve V2, Philips, Vantaa, Finland): acoustic power, number of cycles/pulse, total sonication time, and pulse repetition frequency (PRF). A 3x3x3 pattern was sonicated inside TMP's and ex vivo tissues. Post sonication, lesion volumes were quantified using 3D ultrasonography and temperature and thermal dose distributions were analyzed offline. Ex vivo tissues were sectioned and stained with H&E post sonication to assess tissue damage. Results Significant increase in lesion volume was observed while increasing the number of cycles/pulse and PRF. Other sonication parameters had no significant effect on lesion volume. Temperature full width at half maximum at the end of sonication increased significantly with all parameters except total sonication time. Positive correlation was also found between lethal thermal dose and lesion volume for all parameters except number of cycles/pulse. Gross pathology of ex vivo tissues post sonication displayed either completely or partially damaged tissue at the focal region. Surrounding tissues presented sharp boundaries, with little or no structural damage to adjacent critical structures such as bile duct and nerves. Conclusion Our characterization of effects of HIFU sonication parameters on the resulting lesion demonstrates the ability to control lesion morphologic and thermal characteristics with a clinical MR-HIFU system in TMP's and ex vivo tissues. We demonstrate that this system can produce spatially precise lesions in both phantoms and ex vivo tissues. The results provide guidance on a preliminary set of BH sonication parameters for this system, with a potential to facilitate BH translation to the clinic. C1 [Eranki, Avinash; Sharma, Karun V.; Rossi, Christopher T.; Oetgen, Matthew; Kim, AeRang; Kim, Peter C. W.; Yarmolenko, Pavel S.] Childrens Natl Hlth Syst, Sheikh Zayed Inst Pediat Surg Innovat, Washington, DC USA. [Eranki, Avinash; Farr, Navid; Negussie, Ayele H.; Woods, David; Wood, Bradford J.] Natl Inst Hlth, Ctr Intervent Oncol Radiol & Imaging Sci, Ctr Clin, Bethesda, MD USA. [Partanen, Ari] Clin Sci MR Therapy, Andover, MA USA. [Chen, Hong; Kothapalli, Satya V. V. N.] Washington Univ, Sch Engn & Appl Sci, Dept Biomed Engn, St Louis, MO USA. RP Eranki, A (reprint author), Childrens Natl Hlth Syst, Sheikh Zayed Inst Pediat Surg Innovat, Washington, DC USA.; Eranki, A (reprint author), Natl Inst Hlth, Ctr Intervent Oncol Radiol & Imaging Sci, Ctr Clin, Bethesda, MD USA. EM aeranki@childrensnational.org FU Sheikh Zayed Institute for Pediatric Surgical Innovation, Joseph E. Robert, Jr. Center for Surgical Care at Children's National Health System; National Cancer Institute [ZID BC 011242-08]; NIH Clinical Center [ZIA CL040012-0]; Center for Interventional Oncology and Intramural Research Program of the National Institutes of Health (NIH); Philips; Intramural Research Program of the NIH; Center for Interventional Oncology, NIH Clinical Center; National Cancer Institute FX This research was supported by Sheikh Zayed Institute for Pediatric Surgical Innovation, Joseph E. Robert, Jr. Center for Surgical Care at Children's National Health System; National Cancer Institute - ZID BC 011242-08; NIH Clinical Center - ZIA CL040012-0. This research was also supported by the Center for Interventional Oncology and Intramural Research Program of the National Institutes of Health (NIH), and through a Cooperative Research and Development Agreement (CRADA) with Philips. Ari Partanen is a paid employee of Philips. The mention of commercial products, their source, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the National Institutes of Health. Philips provided support in the form of salaries for authors [AP], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section.; This work was supported by Sheikh Zayed Institute for Pediatric Surgical Innovation, Joseph E. Robert, Jr. Center for Surgical Care at Children's National Health System and the Intramural Research Program of the NIH and the Center for Interventional Oncology, NIH Clinical Center and the National Cancer Institute. NR 56 TC 0 Z9 0 U1 0 U2 0 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 16 PY 2017 VL 12 IS 3 AR e0173867 DI 10.1371/journal.pone.0173867 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN9KE UT WOS:000396318300086 PM 28301597 ER PT J AU Chlanda, P Locker, JK AF Chlanda, Petr Locker, Jacomine Krijnse TI The sleeping beauty kissed awake: new methods in electron microscopy to study cellular membranes SO BIOCHEMICAL JOURNAL LA English DT Review ID PRESSURE FROZEN SAMPLES; INNER NUCLEAR-MEMBRANE; CRYOELECTRON TOMOGRAPHY; STRUCTURAL-ANALYSIS; PHASE-PLATE; CRYO-EM; BIOLOGICAL ULTRASTRUCTURE; FREEZE-SUBSTITUTION; ATOMIC-RESOLUTION; DENDRITIC CELLS AB Electron microscopy (EM) for biological samples, developed in the 1940-1950s, changed our conception about the architecture of eukaryotic cells. It was followed by a period where EM applied to cell biology had seemingly fallen asleep, even though new methods with important implications for modern EM were developed. Among these was the discovery that samples can be preserved by chemical fixation and most importantly by rapid freezing without the formation of crystalline ice, giving birth to the world of cryo-EM. The past 15-20 years are hallmarked by a tremendous interest in EM, driven by important technological advances. Cryo-EM, in particular, is now capable of revealing structures of proteins at a near-atomic resolution owing to improved sample preparation methods, microscopes and cameras. In this review, we focus on the challenges associated with the imaging of membranes by EM and give examples from the field of host-pathogen interactions, in particular of virus-infected cells. Despite the advantages of imaging membranes under native conditions in cryo-EM, conventional EM will remain an important complementary method, in particular if large volumes need to be imaged. C1 [Chlanda, Petr] NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Locker, Jacomine Krijnse] Inst Pasteur, Ultrapole Ultra Struct Bio Imaging, 28 Rue Dr Roux, F-75015 Paris, France. RP Chlanda, P (reprint author), NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA.; Locker, JK (reprint author), Inst Pasteur, Ultrapole Ultra Struct Bio Imaging, 28 Rue Dr Roux, F-75015 Paris, France. EM petr.chlanda@nih.gov; jacomina.krijnse-locker@pasteur.fr NR 88 TC 0 Z9 0 U1 3 U2 3 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0264-6021 EI 1470-8728 J9 BIOCHEM J JI Biochem. J. PD MAR 15 PY 2017 VL 474 BP 1041 EP 1053 DI 10.1042/BCJ20160990 PN 6 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EN2DK UT WOS:000395819600012 PM 28270563 ER PT J AU Rosu, S Cohen-Fix, O AF Rosu, Simona Cohen-Fix, Orna TI Live-imaging analysis of germ cell proliferation in the C-elegans adult supports a stochastic model for stem cell proliferation SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Germline; Stem cells; Proliferation; Lineage tracing ID CAENORHABDITIS-ELEGANS; LINE; DIFFERENTIATION; PROGRESSION; DECISION; MITOSIS; GLP-1; CYCLE; FATE AB The C. elegans adult hermaphrodite contains a renewable pool of mitotically dividing germ cells that are contained within the progenitor zone (PZ), at the distal region of the germline. From the PZ, cells enter meiosis and differentiate, ensuring the continued production of oocytes. In this study, we investigated the proliferation strategy used to maintain the PZ pool by using a photoconvertible marker to follow the fate of selected germ cells and their descendants in live worms. We found that the most distal pool of 6-8 rows of cells in the PZ (the distal third) behave similarly, with a fold expansion corresponding to one cell division every 6 h on average. Proximal to this region, proliferation decreases, and by the proximal third of the PZ, most cells have stopped dividing. In addition, we show that all the descendants of cells in rows 3 and above move proximally and leave the PZ over time. Combining our data with previous studies, we propose a stochastic model for the C. elegans PZ proliferation, where a pool of proliferating stem cells divide symmetrically within the distal most 6-8 rows of the germline and exit from this stem cell niche occurs by displacement due to competition for limited space. C1 [Rosu, Simona; Cohen-Fix, Orna] NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Cohen-Fix, O (reprint author), 8 Ctr Dr,Bldg 8,Room 319, Bethesda, MD 20892 USA. EM simona.rosu@nih.gov; ornac@niddk.nih.gov FU intramural grant from NIDDK [DK069012]; NIDDK Nancy Nossal Fellowship; NIH Office of Research Infrastructure Programs [P40 OD010440] FX We thank Michael Krause, Eric Haag, and Alison Walters for comments on the manuscript, Christian Frokjr-Jensen for advice regarding MosSCI, Michael Koelle for the LX850 strain, Hari Shroff, George Patterson, and Kevin O'Connell for microscopy advice, and members of the Cohen-Fix lab for helpful discussions. Work in the Cohen-Fix lab is supported by an intramural grant from NIDDK (#DK069012) and an NIDDK Nancy Nossal Fellowship to SR. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). NR 32 TC 0 Z9 0 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 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD MAR 15 PY 2017 VL 423 IS 2 BP 93 EP 100 DI 10.1016/j.ydbio.2017.02.008 PG 8 WC Developmental Biology SC Developmental Biology GA EO8VA UT WOS:000396967400001 PM 28215939 ER PT J AU Audiger, C Rahman, MJ Yun, TJ Tarbell, KV Lesage, S AF Audiger, Cindy Rahman, M. Jubayer Yun, Tae Jin Tarbell, Kristin V. Lesage, Sylvie TI The Importance of Dendritic Cells in Maintaining Immune Tolerance SO JOURNAL OF IMMUNOLOGY LA English DT Review ID REGULATORY T-CELLS; MHC CLASS-II; NONOBESE DIABETIC MICE; NF-KAPPA-B; SYSTEMIC-LUPUS-ERYTHEMATOSUS; STEADY-STATE CONDITIONS; VERSUS-HOST-DISEASE; IN-VIVO; ANTIGEN PRESENTATION; LYMPH-NODES AB Immune tolerance is necessary to prevent the immune system from reacting against self, and thus to avoid the development of autoimmune diseases. In this review, we discuss key findings that position dendritic cells (DCs) as critical modulators of both thymic and peripheral immune tolerance. Although DCs are important for inducing both immunity and tolerance, increased auto-immunity associated with decreased DCs suggests their nonredundant role in tolerance induction. DC-mediated T cell immune tolerance is an active process that is influenced by genetic variants, environmental signals, as well as the nature of the specific DC subset presenting Ag to T cells. Answering the many open questions with regard to the role of DCs in immune tolerance could lead to the development of novel therapies for the prevention of autoimmune diseases. C1 [Audiger, Cindy; Lesage, Sylvie] Maisonneuve Rosemont Hosp, Dept Immunol Oncol, Montreal, PQ H1T 2M4, Canada. [Audiger, Cindy; Lesage, Sylvie] Univ Montreal, Dept Microbiol Infectiol & Immunol, Montreal, PQ H3C 3J7, Canada. [Rahman, M. Jubayer; Tarbell, Kristin V.] Natl Inst Diabet & Digest & Kidney Dis, Immune Tolerance Sect, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Yun, Tae Jin] Clin Res Inst Montreal, Lab Cellular Physiol & Immunol, Montreal, PQ H2W 1R7, Canada. [Yun, Tae Jin] McGill Univ, Div Expt Med, Dept Med, Montreal, PQ H3A 1A3, Canada. RP Lesage, S (reprint author), Maisonneuve Rosemont Hosp, Res Ctr, 5415 Assompt Blvd, Montreal, PQ H1T 2M4, Canada. EM sylvie.lesage@umontreal.ca FU intramural research programs of the National Institute of Diabetes and Digestive and Kidney Diseases; Montreal Diabetes Research Center in collaboration with Diabete Quebec and by Fondation Lucie-Besner; Fonds de Recherche en Sante du Quebec; Natural Sciences and Engineering Research Council; Cancer Research Society FX M.J.R. and K.V.T. are supported by the intramural research programs of the National Institute of Diabetes and Digestive and Kidney Diseases. C.A. is supported by a scholarship from the Montreal Diabetes Research Center in collaboration with Diabete Quebec and by Fondation Lucie-Besner. S.L. is supported by Fonds de Recherche en Sante du Quebec, and by grants from the Natural Sciences and Engineering Research Council and the Cancer Research Society. NR 165 TC 1 Z9 1 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 15 PY 2017 VL 198 IS 6 BP 2223 EP 2231 DI 10.4049/jimmunol.1601629 PG 9 WC Immunology SC Immunology GA EN3MD UT WOS:000395911700002 PM 28264998 ER PT J AU Ramsuran, V Hernandez-Sanchez, PG O'hUigin, C Sharma, G Spence, N Augusto, DG Gao, XJ Garcia-Sepulveda, CA Kaur, G Mehra, NK Carrington, M AF Ramsuran, Veron Hernandez-Sanchez, Pedro G. O'hUigin, Colm Sharma, Gaurav Spence, Niamh Augusto, Danillo G. Gao, Xiaojiang Garcia-Sepulveda, Christian A. Kaur, Gurvinder Mehra, Narinder K. Carrington, Mary TI Sequence and Phylogenetic Analysis of the Untranslated Promoter Regions for HLA Class I Genes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MHC CLASS-I; CELL-SURFACE EXPRESSION; C EXPRESSION; HIV CONTROL; TRANSCRIPTIONAL REGULATION; DIFFERENTIAL EXPRESSION; ALLELIC VARIANTS; HIGH-FREQUENCY; DP EXPRESSION; COMPLEX AB Polymorphisms located within the MHC have been linked to many disease outcomes by mechanisms not yet fully understood in most cases. Variants located within untranslated regions of HLA genes are involved in allele-specific expression and may therefore underlie some of these disease associations. We determined sequences extending nearly 2 kb upstream of the transcription start site for 68 alleles from 57 major lineages of classical HLA class I genes. The nucleotide diversity within this promoter segment roughly follows that seen within the coding regions, with HLA-B showing the highest (similar to 1.9%), followed by HLA-A (similar to 1.8%), and HLA-C showing the lowest diversity (similar to 0.9%). Despite its greater diversity, HLA-B mRNA expression levels determined in 178 European Americans do not vary in an allele-or lineage-specific manner, unlike the differential expression levels of HLA-A or HLA-C reported previously. Close proximity of promoter sequences in phylogenetic trees is roughly reflected by similarity of expression pattern for most HLA-A and -C loci. Although promoter sequence divergence might impact promoter activity, we observed no clear link between the phylogenetic structures as represented by pairwise nucleotide differences in the promoter regions with estimated differences in mRNA expression levels for the classical class I loci. Further, no pair of class I loci showed coordinated expression levels, suggesting that distinct mechanisms across loci determine their expression level under nonstimulated conditions. These data serve as a foundation for more in-depth analysis of the functional consequences of promoter region variation within the classical HLA class I loci. C1 [Ramsuran, Veron; Hernandez-Sanchez, Pedro G.; O'hUigin, Colm; Spence, Niamh; Gao, Xiaojiang; Carrington, Mary] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. [Ramsuran, Veron; Carrington, Mary] Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA. [Hernandez-Sanchez, Pedro G.; Garcia-Sepulveda, Christian A.] Univ Autonoma San Luis Potosi, Fac Med, Lab Genom Viral & Humana, San Luis Potosi 78210, Mexico. [Sharma, Gaurav; Kaur, Gurvinder; Mehra, Narinder K.] All India Inst Med Sci, Dept Transplant Immunol & Immunogenet, New Delhi 110029, India. [Sharma, Gaurav; Spence, Niamh] All India Inst Med Sci, Lab Oncol, Dr BR Ambedkar Inst Rotary Canc Hosp, New Delhi 110029, India. [Augusto, Danillo G.] Univ Fed Parana, Dept Genet, Lab Genet Mol Humana, BR-81531980 Curitiba, Parana, Brazil. [Ramsuran, Veron] Univ KwaZulu Natal, Ctr AIDS Program Res South Africa, Sch Lab Med & Med Sci, Coll Hlth Sci, Durban, South Africa. RP Carrington, M (reprint author), NCI, Frederick, MD 21702 USA. EM carringm@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E, N02-CP-55504, R01DA04334, R01-DA12568]; Intramural Research Program of the National Institute of Health; Frederick National Laboratory; Center for Cancer Research; South African Medical Research Council [MRC-RFA-UFSP-01-2013/UKZN HIVEPI]; Indian Council of Medical Research, Government of India FX This work was supported by federal funds from the National Cancer Institute, National Institutes of Health (Grants HHSN261200800001E, N02-CP-55504, R01DA04334, and R01-DA12568). The content of this publication does not necessarily reflect the views or policies of the U.S. Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported in part by the Intramural Research Program of the National Institute of Health, Frederick National Laboratory, Center for Cancer Research, a research Flagship grant from the South African Medical Research Council (Grant MRC-RFA-UFSP-01-2013/UKZN HIVEPI), and the Indian Council of Medical Research, Government of India. NR 50 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 15 PY 2017 VL 198 IS 6 BP 2320 EP 2329 DI 10.4049/jimmunol.1601679 PG 10 WC Immunology SC Immunology GA EN3MD UT WOS:000395911700012 PM 28148735 ER PT J AU Gao, P Liu, HT Huang, HR Zhang, Q Strober, W Zhang, FP AF Gao, Ping Liu, Hongtao Huang, Huarong Zhang, Qi Strober, Warren Zhang, Fuping TI The Inflammatory Bowel Disease-Associated Autophagy Gene Atg16L1T300A Acts as a Dominant Negative Variant in Mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTESTINAL EPITHELIAL-CELLS; GENOME-WIDE ASSOCIATION; CROHNS-DISEASE; SELECTIVE AUTOPHAGY; ADAPTIVE IMMUNITY; T300A VARIANT; PANETH CELLS; SALMONELLA; PATHOGENESIS; INFECTION AB The basis of the increased risk for Crohn's disease conferred by the Atg16L1T300A polymorphism is incompletely understood. An important step forward came from the recent demonstration that the murine equivalent of Atg16L1T300A (Atg16L1T316A) exhibits increased susceptibility to caspase 3-mediated cleavage and resulting decreased levels of full-length Atg16L1 in macrophages. However, although this finding showed that this polymorphism is a loss-of-function abnormality, it did not address the possibility that this polymorphism also affects the function of a normal Atg16L1 allele in heterozygous mice. Therefore, we evaluated the function of the Atg16L1T300A polymorphism heterozygote and homozygote in knock-in (KI) mice. Surprisingly, we found that macrophages from both types of KI mice exhibit defective autophagic induction; accordingly, both types of mice exhibit defects in bacterial clearance coupled with increased inflammasome cytokine (IL-1 beta) responses. Furthermore, macrophages from both types of KI mice displayed defects in TNF-alpha-induced Atg16L1T300A cleavage, increased retention of bacteria, bacterial dissemination, and Salmonella-induced colitis. These studies suggested that chromosomes bearing the Atg16L1T300A polymorphism can interfere with the function of the wild-type (WT) Atg16L1 allele and, thus, that the Crohn's disease risk polymorphism is a dominant-negative variant with the potential to act as a disease factor, even when present on only one chromosome. This conclusion was supported by the finding that mice bearing a WT Atg16L1 allele and a null allele (Atg16L1(KO/+) mice) exhibit normal autophagic function equivalent to that of WT mice. C1 [Gao, Ping; Liu, Hongtao; Huang, Huarong; Zhang, Qi; Zhang, Fuping] Chinese Acad Sci, Inst Microbiol, CAS Key Lab Pathogen Microbiol & Immunol, 1 Beichen West Rd, Beijing 100101, Peoples R China. [Liu, Hongtao; Huang, Huarong] Univ Chinese Acad Sci, Beijing 100049, Peoples R China. [Strober, Warren] NIAID, Mucosal Immun Sect, Lab Host Defenses, NIH, Bethesda, MD 20892 USA. [Zhang, Fuping] Univ Chinese Acad Sci, Savaid Med Sch, Beijing 101408, Peoples R China. RP Zhang, FP (reprint author), Chinese Acad Sci, Inst Microbiol, CAS Key Lab Pathogen Microbiol & Immunol, 1 Beichen West Rd, Beijing 100101, Peoples R China. EM zhangfp@im.ac.cn FU National Key Research and Development Project Grant [2016YFC1200302]; National Natural Science Foundation of China Grants [31300719, 31470861] FX This work was supported by National Key Research and Development Project Grant 2016YFC1200302 and National Natural Science Foundation of China Grants 31300719 and 31470861. NR 37 TC 0 Z9 0 U1 0 U2 0 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 15 PY 2017 VL 198 IS 6 BP 2457 EP 2467 DI 10.4049/j.immunol.1502652 PG 11 WC Immunology SC Immunology GA EN3MD UT WOS:000395911700025 PM 28202618 ER PT J AU Blazkova, J Gupta, S Liu, YD Gaudilliere, B Ganio, EA Bolen, CR Saar-Dover, R Fragiadakis, GK Angst, MS Hasni, S Aghaeepour, N Stevenson, D Baldwin, N Anguiano, E Chaussabel, D Altman, MC Kaplan, MJ Davis, MM Furman, D AF Blazkova, Jana Gupta, Sarthak Liu, Yudong Gaudilliere, Brice Ganio, Edward A. Bolen, Christopher R. Saar-Dover, Ron Fragiadakis, Gabriela K. Angst, Martin S. Hasni, Sarfaraz Aghaeepour, Nima Stevenson, David Baldwin, Nicole Anguiano, Esperanza Chaussabel, Damien Altman, Matthew C. Kaplan, Mariana J. Davis, Mark M. Furman, David TI Multicenter Systems Analysis of Human Blood Reveals Immature Neutrophils in Males and During Pregnancy SO JOURNAL OF IMMUNOLOGY LA English DT Article ID COLONY-STIMULATING FACTOR; T-CELL RESPONSES; IMMUNE-SYSTEM; LUPUS-ERYTHEMATOSUS; SUPPRESSOR-CELLS; RHEUMATOID-ARTHRITIS; INFLUENZA VACCINATION; MULTIPLE-SCLEROSIS; SIGNALING PATHWAY; REVISED CRITERIA AB Despite clear differences in immune system responses and in the prevalence of autoimmune diseases between males and females, there is little understanding of the processes involved. In this study, we identified a gene signature of immature-like neutrophils, characterized by the overexpression of genes encoding for several granule-containing proteins, which was found at higher levels (up to 3-fold) in young (20-30 y old) but not older (60 to >89 y old) males compared with females. Functional and phenotypic characterization of peripheral blood neutrophils revealed more mature and responsive neutrophils in young females, which also exhibited an elevated capacity in neutrophil extracellular trap formation at baseline and upon microbial or sterile autoimmune stimuli. The expression levels of the immature-like neutrophil signature increased linearly with pregnancy, an immune state of increased susceptibility to certain infections. Using mass cytometry, we also find increased frequencies of immature forms of neutrophils in the blood of women during late pregnancy. Thus, our findings show novel sex differences in innate immunity and identify a common neutrophil signature in males and in pregnant women. C1 [Fragiadakis, Gabriela K.; Kaplan, Mariana J.; Furman, David] Div Translat Med, Dept Syst Biol, Sidra Med & Res Ctr, Doha 26999, Qatar. [Liu, Yudong; Bolen, Christopher R.; Saar-Dover, Ron] Natl Inst Arthrit & Musculoskeletal & Skin Dis, Natl Inst Hlth, System Autoimmun Branch, Bethesda, MD 20892 USA. [Liu, Yudong; Bolen, Christopher R.; Saar-Dover, Ron] Stanford Univ, Dept Anesthesiol, Perioperat & Pain Med, Stanford, CA 94305 USA. [Bolen, Christopher R.; Angst, Martin S.; Hasni, Sarfaraz] Stanford Univ, Dept Microbiol & Immunol, Sch Med, Stanford, CA 94305 USA. [Liu, Yudong; Ganio, Edward A.; Bolen, Christopher R.] Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA. [Liu, Yudong; Bolen, Christopher R.] Baylor Scott & White Hlth, Dallas, TX 75246 USA. [Liu, Yudong; Bolen, Christopher R.; Angst, Martin S.] Jackson Lab Genom Med, Farmington, CT 06032 USA. RP Furman, D (reprint author), Div Translat Med, Dept Syst Biol, Sidra Med & Res Ctr, Doha 26999, Qatar. EM furmand@stanford.edu FU Intramural Research Program at the National Institute of Arthritis and Musculoskeletal; Skin Diseases/National Institutes of Health [ZIA AR041199]; Ellison Foundation, National Institutes of Health [U19 AI090019]; Discovery Foundation; Sidra Medical and Research Center FX This work was supported by the Intramural Research Program at the National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health (Project ZIA AR041199 to M.J.K.), the Ellison Foundation, National Institutes of Health Grant U19 AI090019 (both to M.M.D.), the Discovery Foundation (for the Baylor study), and intramural funds from the Sidra Medical and Research Center (to D.F.). NR 88 TC 0 Z9 0 U1 0 U2 0 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 15 PY 2017 VL 198 IS 6 BP 2479 EP 2488 DI 10.4049/jimmunol.1601855 PG 10 WC Immunology SC Immunology GA EN3MD UT WOS:000395911700027 PM 28179497 ER PT J AU Jiang, JJ Wu, XF Shen, D Dong, LJ Jiao, XD Hejtmancik, JF Li, ND AF Jiang, Jingjing Wu, Xiaofei Shen, Di Dong, Lijin Jiao, Xiaodong Hejtmancik, J. Fielding Li, Ningdong TI Analysis of RP2 and RPGR Mutations in Five X-Linked Chinese Families with Retinitis Pigmentosa SO SCIENTIFIC REPORTS LA English DT Article ID NORTH-AMERICAN COHORT; RETINITIS-PIGMENTOSA-2 PROTEIN; COFACTOR-C; GENE; IDENTIFICATION; LOCUS; DYSTROPHY; LINKAGE; TRANSCRIPTION; SPECTRUM AB Mutations in RP2 and RPGR genes are responsible for the X-linked retinitis pigmentosa (XLRP). In this study, we analyzed the RP2 and RPGR gene mutations in five Han Chinese families with XLRP. An approximately 17Kb large deletion including the exon 4 and exon 5 of RP2 gene was found in an XLRP family. In addition, four frameshift mutations including three novel mutations of c. 1059 +1 G > T, c. 2002dupC and c. 2236_2237del CT, as well as a previously reported mutation of c. 2899delG were detected in the RPGR gene in the other four families. Our study further expands the mutation spectrum of RP2 and RPGR, and will be helpful for further study molecular pathogenesis of XLRP. C1 [Jiang, Jingjing; Li, Ningdong] Capital Univ Med Sci, Beijing Childrens Hosp, MOE Key Lab Major Dis Children, Beijing, Peoples R China. [Wu, Xiaofei; Li, Ningdong] Tianjin Med Univ, Tianjin, Peoples R China. [Shen, Di] XiAn 1 Hosp, XiAn Ophthalmol Hosp, Xian 710002, Shanxi Province, Peoples R China. [Dong, Lijin] NEI, Genet Engn Lab, NIH, Bethesda, MD 20892 USA. [Jiao, Xiaodong; Hejtmancik, J. Fielding; Li, Ningdong] NEI, OGVFB, NIH, Bethesda, MD 20892 USA. RP Li, ND (reprint author), Capital Univ Med Sci, Beijing Childrens Hosp, MOE Key Lab Major Dis Children, Beijing, Peoples R China.; Li, ND (reprint author), Tianjin Med Univ, Tianjin, Peoples R China.; Hejtmancik, JF; Li, ND (reprint author), NEI, OGVFB, NIH, Bethesda, MD 20892 USA. EM f3h@helix.nih.gov; lnd30@163.com FU National Eye Institute Intramural Program, National Institutes for Health, Bethesda USA; National Natural Science Foundation of China [81670883, 81170884] FX We acknowledge the family members who donated samples to make this work possible. Financial support was provided by the National Eye Institute Intramural Program, National Institutes for Health, Bethesda USA, and by the National Natural Science Foundation of China (No. 81670883 and 81170884). NR 44 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 15 PY 2017 VL 7 AR 44465 DI 10.1038/srep44465 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN9RI UT WOS:000396336900001 PM 28294154 ER PT J AU Li, QQ Hao, JJ Zhang, Z Krane, LS Hammerich, KH Sanford, T Trepel, JB Neckers, L Agarwal, PK AF Li, Qingdi Quentin Hao, Jian-Jiang Zhang, Zheng Krane, L. Spencer Hammerich, Kai H. Sanford, Thomas Trepel, Jane B. Neckers, Len Agarwal, Piyush K. TI Proteomic analysis of proteome and histone post-translational modifications in heat shock protein 90 inhibition-mediated bladder cancer therapeutics SO SCIENTIFIC REPORTS LA English DT Article ID SPECTRAL ABUNDANCE FACTORS; POTENT ANTITUMOR-ACTIVITY; CELL LUNG-CANCER; HSP90 INHIBITOR; IN-VIVO; HEAT-SHOCK-PROTEIN-90 INHIBITOR; GANETESPIB STA-9090; CHROMATIN; EXPRESSION; 17-ALLYLAMINO-17-DEMETHOXYGELDANAMYCIN AB Heat shock protein 90 (HSP90) inhibition is an attractive strategy for cancer treatment. Several HSP90 inhibitors have shown promising effects in clinical oncology trials. However, little is known about HSP90 inhibition-mediated bladder cancer therapy. Here, we report a quantitative proteomic study that evaluates alterations in protein expression and histone post-translational modifications (PTMs) in bladder carcinoma in response to HSP90 inhibition. We show that 5 HSP90 inhibitors (AUY922, ganetespib, SNX2112, AT13387, and CUDC305) potently inhibited the proliferation of bladder cancer 5637 cells in a dose-and time-dependent manner. Our proteomic study quantified 518 twofold up-regulated and 811 twofold down-regulated proteins common to both AUY922 and ganetespib treatment. Bioinformatic analyses revealed that those differentially expressed proteins were involved in multiple cellular processes and enzyme-regulated signaling pathways, including chromatin modifications and cell death-associated pathways. Furthermore, quantitative proteome studies identified 14 types of PTMs with 93 marks on the core histones, including 34 novel histone marks of butyrylation, citrullination, 2-hydroxyisobutyrylation, methylation, O-GlcNAcylation, propionylation, and succinylation in AUY922-and ganetespib-treated 5637 cells. Together, this study outlines the association between proteomic changes and histone PTMs in response to HSP90 inhibitor treatment in bladder carcinoma cells, and thus intensifies the understanding of HSP90 inhibition-mediated bladder cancer therapeutics. C1 [Li, Qingdi Quentin; Krane, L. Spencer; Hammerich, Kai H.; Sanford, Thomas; Trepel, Jane B.; Agarwal, Piyush K.] Natl Inst Hlth, Ctr Canc Res, Natl Canc Inst, Urol Oncol Branch, Bethesda, MD 20892 USA. [Hao, Jian-Jiang; Zhang, Zheng] Poochon Sci, Frederick, MD 21701 USA. [Trepel, Jane B.] Natl Inst Hlth, Ctr Canc Res, Natl Canc Inst, Dev Therapeut Branch, Bethesda, MD 20892 USA. RP Li, QQ; Trepel, JB; Agarwal, PK (reprint author), Natl Inst Hlth, Ctr Canc Res, Natl Canc Inst, Urol Oncol Branch, Bethesda, MD 20892 USA. EM liquenti@mail.nih.gov; trepelj@mail.nih.gov; agarwalpk2@mail.nih.gov FU Intramural Research Program of the U.S. National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the U.S. National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 56 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 15 PY 2017 VL 7 AR 201 DI 10.1038/s41598-017-00143-6 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EO7KT UT WOS:000396870300002 PM 28298630 ER PT J AU Matsuura, E Enose-Akahata, Y Yao, K Oh, U Tanaka, Y Takashima, H Jacobson, S AF Matsuura, Eiji Enose-Akahata, Yoshimi Yao, Karen Oh, Unsong Tanaka, Yuetsu Takashima, Hiroshi Jacobson, Steven TI Dynamic acquisition of HTLV-1 tax protein by mononuclear phagocytes: Role in neurologic disease SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE HAM/TSP; HTLV-1; CTL; Tax ID I-ASSOCIATED MYELOPATHY; VIRUS-TYPE-I; TROPICAL SPASTIC PARAPARESIS; CYTOTOXIC T-LYMPHOCYTES; SPINAL-CORD LESIONS; PROVIRAL LOAD; CELL TRANSMISSION; PERIPHERAL-BLOOD; DENDRITIC CELLS; MACROPHAGES AB Pathology of HTLV-1 associated myelopathy/Tropical spastic paraparesis (HAM/rsp) is believed to be the result of "bystander damage" involving effector CD8 (+) T lymphocytes (CTLs) killing of virus infected cells. But the specific cellular events leading up to tissue injury are still unclear. Here, we developed the Microscopy Imaging of Cytotoxic T lymphocyte assay with Fluorescence emission (MI-CaFe), an optimized visualization analysis to explore the interactions between CTLs and virus infected or viral antigen presenting target cells. Various cell-to -cell formations can be observed and our results demonstrate elevated frequencies of CTL-target cell conjugates in HAM/TSP patient PBMCs compared to control PBMCs. Furthermore, HTLV-1 Tax protein expression can be localized at the cell -cell junctions and also tracked moving from an infected cell to a CD14 (+) mononuclear phagocyte (MP). Activation of CD14 (+) MPs in HAM/TSP patient PBMCs and antigenic presentation of HTLV-1 Tax by MPs can be inferred by their spontaneous cytotoxicity after 18 h of in vitro culture. Given that CD4 (+) T lymphocytes are the primary reservoirs of HTLV-1 and MPs are scavenger cells responsible for pathogen clearance, spontaneous cytotoxicity against MPs in HAM/TSP PBMCs suggests a mechanism of chronic inflammation, secondary to low level of persistent virus infection within the central nervous system. Published by Elsevier B.V. C1 [Matsuura, Eiji; Enose-Akahata, Yoshimi; Yao, Karen; Oh, Unsong; Jacobson, Steven] NIH, NINDS, Neuroimmunol Branch, Viral Immunol Sect, Bethesda, MD 20892 USA. [Matsuura, Eiji; Takashima, Hiroshi] Kagoshima Univ, Grad Sch Med & Dent Sci, Dept Neurol & Geriatr, 8-35-1 Sakuragaoka, Kagoshima 8908520, Japan. [Tanaka, Yuetsu] Univ Ryukyus, Grad Sch Med, Dept Immunol, Nishihara, Okinawa 9030215, Japan. RP Jacobson, S (reprint author), NIH, NINDS, Viral Immunol Sect, 9000 Rockville Pike,Bldg 10 Room 5C-103, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov FU Intramural Research Program of the NINDS, National Institute of Health (NIH) FX This research was supported by the Intramural Research Program of the NINDS, National Institute of Health (NIH). NR 35 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 EI 1872-8421 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD MAR 15 PY 2017 VL 304 BP 43 EP 50 DI 10.1016/j.jneuroim.2016.09.014 PG 8 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA EN2KX UT WOS:000395840100009 PM 27769524 ER PT J AU Reich, DS AF Reich, Daniel S. TI Imag(in)ing multiple sclerosis: Time to take better pictures SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE Multiple sclerosis; Magnetic resonance imaging ID BLOOD-BRAIN-BARRIER; WHITE-MATTER; VENTRICULAR ENLARGEMENT; PARENCHYMAL VEINS; LESIONS; MRI; MS; DEMYELINATION; DISABILITY; ATROPHY AB Magnetic resonance imaging (MRI) has led to the identification of widespread brain abnormalities in multiple sclerosis (MS) that extend far beyond the classic white matter lesion. These findings have generated the idea that MS should be understood as a disease of the whole brain, not just the white matter. While it is no doubt the case that many different pathways are ultimately involved in the destruction of brain tissue that occurs in MS, the implications of the accumulated evidence for understanding disease pathophysiology - and hence the overall significance of these imaging findings - are doubtful. Here, I argue that the principled use of imaging can, in fact, address questions about the genesis of these whole-brain abnormalities, rather than simply describe them. Published by Elsevier B.V. C1 [Reich, Daniel S.] NCI, Translat Neuroradiol Sect, Bldg 10,Room 5C103, Bethesda, MD 20892 USA. RP Reich, DS (reprint author), NCI, Translat Neuroradiol Sect, Bldg 10,Room 5C103, Bethesda, MD 20892 USA. EM reichds@ninds.nih.gov FU Intramural Research Program at NINDS FX The ideas presented here in no small measure derive from conversations with trainees, colleagues, and mentors, notably Irene Cortese, Henry McFarland, Steven Jacobson, Peter Calabresi, Pascal Sati, and Govind Nair. I thank them as well as the many participants in research studies at the NIH Neuroimmunology Branch and Johns Hopkins MS Center from whom I've learned a great deal. My work is supported by the Intramural Research Program at NINDS. NR 43 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 EI 1872-8421 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD MAR 15 PY 2017 VL 304 BP 72 EP 80 DI 10.1016/j.jneuroim.2016.09.015 PG 9 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA EN2KX UT WOS:000395840100013 PM 27742080 ER PT J AU Maggi, P Sati, P Massacesi, L AF Maggi, Pietro Sati, Pascal Massacesi, Luca TI Magnetic resonance imaging of experimental autoimmune encephalomyelitis in the common marmoset SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE Multiple sclerosis; Experimental autoimmune encephalomyelitis; Marmoset; Magnetic resonance imaging; Brain; Inflammation; Demyelination ID MULTIPLE-SCLEROSIS LESIONS; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; BLOOD-BRAIN-BARRIER; WHITE-MATTER; NONHUMAN PRIMATE; ENHANCING LESIONS; MODEL; MRI; DEMYELINATION; PATHOGENESIS AB Magnetic resonance imaging (MRI) is an invaluable tool for the diagnosis and monitoring of patients with multiple sclerosis (MS) as well as for the study of the disease pathophysiology. Because of its strong clinical, radiological and histopathological similarities with the human disease, experimental autoimmune encephalomyelitis (EAE) in the common marmoset has been studied more intensively over the past several years. Here, we review the current knowledge on MRI in the marmoset EAE, and we outline the physiopathological significance and translational values of these studies with respect to MS. Accumulating evidences suggest that the application of conventional, as well as non-conventional, MRI techniques in the marmoset EAE is a promising approach to elucidate the pathological processes underlying the development of inflammatory demyelinated lesions in the central nervous system, potentially improving the identification and development of new therapeutics. (C) 2016 Elsevier B.V. All rights reserved. C1 [Maggi, Pietro] Hosp Erasme Univ Libre Brussel, Dept Neurol, Brussels, Belgium. [Sati, Pascal] NIH, Natl Inst Neurol Disorders & Stroke, Translat Neuroradiol Unit, Bethesda, MD USA. [Massacesi, Luca] Univ Florence, Dept Nurosci Drug Res & Child Hlth, Florence, Italy. RP Maggi, P (reprint author), Hosp Erasme Univ Libre Brussel, Dept Neurol, Brussels, Belgium. NR 55 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 EI 1872-8421 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD MAR 15 PY 2017 VL 304 BP 86 EP 92 DI 10.1016/j.jneuroim.2016.09.016 PG 7 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA EN2KX UT WOS:000395840100015 ER PT J AU Rogers, T Steinvil, A Gai, JX Torguson, R Koifman, E Kiramijyan, S Negi, S Lee, SY Okubagzi, P Satler, LF Ben-Dor, I Pichard, AD Waksman, R AF Rogers, Toby Steinvil, Arie Gai, Jiaxiang Torguson, Rebecca Koifman, Edward Kiramijyan, Sarkis Negi, Smita Lee, Sang Yeub Okubagzi, Petros Satler, Lowell F. Ben-Dor, Itsik Pichard, Augusto D. Waksman, Ron TI Choice of Balloon-Expandable Versus Self-Expanding Transcatheter Aortic Valve Impacts Hemodynamics Differently According to Aortic Annular Size SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID PARTNER TRIAL; IN-VITRO; REPLACEMENT; OUTCOMES; IMPLANTATION; PERFORMANCE; STENOSIS AB We sought to determine whether balloon-expandable valve (BEV) and self-expanding valve (SEV) affect valve hemodynamics differently according to native aortic annulus size. Transcatheter aortic valve replacement can achieve superior prosthetic valve hemodynamics compared with surgical aortic valve replacement, particularly in patients with small aortic annulus. One hundred ninety-three consecutive transcatheter aortic valve replacement patients were grouped into tertiles defined by computed tomography derived aortic annulus systolic perimeter. The predischarge echocardiogram was analyzed for prosthetic valve hemodynamics. Tertile perimeter cutoffs were 73 and 80 mm. STS score decreased as annulus size increased (7.8% vs 7.6% vs 6.0%, p <= 0.05 for small, medium, and large annulus, respectively). In patients with small aortic annulus, SEV was associated with significantly higher dimensionless index (0.64 vs 0.53, p = 0.02) and lower peak velocity (1.8 vs 2.4 m/sec, p <0.001) and a trend toward lower mean gradient (7.5 vs 10.0 mm Hg, p = 0.07) compared with BEV. These differences were attenuated and absent in patients with medium and large annulus, respectively. Few patients had moderate/severe paravalvular leak, with no association with valve type or annulus size. There was no difference in mortality between tertiles or valve type at 30 days or 1 year. There was no association between aortic annulus perimeter and 1-year mortality by univariate analysis (hazard ratio 1.00, 95% CI 0.95 to 1.05, p = 0.86) or multivariate analysis (hazard ratio 1.02, 95% CI 0.95 to 1.09, p = 0.60). In conclusion, SEV hemodynamics was superior to BEV in patients with small aortic annulus. This difference was diminished in patients with larger aortic annulus. This study highlights the importance of valve selection in patients with small aortic annulus. (C) 2016 Elsevier Inc. All rights reserved. C1 [Rogers, Toby; Steinvil, Arie; Gai, Jiaxiang; Torguson, Rebecca; Koifman, Edward; Kiramijyan, Sarkis; Negi, Smita; Lee, Sang Yeub; Okubagzi, Petros; Satler, Lowell F.; Ben-Dor, Itsik; Pichard, Augusto D.; Waksman, Ron] MedStar Washington Hosp Ctr, Sect Intervent Cardiol, Washington, DC 20010 USA. [Rogers, Toby] NHLBI, Cardiovasc & Pulm Branch, Div Intramural Res, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Waksman, R (reprint author), MedStar Washington Hosp Ctr, Sect Intervent Cardiol, Washington, DC 20010 USA. EM ron.waksman@medstar.net FU AstraZeneca; Biotronik; Boston Scientific; Biosensors International; Medicines Company; Edwards Lifesciences FX Dr Waksman is a consultant for Abbott Vascular, Biotronik, Boston Scientific, Medtronic, St. Jude Medical, Biosensors International; is on the speaker's bureau of AstraZeneca, Boston Scientific, Merck; and receives grant support from AstraZeneca, Biotronik, and Boston Scientific, Biosensors International, the Medicines Company, Edwards Lifesciences. The other authors have no conflicts of interest to disclose. NR 11 TC 0 Z9 0 U1 1 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAR 15 PY 2017 VL 119 IS 6 BP 900 EP 904 DI 10.1016/j.amjcard.2016.11.044 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EP0LR UT WOS:000397079300013 PM 28109558 ER PT J AU Derakhshan, A Chen, Z Van Waes, C AF Derakhshan, Adeeb Chen, Zhong Van Waes, Carter TI Therapeutic Small Molecules Target Inhibitor of Apoptosis Proteins in Cancers with Deregulation of Extrinsic and Intrinsic Cell Death Pathways SO CLINICAL CANCER RESEARCH LA English DT Review ID NF-KAPPA-B; ALPHA-DEPENDENT APOPTOSIS; TNF-ALPHA; STRUCTURAL BASIS; MIMETIC BIRINAPANT; IAP PROTEINS; SOLID TUMORS; CYCLIN D1; PHASE-I; XIAP AB The Cancer Genome Atlas (TCGA) has unveiled genomic deregulation of various components of the extrinsic and intrinsic apoptotic pathways in different types of cancers. Such alterations are particularly common in head and neck squamous cell carcinomas (HNSCC), which frequently display amplification and overexpression of the Fas-associated via death domain (FADD) and inhibitor of apoptosis proteins (IAP) that complex with members of the TNF receptor family. Second mitochondria-derived activator of caspases (SMAC) mimetics, modeled after the endogenous IAP antagonist SMAC, and IAP inhibitors represent important classes of novel small molecules currently in phase I/II clinical trials. Here we review the physiologic roles of IAPs, FADD, and other components involved in cell death, cell survival, and NF-kappa B signaling pathways in cancers, including HNSCC. We summarize the results of targeting IAPs in preclinical models of HNSCC using SMAC mimetics. Synergistic activity of SMAC mimetics together with death agonists TNF alpha or TRAIL occurred in vitro, whereas their antitumor effects were augmented when combined with radiation and chemotherapeutic agents that induce TNFa in vivo. In addition, clinical trials testing SMAC mimetics as single agents or together with chemo- or radiation therapies in patients with HNSCC and solid tumors are summarized. As we achieve a deeper understanding of the genomic alterations and molecular mechanisms underlying deregulated death and survival pathways in different cancers, the role of SMAC mimetics and IAP inhibitors in cancer treatment will be elucidated. Such developments could enhance precision therapeutics and improve outcomes for cancer patients. (C) 2016 AACR. C1 [Derakhshan, Adeeb; Chen, Zhong; Van Waes, Carter] NIDCD, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD USA. RP Chen, Z; Van Waes, C (reprint author), NIH, Room 7N240D,10 Ctr Dr, Bethesda, MD 20892 USA. EM chenz@nidcd.nih.gov; vanwaesc@nidcd.nih.gov FU National Institute on Deafness and Other Communication Disorders intramural projects [ZIA-DC-000016, ZIA-DC-000073, ZIA-DC-000074]; NIH-Medical Research Scholars Program; NIH FX A. Derakhshan, Z. Chen, and C. Van Waes were supported by the National Institute on Deafness and Other Communication Disorders intramural projects ZIA-DC-000016, ZIA-DC-000073, and ZIA-DC-000074. A. Derakhshan was supported through the NIH-Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation, The American Association for Dental Research, The Howard Hughes Medical Institute, and the Colgate-Palmolive Company, as well as other private donors. NR 74 TC 0 Z9 0 U1 3 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2017 VL 23 IS 6 BP 1379 EP 1387 DI 10.1158/1078-0432.CCR-16-2172 PG 9 WC Oncology SC Oncology GA EP4IS UT WOS:000397344800004 PM 28039268 ER PT J AU Lee, JM Peer, CJ Yu, MS Amable, L Gordon, N Annunziata, CM Houston, N Goey, AKL Sissung, TM Parker, B Minasian, L Chiou, VL Murphy, RF Widemann, BC Figg, WD Kohn, EC AF Lee, Jung-Min Peer, Cody J. Yu, Minshu Amable, Lauren Gordon, Nicolas Annunziata, Christina M. Houston, Nicole Goey, Andrew K. L. Sissung, Tristan M. Parker, Bernard Minasian, Lori Chiou, Victoria L. Murphy, Robert F. Widemann, Brigitte C. Figg, William D. Kohn, Elise C. TI Sequence-Specific Pharmacokinetic and Pharmacodynamic Phase I/Ib Study of Olaparib Tablets and Carboplatin in Women's Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID SENSITIVE OVARIAN-CANCER; DNA-REPAIR; POLY(ADP-RIBOSE) POLYMERASE-1; RANDOMIZED PHASE-2; PARP INHIBITOR; MAINTENANCE THERAPY; EXCISION-REPAIR; BREAST-CANCER; SOLID TUMORS; PLATINUM AB Purpose: Our preclinical studies showed that the PARP inhibitor, olaparib, prior to carboplatin attenuated carboplatin cytotoxicity. We evaluated sequence-specific pharmacokinetic and pharmacodynamic effects, safety, and activity of the combination. Experimental Design: Eligible patients had metastatic or recurrent women's cancer. Olaparib tablets were introduced (100 or 200 mg twice daily, days 1-7) in a 3 + 3 dose escalation with carboplatin AUC4 or 5 every 21 days, up to eight cycles, followed by olaparib 300 mg twice daily maintenance. Patients were randomly assigned to starting schedule: cohort A (olaparib days 1-7, carboplatin on day 8) or B (carboplatin on day 1, olaparib days 2-8) during cycle 1. Patients received the reversed scheme in cycle 2. Blood was collected for olaparib pharmacokinetics, platinum-DNA adducts, comet assay, and PAR concentrations. The primary objectives were to examine schedule-dependent effects on olaparib pharmacokinetics and platinum-DNA adducts. Results: A total of 77 (60 ovarian, 14 breast, and 3 uterine cancer) patients were treated. Dose-limiting toxicity was thrombocytopenia and neutropenia, defining olaparib 200 mg twice daily + carboplatin AUC4 as the MTD. Olaparib clearance was increased approximately 50% when carboplatin was given 24 hours before olaparib. In vitro experiments demonstrated carboplatin preexposure increased olaparib clearance due to intracellular olaparib uptake. Quantities of platinum-DNA adducts were not different as a function of the order of drug administration. Responses included 2 CRs and 31 PRs (46%) with a higher RR in BRCA mutation carriers compared with nonmutation carriers (68% vs. 19%). Conclusions: Tablet olaparib with carboplatin is a safe and active combination. Carboplatin preexposure causes intracellular olaparib accumulation reducing bioavailable olaparib, suggesting carboplatin should be administered prior to olaparib. (C) 2016 AACR. C1 [Lee, Jung-Min; Yu, Minshu; Gordon, Nicolas; Annunziata, Christina M.; Houston, Nicole; Parker, Bernard; Minasian, Lori; Chiou, Victoria L.; Kohn, Elise C.] NCI, Womens Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Peer, Cody J.; Goey, Andrew K. L.; Sissung, Tristan M.; Figg, William D.] NCI, Clin Pharmacol Program, Ctr Canc Res, Bethesda, MD 20892 USA. [Amable, Lauren] Natl Inst Minor Hlth & Hlth Disparities, Bethesda, MD USA. [Murphy, Robert F.; Widemann, Brigitte C.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lee, JM (reprint author), NCI, 10 Ctr Dr,Bldg 10,Rm4B54, Bethesda, MD 20892 USA. EM leej6@mail.nih.gov FU Jane C. Wright MD ASCO Young Investigator Award from Conquer Cancer Foundation; Intramural Program of the Center for Cancer Research, NCI and NIMHD, NIH FX This work was funded in part by the 2011 Jane C. Wright MD ASCO Young Investigator Award from Conquer Cancer Foundation (to J.-M. Lee) and by the Intramural Program of the Center for Cancer Research, NCI and NIMHD, NIH. NR 33 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2017 VL 23 IS 6 BP 1397 EP 1406 DI 10.1158/1078-0432.CCR-16-1546 PG 10 WC Oncology SC Oncology GA EP4IS UT WOS:000397344800006 PM 27663600 ER PT J AU Matas-Cespedes, A Vidal-Crespo, A Rodriguez, V Villamor, N Delgado, J Gine, E Roca-Ho, H Menendez, P Campo, E Lopez-Guillermo, A Colomer, D Roue, G Wiestner, A Parren, PWHI Doshi, P van Bueren, JL Perez-Galan, P AF Matas-Cespedes, Alba Vidal-Crespo, Anna Rodriguez, Vanina Villamor, Neus Delgado, Julio Gine, Eva Roca-Ho, Heleia Menendez, Pablo Campo, Elias Lopez-Guillermo, Armando Colomer, Dolors Roue, Gael Wiestner, Adrian Parren, Paul W. H. I. Doshi, Parul van Bueren, Jeroen Lammerts Perez-Galan, Patricia TI The Human CD38 Monoclonal Antibody Daratumumab Shows Antitumor Activity and Hampers Leukemia-Microenvironment Interactions in Chronic Lymphocytic Leukemia SO CLINICAL CANCER RESEARCH LA English DT Article ID REFRACTORY MULTIPLE-MYELOMA; B-CELLS; CD38-TARGETED IMMUNOCHEMOTHERAPY; BONE-MARROW; EXPRESSION; CLL; LENALIDOMIDE; BIOLOGY; DISEASE; MATRIX-METALLOPROTEINASE-9 AB Purpose: To establish a proof-of-concept for the efficacy of the anti-CD38 antibody daratumumab in the poor prognosis CD38(+) chronic lymphocytic leukemia (CLL) subtype. Experimental Design: The mechanism of action of daratumumab was assessed in CLL primary cells and cell lines using peripheral blood mononuclear cells to analyze antibodydependent cell cytotoxicity (ADCC), murine and human macrophages to study antibody-dependent cell phagocytosis (ADCP), or human serum to analyze complement-dependent cytotoxicity (CDC). The effect of daratumumab on CLL cell migration and adhesion to extracellular matrix was characterized. Daratumumab activity was validated in two in vivo models. Results: Daratumumab demonstrated efficient lysis of patientderived CLL cells and cell lines by ADCC in vitro and ADCP both in vitro and in vivo whereas exhibited negligible CDC in these cells. To demonstrate the therapeutic effect of daratumumab in CLL, we generated a disseminated CLL mouse model with the CD38(+) MEC2 cell line and CLL patient-derived xenografts (CLL-PDX). Daratumumab significantly prolonged overall survival of MEC2 mice, completely eliminated cells from the infiltrated organs, and significantly reduced disease burden in the spleen of CLL-PDX. The effect of daratumumab on patient-derived CLL cell dissemination was demonstrated in vitro by its effect on CXCL12-induced migration and in vivo by interfering with CLL cell homing to spleen inNSGmice. Daratumumab also reduced adhesion of CLL cells to VCAM-1, accompanied by downregulation of the matrix metal-loproteinase MMP9. Conclusions: These unique and substantial effects of daratumumab on CLL viability and dissemination support the investigation of its use in a clinical setting of CLL. (C) 2016 AACR. C1 [Matas-Cespedes, Alba; Vidal-Crespo, Anna; Rodriguez, Vanina; Villamor, Neus; Colomer, Dolors; Roue, Gael; Perez-Galan, Patricia] Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain. [Villamor, Neus; Campo, Elias; Colomer, Dolors] Hosp Clin Barcelona, Dept Pathol, Hematopathol Unit, Barcelona, Spain. [Delgado, Julio; Gine, Eva; Lopez-Guillermo, Armando] Hosp Clin Barcelona, Dept Hematol, Barcelona, Spain. [Roca-Ho, Heleia; Menendez, Pablo] Univ Barcelona, Dept Biomed, Josep Carreras Leukaemia Res Inst, Barcelona, Spain. [Menendez, Pablo] ICREA, Barcelona, Spain. [Wiestner, Adrian] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Parren, Paul W. H. I.; van Bueren, Jeroen Lammerts] Genmab, Utrecht, Netherlands. [Parren, Paul W. H. I.] Univ Southern Denmark, Inst Mol Med, Dept Canc & Inflammat Res, Odense, Denmark. [Parren, Paul W. H. I.] Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, Leiden, Netherlands. [Doshi, Parul] Janssen R&D, Spring House, PA USA. RP Perez-Galan, P (reprint author), IDIBAPS, Dept Hematooncol, Rosello 149-153, Barcelona 08036, Spain. EM pperez@clinic.ub.es FU Genmab and Janssen pharmaceuticals; Spanish Ministry of Economy and Competitivity [RYC2009-05134, SAF11/29326, SAF12/31242, IPT.2012-0673-010000, PI12/01847]; Instituto de Salud Carlos III (ISCIII) [PIE1313/00033]; Redes Tematicas de Investigacion Cooperativa de Cancer from the Instituto de Salud Carlos III ( ISCIII); Spanish Ministry of Economy and Competitiveness & European Regional Development Fund (ERDF) "Una manera de hacer Europa" [RD12/0036/0004, RD12/0036/0023] FX Genmab and Janssen pharmaceuticals funded this research. Additional grants that contributed to this work included: grants from the Spanish Ministry of Economy and Competitivity (RYC2009-05134 and SAF11/29326 to P. PerezGalan, SAF12/31242 and IPT.2012-0673-010000 to D. Colomer, and PI12/01847 to G. Roue), Integrated Excellence Grant from the Instituto de Salud Carlos III (ISCIII) PIE1313/00033 to E. Campo and P. Perez Galan, Redes Tematicas de Investigacion Cooperativa de Cancer from the Instituto de Salud Carlos III ( ISCIII), Spanish Ministry of Economy and Competitiveness & European Regional Development Fund (ERDF) "Una manera de hacer Europa" (RD12/0036/0004 to D. Colomer and RD12/0036/0023 to A. Lopez-Guillermo). NR 48 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2017 VL 23 IS 6 BP 1493 EP 1505 DI 10.1158/1078-0432.CCR-15-2095 PG 13 WC Oncology SC Oncology GA EP4IS UT WOS:000397344800016 PM 27637890 ER PT J AU Zhang, JL Khanna, S Jiang, Q Alewine, C Miettinen, M Pastan, I Hassan, R AF Zhang, Jingli Khanna, Swati Jiang, Qun Alewine, Christine Miettinen, Markku Pastan, Ira Hassan, Raffit TI Efficacy of Anti-mesothelin Immunotoxin RG7787 plus Nab-Paclitaxel against Mesothelioma Patient-Derived Xenografts and Mesothelin as a Biomarker of Tumor Response SO CLINICAL CANCER RESEARCH LA English DT Article ID MALIGNANT PLEURAL MESOTHELIOMA; CELL LUNG-CANCER; SERUM MESOTHELIN; IN-VITRO; PANCREATIC-CANCER; OVARIAN CANCERS; PHASE-III; SS1P; COMBINATION; THERAPY AB Purpose: The purpose of this study was to evaluate the antitumor efficacy of the reduced immunogenicity anti-mesothelin immunotoxin RG7787 plus nab-paclitaxel against primary mesothelioma cell lines and tumor xenografts and the utility of mesothelin as a biomarker of tumor response. Experimental Design: Early-passage human malignant mesothelioma cell lines NCI-Meso16, NCI-Meso19, NCI-Meso21, and NCI-Meso29 were evaluated for sensitivity to RG7787 or nab-paclitaxel alone or in combination. In addition, the antitumor activity of RG7787 plus nab-paclitaxel was evaluated using NCI-Meso16, NCI-Meso21, and NCI-Meso29 tumor xenografts in immunodeficient mice. Serum mesothelin was measured at different time points to determine whether its levels correlated with tumor response. Results: All four primary mesothelioma cell lines highly expressed mesothelin with 41 X 10(3) to 346 X 10(3) mesothelin sites per cell and were sensitive to RG7787, with IC50 ranging from 0.3 to 10 ng/mL. Except for NCI-Meso19, these cells were also sensitive to nab-paclitaxel, with IC50 of 10 to 25 ng/mL. In vitro, RG7787 plus nab-paclitaxel led to decreased cell viability compared with either agent alone. In NCI-Meso16 tumor xenografts, treatment with RG7787 plus nab-paclitaxel led to sustained complete tumor regressions. Similar antitumor efficacy was observed against NCI-Meso21 and NCI-Meso29 tumor xenografts. In all three tumor xenograft models, changes in human serum mesothelin correlated with response to therapy and were undetectable in mice with complete tumor regression with RG7787 and nab-paclitaxel. Conclusions: RG7787 plus nab-paclitaxel is very active against primary human mesothelioma cells in vitro as well as in vivo, with serum mesothelin levels correlating with tumor response. These results indicate that this combination could be useful for treating patients with mesothelioma. (C) 2016 AACR. C1 [Zhang, Jingli; Khanna, Swati; Jiang, Qun; Hassan, Raffit] NCI, Thorac & Gastrointestinal Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Alewine, Christine; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. [Miettinen, Markku] NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Hassan, R (reprint author), NCI, NIH, Bld 10 Room 4-5553, Bethesda, MD 20892 USA. EM hassanr@mail.nih.gov FU NIH; NCI; Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, NCI, Center for Cancer Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 34 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2017 VL 23 IS 6 BP 1564 EP 1574 DI 10.1158/1078-0432.CCR-16-1667 PG 11 WC Oncology SC Oncology GA EP4IS UT WOS:000397344800022 PM 27635089 ER PT J AU Patel, EU Kirkpatrick, AR Grabowski, MK Kigozi, G Gray, RH Prodger, JL Redd, AD Nalugoda, F Serwadda, D Wawer, MJ Quinn, TC Tobian, AAR AF Patel, Eshan U. Kirkpatrick, Allison R. Grabowski, Mary Kate Kigozi, Godfrey Gray, Ronald H. Prodger, Jessica L. Redd, Andrew D. Nalugoda, Fred Serwadda, David Wawer, Maria J. Quinn, Thomas C. Tobian, Aaron A. R. TI Penile Immune Activation and Risk of HIV Shedding: A Prospective Cohort Study SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE human immunodeficiency virus (HIV); male circumcision; immune activation; genital inflammation; sexual transmission ID PLASMA VIRAL LOAD; MALE CIRCUMCISION; GENITAL-TRACT; SEXUAL TRANSMISSION; INFECTION; SEMEN; INFLAMMATION; PREVENTION; UGANDA; RAKAI AB Background. Genital immune activation is suspected to modulate local human immunodeficiency virus (HIV) RNA levels and the risk of sexual HIV transmission. Methods. A prospective, observational cohort study of 221 HIV-infected men undergoing male circumcision (MC) was conducted in Rakai, Uganda. Penile lavage samples collected from the coronal sulcus at baseline and 4 weekly visits after MC were assayed for pro-inflammatory cytokines and HIV RNA. The main analysis was limited to 175 men with detectable HIV plasma viral load (VL > 400 copies/mL; n = 808 visits). The primary exposures of interest were individual and total cytokine detection at the previous postoperative visit. Adjusted prevalence risk ratios (adjPRR) of detectable HIV shedding (VL > 40 copies/mL) were estimated by Poisson regression models with generalized estimating equations and robust variance estimators and included adjustment for plasma HIV VL. Findings. Among men with a detectable plasma VL, penile HIV shedding was detected at 136 visits (16.8%). Detectable interleukin (IL)-1 beta (adjPRR = 2.14; 95% confidence interval (CI) = 1.02-4.48), IL-6 (adjPRR = 2.24; 95% CI = 1.28-3.90), IL-8 (adjPRR = 2.42; 95% CI = 1.15-5.08), IL-10 (adjPRR = 2.51; 95% CI = 1.67-3.80), and IL-13 (adjPRR = 1.87; 95% CI = 1.15-3.03) were associated with penile HIV shedding at the subsequent visit. Men with 2-4 (adjPRR = 2.36; 95% CI = 1.08-5.14) and 5-7 (adjPRR = 3.00; 95% CI = 1.28-7.01) detectable cytokines had a greater likelihood of detectable penile HIV shedding at the subsequent visit, compared to men with = 1 detectable cytokine. The total number of detectable cytokines was also associated with a higher penile log 10 HIV VL at the subsequent visit among HIV shedders. Interpretation. Pro-inflammatory cytokine production had a dose-dependent and temporal association with penile HIV shedding, suggesting that genital immune activation may increase the risk of sexual HIV transmission by driving local HIV replication. C1 [Patel, Eshan U.; Kirkpatrick, Allison R.; Prodger, Jessica L.; Redd, Andrew D.; Quinn, Thomas C.] NIAID, Immunogenet Lab, Div Intramural Res, Baltimore, MD USA. [Patel, Eshan U.; Grabowski, Mary Kate; Gray, Ronald H.; Prodger, Jessica L.; Wawer, Maria J.; Quinn, Thomas C.; Tobian, Aaron A. R.] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Grabowski, Mary Kate; Kigozi, Godfrey; Gray, Ronald H.; Nalugoda, Fred; Serwadda, David; Wawer, Maria J.; Quinn, Thomas C.] Rakai Hlth Sci Program, Entebbe, Uganda. [Redd, Andrew D.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Serwadda, David] Makerere Univ, Inst Publ Hlth, Kampala, Uganda. [Tobian, Aaron A. R.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. RP Tobian, AAR (reprint author), Johns Hopkins Univ, Dept Pathol, Carnegie 437,600 N Wolfe St, Baltimore, MD 21287 USA. EM atobian1@jhmi.edu FU Bill and Melinda Gates Foundation [22006.03]; Doris Duke Charitable Foundation [2011036]; Fogarty International Center [1D43TWOO9578-01]; National Institutes of Health [K01AI125086-01, 1K23AI093152-01A1]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Bill and Melinda Gates Foundation [22006.03]; the Doris Duke Charitable Foundation [2011036 to A.A.R.T.]; the Fogarty International Center [1D43TWOO9578-01]; the National Institutes of Health [K01AI125086-01 and 1K23AI093152-01A1 to M.K.G. and A.A.R.T., respectively]; and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 40 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAR 15 PY 2017 VL 64 IS 6 BP 776 EP 784 DI 10.1093/cid/ciw847 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP3TI UT WOS:000397304200013 PM 28011606 ER PT J AU Leroy, B Ballinger, ML Baran-Marszak, F Bond, GL Braithwaite, A Concin, N Donehower, LA El-Deiry, WS Fenaux, P Gaidano, G Langerod, A Hellstrom-Lindberg, E Iggo, R Lehmann-Che, J Mai, PL Malkin, D Moll, UM Myers, JN Nichols, KE Pospisilova, S Ashton-Prolla, P Rossi, D Savage, SA Strong, LC Tonin, PN Zeillinger, R Zenz, T Fraumeni, JF Taschner, PEM Hainaut, P Soussi, T AF Leroy, Bernard Ballinger, Mandy L. Baran-Marszak, Fanny Bond, Gareth L. Braithwaite, Antony Concin, Nicole Donehower, Lawrence A. El-Deiry, Wafik S. Fenaux, Pierre Gaidano, Gianluca Langerod, Anita Hellstrom-Lindberg, Eva Iggo, Richard Lehmann-Che, Jacqueline Mai, Phuong L. Malkin, David Moll, Ute M. Myers, Jeffrey N. Nichols, Kim E. Pospisilova, Sarka Ashton-Prolla, Patricia Rossi, Davide Savage, Sharon A. Strong, Louise C. Tonin, Patricia N. Zeillinger, Robert Zenz, Thorsten Fraumeni, Joseph F., Jr. Taschner, Peter E. M. Hainaut, Pierre Soussi, Thierry TI Recommended Guidelines for Validation, Quality Control, and Reporting of TP53 Variants in Clinical Practice SO CANCER RESEARCH LA English DT Review ID LI-FRAUMENI-SYNDROME; CHRONIC LYMPHOCYTIC-LEUKEMIA; MUTANT P53; BREAST-CANCER; GENE-MUTATIONS; TUMOR SUPPRESSION; IN-VIVO; OSTEOSARCOMA; CARRIERS; SARCOMAS AB Accurate assessment of TP53 gene status in sporadic tumors and in the germline of individuals at high risk of cancer due to Li-Fraumeni Syndrome (LFS) has important clinical implications for diagnosis, surveillance, and therapy. Genomic data from more than 20,000 cancer genomes provide a wealth of information on cancer gene alterations and have confirmed TP53 as the most commonly mutated gene in human cancer. Analysis of a database of 70,000 TP53 variants reveals that the two newly discovered exons of the gene, exons 9 beta and 9 gamma, generated by alternative splicing, are the targets of inactivating mutation events in breast, liver, and head and neck tumors. Furthermore, germline rearrangements in intron 1 of TP53 are associated with LFS and are frequently observed in sporadic osteosarcoma. In this context of constantly growing genomic data, we discuss how screening strategies must be improved when assessing TP53 status in clinical samples. Finally, we discuss how TP53 alterations should be described by using accurate nomenclature to avoid confusion in scientific and clinical reports. (C)2017 AACR. C1 [Leroy, Bernard; Soussi, Thierry] UPMC, Univ Paris 06, Sorbonne Univ, Paris, France. [Ballinger, Mandy L.] Garvan Inst Med Res, Canc Div, Darlinghurst, NSW, Australia. [Baran-Marszak, Fanny] Hop Avicenne Assistance Publ Hop Paris, Bobigny, Serv DH Ematol Biol, Paris, France. [Bond, Gareth L.] Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Old Rd Campus Res Bldg, Oxford, England. [Braithwaite, Antony] Univ Otago, Sch Med, Dept Pathol, Dunedin, New Zealand. [Braithwaite, Antony] Univ Sydney, Childrens Med Res Inst, Westmead, NSW, Australia. [Concin, Nicole] Med Univ Innsbruck, Dept Gynecol & Obstet, Innsbruck, Austria. [Donehower, Lawrence A.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX USA. [El-Deiry, Wafik S.] Fox Chase Canc Ctr, Dept Hematol Oncol & Mol Therapeut Program, Philadelphia, PA USA. [Fenaux, Pierre] Hop St Louis, Univ Paris 7, Serv Hematol Seniors, 1 Ave Claude Vellefaux, Paris, France. [Gaidano, Gianluca; Rossi, Davide] Amedeo Avogadro Univ Eastern Piedmont, Dept Translat Med, Div Hematol, Novara, Italy. [Langerod, Anita] Oslo Univ Hosp, Inst Canc Res, Dept Genet, Oslo, Norway. [Hellstrom-Lindberg, Eva] Karolinska Univ Hosp, Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden. [Iggo, Richard] Univ Bordeaux, Bergonie Canc Inst, 229 Cours Argonne, F-33076 Bordeaux, France. [Lehmann-Che, Jacqueline] Hosp St Louis, Mol Oncol Unit, Paris, France. [Mai, Phuong L.] Univ Pittsburgh, Magee Womens Hosp, Med Ctr, Canc Genet Program, Pittsburgh, PA USA. [Malkin, David] Univ Toronto, Hosp Sick Children, Dept Pediat, Div Hematol Oncol, Toronto, ON, Canada. [Moll, Ute M.] SUNY Stony Brook, Dept Pathol, Stony Brook, NY USA. [Myers, Jeffrey N.; Strong, Louise C.] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX USA. [Nichols, Kim E.] St Jude Childrens Res Hosp, Dept Oncol, Div Canc Predisposit, Memphis, TN USA. [Pospisilova, Sarka] Masaryk Univ, CEITEC Mol Med, Brno, Czech Republic. [Pospisilova, Sarka] Univ Hosp Brno, Dept Internal Med Hematol & Oncol, Brno, Czech Republic. [Ashton-Prolla, Patricia] Univ Fed Rio Grande do Sul, Serv Genet Med HCPA, Rua Ramiro Barcelos, Porto Alegre, RS, Brazil. [Savage, Sharon A.] Natl Canc Inst, Div Canc Epidemiol & Genet, Clin Genet Branch, Bethesda, MD USA. [Tonin, Patricia N.] McGill Univ, Dept Med, Montreal, PQ, Canada. [Tonin, Patricia N.] McGill Univ, Dept Human Genet, Montreal, PQ, Canada. [Tonin, Patricia N.] McGill Univ, Res Inst, Ctr Hlth, Canc Res Program, Montreal, PQ, Canada. [Zeillinger, Robert] Med Univ Vienna, Dept Obstet & Gynaecol, Mol Oncol Grp, Vienna, Austria. [Zenz, Thorsten] Heidelberg Univ, Dept Med V, Heidelberg, Germany. [Zenz, Thorsten] Natl Ctr Tumor Dis, Dept Translat Oncol, Heidelberg, Germany. [Zenz, Thorsten] German Canc Res Ctr, Heidelberg, Germany. [Fraumeni, Joseph F., Jr.] Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Taschner, Peter E. M.] Univ Appl Sci Leiden, Generade Ctr Expertise Genom, Leiden, Netherlands. [Hainaut, Pierre] Univ Grenoble Alpes, Inst Albert Bonniot, Inserm 823, Rond Point Chantourne, La Tronche, France. [Soussi, Thierry] Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, Stockholm, Sweden. [Soussi, Thierry] INSERM, Ctr Rech Cordeliers, U1138, Paris, France. RP Soussi, T (reprint author), UPMC, Univ Paris 06, Sorbonne Univ, Paris, France.; Soussi, T (reprint author), Karolinska Inst, Canc Centrum Karolinska, S-17176 Stockholm, Sweden. EM thierry.soussi@ki.se OI Taschner, Peter/0000-0001-9621-465X NR 87 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2017 VL 77 IS 6 BP 1250 EP 1260 DI 10.1158/0008-5472.CAN-16-2179 PG 11 WC Oncology SC Oncology GA EO7BG UT WOS:000396845600002 PM 28254861 ER PT J AU Valent, P Akin, C Hartmann, K Nilsson, G Reiter, A Hermine, O Sotlar, K Sperr, WR Escribano, L George, TI Kluin-Nelemans, HC Ustun, C Triggiani, M Brockow, K Gotlib, J Orfao, A Schwartz, LB Broesby-Olsen, S Bindslev-Jensen, C Kovanen, PT Galli, SJ Austen, KF Arber, DA Horny, HP Arock, M Metcalfe, DD AF Valent, Peter Akin, Cem Hartmann, Karin Nilsson, Gunnar Reiter, Andreas Hermine, Olivier Sotlar, Karl Sperr, Wolfgang R. Escribano, Luis George, Tracy I. Kluin-Nelemans, Hanneke C. Ustun, Celalettin Triggiani, Massimo Brockow, Knut Gotlib, Jason Orfao, Alberto Schwartz, Lawrence B. Broesby-Olsen, Sigurd Bindslev-Jensen, Carsten Kovanen, Petri T. Galli, Stephen J. Austen, K. Frank Arber, Daniel A. Horny, Hans-Peter Arock, Michel Metcalfe, Dean D. TI Advances in the Classification and Treatment of Mastocytosis: Current Status and Outlook toward the Future SO CANCER RESEARCH LA English DT Review ID ADVANCED SYSTEMIC MASTOCYTOSIS; NEOPLASTIC MAST-CELLS; KIT D816V MUTATION; OF-THE-ART; BONE-MARROW MASTOCYTOSIS; C-KIT; URTICARIA PIGMENTOSA; CONSENSUS PROPOSAL; PERIPHERAL-BLOOD; IN-VITRO AB Mastocytosis is a term used to denote a heterogeneous group of conditions defined by the expansion and accumulation of clonal (neoplastic) tissue mast cells in various organs. The classification of the World Health Organization (WHO) divides the disease into cutaneous mastocytosis, systemic mastocytosis, and localized mast cell tumors. On the basis of histomorphologic criteria, clinical parameters, and organ involvement, systemic mastocytosis is further divided into indolent systemic mastocytosis and advanced systemic mastocytosis variants, including aggressive systemic mastocytosis and mast cell leukemia. The clinical impact and prognostic value of this classification has been confirmed in numerous studies, and its basic concept remains valid. However, refinements have recently been proposed by the consensus group, the WHO, and the European Competence Network on Mastocytosis. In addition, new treatment options are available for patients with advanced systemic mastocytosis, including allogeneic hematopoietic stem cell transplantation and multikinase inhibitors directed against KIT D816V and other key signaling molecules. Our current article provides an overview of recent advances in the field of mastocytosis, with emphasis on classification, prognostication, and emerging new treatment options in advanced systemic mastocytosis. (C)2017 AACR. C1 [Valent, Peter; Sperr, Wolfgang R.] Med Univ Vienna, Dept Med 1, Div Hematol, Vienna, Austria. [Valent, Peter; Sperr, Wolfgang R.] Med Univ Vienna, Ludwig Boltzmann Cluster Oncol, Waehringer Guertel 18-20, A-1090 Vienna, Austria. [Akin, Cem; Austen, K. Frank] Brigham & Womens Hosp, Harvard Med Sch, Dept Med, Div Allergy & Immunol, Boston, MA 02115 USA. [Hartmann, Karin] Univ Lubeck, Dept Dermatol, Lubeck, Germany. [Nilsson, Gunnar] Karolinska Inst, Solna & Mastocytosis Ctr, Dept Med, Stockholm, Sweden. [Nilsson, Gunnar] Karolinska Univ Hosp, Stockholm, Sweden. [Reiter, Andreas] Heidelberg Univ, Univ Hosp Mannheim, Dept Hematol & Oncol, Mannheim, Germany. [Hermine, Olivier] Univ Paris 05, Imagine Inst, Ctr Natl Reference Mastocytoses, Paris Cite, Paris, France. [Sotlar, Karl] Paracelsus Med Univ Salzburg, Inst Pathol, Salzburg, Austria. [Escribano, Luis; Orfao, Alberto] Univ Salamanca, Inst Biosanitario Salamanca IBSAL, Cent Investigac Canc IBMCC CSIC USAL, Serv Cent Citometria, Salamanca, Spain. [Escribano, Luis; Orfao, Alberto] Univ Salamanca, Dept Med, Salamanca, Spain. [George, Tracy I.] Univ New Mexico, Dept Pathol, Albuquerque, NM 87131 USA. [Kluin-Nelemans, Hanneke C.] Univ Groningen, Univ Med Ctr Groningen, Dept Hematol, Groningen, Netherlands. [Ustun, Celalettin] Univ Minnesota, Dept Med, Div Hematol Oncol & Transplantat, Minneapolis, MN USA. [Triggiani, Massimo] Univ Salerno, Div Allergy & Clin Immunol, Salerno, Italy. [Brockow, Knut] Tech Univ Munich, Dept Dermatol & Allergy Biederstein, Munich, Germany. [Gotlib, Jason] Stanford Univ, Sch Med, Stanford Canc Inst, Div Hematol, Stanford, CA USA. [Schwartz, Lawrence B.] Virginia Commonwealth Univ, Dept Med, Div Rheumatol Allergy & Immunol, Richmond, VA USA. [Broesby-Olsen, Sigurd; Bindslev-Jensen, Carsten] Odense Univ Hosp, Dept Dermatol, Odense, Denmark. [Broesby-Olsen, Sigurd; Bindslev-Jensen, Carsten] Odense Univ Hosp, Allergy Ctr, Odense, Denmark. [Kovanen, Petri T.] Wihuri Res Inst, Helsinki, Finland. [Galli, Stephen J.; Arber, Daniel A.] Univ Chicago, Inst Pathol, Chicago, IL USA. [Horny, Hans-Peter] Ludwig Maximilians Univ Munchen, Inst Pathol, Munich, Germany. [Arock, Michel] Ecole Normale Super, CNRS, LBPA, UMR 8113, Cachan, France. [Metcalfe, Dean D.] Natl Inst Allergy & Infect Dis, NIH, Lab Allerg Dis, Bethesda, MD USA. RP Valent, P (reprint author), Med Univ Vienna, Ludwig Boltzmann Cluster Oncol, Waehringer Guertel 18-20, A-1090 Vienna, Austria.; Valent, P (reprint author), Med Univ Vienna, Dept Internal Med 1, Div Hematol & Hemostaseol, Waehringer Guertel 18-20, A-1090 Vienna, Austria. EM peter.valent@meduniwien.ac.at FU Austrian Science Funds; SFB grant [F4701, F4704]; NIAID Division of Intramural Research FX This work was supported by the Austrian Science Funds, SFB grant F4701 and F4704 to P. Valent and by the NIAID Division of Intramural Research to D. Metcalfe. NR 100 TC 0 Z9 0 U1 3 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2017 VL 77 IS 6 BP 1261 EP 1270 DI 10.1158/0008-5472.CAN-16-2234 PG 10 WC Oncology SC Oncology GA EO7BG UT WOS:000396845600003 PM 28254862 ER PT J AU Cui, Y Steagall, WK Lamattina, AM Pacheco-Rodriguez, G Stylianou, M Kidambi, P Stump, B Golzarri, F Rosas, IO Priolo, C Henske, EP Moss, J El-Chemaly, S AF Cui, Ye Steagall, Wendy K. Lamattina, Anthony M. Pacheco-Rodriguez, Gustavo Stylianou, Mario Kidambi, Pranav Stump, Benjamin Golzarri, Fernanda Rosas, Ivan O. Priolo, Carmen Henske, Elizabeth P. Moss, Joel El-Chemaly, Souheil TI Aberrant SYK Kinase Signaling Is Essential for Tumorigenesis Induced by TSC2 Inactivation SO CANCER RESEARCH LA English DT Article ID TUBEROUS SCLEROSIS COMPLEX; SPLEEN TYROSINE KINASE; GROWTH FACTOR-D; LYMPHANGIOLEIOMYOMATOSIS CELLS; RHEUMATOID-ARTHRITIS; THERAPEUTIC TARGET; OXIDATIVE STRESS; MOUSE MODEL; ACTIVATION; SIROLIMUS AB Somatic or germline mutations in the tuberous sclerosis complex (TSC) tumor suppressor genes are associated closely with the pathogenesis of lymphangioleiomyomatosis, a rare and progressive neoplastic disease that predominantly affects women in their childbearing years. Serum levels of the lym-phangiogenic growth factor VEGF-D are elevated significantly in lymphangioleiomyomatosis. However, there are gaps in knowledge regarding VEGF-D dysregulation and its cellular origin in lymphangioleiomyomatosis. Here, we show that increased expression and activation of the tyrosine kinase Syk in TSC2-deficient cells and pulmonary nodules from lymphan-gioleiomyomatosis patients contributes to tumor growth. Syk kinase inhibitors blocked Syk signaling and exhibited potent antiproliferative activities in TSC2-deficient cells and an immunodeficient mouse xenograft model of lymphangioleio-myomatosis. In TSC2-deficient cells, Syk signaling increased the expression of monocyte chemoattractant protein MCP-1, which in peripheral blood mononuclear cells (PBMC) stimulated the production of VEGF-D. In clinical isolates of PBMCs from lymphangioleiomyomatosis patients, VEGF-D expression was elevated. Furthermore, levels of VEGF-D and MCP1 in patient sera correlated positively with each other. Our results illuminate the basis for lymphangioleiomyomatosis growth and demonstrate the therapeutic potential of targeting Syk in this and other settings driven by TSC genetic mutation. (C)2017 AACR. C1 [Cui, Ye; Lamattina, Anthony M.; Kidambi, Pranav; Stump, Benjamin; Golzarri, Fernanda; Rosas, Ivan O.; Priolo, Carmen; Henske, Elizabeth P.; El-Chemaly, Souheil] Brigham & Womens Hosp, Harvard Med Sch, Div Pulm & Crit Care Med, 75 Francis St, Boston, MA 02115 USA. [Steagall, Wendy K.; Pacheco-Rodriguez, Gustavo; Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Stylianou, Mario] NHLBI, Off Biostat Res, NIH, Bldg 10, Bethesda, MD 20892 USA. RP El-Chemaly, S (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM sel-chemaly@partners.org FU Department of Defense [TS130031]; NIH [R01 HL130275]; Anne Levine LAMResearch Fund; Lucy J. Engles TSC/LAM Research Program; Division of Intramural Research NIH/NHLBI; BRI microgrant FX This work was supported in part by the Department of Defense (TS130031 to S. El-Chemaly), NIH grant R01 HL130275 to S. El-Chemaly, the Anne Levine LAMResearch Fund to S. El-Chemaly, BRI microgrant (Y. Cui), The Lucy J. Engles TSC/LAM Research Program (EP. Henske) and the Division of Intramural Research NIH/NHLBI. NR 49 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2017 VL 77 IS 6 BP 1492 EP 1502 DI 10.1158/0008-5472.CAN-16-2755 PG 11 WC Oncology SC Oncology GA EO7BG UT WOS:000396845600023 PM 28202529 ER PT J AU Olivier, KN Griffith, DE Eagle, G McGinnis, JP Micioni, L Liu, K Daley, CL Winthrop, KL Ruoss, S Addrizzo-Harris, DJ Flume, PA Dorgan, D Salathe, M Brown-Elliott, BA Gupta, R Wallace, RJ AF Olivier, Kenneth N. Griffith, David E. Eagle, Gina McGinnis, John P., II Micioni, Liza Liu, Keith Daley, Charles L. Winthrop, Kevin L. Ruoss, Stephen Addrizzo-Harris, Doreen J. Flume, Patrick A. Dorgan, Daniel Salathe, Matthias Brown-Elliott, Barbara A. Gupta, Renu Wallace, Richard J., Jr. TI Randomized Trial of Liposomal Amikacin for Inhlation in Nontuberculous Mycobacterial Lung Disease SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE culture conversion; efficacy; safety; nontuberculous mycobacteria ID GUIDELINE-BASED THERAPY; INHALATION LAI; AVIUM COMPLEX; CULTURE NEGATIVITY; PULMONARY; INFECTION; IDENTIFICATION; PREVALENCE; EFFICACY; GENE AB Rationale: Lengthy, multidrug, toxic, and low-efficacy regimens limit management of pulmonary nontuberculous mycobacterial disease. Objectives: In this phase II study, we investigated the efficacy and safety of liposomal amikacin for inhalation (LAI) in treatment-refractory pulmonary nontuberculous mycobacterial (Mycobacterium avium complex [MAC] or Mycobacterium abscessus) disease. Methods: During the double-blind phase, patients were randomly assigned to LAI (590 mg) or placebo once daily added to their multidrug regimen for 84 days. Both, groups could receive open-label LAI for 84 additional days. The primary endpoint was change from baseline to Day 84 on a semiquantitative mycobacterial growth scale. Other endpoints included sputum conversion, 6-minute-walk distance, and adverse events. Measurements and Main Results: The modified intention-to-treat population included 89 (LAI = 44; placebo = 45) patients. The average age of the sample was 59 years; 88% were female; 92% were white; and 80 and 59 patients completed study drug dosing during the double-blind and open-label phases, respectively. The primary endpoint was not achieved (P = 0.072); however, a greater proportion of the LAI group demonstrated at least one negative sputum culture (14 [32%] of 44 vs. 4 [9%] of 45; P = 0.006) and improvement in 6-minute-walk test (+20.6 m vs. 25.0 m; P = 0.017) at Day 84. A treatment effect was seen predominantly in patients without cystic fibrosis with MAC and was sustained 1 year after LAI. Most adverse events were respiratory, and in some patients it led to drug discontinuation. Conclusions: Although the primary endpoint was not reached, LAI added to a multidrug regimen produced improvements in sputum conversion and 6-minute-walk distance versus placebo with limited systemic toxicity in patients with refractory MAC lung disease. Further research in this area is needed. C1 [Olivier, Kenneth N.] NHLBI, NIH, 10 Ctr Dr,MSC 1458,Bldg 10 CRC,Room 5-1408A, Bethesda, MD 20892 USA. [Griffith, David E.; Brown-Elliott, Barbara A.; Wallace, Richard J., Jr.] Univ Texas Hlth Sci Ctr Tyler, Tyler, TX USA. [Eagle, Gina; McGinnis, John P., II; Micioni, Liza; Liu, Keith; Gupta, Renu] Insmed Inc, Bridgewater, NJ USA. [Daley, Charles L.] Natl Jewish Hlth, Denver, CO USA. [Winthrop, Kevin L.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Ruoss, Stephen] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Addrizzo-Harris, Doreen J.] NYU, Sch Med, New York, NY USA. [Flume, Patrick A.] Med Univ South Carolina, Charleston, SC USA. [Dorgan, Daniel] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Salathe, Matthias] Univ Miami, Leonard M Miller Sch Med, Miami, FL USA. [Gupta, Renu] Global Biopharma, Moorestown, NJ USA. RP Olivier, KN (reprint author), NHLBI, NIH, 10 Ctr Dr,MSC 1458,Bldg 10 CRC,Room 5-1408A, Bethesda, MD 20892 USA. EM olivierk@nhlbi.nih.gov FU Insmed Incorporated; intramural research programs of the National Institute of Allergy and Infectious Diseases (NIAID) [2011-0473]; NHLBI; National Institutes of Health (NIH) FX This study was supported by Insmed Incorporated, and in part (K.N.O.) by the intramural research programs of the National Institute of Allergy and Infectious Diseases (NIAID) (Cooperative-Research and Development Agreement 2011-0473) and the NHLBI and the National Institutes of Health (NIH). NR 38 TC 2 Z9 2 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 15 PY 2017 VL 195 IS 6 BP 814 EP 823 DI 10.1164/rccm.201604-0700OC PG 10 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EO4BX UT WOS:000396640500016 PM 27748623 ER PT J AU de Bree, GJ Wheatley, AK Lynch, RM Prabhakaran, M Grijsen, ML Prins, JM Schmidt, SD Koup, RA Mascola, JR McDermott, AB AF de Bree, Godelieve J. Wheatley, Adam K. Lynch, Rebecca M. Prabhakaran, Madhu Grijsen, Marlous L. Prins, Jan M. Schmidt, Stephen D. Koup, Richard A. Mascola, John R. McDermott, Adrian B. TI Longitudinal dynamics of the HIV-specific B cell response during intermittent treatment of primary HIV infection SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; NEUTRALIZATION IN-VITRO; ANTIRETROVIRAL THERAPY; ANTIBODY NEUTRALIZATION; MONOCLONAL-ANTIBODIES; CD4-BINDING SITE; SHIV CHALLENGE; FOUNDER VIRUS; HELPER-CELLS; INDIVIDUALS AB Background Neutralizing antibodies develop in natural HIV-1 infection. Their development often takes several years and may rely on chronic virus exposure. At the same time recent studies show that treatment early in infection may provide opportunities for immune preservation. However, it is unknown how intermittent treatment in early infection affects development of the humoral immune response over time. We investigate the effect of cART in early HIV infection on the properties of the memory B cell compartment following 6 months of cART or in the absence of treatment. The patients included participated in the Primo-SHM trial where patients with an early HIV-1 infection were randomized to no treatment or treatment for 24 or 60 weeks. Methods Primo-SHM trial patients selected for the present study were untreated (n = 23) or treated for 24 weeks (n = 24). Here we investigate memory B cell properties at viral set-point and at a late time point (respectively median 54 and 73 weeks) before (re)-initiation of treatment. Results At viral set-point, the memory B cell compartment in treated patients demonstrated significantly lower fractions of antigen-primed, activated, memory B cells (p = 0.006). In contrast to untreated patients, in treated patients the humoral HIV-specific response reached a set point over time. At a transcriptional level, sets of genes that showed enhanced expression in memory B cells at viral setpoint in untreated patients, conversely showed rapid increase of expression of the same genes in treated patients at the late time point. Conclusion These data suggest that, although the memory B cell compartment is phenotypically preserved until viral setpoint after treatment interruption, the development of the HIV-specific antibody response may benefit from exposure to HIV. The effect of viral exposure on B cell properties is also reflected by longitudinal changes in transcriptional profile in memory B cells over time in early treated patients. C1 [de Bree, Godelieve J.; Grijsen, Marlous L.; Prins, Jan M.] Acad Med Ctr, Dept Internal Med, Amsterdam, Netherlands. [de Bree, Godelieve J.] Univ Amsterdam, Inst Global Hlth & Dev, Amsterdam, Netherlands. [Wheatley, Adam K.; Lynch, Rebecca M.; Prabhakaran, Madhu; Schmidt, Stephen D.; Koup, Richard A.; Mascola, John R.; McDermott, Adrian B.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP de Bree, GJ (reprint author), Acad Med Ctr, Dept Internal Med, Amsterdam, Netherlands.; de Bree, GJ (reprint author), Univ Amsterdam, Inst Global Hlth & Dev, Amsterdam, Netherlands. EM g.j.debree@amc.uva.nl FU Dutch Infectious Diseases Society FX GJdB received a travelgrant from the Dutch Infectious Diseases Society. NR 54 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 15 PY 2017 VL 12 IS 3 AR e0173577 DI 10.1371/journal.pone.0173577 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN9HQ UT WOS:000396311700042 PM 28296911 ER PT J AU Sakchaisri, K Kim, SO Hwang, J Soung, NK Lee, KH Choi, TW Lee, Y Park, CM Thimmegowda, NR Lee, PY Shwetha, B Srinivasrao, G Pham, TTH Jang, JH Yum, HW Surh, YJ Lee, KS Park, H Kim, SJ Kwon, YT Ahn, JS Kim, BY AF Sakchaisri, Krisada Kim, Sun-Ok Hwang, Joonsung Soung, Nak Kyun Lee, Kyung Ho Choi, Tae Woong Lee, Yongjun Park, Chan-Mi Thimmegowda, Naraganahalli R. Lee, Phil Young Shwetha, Bettaswamigowda Srinivasrao, Ganipisetti Pham, Thi Thu Huong Jang, Jae-Hyuk Yum, Hye-Won Surh, Young-Joon Lee, Kyung S. Park, Hwangseo Kim, Seung Jun Kwon, Yong Tae Ahn, Jong Seog Kim, Bo Yeon TI Anticancer activity of a novel small molecule tubulin inhibitor STK899704 SO PLOS ONE LA English DT Article ID MICROTUBULE DYNAMICS; DUAL INHIBITORS; ACYLHYDRAZONE DERIVATIVES; CHROMOSOME CONDENSATION; MULTIDRUG-RESISTANCE; MAMMALIAN-CELLS; GENE-EXPRESSION; BINDING AGENTS; P-GLYCOPROTEIN; HISTONE H3 AB We have identified the small molecule STK899704 as a structurally novel tubulin inhibitor. STK899704 suppressed the proliferation of cancer cell lines from various origins with IC50 values ranging from 0.2 to 1.0 mu M. STK899704 prevented the polymerization of purified tubulin in vitro and also depolymerized microtubule in cultured cells leading to mitotic arrest, associated with increased Cdc25C phosphorylation and the accumulation of both cyclin B1 and polo-like kinase 1 (Plk1), and apoptosis. Unlike many anticancer drugs such as Taxol and doxorubicin, STK899704 effectively displayed antiproliferative activity against multi-drug-resistant cancer cell lines. The proposed binding mode of STK899704 is at the interface between alpha beta-tubulin heterodimer overlapping with the colchicine-binding site. Our in vivo carcinogenesis model further showed that STK 899704 is potent in both the prevention and regression of tumors, remarkably reducing the number and volume of skin tumor by STK899704 treatment. Moreover, it was significant to note that the efficacy of STK899704 was surprisingly comparable to 5-fluorouracil, a widely used anticancer therapeutic. Thus, our results demonstrate the potential of STK899704 to be developed as an anticancer chemotherapeutic and an alternative candidate for existing therapies. C1 [Sakchaisri, Krisada; Kim, Sun-Ok; Hwang, Joonsung; Soung, Nak Kyun; Lee, Kyung Ho; Choi, Tae Woong; Lee, Yongjun; Park, Chan-Mi; Thimmegowda, Naraganahalli R.; Lee, Phil Young; Shwetha, Bettaswamigowda; Srinivasrao, Ganipisetti; Pham, Thi Thu Huong; Jang, Jae-Hyuk; Ahn, Jong Seog; Kim, Bo Yeon] KRIBB, Anticanc Agents Res Ctr, Ochang, Cheongwon, South Korea. [Sakchaisri, Krisada] Mahidol Univ, Dept Pharmacol, Fac Pharm, Bangkok, Thailand. [Pham, Thi Thu Huong] Vietnam Natl Univ, VNU Univ Sci, KLEPT, Hanoi, Vietnam. [Yum, Hye-Won; Surh, Young-Joon] Seoul Natl Univ, Coll Pharm, Seoul, South Korea. [Lee, Kyung S.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Park, Hwangseo] Sejong Univ, Dept Biosci & Biotechnol, Seoul, South Korea. [Kim, Seung Jun] Korea Res Inst Biosci & Biotechnol, Dis Target Struct Res Ctr, Daejeon, South Korea. [Kwon, Yong Tae] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea. [Kwon, Yong Tae] Seoul Natl Univ, Coll Med, Prot Metab Med Res Ctr, Seoul, South Korea. RP Ahn, JS; Kim, BY (reprint author), KRIBB, Anticanc Agents Res Ctr, Ochang, Cheongwon, South Korea.; Kwon, YT (reprint author), Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea.; Kwon, YT (reprint author), Seoul Natl Univ, Coll Med, Prot Metab Med Res Ctr, Seoul, South Korea. EM yok5@snu.ac.kr; jsahn@kribb.re.kr; bykim@kribb.re.kr FU Bio and Medical Technology Development Program [NRF-2014M3A9B5073938]; National Research Council of Science & Technology grant [CAP-16-03-KRIBB]; Global R&D Center program [NRF-2010-00719]; World Class Institute Program of the Ministry of Science, ICT and Future Planning of Korea [WCI2009-002]; KRIBB Research Initiative Program [KGS531162]; International Cooperation Research Program of National Research Council of Science & Technology (NST) of Republic of Korea; R&D Convergence Program of National Research Council of Science & Technology (NST) of Republic of Korea [CAP-16-03-KRIBB]; Basic Science Research Program of the Ministry of Science, ICT and Future Planning (MSIP) of Korea [NRF-2016R1A2B3011389] FX This work was supported by the Bio and Medical Technology Development Program (NRF-2014M3A9B5073938), the National Research Council of Science & Technology grant (CAP-16-03-KRIBB), Global R&D Center (NRF-2010-00719) program and the World Class Institute Program (WCI2009-002) of the Ministry of Science, ICT and Future Planning of Korea and KRIBB Research Initiative Program (KGS531162). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; This work was supported by the R&D Convergence Program (CAP-16-03-KRIBB) and the International Cooperation Research Program of National Research Council of Science & Technology (NST) of Republic of Korea. This work was also supported the Bio and Medical Technology Development Program (NRF-2014M3A9B5073938), the Basic Science Research Program (NRF-2016R1A2B3011389) of the Ministry of Science, ICT and Future Planning (MSIP) of Korea and KRIBB Research Initiative Program. NR 49 TC 0 Z9 0 U1 10 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 15 PY 2017 VL 12 IS 3 AR e0173311 DI 10.1371/journal.pone.0173311 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN9HQ UT WOS:000396311700033 PM 28296906 ER PT J AU Stephen, J Yokoyama, T Tolman, NJ O'Brien, KJ Nicoli, ER Brooks, BP Huryn, L Titus, SA Adams, DR Chen, D Gahl, WA Gochuico, BR Malicdan, MCV AF Stephen, Joshi Yokoyama, Tadafumi Tolman, Nathanial J. O'Brien, Kevin J. Nicoli, Elena-Raluca Brooks, Brian P. Huryn, Laryssa Titus, Steven A. Adams, David R. Chen, Dong Gahl, William A. Gochuico, Bernadette R. Malicdan, May Christine V. TI Cellular and molecular defects in a patient with Hermansky-Pudlak syndrome type 5 SO PLOS ONE LA English DT Article ID LYSOSOME-RELATED ORGANELLES; PROTEIN TRAFFICKING; COMPLEX; BLOC-2; BIOGENESIS; DISEASE; CELLS; HPS5; AP-3 AB Hermansky-Pudlak syndrome (HPS) is a heterogeneous group of genetic disorders typically manifesting with tyrosinase-positive oculocutaneous albinism, bleeding diathesis, and pulmonary fibrosis, in some subtypes. Most HPS subtypes are associated with defects in Biogenesis of Lysosome-related Organelle Complexes (BLOCs), which are groups of proteins that function together in the formation and/or trafficking of lysosomal-related endosomal compartments. BLOC-2, for example, consists of the proteins HPS3, HPS5, and HPS6. Here we present an HPS patient with defective BLOC-2 due to a novel intronic mutation in HPS5 that activates a cryptic acceptor splice site. This mutation leads to the insertion of nine nucleotides in-frame and results in a reduced amount of HPS5 at the transcript and protein level. In studies using skin fibroblasts derived from the proband and two other individuals with HPS-5, we found a perinuclear distribution of acidified organelles in patient cells compared to controls. Our results suggest the role of HPS5 in the endo-lysosomal dynamics of skin fibroblasts. C1 [Stephen, Joshi; O'Brien, Kevin J.; Huryn, Laryssa; Gochuico, Bernadette R.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Tolman, Nathanial J.; Titus, Steven A.; Adams, David R.; Chen, Dong] NIH, Undiagnosed Dis Program, Bldg 10, Bethesda, MD 20892 USA. [Tolman, Nathanial J.; Brooks, Brian P.; Chen, Dong; Gahl, William A.] NIH, Bldg 10, Bethesda, MD 20892 USA. [O'Brien, Kevin J.; Huryn, Laryssa; Chen, Dong] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD USA. [O'Brien, Kevin J.; Titus, Steven A.; Adams, David R.] Natl Inst Hlth, Div Pre clin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD USA. [Tolman, Nathanial J.; Brooks, Brian P.; Huryn, Laryssa; Titus, Steven A.] Natl Human Genome Res Inst, Natl Inst Hlth, Bethesda, MD USA. [Yokoyama, Tadafumi; Brooks, Brian P.; Huryn, Laryssa] Mayo Clin, Div Hematopathol, Rochester, MN USA. RP Gochuico, BR (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM gochuicb@mail.nih.gov FU Intramural Research Programs of the National Human Genome Research Institute; National Eye Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA FX This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Eye Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA. NR 19 TC 0 Z9 0 U1 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 15 PY 2017 VL 12 IS 3 AR e0173682 DI 10.1371/journal.pone.0173682 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN9HQ UT WOS:000396311700052 PM 28296950 ER PT J AU Alam, SM Aussedat, B Vohra, Y Meyerhoff, RR Cale, EM Walkowicz, WE Radakovich, NA Anasti, K Armand, L Parks, R Sutherland, L Scearce, R Joyce, MG Pancera, M Druz, A Georgiev, IS Von Holle, T Eaton, A Fox, C Reed, SG Louder, M Bailer, RT Morris, L Abdool-Karim, SS Cohen, M Liao, HX Montefiori, DC Park, PK Fernandez-Tejada, A Wiehe, K Santra, S Kepler, TB Saunders, KO Sodroski, J Kwong, PD Mascola, JR Bonsignori, M Moody, MA Danishefsky, S Haynes, BF AF Alam, S. Munir Aussedat, Baptiste Vohra, Yusuf Meyerhoff, R. Ryan Cale, Evan M. Walkowicz, William E. Radakovich, Nathan A. Anasti, Kara Armand, Lawrence Parks, Robert Sutherland, Laura Scearce, Richard Joyce, M. Gordon Pancera, Marie Druz, Aliaksandr Georgiev, Ivelin S. Von Holle, Tarra Eaton, Amanda Fox, Christopher Reed, Steven G. Louder, Mark Bailer, Robert T. Morris, Lynn Abdool-Karim, Salim S. Cohen, Myron Liao, Hua-Xin Montefiori, David C. Park, Peter K. Fernandez-Tejada, Alberto Wiehe, Kevin Santra, Sampa Kepler, Thomas B. Saunders, Kevin O. Sodroski, Joseph Kwong, Peter D. Mascola, John R. Bonsignori, Mattia Moody, M. Anthony Danishefsky, Samuel Haynes, Barton F. TI Mimicry of an HIV broadly neutralizing antibody epitope with a synthetic glycopeptide SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID CHEMICAL-SYNTHESIS; CRYSTAL-STRUCTURE; IMMUNE PRESSURE; ENVELOPE TRIMER; RECOGNITION; ANTIGENS; POTENT; ENV; SELECTION; VACCINES AB A goal for an HIV-1 vaccine is to overcome virus variability by inducing broadly neutralizing antibodies (bnAbs). One key target of bnAbs is the glycan-polypeptide at the base of the envelope (Env) third variable loop (V3). We have designed and synthesized a homogeneous minimal immunogen with high-mannose glycans reflective of a native Env V3-glycan bnAb epitope (Man9-V3). V3-glycan bnAbs bound to Man9-V3 glycopeptide and native-like gp140 trimers with similar affinities. Fluorophore-labeled Man9-V3 glycopeptides bound to bnAb memory B cells and were able to be used to isolate a V3-glycan bnAb from an HIV-1-infected individual. In rhesus macaques, immunization with Man9-V3 induced V3-glycan-targeted antibodies. Thus, the Man9-V3 glycopeptide closely mimics an HIV-1 V3-glycan bnAb epitope and can be used to isolate V3-glycan bnAbs. C1 [Alam, S. Munir; Meyerhoff, R. Ryan; Anasti, Kara; Armand, Lawrence; Parks, Robert; Sutherland, Laura; Scearce, Richard; Von Holle, Tarra; Eaton, Amanda; Liao, Hua-Xin; Montefiori, David C.; Wiehe, Kevin; Saunders, Kevin O.; Bonsignori, Mattia; Moody, M. Anthony; Haynes, Barton F.] Duke Univ, Sch Med, Duke Human Vaccine Inst, Durham, NC 27710 USA. [Alam, S. Munir; Liao, Hua-Xin; Montefiori, David C.; Bonsignori, Mattia; Haynes, Barton F.] Duke Univ, Sch Med, Dept Med, Durham, NC 27710 USA. [Alam, S. Munir] Duke Univ, Sch Med, Dept Pathol, Durham, NC 27710 USA. [Aussedat, Baptiste; Vohra, Yusuf; Walkowicz, William E.; Park, Peter K.; Fernandez-Tejada, Alberto; Danishefsky, Samuel] Mem Sloan Kettering Canc Ctr, Dept Chem Biol, New York, NY 10065 USA. [Meyerhoff, R. Ryan; Moody, M. Anthony; Haynes, Barton F.] Duke Univ, Sch Med, Dept Immunol, Durham, NC 27710 USA. [Cale, Evan M.; Radakovich, Nathan A.; Joyce, M. Gordon; Pancera, Marie; Druz, Aliaksandr; Georgiev, Ivelin S.; Louder, Mark; Bailer, Robert T.; Kwong, Peter D.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Fox, Christopher; Reed, Steven G.] Infect Dis Res Inst, Seattle, WA 98102 USA. [Morris, Lynn; Abdool-Karim, Salim S.] Natl Inst Communicable Dis, ZA-2131 Johannesburg, South Africa. [Morris, Lynn; Abdool-Karim, Salim S.] Univ KwaZulu Natal, Ctr AIDS Programme Res South Africa, ZA-4013 Durban, South Africa. [Cohen, Myron] Univ North Carolina Chapel Hill, Dept Med, Chapel Hill, NC 27599 USA. [Montefiori, David C.; Saunders, Kevin O.] Duke Univ, Sch Med, Dept Surg, Durham, NC 27710 USA. [Santra, Sampa] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Kepler, Thomas B.] Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. [Sodroski, Joseph] Harvard Med Sch, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Moody, M. Anthony] Duke Univ, Sch Med, Dept Pediat, Durham, NC 27710 USA. [Liao, Hua-Xin] Jinan Univ, Coll Life Sci & Technol, Guangzhou 510632, Guangdong, Peoples R China. RP Alam, SM; Haynes, BF (reprint author), Duke Univ, Sch Med, Duke Human Vaccine Inst, Durham, NC 27710 USA.; Alam, SM; Haynes, BF (reprint author), Duke Univ, Sch Med, Dept Med, Durham, NC 27710 USA.; Alam, SM (reprint author), Duke Univ, Sch Med, Dept Pathol, Durham, NC 27710 USA.; Haynes, BF (reprint author), Duke Univ, Sch Med, Dept Immunol, Durham, NC 27710 USA. EM munir.alam@dm.duke.edu; barton.haynes@dm.duke.edu OI Aussedat, Baptiste/0000-0002-8828-8963; Vohra, Yusuf/0000-0003-0385-2965; Meyerhoff, Ryan/0000-0003-1253-2250 FU NIH, National Institute of Allergy and Infectious Diseases (NIAID) [UM-1 AI100645]; Division of AIDS CHAVI-Immunogen Discovery grant [R01 AI120801-01]; Medical Scientist Training Program training grant [T32GM007171]; Ruth L. Kirschstein National Research Service Award [F30-AI122982-0]; NIAID; Vaccine Research Center, NIAID FX This study was supported by UM-1 AI100645 from NIH, National Institute of Allergy and Infectious Diseases (NIAID), Division of AIDS CHAVI-Immunogen Discovery grant, R01 AI120801-01 (K.O.S.), Medical Scientist Training Program training grant T32GM007171 (R.R.M.), Ruth L. Kirschstein National Research Service Award F30-AI122982-0, NIAID (R.R.M.), and the intramural research program of the Vaccine Research Center, NIAID. NR 41 TC 1 Z9 1 U1 6 U2 6 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD MAR 15 PY 2017 VL 9 IS 381 AR eaai7521 DI 10.1126/scitranslmed.aai7521 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EN9GB UT WOS:000396307600005 ER PT J AU Bonsignori, M Kreider, EF Fera, D Meyerhoff, RR Bradley, T Wiehe, K Alam, SM Aussedat, B Walkowicz, WE Hwang, KK Saunders, KO Zhang, R Gladden, MA Monroe, A Kumar, A Xia, SM Cooper, M Louder, MK McKee, K Bailer, RT Pier, BW Jette, CA Kelsoe, G Williams, WB Morris, L Kappes, J Wagh, K Kamanga, G Cohen, MS Hraber, PT Montefiori, DC Trama, A Liao, HX Kepler, TB Moody, MA Gao, F Danishefsky, SJ Mascola, JR Shaw, GM Hahn, BH Harrison, SC Korber, BT Haynes, BF AF Bonsignori, Mattia Kreider, Edward F. Fera, Daniela Meyerhoff, R. Ryan Bradley, Todd Wiehe, Kevin Alam, S. Munir Aussedat, Baptiste Walkowicz, William E. Hwang, Kwan-Ki Saunders, Kevin O. Zhang, Ruijun Gladden, Morgan A. Monroe, Anthony Kumar, Amit Xia, Shi-Mao Cooper, Melissa Louder, Mark K. McKee, Krisha Bailer, Robert T. Pier, Brendan W. Jette, Claudia A. Kelsoe, Garnett Williams, Wilton B. Morris, Lynn Kappes, John Wagh, Kshitij Kamanga, Gift Cohen, Myron S. Hraber, Peter T. Montefiori, David C. Trama, Ashley Liao, Hua-Xin Kepler, Thomas B. Moody, M. Anthony Gao, Feng Danishefsky, Samuel J. Mascola, John R. Shaw, George M. Hahn, Beatrice H. Harrison, Stephen C. Korber, Bette T. Haynes, Barton F. TI Staged induction of HIV-1 glycan-dependent broadly neutralizing antibodies SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID B-CELL-LINEAGE; AFFINITY MATURATION; VACCINE DESIGN; POTENT; ENVELOPE; ENV; RECOGNITION; EVOLUTION; INFECTION; GP120 AB A preventive HIV-1 vaccine should induce HIV-1-specific broadly neutralizing antibodies (bnAbs). However, bnAbs generally require high levels of somatic hypermutation (SHM) to acquire breadth, and current vaccine strategies have not been successful in inducing bnAbs. Because bnAbs directed against a glycosylated site adjacent to the third variable loop (V3) of the HIV-1 envelope protein require limited SHM, the V3-glycan epitope is an attractive vaccine target. By studying the cooperation among multiple V3-glycan B cell lineages and their coevolution with autologous virus throughout 5 years of infection, we identify key events in the ontogeny of a V3-glycan bnAb. Two autologous neutralizing antibody lineages selected for virus escape mutations and consequently allowed initiation and affinity maturation of a V3-glycan bnAb lineage. The nucleotide substitution required to initiate the bnAb lineage occurred at a low-probability site for activation-induced cytidine deaminase activity. Cooperation of B cell lineages and an improbable mutation critical for bnAb activity defined the necessary events leading to breadth in this V3-glycan bnAb lineage. These findings may, in part, explain why initiation of V3-glycan bnAbs is rare, and suggest an immunization strategy for inducing similar V3-glycan bnAbs. C1 [Bonsignori, Mattia; Meyerhoff, R. Ryan; Bradley, Todd; Wiehe, Kevin; Alam, S. Munir; Williams, Wilton B.; Liao, Hua-Xin; Gao, Feng; Haynes, Barton F.] Duke Univ, Med Ctr, Sch Med, Dept Med, Durham, NC 27710 USA. [Bonsignori, Mattia; Meyerhoff, R. Ryan; Bradley, Todd; Wiehe, Kevin; Alam, S. Munir; Hwang, Kwan-Ki; Saunders, Kevin O.; Zhang, Ruijun; Gladden, Morgan A.; Monroe, Anthony; Kumar, Amit; Xia, Shi-Mao; Cooper, Melissa; Kelsoe, Garnett; Williams, Wilton B.; Montefiori, David C.; Trama, Ashley; Liao, Hua-Xin; Moody, M. Anthony; Gao, Feng; Haynes, Barton F.] Duke Human Vaccine Inst, Durham, NC 27710 USA. [Kreider, Edward F.; Shaw, George M.; Hahn, Beatrice H.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Kreider, Edward F.; Shaw, George M.; Hahn, Beatrice H.] Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Fera, Daniela; Pier, Brendan W.; Jette, Claudia A.; Harrison, Stephen C.] Harvard Med Sch, Boston Childrens Hosp, Mol Med Lab, Boston, MA 02115 USA. [Aussedat, Baptiste; Walkowicz, William E.; Danishefsky, Samuel J.] Mem Sloan Kettering Canc Ctr, Dept Biol Chem, New York, NY 10065 USA. [Saunders, Kevin O.; Montefiori, David C.] Duke Univ, Med Ctr, Sch Med, Dept Surg, Durham, NC 27710 USA. [Louder, Mark K.; McKee, Krisha; Bailer, Robert T.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Kelsoe, Garnett; Moody, M. Anthony] Duke Univ, Med Ctr, Sch Med, Dept Immunol, Durham, NC 27710 USA. [Morris, Lynn] Natl Inst Communicable Dis, ZA-2131 Johannesburg, South Africa. [Kappes, John] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Wagh, Kshitij; Hraber, Peter T.; Korber, Bette T.] Los Alamos Natl Lab, Los Alamos, NM 87545 USA. [Kamanga, Gift] Kamuzu Cent Hosp, Univ North Carolina Project, Lilongwe, Malawi. [Cohen, Myron S.] Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. [Cohen, Myron S.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Cohen, Myron S.] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. [Kepler, Thomas B.] Boston Univ, Dept Microbiol, Boston, MA 02215 USA. [Kepler, Thomas B.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Moody, M. Anthony] Duke Univ, Med Ctr, Sch Med, Dept Pediat, Durham, NC 27710 USA. [Kamanga, Gift] FHI 360, Lilongwe, Malawi. RP Bonsignori, M; Haynes, BF (reprint author), Duke Univ, Med Ctr, Sch Med, Dept Med, Durham, NC 27710 USA.; Bonsignori, M; Haynes, BF (reprint author), Duke Human Vaccine Inst, Durham, NC 27710 USA.; Korber, BT (reprint author), Los Alamos Natl Lab, Los Alamos, NM 87545 USA. EM mattia.bonsignori@dm.duke.edu; btk@lanl.gov; barton.haynes@dm.duke.edu OI Hraber, Peter/0000-0002-2920-4897; Aussedat, Baptiste/0000-0002-8828-8963; Meyerhoff, Ryan/0000-0003-1253-2250; Kreider, Edward/0000-0003-2330-8430 FU F30 Ruth L. Kirschstein National Research Service Award [AI112426, AI122982-0]; F32 fellowship from the NIH [1F32AI116355-01]; Medical Scientist Training Program grant [T32GM007171]; National Institute of Allergy and Infectious Diseases (NIAID) [R01-AI120801]; Duke CHAVI-Immunogen Discovery, Division of AIDS, NIAID, NIH [UM1 AI100645] FX E.F.K. and R.R.M. are supported by the F30 Ruth L. Kirschstein National Research Service Award (AI112426 and AI122982-0, respectively). D.F. is supported by an F32 fellowship (1F32AI116355-01) from the NIH. R.R.M. is supported by a Medical Scientist Training Program grant (T32GM007171). K.O.S. is supported by a National Institute of Allergy and Infectious Diseases (NIAID) grant (R01-AI120801). This work was funded by UM1 AI100645 from the Duke CHAVI-Immunogen Discovery, Division of AIDS, NIAID, NIH (to B.F.H.). NR 50 TC 1 Z9 1 U1 5 U2 5 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD MAR 15 PY 2017 VL 9 IS 381 AR eaai7514 DI 10.1126/scitranslmed.aai7514 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EN9GB UT WOS:000396307600004 ER PT J AU Pan, YG Sun, ZQ Maiti, A Kanai, T Matsuo, H Li, M Harris, RS Shlyakhtenko, LS Lyubchenko, YL AF Pan, Yangang Sun, Zhiqiang Maiti, Atanu Kanai, Tapan Matsuo, Hiroshi Li, Ming Harris, Reuben S. Shlyakhtenko, Luda S. Lyubchenko, Yuri L. TI Nanoscale Characterization of Interaction of APOBEC3G with RNA SO BIOCHEMISTRY LA English DT Article ID SINGLE-STRANDED-DNA; CYTIDINE DEAMINASE ACTIVITY; CRYSTAL-STRUCTURE; CATALYTIC DOMAIN; BINDING PROTEIN; RESTRICTION; HIV-1; OLIGOMERIZATION; SPECIFICITY; ENZYME AB The human cytidine deaminase APOBEC3G (A3G) is a potent inhibitor of the HIV-1 virus in the absence of viral infectivity factor (Vif). The molecular mechanism of A3G antiviral activity is primarily attributed to deamination of single stranded DNA (ssDNA); however, the nondeamination mechanism also contributes to HIV-1 restriction. The interaction of A3G with ssDNA and RNA is required for its antiviral activity. Here we used atomic force microscopy to directly visualize A3G RNA and A3G ssDNA complexes and compare them to each other. Our results showed that A3G in A3G RNA complexes exists primarily in monomeric dimeric states, similar to its stoichiometry in complexes with ssDNA. New A3G RNA complexes in which A3G binds to two RNA molecules were identified. These data suggest the existence of two separate RNA binding sites on A3G. Such complexes were not observed with ssDNA substrates. Time-lapse high-speed atomic force microscopy was applied to characterize the dynamics of the complexes. The data revealed that the two RNA binding sites have different affinities for A3G. On the basis of the obtained results, a model for the interaction of A3G with RNA is proposed. C1 [Pan, Yangang; Sun, Zhiqiang; Shlyakhtenko, Luda S.; Lyubchenko, Yuri L.] Univ Nebraska Med Ctr, WSH, Coll Pharm, Department Pharmaceut Sci, 986025 Nebraska Med Ctr, Omaha, NE 68198 USA. [Maiti, Atanu; Kanai, Tapan; Matsuo, Hiroshi] Leidos Biomedical Res Inc, Adv Technol Res Facil, Frederick Natl Lab Canc Res, 8560 Progress Dr, Frederick, MD 21702 USA. [Li, Ming; Harris, Reuben S.] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Inst Mol Virol, Ctr Genome Engn,Mason Canc Ctr, Minneapolis, MN 55455 USA. [Harris, Reuben S.] Univ Minnesota, Howard Hughes Med Inst, Minneapolis, MN 55455 USA. RP Lyubchenko, YL (reprint author), Univ Nebraska Med Ctr, WSH, Coll Pharm, Department Pharmaceut Sci, 986025 Nebraska Med Ctr, Omaha, NE 68198 USA. EM ylyubchenko@unmc.edu FU National Institute of General Medical Sciences [R01-GM118006, GM096039, GM100156, P01-GM091743]; National Science Foundation [MCB 1515346]; federal funds from the National Cancer Institute, National Institutes of Health [HHSN26120080001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by grants from the National Institute of General Medical Sciences (R01-GM118006, GM096039, and GM100156 to Y.L.L. and P01-GM091743 to R.S.H.) and from the National Science Foundation (MCB 1515346 to Y.L.L.). R.S.H. is an Investigator of the Howard Hughes Medical Institute. For T.K., A.M. and H.M., this project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This Research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 38 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 14 PY 2017 VL 56 IS 10 BP 1473 EP 1481 DI 10.1021/acs.biochem.6b01189 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EO4BV UT WOS:000396640300009 PM 28029777 ER PT J AU Keefer, AB Asare, EK Pomerantsev, AP Moayeri, M Martens, C Porcella, SF Gottesman, S Leppla, SH Vrentas, CE AF Keefer, Andrea B. Asare, Eugenia K. Pomerantsev, Andrei P. Moayeri, Mahtab Martens, Craig Porcella, Stephen F. Gottesman, Susan Leppla, Stephen H. Vrentas, Catherine E. TI In vivo characterization of an Hfq protein encoded by the Bacillus anthracis virulence plasmid pXO1 SO BMC MICROBIOLOGY LA English DT Article DE Hfq; Bacillus anthracis; anthrax; mRNA; sRNA; gene expression; pXO1 ID ESCHERICHIA-COLI HFQ; MESSENGER-RNA DECAY; SM-LIKE PROTEIN; STAPHYLOCOCCUS-AUREUS; LISTERIA-MONOCYTOGENES; INTERACTION SURFACES; TEICHOIC-ACIDS; HOST FACTOR; CELL-WALL; BINDING AB Background: Bacterial Hfq proteins post-transcriptionally regulate gene expression, primarily by mediating the interaction between sRNAs (small RNAs) and their target mRNAs. The role of Hfq-based regulation has been well defined in Gram-negative bacteria, but comparatively less is known about the impact of Hfq proteins in Gram-positive species. The Gram-positive pathogen Bacillus anthracis (causative agent of anthrax) is distinct in that it expresses three homologs of Hfq: Hfq1 and Hfq2 from the chromosome, and Hfq3 from the pXO1 virulence plasmid. Results: In this study, we utilized overexpression as a strategy to examine the impact of Hfq3 on B. anthracis physiology. The increase in Hfq3 protein levels led to anomalous cell shape and chain formation, which manifested as a severe growth defect. This phenotype was specific to B. anthracis, as Hfq3 expression in B. subtilis at similar levels was not toxic. Toxicity was dependent on residues on the distal face of Hfq3 that are involved in mRNA binding in other bacterial species. Conclusions: Thus, we hypothesize that Hfq3 interacts with RNA(s) involved in essential functions in the B. anthracis cell, leading to increased binding upon overexpression that either sequesters or accelerates degradation of RNAs important for growth. These results not only aid in elucidating the role of Hfq proteins in B. anthracis, but also contribute to our current understanding of Hfq in Gram-positive bacteria. C1 [Keefer, Andrea B.; Asare, Eugenia K.; Pomerantsev, Andrei P.; Moayeri, Mahtab; Leppla, Stephen H.; Vrentas, Catherine E.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Asare, Eugenia K.] Frostburg State Univ, Dept Biol, Frostburg, MD 21532 USA. [Martens, Craig; Porcella, Stephen F.] NIAID, Genom Unit, Res Technol Sect, NIH, Hamilton, MT USA. [Gottesman, Susan] NCI, NIH, Bethesda, MD 20892 USA. [Vrentas, Catherine E.] Agr Res Serv, Natl Anim Dis Ctr, USDA, Ames, IA 50011 USA. RP Vrentas, CE (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Vrentas, CE (reprint author), Agr Res Serv, Natl Anim Dis Ctr, USDA, Ames, IA 50011 USA. EM catherine.vrentas@ars.usda.gov FU Intramural research programs of the National Institute of Allergy and Infectious Diseases; National Cancer Institute, National Institutes of Health FX This work was funded by the Intramural research programs of the National Institute of Allergy and Infectious Diseases and of the National Cancer Institute, National Institutes of Health. The opinions expressed in this manuscript are entirely those of the authors and are not necessarily official positions of the National Institutes of Health or the U.S. Department of Agriculture. Inclusion of specific product brand names does not imply endorsement. NR 43 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD MAR 14 PY 2017 VL 17 AR 63 DI 10.1186/s12866-017-0973-y PG 13 WC Microbiology SC Microbiology GA EO5YW UT WOS:000396769900003 PM 28288571 ER PT J AU Lopes, ACBD Silbergeld, EK Navas-Acien, A Zamoiski, R Martins, AD Camargo, AEI Urbano, MR Mesas, AE Paoliello, MMB AF de Almeida Lopes, Ana Carolina Bertin Silbergeld, Ellen Kovner Navas-Acien, Ana Zamoiski, Rachel Martins, Airton da Cunha, Jr. Iakmiu Camargo, Alissana Ester Urbano, Mariana Ragassi Mesas, Arthur Eumann Bastos Paoliello, Monica Maria TI Association between blood lead and blood pressure: a population-based study in Brazilian adults SO ENVIRONMENTAL HEALTH LA English DT Article DE Blood lead; Blood pressure; Hypertension; Population-based ID CARDIOVASCULAR-DISEASE; INDUCED HYPERTENSION; GLUTATHIONE-PEROXIDASE; OXIDATIVE STRESS; NATIONAL-HEALTH; UNITED-STATES; NITRIC-OXIDE; EXPOSURE; RISK; PATHOGENESIS AB Background: Environmental lead exposure among adults may increase blood pressure and elevate the risk of hypertension. The availability of data on blood lead levels (BLL) in adult Brazilian population is scarce and population-based studies are important for screening the population exposure and also to evaluate associations with adverse health effects. The goal of this study was to examine the association of BLL with blood pressure and hypertension in a population-based study in a city in Southern Brazil. Methods: A total of 948 adults, aged 40 years or older, were randomly selected. Information on socioeconomic, dietary, lifestyle and occupational background was obtained by orally administered household interviews. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured according to the guidelines VI Brazilian Guidelines on Hypertension. BLL were measured by inductively coupled plasma mass spectrometry technique. Multiple linear and logistic regression models were performed to evaluate associations of BLL with SBP and DBP, and with the chance of hypertension and of elevated SBP and DBP. Results: The geometric mean of BLL was 1.97 mu g/dL (95% CI: 1.90-2.04 mu g/dL). After multivariable adjustment, participants in the quartile 4 of blood lead presented 0.06 mm/Hg (95% CI, 0.04-0.09) average difference in DBP comparing with those in quartile 1. Participants in the 90th percentile of blood lead distribution had 0.07 mmHg (95% CI, 0.03 to 0.11) higher DBP compared with those participants in the 10th percentile of blood lead. The adjusted OR for hypertension was 2.54 (95% CI, 1.17-5.53), comparing the highest to the lowest blood lead quartiles. Compared with participants in the 10th percentile of blood lead, participants in the 90th percentile presented higher OR for hypertension (OR: 2.77; 95% CI, 1.41 to 5.46). Conclusion: At low concentrations, BLL were positively associated with DBP and with the odds for hypertension in adults aged 40 or older. It is important to enforce lead exposure monitoring and the enactment of regulatory laws to prevent lead contamination in urban settings. C1 [de Almeida Lopes, Ana Carolina Bertin; Urbano, Mariana Ragassi; Mesas, Arthur Eumann; Bastos Paoliello, Monica Maria] State Univ Londrina UEL, Ctr Hlth Sci, Grad Program Publ Hlth, Londrina, Parana, Brazil. [Silbergeld, Ellen Kovner; Navas-Acien, Ana] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. [Zamoiski, Rachel] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Washington, DC USA. [Martins, Airton da Cunha, Jr.] Univ Sao Paulo, Fac Pharmaceut Sci, Grad Program Toxicol, Sao Paulo, Brazil. [Iakmiu Camargo, Alissana Ester] State Univ Londrina UEL, Ctr Hlth Sci, Grad Program Hlth Sci, Londrina, Parana, Brazil. [Urbano, Mariana Ragassi] State Univ Londrina UEL, Dept Stat, Londrina, Parana, Brazil. [Mesas, Arthur Eumann] State Univ Londrina UEL, Dept Publ Hlth, Londrina, Parana, Brazil. [Bastos Paoliello, Monica Maria] Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA. RP Paoliello, MMB (reprint author), State Univ Londrina UEL, Ctr Hlth Sci, Grad Program Publ Hlth, Londrina, Parana, Brazil.; Paoliello, MMB (reprint author), Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA. EM monibas2@gmail.com FU Coordination for the Improvement of Higher Level or Education Personnel (CAPES), through the Ministry of Health, Brazil FX This work was supported by the Coordination for the Improvement of Higher Level or Education Personnel (CAPES), through the Ministry of Health, Brazil. NR 56 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-069X J9 ENVIRON HEALTH-GLOB JI Environ. Health PD MAR 14 PY 2017 VL 16 AR 27 DI 10.1186/s12940-017-0233-5 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA EO7XA UT WOS:000396902200001 ER PT J AU Sim, MJW Malaker, SA Khan, A Stowell, JM Shabanowitz, J Peterson, ME Rajagopalan, S Hunt, DF Altmann, DM Long, EO Boyton, RJ AF Sim, Malcolm J. W. Malaker, Stacy A. Khan, Ayesha Stowell, Janet M. Shabanowitz, Jeffrey Peterson, Mary E. Rajagopalan, Sumati Hunt, Donald F. Altmann, Daniel M. Long, Eric O. Boyton, Rosemary J. TI Canonic and Cross-reacrtive Binding of NK cell Inhibitory Recweptors to HLA-C Allotypes Is Dication by Peptides Bound to HLA-C SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE innate immunity; immunogenetics; natural killer cell; killer cell Ig-like receptors; human leukocyte antigen ID NATURAL-KILLER-CELLS; IMMUNOGLOBULIN-LIKE RECEPTOR; SINGLE AMINO-ACID; CLASS-I; CRYSTAL-STRUCTURE; GENES INFLUENCE; T-LYMPHOCYTES; MATERNAL KIR; KIR2DL3; RECOGNITION AB Background: Human natural killer (NK) cell activity is regulated by a family of killer cell immunoglobulin-like receptors (KIRs) that bind human leukocyte antigen (HLA) class I. Combinations of KIR and HLA genotypes are associated with disease, including susceptibility to viral infection and disorders of pregnancy. KIR2DL1 binds HLA-C alleles of group C2 (Lys(80)). KIR2DL2 and KIR2DL3 bind HLA-C alleles of group C1 (Asn(80)). However, this model cannot explain HLA-C allelic effects in disease or the impact of HLA-bound peptides. The goal of this study was to determine the extent to which the endogenous HLA-C peptide repertoire can influence the specific binding of inhibitory KIR to HLA-C allotypes. Results: The impact of HLA-C bound peptide on inhibitory KIR binding was investigated taking advantage of the fact that HLA-C*05:01 (HLA-C group 2,C2) and HLA-C*08:02 (HLA-C group 1, C1) have identical sequences apart from the key KIR specificity determining epitope at residues 77 and 80. Endogenous peptides were eluted from HLAC*05:01 and used to test the peptide dependence of KIR2DL1 and KIR2DL2/3 binding to HLA-C*05:01 and HLA-C*08:02 and subsequent impact on NK cell function. Specific binding of KIR2DL1 to the C2 allotype occurred with the majority of peptides tested. In contrast, KIR2DL2/3 binding to the C1 allotype occurred with only a subset of peptides. Cross-reactive binding of KIR2DL2/3 with the C2 allotype was restricted to even fewer peptides. Unexpectedly, two peptides promoted binding of the C2 allotype-specific KIR2DL1 to the C1 allotype. We showed that presentation of endogenous peptides or HIV Gag peptides by HLA-C can promote KIR cross- reactive binding. conclusion: KIR2DL2/3 binding to C1 is more peptide selective than that of KIR2DL1 binding to C2, providing an explanation for KIR2DL3-C1 interactions appearing weaker than KIR2DL1-C2. In addition, cross-reactive binding of KIR is characterized by even higher peptide selectivity. We demonstrate a hierarchy of functional peptide selectivity of KIR-HLA-C interactions with relevance to NK cell biology and human disease associations. This selective peptide sequence-driven binding of KIR provides a potential mechanism for pathogen as well as self-peptide to modulate NK cell activation through altering levels of inhibition. C1 [Sim, Malcolm J. W.; Peterson, Mary E.; Rajagopalan, Sumati; Long, Eric O.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Sim, Malcolm J. W.; Khan, Ayesha; Stowell, Janet M.; Altmann, Daniel M.; Boyton, Rosemary J.] Imperial Coll London, Dept Med, Lung Immunol Grp, London, England. [Malaker, Stacy A.; Shabanowitz, Jeffrey; Hunt, Donald F.] Univ Virginia, Dept Chem, Charlottesville, VA USA. [Malaker, Stacy A.] Stanford Univ, Dept Chem, Stanford, CA 94305 USA. [Hunt, Donald F.] Univ Virginia, Dept Pathol, Charlottesville, VA 22903 USA. RP Long, EO (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA.; Boyton, RJ (reprint author), Imperial Coll London, Dept Med, Lung Immunol Grp, London, England. EM elong@nih.gov; r.boyton@imperial.ac.uk FU Wellcome Trust-NIH PhD studentship [WT095472MA]; Imperial College London, UK; NIHR BRC [P46708]; NIH [HHSN272200900046C, AI033993]; Wellcome Trust [087999/B/08/Z]; Welton Foundation [P14475]; Intramural Research Program of the NIH; National Institute of Allergy and Infectious Diseases; National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London FX MS was supported by a 4-year Wellcome Trust-NIH PhD studentship (WT095472MA) and registered for a PhD at Imperial College London, UK. This work was supported by the following grants: NIHR BRC (P46708; RB), NIH (HHSN272200900046C; RB and DA), Wellcome Trust (087999/B/08/Z; RB and DA) and Welton Foundation (P14475; RB), and NIH (AI033993; DH). This work was supported in part by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases (EL). The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The funding bodies had no role in the design of the study, data collection, analysis, and interpretation of data, writing the manuscript or decision to publish. NR 56 TC 0 Z9 0 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD MAR 14 PY 2017 VL 8 AR 193 DI 10.3389/fimmu.2017.00193 PG 16 WC Immunology SC Immunology GA EN7UG UT WOS:000396207100001 PM 28352266 ER PT J AU Garcia, GR Maruyama, SR Nelson, KT Ribeiro, JMC Gardinassi, LG Maia, AAM Ferreira, BR Kooyman, FNJ Santos, IKFD AF Garcia, Gustavo Rocha Maruyama, Sandra Regina Nelson, Kristina T. Chaves Ribeiro, Jose Marcos Gardinassi, Luiz Gustavo Mendes Maia, Antonio Augusto Ferreira, Beatriz Rossetti Kooyman, Frans N. J. de Miranda Santos, Isabel K. F. TI Immune recognition of salivary proteins from the cattle tick Rhipicephalus microplus differs according to the genotype of the bovine host SO PARASITES & VECTORS LA English DT Article DE Immunoglobulins; Proteome; Immunoproteome; Antibody response; Rhipicephalus microplus; Tick saliva; Bos taurus; Bos indicus ID SERINE-PROTEASE INHIBITORS; NEONATAL FC-RECEPTOR; BOS-INDICUS CATTLE; BOOPHILUS-MICROPLUS; HAEMAPHYSALIS-LONGICORNIS; IXODES-RICINUS; ZEBU CATTLE; IN-VIVO; RESISTANCE; EXPRESSION AB Background: Males of the cattle tick Rhipicephalus microplus produce salivary immunoglobulin-binding proteins and allotypic variations in IgG are associated with tick loads in bovines. These findings indicate that antibody responses may be essential to control tick infestations. Infestation loads with cattle ticks are heritable: some breeds carry high loads of reproductively successful ticks, in others, few ticks feed and they reproduce inefficiently. Different patterns of humoral immunity against tick salivary proteins may explain these phenotypes. Methods: We describe the profiles of humoral responses against tick salivary proteins elicited during repeated artificial infestations of bovines of a tick-resistant (Nelore) and a tick-susceptible (Holstein) breed. We measured serum levels of total IgG1, IgG2 and IgE immunoglobulins and of IgG1 and IgG2 antibodies specific for tick salivary proteins. With liquid chromatography followed by mass spectrometry we identified tick salivary proteins that were differentially recognized by serum antibodies from tick-resistant and tick-susceptible bovines in immunoblots of tick salivary proteins separated by two-dimensional electrophoresis. Results: Baseline levels of total IgG1 and IgG2 were significantly higher in tick-susceptible Holsteins compared with resistant Nelores. Significant increases in levels of total IgG1, but not of IgG2 accompanied successive infestations in both breeds. Resistant Nelores presented with significantly higher levels of salivary-specific antibodies before and at the first challenge with tick larvae; however, by the third challenge, tick-susceptible Holsteins presented with significantly higher levels of IgG1 and IgG2 tick salivary protein-specific antibodies. Importantly, sera from tick-resistant Nelores reacted with 39 tick salivary proteins in immunoblots of salivary proteins separated in two dimensions by electrophoresis versus only 21 spots reacting with sera from tick-susceptible Holsteins. Conclusions: Levels of tick saliva-specific antibodies were not directly correlated with infestation phenotypes. However, in spite of receiving apparently lower amounts of tick saliva, tick-resistant bovines recognized more tick salivary proteins. These reactive salivary proteins are putatively involved in several functions of parasitism and blood-feeding. Our results indicate that neutralization by host antibodies of tick salivary proteins involved in parasitism is essential to control tick infestations. C1 [Garcia, Gustavo Rocha; Maruyama, Sandra Regina; Gardinassi, Luiz Gustavo; Ferreira, Beatriz Rossetti; de Miranda Santos, Isabel K. F.] Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Biochem & Immunol, Sao Paulo, Brazil. [Nelson, Kristina T.] Virginia Commonwealth Univ, Ctr Study Biol Complex, Richmond, VA USA. [Chaves Ribeiro, Jose Marcos] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Mendes Maia, Antonio Augusto] Univ Sao Paulo, Sch Anim Sci & Food Technol, Dept Basic Sci, Sao Paulo, Brazil. [Ferreira, Beatriz Rossetti] Univ Sao Paulo, Ribeirao Preto Sch Nursing, Dept Maternal Child Nursing & Publ Hlth, Ribeirao Preto, SP, Brazil. [Kooyman, Frans N. J.] Univ Utrecht, Dept Infect Dis & Immunol, Fac Vet Med, Utrecht, Netherlands. RP Santos, IKFD (reprint author), Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Biochem & Immunol, Sao Paulo, Brazil. EM imsantos@fmrp.usp.br FU Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [559603/2009-6]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2009/53645-3, 2007/51532-1, 2009/51212-2, 2013/00382-0]; FAPESP [2006/54041-6, 2007/59357-4, 2012/15464-0, 2012/04087-0] FX This study was supported by a grant to IKFMS from the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq grant number 559603/2009-6) and from the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP grant number 2009/53645-3). GRG. was supported by scholarships from the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP, fellowships: 2007/51532-1, 2009/51212-2 and 2013/00382-0). SRM was supported by scholarships from FAPESP (2006/54041-6, 2007/59357-4, 2012/15464-0 and 2012/04087-0). Because JMCR, JGV and JMA are government employees and this is a government work, the work is in the public domain in the United States. Notwithstanding any other agreements, the NIH reserves the right to provide the work to PubMedCentral for display and use by the public, and PubMedCentral may tag or modify the work consistent with its customary practices. Rights can be established outside of the United States subject to a government use license. NR 83 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-3305 J9 PARASITE VECTOR JI Parasites Vectors PD MAR 14 PY 2017 VL 10 AR 144 DI 10.1186/s13071-017-2077-9 PG 18 WC Parasitology SC Parasitology GA EO7VW UT WOS:000396899200001 PM 28288696 ER PT J AU Shi, JJ Zhao, JJ Zhang, X Cheng, YQ Hu, JH Li, YY Zhao, X Shang, QH Sun, YL Tu, B Shi, L Gao, B Wang, FS Zhang, Z AF Shi, Jijing Zhao, Juanjuan Zhang, Xin Cheng, Yongqian Hu, Jinhua Li, Yuanyuan Zhao, Xin Shang, Qinghua Sun, Yanling Tu, Bo Shi, Lei Gao, Bin Wang, Fu-Sheng Zhang, Zheng TI Activated hepatic stellate cells impair NK cell anti-fibrosis capacity through a TGF-beta-dependent emperipolesis in HBV cirrhotic patients SO SCIENTIFIC REPORTS LA English DT Article ID NATURAL-KILLER-CELLS; LIVER FIBROSIS; AUTOIMMUNE HEPATITIS; C VIRUS; T-CELLS; KUPFFER CELLS; INJURY; MICE; FIBROGENESIS; PATHOGENESIS AB Natural killer (NK) cells can induce liver fibrosis remission by killing hepatic stellate cells (HSCs) and producing interferon (IFN)-gamma in a mouse model; however, their anti-fibrotic immune-characteristics and regulatory mechanisms by HSCs remain to be determined, especially in livers from HBV-infected liver cirrhosis (LC) patients. We analyzed frequency, phenotype and anti-fibrotic function of hepatic and peripheral NK subsets in 43 HBV-LC patients. We found that hepatic NK subsets from LC patients displayed a decreased frequency, activation status and anti-fibrotic activity compared with those from chronic hepatitis B patients, which were mainly mediated by increased intrahepatic tumour-growth factor (TGF)-beta because blockade of TGF-beta significantly reversed NK anti-fibrotic function in vitro. In vivo, hepatic NK cells were enriched in proximity to the alpha-smooth muscle actin (alpha-SMA+) area within mild fibrosis regions; while in severe fibrotic areas, they were either directly attached to or separated from the alpha-SMA+ region. NK cells from LC patients could enter HSCs to form emperipolesis (a cell-in-cell structure) and become apoptotic; anti-TGF-beta treatment ameliorated this emperipolesis. This finding suggested a novel mechanism by which activated HSCs impair NK cells' anti-fibrosis capacity through a TGF-beta-dependent emperipolesis in LC patients, providing an anti-fibrotic rational by enhancing NK cell activity. C1 [Shi, Jijing; Wang, Fu-Sheng] Peking Univ, Teaching Hosp, Mil Hosp China 302, Dept Infect Dis, Beijing 100039, Peoples R China. [Zhao, Juanjuan; Sun, Yanling; Zhang, Zheng] Beijing 302 Hosp, Res Ctr Clin & Translat Med, Beijing 100039, Peoples R China. [Zhang, Xin; Li, Yuanyuan; Tu, Bo; Shi, Lei] Beijing 302 Hosp, Dept Infect Dis, Beijing 100039, Peoples R China. [Cheng, Yongqian] Beijing 302 Hosp, Res Ctr Int Liver Dis, Beijing 100039, Peoples R China. [Hu, Jinhua] Beijing 302 Hosp, Res Ctr Liver Failure, Beijing 100039, Peoples R China. [Zhao, Xin] Beijing 302 Hosp, Forens Sursery Ctr, Beijing 100039, Peoples R China. [Shang, Qinghua] 88th Hosp PLA, Dept Infect Dis, Tai An 271000, Shandong, Peoples R China. [Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. RP Wang, FS (reprint author), Peking Univ, Teaching Hosp, Mil Hosp China 302, Dept Infect Dis, Beijing 100039, Peoples R China.; Zhang, Z (reprint author), Beijing 302 Hosp, Res Ctr Clin & Translat Med, Beijing 100039, Peoples R China. EM fswang302@163.com; zhangzheng1975@aliyun.com FU National Natural Science Foundation of China [91442127]; National Science Fund for Outstanding Young Scholars [81222024]; National Key Basic Research Program of China [2012CB519005] FX This work was supported by the the National Natural Science Foundation of China (91442127), the National Science Fund for Outstanding Young Scholars (81222024), and the National Key Basic Research Program of China (2012CB519005). We thank all patients, study-site staff, and all participating consultants for their contributions, which made this study possible. NR 50 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 14 PY 2017 VL 7 AR 44544 DI 10.1038/srep44544 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN8DI UT WOS:000396230700002 PM 28291251 ER PT J AU Buyego, P Nakiyingi, L Ddungu, H Walimbwa, S Nalwanga, D Reynolds, SJ Parkes-Ratanshi, R AF Buyego, Paul Nakiyingi, Lydia Ddungu, Henry Walimbwa, Stephen Nalwanga, Damalie Reynolds, Steven J. Parkes-Ratanshi, Rosalind TI Possible misdiagnosis of HIV associated lymphoma as tuberculosis among patients attending Uganda Cancer Institute SO AIDS RESEARCH AND THERAPY LA English DT Article DE Tuberculosis; Uganda; Lymphoma; HIV; Misdiagnosis AB Background: Early diagnosis of HIV associated lymphoma is challenging because the definitive diagnostic procedure of biopsy, requires skills and equipment that are not readily available. As a consequence, diagnosis may be delayed increasing the risk of mortality. We set out to determine the frequency and risk factors associated with the misdiagnosis of HIV associated lymphoma as tuberculosis (TB) among patients attending the Uganda Cancer Institute (UCI). Methods: A retrospective cohort study design was used among HIV patients with associated lymphoma patients attending the UCI, Kampala, Uganda between February and March 2015. Eligible patient charts were reviewed for information on TB treatment, socio-demographics, laboratory parameters (Hemoglobin, CD4cells count and lactate dehydrogenase) and clinical presentation using a semi structured data extraction form. Results: A total of 183 charts were reviewed; 106/183 were males (57.9%), the median age was 35 (IQR, 28-45). Fifty six (30.6%) patients had a possible misdiagnosis as TB and their median time on TB treatment was 3.5 (1-5.3) months. In multivariate analysis the presence of chest pain had an odd ratio (OR) of 4.4 (95% CI 1.89-10.58, p < 0.001) and stage III and IV lymphoma disease had an OR of 3.22 (95% CI 1.08-9.63, p < 0.037) for possible misdiagnosis of lymphoma as TB. Conclusion: A high proportion of patients with HIV associated lymphoma attending UCI are misdiagnosed and treated as TB. Chest pain and stage III and IV of lymphoma were associated with an increased risk of a possible misdiagnosis of lymphoma as TB. C1 [Buyego, Paul; Nakiyingi, Lydia; Ddungu, Henry] Makerere Univ, Coll Hlth Sci, Dept Med, Kampala, Uganda. [Ddungu, Henry] Uganda Canc Inst Mulago Hosp, Kampala, Uganda. [Buyego, Paul; Nakiyingi, Lydia; Walimbwa, Stephen; Nalwanga, Damalie; Parkes-Ratanshi, Rosalind] Makerere Univ, Coll Hlth Sci, Infect Dis Inst, POB 22418, Kampala, Uganda. [Reynolds, Steven J.] NIAID, Div Intramural Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Reynolds, Steven J.] Johns Hopkins Sch Med, Baltimore, MD USA. [Parkes-Ratanshi, Rosalind] Univ Cambridge, Cambridge, England. RP Buyego, P (reprint author), Makerere Univ, Coll Hlth Sci, Dept Med, Kampala, Uganda.; Buyego, P (reprint author), Makerere Univ, Coll Hlth Sci, Infect Dis Inst, POB 22418, Kampala, Uganda. EM pbuyego@idi.co.ug FU Fogarty International Center, National Institutes of Health [D43TW009771]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This study was self-sponsored as part of a master's project.; Support for manuscript writing was provided by Fogarty International Center, National Institutes of Health (Grant #D43TW009771 "HIV co-infections in Uganda: TB, Cryptococcus, and Viral Hepatitis").; Supported in part (SJR) by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 12 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-6405 J9 AIDS RES THER JI Aids Res. Ther. PD MAR 14 PY 2017 VL 14 AR 13 DI 10.1186/s12981-017-0139-x PG 6 WC Infectious Diseases SC Infectious Diseases GA EQ0IP UT WOS:000397755200001 PM 28292305 ER PT J AU Powell, EM Ragozzino, ME AF Powell, E. M. Ragozzino, M. E. TI COGNITIVE FLEXIBILITY: DEVELOPMENT, DISEASE AND TREATMENT SO NEUROSCIENCE LA English DT Editorial Material C1 [Powell, E. M.] Univ Maryland, Sch Med, Baltimore, MD 21774 USA. [Ragozzino, M. E.] Univ Illinois, Dept Psychol, Chicago, IL 60607 USA. RP Powell, EM (reprint author), NIAAA, Baltimore, MD 20849 USA. EM epowel@gmail.com; mrago@uic.edu NR 25 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 EI 1873-7544 J9 NEUROSCIENCE JI Neuroscience PD MAR 14 PY 2017 VL 345 SI SI BP 1 EP 2 DI 10.1016/j.neuroscience.2016.12.023 PG 2 WC Neurosciences SC Neurosciences & Neurology GA EL6IZ UT WOS:000394726700001 PM 28034728 ER PT J AU Izquierdo, A Brigman, JL Radke, AK Rudebeck, PH Holmes, A AF Izquierdo, A. Brigman, J. L. Radke, A. K. Rudebeck, P. H. Holmes, A. TI THE NEURAL BASIS OF REVERSAL LEARNING: AN UPDATED PERSPECTIVE SO NEUROSCIENCE LA English DT Review DE frontal cortex; striatum; amygdala; dopamine; serotonin; glutamate ID MEDIAL PREFRONTAL CORTEX; PRELIMBIC-INFRALIMBIC AREAS; ANTERIOR CINGULATE CORTEX; FRONTAL-LOBE DAMAGE; ORBITOFRONTAL CORTEX; BEHAVIORAL FLEXIBILITY; SPATIAL REVERSAL; BASOLATERAL AMYGDALA; RHESUS-MONKEYS; DORSOMEDIAL STRIATUM AB Reversal learning paradigms are among the most widely used tests of cognitive flexibility and have been used as assays, across species, for altered cognitive processes in a host of neuropsychiatric conditions. Based on recent studies in humans, non-human primates, and rodents, the notion that reversal learning tasks primarily measure response inhibition, has been revised. In this review, we describe how cognitive flexibility is measured by reversal learning and discuss new definitions of the construct validity of the task that are serving as a heuristic to guide future research in this field. We also provide an update on the available evidence implicating certain cortical and subcortical brain regions in the mediation of reversal learning, and an overview of the principal neurotransmitter systems involved. This article is part of a Special issue entitled: Cognitive Flexibility (C) 2016 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Izquierdo, A.] Univ Calif Los Angeles, Brain Res Inst, Dept Psychol, Los Angeles, CA 90024 USA. [Brigman, J. L.] Univ New Mexico, Sch Med, Dept Neurosci, Albuquerque, NM 87131 USA. [Radke, A. K.; Holmes, A.] NIAAA, Lab Behav & Genom Neurosci, Bethesda, MD USA. [Rudebeck, P. H.] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Rudebeck, P. H.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. RP Izquierdo, A (reprint author), Univ Calif Los Angeles, Brain Res Inst, Dept Psychol, Los Angeles, CA 90024 USA. EM aizquie@psych.ucla.edu OI Izquierdo, Alicia/0000-0001-9897-2091 FU UCLA Division of Life Sciences Recruitment and Retention fund; National Institute on Alcohol Abuse and Alcoholism grant [1P50AA022534-01]; Icahn School of Medicine at Mount Sinai; Brain and Behavior Research Foundation Young Investigator NARSAD award; NIAAA intramural research program FX We are very grateful to Dr. Russel Morton for constructing some of the figures and helpful comments from the Izquierdo lab on a previous version of this manuscript. Al is supported by the UCLA Division of Life Sciences Recruitment and Retention fund. JLB is supported by National Institute on Alcohol Abuse and Alcoholism grant 1P50AA022534-01. PHR is supported by generous seed funds from the Icahn School of Medicine at Mount Sinai and a Brain and Behavior Research Foundation Young Investigator NARSAD award. AKR and AH are supported by the NIAAA intramural research program NR 219 TC 5 Z9 5 U1 3 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 EI 1873-7544 J9 NEUROSCIENCE JI Neuroscience PD MAR 14 PY 2017 VL 345 SI SI BP 12 EP 26 DI 10.1016/j.neuroscience.2016.03.021 PG 15 WC Neurosciences SC Neurosciences & Neurology GA EL6IZ UT WOS:000394726700003 PM 26979052 ER PT J AU Prasad, JA Abela, AR Chudasama, Y AF Prasad, J. A. Abela, A. R. Chudasama, Y. TI MIDLINE THALAMIC REUNIENS LESIONS IMPROVE EXECUTIVE BEHAVIORS SO NEUROSCIENCE LA English DT Article DE cognition; thalamocortical; hippocampus; prefrontal; arousal ID MEDIAL PREFRONTAL CORTEX; PHASEOLUS-VULGARIS-LEUKOAGGLUTININ; PRELIMBIC-INFRALIMBIC AREAS; DORSAL ANTERIOR CINGULATE; SPATIAL WORKING-MEMORY; REACTION-TIME-TASK; NUCLEUS-REUNIENS; ORBITOFRONTAL CORTEX; ATTENTIONAL PERFORMANCE; RHOMBOID NUCLEI AB The role of the thalamus in complex cognitive behavior is a topic of increasing interest. Here we demonstrate that lesions of the nucleus reuniens (NRe), a midline thalamic nucleus interconnected with both hippocampal and prefrontal circuitry, lead to enhancement of executive behaviors typically associated with the prefrontal cortex. Rats were tested on four behavioral tasks: (1) the combined attention-memory (CAM) task, which simultaneously assessed attention to a visual target and memory for that target over a variable delay; (2) spatial memory using a radial arm maze, (3) discrimination and reversal learning using a touchscreen operant platform, and (4) decision making with delayed outcomes. Following NRe lesions, the animals became more efficient in their performance, responding with shorter reaction times but also less impulsively than controls. This change, combined with a decrease in perseverative responses, led to focused attention in the CAM task and accelerated learning in the visual discrimination task. There were no observed changes in tasks involving either spatial memory or value-based decision making. These data complement ongoing efforts to understand the role of midline thalamic structures in human cognition, including the development of thalamic stimulation as a therapeutic strategy for acquired cognitive disabilities (Schiff, 2008; Mair et al., 2011), and point to the NRe as a potential target for clinical intervention. C1 [Prasad, J. A.; Abela, A. R.; Chudasama, Y.] McGill Univ, Dept Psychol, Montreal, PQ H3A 1B1, Canada. [Chudasama, Y.] NIMH, Bethesda, MD 20892 USA. RP Chudasama, Y (reprint author), NIMH, Sect Behav Neurosci, Bethesda, MD 20892 USA.; Chudasama, Y (reprint author), NIMH, Bethesda, MD 20892 USA. EM yogita.chudasama@nih.gov FU Natural Sciences and Engineering Research Council of Canada [341600]; Canadian Foundation for Innovation Leaders Opportunity Award [14033] FX This work was supported by grants from the Natural Sciences and Engineering Research Council of Canada (No: 341600) and the Canadian Foundation for Innovation Leaders Opportunity Award (No: 14033). We thank Priya Patel, Cynthia Berthiaume, Benjamin Hatch and Elizabeth Waring for their help with behavioral testing, and Hyun Choong Yong for help with data input. Judy Prasad is now at The University of Chicago, Department of Neurobiology, Illinois, USA. Andrew Abela is now at the Centre for Addiction and Mental Health (CAMH), Toronto, Canada. Yogita Chudasama is now at the National Institute of Mental Health, Bethesda, MD, USA. NR 76 TC 2 Z9 2 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 EI 1873-7544 J9 NEUROSCIENCE JI Neuroscience PD MAR 14 PY 2017 VL 345 SI SI BP 77 EP 88 DI 10.1016/j.neuroscience.2016.01.071 PG 12 WC Neurosciences SC Neurosciences & Neurology GA EL6IZ UT WOS:000394726700008 PM 26868974 ER PT J AU Sadacca, BF Wikenheiser, AM Schoenbaum, G AF Sadacca, Brian F. Wikenheiser, Andrew M. Schoenbaum, Geoffrey TI TOWARD A THEORETICAL ROLE FOR TONIC NOREPINEPHRINE IN THE ORBITOFRONTAL CORTEX IN FACILITATING FLEXIBLE LEARNING SO NEUROSCIENCE LA English DT Review DE orbitofrontal cortex; norepinephrine; reinforcement learning; ensemble states; flexible learning ID LOCUS-COERULEUS; PREFRONTAL CORTEX; DECISION-MAKING; FRONTAL-CORTEX; COGNITIVE INFLEXIBILITY; BEHAVIORAL FLEXIBILITY; BASOLATERAL AMYGDALA; NEGATIVE FEEDBACK; REVERSAL; RATS AB To adaptively respond in a complex, changing world, animals need to flexibly update their understanding of the world when their expectations are violated. Though several brain regions in rodents and primates have been implicated in aspects of this updating, current models of orbitofrontal cortex (OFC) and norepinephrine neurons of the locus coeruleus (LC-NE) suggest that each plays a role in responding to environmental change, where the OFC allows updating of prior learning to occur without overwriting or unlearning one's previous understanding of the world that changed, while elevated tonic NE allows for increased flexibility in behavior that tracks an animal's uncertainty. In light of recent studies highlighting a specific LC-NE projection to the OFC, in this review we discuss current models of OFC and NE function, and their potential synergy in the updating of associations following environmental change. This article is part of a Special Issue entitled. C1 [Sadacca, Brian F.; Wikenheiser, Andrew M.; Schoenbaum, Geoffrey] NIDA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Schoenbaum, Geoffrey] Univ Maryland, Dept Anat & Neurobiol, Sch Med, College Pk, MD 20742 USA. [Schoenbaum, Geoffrey] Johns Hopkins Sch Med, Dept Neurosci, Baltimore, MD USA. RP Sadacca, BF; Schoenbaum, G (reprint author), NIDA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. EM brian.sadacca@nih.gov; schoenbaum@nih.gov FU National Institute on Drug Abuse FX This work was supported by the Intramural Research Program at the National Institute on Drug Abuse. The opinions expressed in this article are the authors' own and do not reflect the view of the NIH/DHHS. NR 71 TC 1 Z9 1 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 EI 1873-7544 J9 NEUROSCIENCE JI Neuroscience PD MAR 14 PY 2017 VL 345 SI SI BP 124 EP 129 DI 10.1016/j.neuroscience.2016.04.017 PG 6 WC Neurosciences SC Neurosciences & Neurology GA EL6IZ UT WOS:000394726700012 PM 27102419 ER PT J AU Dong, JS Aitken, CE Thakur, A Shin, BS Lorsch, JR Hinnebusch, AG AF Dong, Jinsheng Aitken, Colin Echeverria Thakur, Anil Shin, Byung-Sik Lorsch, Jon R. Hinnebusch, Alan G. TI Rps3/uS3 promotes mRNA binding at the 40S ribosome entry channel and stabilizes preinitiation complexes at start codons SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE translation; initiation; uS3; ribosome; yeast ID EUKARYOTIC TRANSLATION INITIATION; FACTOR 1 EIF1; SACCHAROMYCES-CEREVISIAE; SCANNING MECHANISM; CRYSTAL-STRUCTURE; SELECTION; RECOGNITION; ACCURACY; SUBUNIT; RECRUITMENT AB The eukaryotic 43S preinitiation complex (PIC) bearingMet-tRNAi Met in a ternary complex (TC) with eukaryotic initiation factor (eIF) 2-GTP scans the mRNA leader for an AUG codon in favorable "Kozak" context. AUG recognition provokes rearrangement from an open PIC conformation with TC bound in a state not fully engaged with the P site ("P-OUT") to a closed, arrested conformation with TC tightly bound in the "P-IN" state. Yeast ribosomal protein Rps3/uS3 resides in the mRNA entry channel of the 40S subunit and contacts mRNA via conserved residues whose functional importance was unknown. We show that substitutions of these residues reduce bulk translation initiation and diminish initiation at near-cognate UUG start codons in yeast mutants in which UUG selection is abnormally high. Two such substitutions-R116D and R117D-also increase discrimination against an AUG codon in suboptimal Kozak context. Consistently, the Arg116 and Arg117 substitutions destabilize TC binding to 48S PICs reconstituted in vitro with mRNA harboring a UUG start codon, indicating destabilization of the closed P-IN state with a UUGanticodon mismatch. Using model mRNAs lacking contacts with either the mRNA entry or exit channels of the 40S subunit, we demonstrate that Arg116/Arg117 are crucial for stabilizing PIC-mRNA contacts at the entry channel, augmenting the function of eIF3 at both entry and exit channels. The corresponding residues in bacterial uS3 promote the helicase activity of the elongating ribosome, suggesting that uS3 contacts with mRNA enhance multiple phases of translation across different domains of life. C1 [Dong, Jinsheng; Thakur, Anil; Shin, Byung-Sik; Hinnebusch, Alan G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Aitken, Colin Echeverria; Lorsch, Jon R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Mech & Regulat Prot Synth, NIH, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA.; Lorsch, JR (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Mech & Regulat Prot Synth, NIH, Bethesda, MD 20892 USA. EM jon.lorsch@nih.gov; ahinnebusch@nih.gov FU Intramural Research Program of the NIH; NIH [GM62128]; Leukemia & Lymphoma Society Career Development Program Fellowship FX We thank Jagpreet Nanda, Jyothsna Visweswaraiah, and Fan Zhang for advice on koff determinations. We are grateful to members of our laboratories and Tom Dever's group for helpful suggestions. This work was supported in part by the Intramural Research Program of the NIH (A.G.H. and J.R.L.) and NIH Grant GM62128 (previously to J.R.L.). C.E.A. was further supported by an NIH minority supplement to NIH Grant GM62128 and by a Leukemia & Lymphoma Society Career Development Program Fellowship. NR 37 TC 0 Z9 0 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 14 PY 2017 VL 114 IS 11 BP E2126 EP E2135 DI 10.1073/pnas.1620569114 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6DH UT WOS:000396094200007 PM 28223523 ER PT J AU Dunn, AR Stout, KA Ozawa, M Lohr, KM Hoffman, CA Bernstein, AI Li, YJ Wang, MZ Sgobio, C Sastry, N Cai, HB Caudle, WM Miller, GW AF Dunn, Amy R. Stout, Kristen A. Ozawa, Minagi Lohr, Kelly M. Hoffman, Carlie A. Bernstein, Alison I. Li, Yingjie Wang, Minzheng Sgobio, Carmelo Sastry, Namratha Cai, Huaibin Caudle, W. Michael Miller, Gary W. TI Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Parkinson disease; SV2C; synaptic vesicles; dopamine; alpha-synuclein ID REDUCED VESICULAR STORAGE; OLIGOMERIC ALPHA-SYNUCLEIN; BOTULINUM-NEUROTOXIN-A; NEUROTRANSMITTER RELEASE; MONOAMINE STORAGE; BINDING-SITE; PROTEIN; MICE; NEURODEGENERATION; EXPRESSION AB Members of the synaptic vesicle glycoprotein 2 (SV2) family of proteins are involved in synaptic function throughout the brain. The ubiquitously expressed SV2A has been widely implicated in epilepsy, although SV2C with its restricted basal ganglia distribution is poorly characterized. SV2C is emerging as a potentially relevant protein in Parkinson disease (PD), because it is a genetic modifier of sensitivity to (L)-DOPA and of nicotine neuroprotection in PD. Here we identify SV2C as a mediator of dopamine homeostasis and report that disrupted expression of SV2C within the basal ganglia is a pathological feature of PD. Genetic deletion of SV2C leads to reduced dopamine release in the dorsal striatum as measured by fast-scan cyclic voltammetry, reduced striatal dopamine content, disrupted alpha-synuclein expression, deficits in motor function, and alterations in neurochemical effects of nicotine. Furthermore, SV2C expression is dramatically altered in postmortem brain tissue from PD cases but not in Alzheimer disease, progressive supranuclear palsy, or multiple system atrophy. This disruption was paralleled in mice overexpressing mutated alpha-synuclein. These data establish SV2C as a mediator of dopamine neuron function and suggest that SV2C disruption is a unique feature of PD that likely contributes to dopaminergic dysfunction. C1 [Dunn, Amy R.; Stout, Kristen A.; Ozawa, Minagi; Lohr, Kelly M.; Hoffman, Carlie A.; Bernstein, Alison I.; Li, Yingjie; Wang, Minzheng; Caudle, W. Michael; Miller, Gary W.] Emory Univ, Rollins Sch Publ Hlth, Dept Environm Hlth, Atlanta, GA 30322 USA. [Li, Yingjie; Miller, Gary W.] Emory Univ, Sch Med, Ctr Neurodegenerat Dis, Atlanta, GA 30322 USA. [Sgobio, Carmelo; Sastry, Namratha; Cai, Huaibin] NIA, Transgen Sect, NIH, Bethesda, MD 20892 USA. [Miller, Gary W.] Emory Univ, Dept Pharmacol, Sch Med, Atlanta, GA 30322 USA. [Miller, Gary W.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. RP Miller, GW (reprint author), Emory Univ, Rollins Sch Publ Hlth, Dept Environm Hlth, Atlanta, GA 30322 USA. EM gary.miller@emory.edu FU National Institute of Environmental Health Services (NIEHS) [R01ES023839, P30ES019776]; Lewis Dickey Memorial Fund; National Institute of Neurological Disorders and Stroke (NINDS) [F31NS089242]; NIEHS [K99ES024570]; Neuropathology Core of the Emory Neuroscience NINDS Core Facilities; NIH Grant [P30NS055077, P50AB005136]; Udall Parkinson's Disease Center at Emory University; NINDS Grant [P50NS071669]; University of Washington Aging and Disability Resource Center Brain Bank; National Institute on Aging Intramural Research Program Grant [NIA AG000928, AG000929] FX We thank Dr. Marla Gearing for expert insight and Merry Chen for excellent technical assistance. This research project was supported by National Institute of Environmental Health Services (NIEHS) Grants R01ES023839 and P30ES019776 (to G.W.M.), the Lewis Dickey Memorial Fund (G.W.M.), National Institute of Neurological Disorders and Stroke (NINDS) Grant F31NS089242 (to A.R.D.), NIEHS Grant K99ES024570 (to A.I.B.), the Neuropathology Core of the Emory Neuroscience NINDS Core Facilities supported by NIH Grant P30NS055077, The Udall Parkinson's Disease Center at Emory University supported by NINDS Grant P50NS071669, The University of Washington Aging and Disability Resource Center Brain Bank supported by NIH Grant P50AB005136, and National Institute on Aging Intramural Research Program Grants NIA AG000928 and AG000929 (to H.C.). NR 66 TC 0 Z9 0 U1 3 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 14 PY 2017 VL 114 IS 11 BP E2253 EP E2262 DI 10.1073/pnas.1616892114 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6DH UT WOS:000396094200020 PM 28246328 ER PT J AU Esplin, MS Elovitz, MA Iams, JD Parker, CB Wapner, RJ Grobman, WA Simhan, HN Wing, DA Haas, DM Silver, RM Hoffman, MK Peaceman, AM Caritis, SN Parry, S Wadhwa, P Foroud, T Mercer, BM Hunter, SM Saade, GR Reddy, UM AF Esplin, M. Sean Elovitz, Michal A. Iams, Jay D. Parker, Corette B. Wapner, Ronald J. Grobman, William A. Simhan, Hyagriv N. Wing, Deborah A. Haas, David M. Silver, Robert M. Hoffman, Matthew K. Peaceman, Alan M. Caritis, Steve N. Parry, Samuel Wadhwa, Pathik Foroud, Tatiana Mercer, Brian M. Hunter, Shannon M. Saade, George R. Reddy, Uma M. CA NuMoMb Network TI Predictive Accuracy of Serial Transvaginal Cervical Lengths and Quantitative Vaginal Fetal Fibronectin Levels for Spontaneous Preterm Birth Among Nulliparous Women SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ASYMPTOMATIC WOMEN; CONTROLLED-TRIAL; RISK WOMEN; DELIVERY; PREVENTION; PROGESTERONE; LABOR AB IMPORTANCE Spontaneous preterm birth is a leading cause of infant mortality. Prediction, largely based on prior pregnancy outcomes, is not possible in women pregnant for the first time. OBJECTIVE To assess the accuracy of universal screening to predict spontaneous preterm birth in nulliparous women using serial measurements of vaginal fetal fibronectin levels and cervical length. DESIGN, SETTINGS, AND PARTICIPANTS A prospective observational cohort study of nulliparous women with singleton pregnancies, from 8 clinical sites across the United States between October 2010 and May 2014. Women and clinicians were blinded to results unless cervical shortening less than 15 mm was identified. EXPOSURES Transvaginal cervical length and quantitative vaginal fetal fibronectin levels were reviewed at 2 study visits 4 or more weeks apart. MAIN OUTCOMES AND MEASURES Spontaneous preterm birth at less than 37 weeks was the primary outcome. Cervical length and quantitative fetal fibronectin were considered independently and together at each visit. Measurement distributions were compared for spontaneous preterm birth vs all other births. Spontaneous preterm birth before 32 weeks was a secondary outcome. RESULTS The study included 9410 women (median age, 27.0 [interquartile range, 9.0] years; 60.7% non-Hispanic white, 13.8% non-Hispanic black, 16.5% Hispanic, 4.0% Asian, and 5.1% other), of whom 474 (5.0%) had spontaneous preterm births, 335 (3.6%) had medically indicated preterm births, and 8601 (91.4%) had term births. Among women with spontaneous preterm birth, cervical length of 25 mm or less occurred in 35 of 439 (8.0%) at 16 to 22 weeks' gestation and in 94 of 403 (23.3%) at 22 to 30 weeks' gestation. Fetal fibronectin levels of 50 ng/mL or greater at 16 to 22 weeks identified 30 of 410 women (7.3%) with spontaneous preterm birth and 31 of 384 (8.1%) at 22 to 30 weeks. The area under the receiver operating characteristic curve for screening between 22 and 30 weeks for fetal fibronectin level alone was 0.59 (95% CI, 0.56-0.62), for transvaginal cervical length alone was 0.67 (95% CI, 0.64-0.70), and for the combination as continuous variables was 0.67 (95% CI, 0.64-0.70). CONCLUSIONS AND RELEVANCE Among nulliparous women with singleton pregnancies, quantitative vaginal fetal fibronectin and serial transvaginal ultrasound cervical length had low predictive accuracy for spontaneous preterm birth. These findings do not support routine use of these tests in such women. C1 [Esplin, M. Sean; Silver, Robert M.] Intermt Healthcare, Salt Lake City, UT USA. [Esplin, M. Sean; Silver, Robert M.] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. [Elovitz, Michal A.; Parry, Samuel] Univ Penn, Philadelphia, PA 19104 USA. [Iams, Jay D.] Ohio State Univ, Columbus, OH 43210 USA. [Parker, Corette B.; Hunter, Shannon M.] RTI Int, Res Triangle Pk, NC USA. [Wapner, Ronald J.] Columbia Univ, New York, NY USA. [Grobman, William A.; Peaceman, Alan M.] Northwestern Univ, Evanston, IL USA. [Simhan, Hyagriv N.; Caritis, Steve N.] Univ Pittsburgh, Pittsburgh, PA USA. [Wing, Deborah A.; Wadhwa, Pathik] Univ Calif Irvine, Irvine, CA 92717 USA. [Haas, David M.; Foroud, Tatiana] Indiana Univ, Bloomington, IN 47405 USA. [Hoffman, Matthew K.] Christiana Care, Newark, DE USA. [Mercer, Brian M.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Saade, George R.] Univ Texas Med Branch, Galveston, TX 77555 USA. [Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Esplin, MS (reprint author), Intermt Healthcare, 5121 S Cottonwood St,Ste 100, Murray, UT 84107 USA. EM sean.esplin@imail.org FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [U10 HD063036]; Case Western Reserve University [U10 HD063072]; Columbia University [U10 HD063047]; Indiana University [U10 HD063037]; Magee-Women's Hospital [U10 HD063041]; Northwestern University [U10 HD063020]; University of California at Irvine [U10 HD063046]; University of Pennsylvania [U10 HD063048]; University of Utah [U10 HD063053] FX This study is supported by grant funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) to Research Triangle Institute (U10 HD063036); Case Western Reserve University (U10 HD063072); Columbia University (U10 HD063047); Indiana University (U10 HD063037); Magee-Women's Hospital (U10 HD063041); Northwestern University (U10 HD063020); University of California at Irvine (U10 HD063046); University of Pennsylvania (U10 HD063048); and University of Utah (U10 HD063053). Hologic USA (Marlborough, Massachusetts) provided fetal fibronectin collection kits and prepaid shipping materials and performed the fetal fibronectin assays in a blinded fashion and without charge. NR 28 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 14 PY 2017 VL 317 IS 10 BP 1047 EP 1056 DI 10.1001/jama.2017.1373 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA EO5DO UT WOS:000396713400017 PM 28291893 ER PT J AU Merz, CNB Pepine, CJ Walsh, MN Fleg, JL AF Merz, C. Noel Bairey Pepine, Carl J. Walsh, Mary Norine Fleg, Jerome L. TI Ischemia and No Obstructive Coronary Artery Disease (INOCA) Developing Evidence-Based Therapies and Research Agenda for the Next Decade SO CIRCULATION LA English DT Article DE heart diseases; ischemia ID CARDIAC SYNDROME-X; SYNDROME EVALUATION WISE; POSITRON-EMISSION-TOMOGRAPHY; ENHANCED EXTERNAL COUNTERPULSATION; INTERNATIONAL MULTICENTER CONFIRM; CARDIOVASCULAR MAGNETIC-RESONANCE; MYOCARDIAL-PERFUSION RESERVE; AMERICAN-HEART-ASSOCIATION; L-ARGININE SUPPLEMENTATION; CALCIUM-CHANNEL BLOCKER AB The Cardiovascular Disease in Women Committee of the American College of Cardiology, in conjunction with interested parties (from the National Heart, Lung, and Blood Institute, American Heart Association, and European Society of Cardiology), convened a working group to develop a consensus on the syndrome of myocardial ischemia with no obstructive coronary arteries. In general, these patients have elevated risk for a cardiovascular event (including acute coronary syndrome, heart failure hospitalization, stroke, and repeat cardiovascular procedures) compared with reference subjects and appear to be at higher risk for development of heart failure with preserved ejection fraction. A subgroup of these patients also has coronary microvascular dysfunction and evidence of inflammation. This document provides a summary of findings and recommendations for the development of an integrated approach for identifying and managing patients with ischemia with no obstructive coronary arteries and outlines knowledge gaps in the area. Working group members critically reviewed available literature and current practices for risk assessment and state-of-the-science techniques in multiple areas, with a focus on next steps needed to develop evidence-based therapies. This report presents highlights of this working group review and a summary of suggested research directions to advance this field in the next decade. C1 [Merz, C. Noel Bairey] Cedars Sinai Heart Inst, Barbra Streisand Womens Heart Ctr, Los Angeles, CA USA. [Pepine, Carl J.] Univ Florida, Div Cardiol, Gainesville, FL USA. [Walsh, Mary Norine] St Vincent Heart Transplant, Indianapolis, IN USA. [Fleg, Jerome L.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. RP Merz, CNB (reprint author), Cedars Sinai Heart Ctr, 8700 Beverly Blvd, Los Angeles, CA 90048 USA. EM merz@cshs.org FU National Heart, Lung, and Blood Institutes [N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, RO1-, HL-073412-01, U01-64829, U01-HL649141, U01-HL649241, UL1-TR001427]; Gustavus and Louis Pfeiffer Research Foundation, Danville, NJ; Women's Guild of Cedars-Sinai Medical Center, Los Angeles, CA; Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, PA; QMED, Inc, Laurence Harbor, NJ; Edythe L. Broad Endowment; Barbra Streisand Women's Cardiovascular Research and Education Program; Linda Joy Pollin Women's Heart Health Program; Constance Austin Fellowship Endowment, Cedars-Sinai Medical Center, Los Angeles; Erika Glazer Women's Heart Health Project, Cedars-Sinai Medical Center, Los Angeles, California; American College of Cardiology FX This work was supported by contracts from the National Heart, Lung, and Blood Institutes, Nos. N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, RO1-and HL-073412-01, and grants U01-64829, U01-HL649141, U01-HL649241, and UL1-TR001427; grants from the Gustavus and Louis Pfeiffer Research Foundation, Danville, NJ, the Women's Guild of Cedars-Sinai Medical Center, Los Angeles, CA, the Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, PA, and QMED, Inc, Laurence Harbor, NJ; the Edythe L. Broad Endowment; the Barbra Streisand Women's Cardiovascular Research and Education Program; the Linda Joy Pollin Women's Heart Health Program; the Constance Austin Fellowship Endowment, Cedars-Sinai Medical Center, Los Angeles; the Erika Glazer Women's Heart Health Project, Cedars-Sinai Medical Center, Los Angeles, California; and the American College of Cardiology. NR 143 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 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 14 PY 2017 VL 135 IS 11 BP 1075 EP 1092 DI 10.1161/CIRCULATIONAHA.116.024534 PG 18 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EN7XL UT WOS:000396215400015 ER PT J AU Yu, WH Mookherjee, S Chaitankar, V Hiriyanna, S Kim, JW Brooks, M Ataeijannati, Y Sun, X Dong, LJ Li, TS Swaroop, A Wu, ZJ AF Yu, Wenhan Mookherjee, Suddhasil Chaitankar, Vijender Hiriyanna, Suja Kim, Jung-Woong Brooks, Matthew Ataeijannati, Yasaman Sun, Xun Dong, Lijin Li, Tiansen Swaroop, Anand Wu, Zhijian TI Nrl knockdown by AAV-delivered CRISPR/Cas9 prevents retinal degeneration in mice SO NATURE COMMUNICATIONS LA English DT Article ID DOMINANT RETINITIS-PIGMENTOSA; STAPHYLOCOCCUS-AUREUS CAS9; TRANSCRIPTION FACTOR NRL; CONE VIABILITY FACTOR; IN-VIVO; GENE-THERAPY; ROD PHOTORECEPTORS; MUSCULAR-DYSTROPHY; MOUSE RETINA; RAT MODEL AB In retinitis pigmentosa, loss of cone photoreceptors leads to blindness, and preservation of cone function is a major therapeutic goal. However, cone loss is thought to occur as a secondary event resulting from degeneration of rod photoreceptors. Here we report a genome editing approach in which adeno-associated virus (AAV)-mediated CRISPR/Cas9 delivery to postmitotic photoreceptors is used to target the Nrl gene, encoding for Neural retina-specific leucine zipper protein, a rod fate determinant during photoreceptor development. Following Nrl disruption, rods gain partial features of cones and present with improved survival in the presence of mutations in rod-specific genes, consequently preventing secondary cone degeneration. In three different mouse models of retinal degeneration, the treatment substantially improves rod survival and preserves cone function. Our data suggest that CRISPR/Cas9-mediated NRL disruption in rods may be a promising treatment option for patients with retinitis pigmentosa. C1 [Yu, Wenhan; Mookherjee, Suddhasil; Hiriyanna, Suja; Ataeijannati, Yasaman; Wu, Zhijian] NEI, Ocular Gene Therapy Core, NIH, 6 Ctr Dr,Room 307, Bethesda, MD 20892 USA. [Chaitankar, Vijender; Kim, Jung-Woong; Brooks, Matthew; Sun, Xun; Li, Tiansen; Swaroop, Anand] NEI, Neurobiology Neurodegenerat & Repair Lab, NIH, 6 Ctr Dr,Room 307, Bethesda, MD 20892 USA. [Dong, Lijin] NEI, Genet Engn Core, NIH, 6 Ctr Dr,Room B102, Bethesda, MD 20892 USA. RP Wu, ZJ (reprint author), NEI, Ocular Gene Therapy Core, NIH, 6 Ctr Dr,Room 307, Bethesda, MD 20892 USA. EM wuzh@mail.nih.gov OI Yu, Wenhan/0000-0002-0125-4358 FU National Eye Institute FX We thank Wei Li, Jacob Nellissery, Jessica Gumerson, Yide Mi, Megan Kopera and Linn Gieser for their assistance. We also thank the Visual Function Core, Flow Cytometry Core, Histopathology Core and Biological Imaging Core of the National Eye Institute and the NIH Intramural Sequencing Center (NISC) for their assistance. This work was supported by the intramural research program of the National Eye Institute. NR 70 TC 0 Z9 0 U1 15 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 14 PY 2017 VL 8 AR 14716 DI 10.1038/ncomms14716 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6HX UT WOS:000396106200001 PM 28291770 ER PT J AU Weinreich, MA Vogel, TP Rao, VK Milner, JD AF Weinreich, Michael Alexander Vogel, Tiphanie P. Rao, V. Koneti Milner, Joshua D. TI Up, Down, and All Around: Diagnosis and Treatment of Novel STAT 3 Variant SO FRONTIERS IN PEDIATRICS LA English DT Article DE STAT 3 transcription factor; gain-of-function mutations; autoimmune lymphoproliferative syndrome; monogenic autoimmunity; human immunology ID AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; HUMAN IMMUNODEFICIENCY; GERMLINE MUTATIONS; DISEASE; MANIFESTATIONS; PATIENT; GENE AB The number of identified monogenic causes of childhood-onset autoimmunity due to nodal and extranodal lymphoproliferation has increased. These pathogenic genetic variants provide the potential for pathway-specific treatment. Novel variants also require pathway-specific verification. In this report, we describe a 14-year-old patient with a novel variant in STAT3. We report clinical and laboratory findings that support STAT3 p. G419R as a novel pathogenic STAT3 gain-of-function variant. C1 [Weinreich, Michael Alexander; Milner, Joshua D.] NIAID, Lab Allerg Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Vogel, Tiphanie P.] Texas Childrens Hosp, Baylor Coll Med, Ctr Human Immunobiol, Houston, TX 77030 USA. [Rao, V. Koneti] NIAID, Div Intramural Res, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Milner, JD (reprint author), NIAID, Lab Allerg Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jdmilner@niaid.nih.gov FU intramural research program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) FX This work was supported in part by the intramural research program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). NR 19 TC 0 Z9 0 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2296-2360 J9 FRONT PEDIATR JI Front. Pediatr. PD MAR 13 PY 2017 VL 5 AR 49 DI 10.3389/fped.2017.00049 PG 4 WC Pediatrics SC Pediatrics GA EN7RB UT WOS:000396198800001 PM 28349047 ER PT J AU Tran, V Zablotska, LB Brenner, AV Little, MP AF Van Tran Zablotska, Lydia B. Brenner, Alina V. Little, Mark P. TI Radiation-associated circulatory disease mortality in a pooled analysis of 77,275 patients from the Massachusetts and Canadian tuberculosis fluoroscopy cohorts SO SCIENTIFIC REPORTS LA English DT Article ID ISCHEMIC-HEART-DISEASE; ATOMIC-BOMB SURVIVORS; CHILDHOOD-CANCER SURVIVOR; LONG-TERM SURVIVORS; BREAST-CANCER; CARDIOVASCULAR-DISEASES; IONIZING-RADIATION; FOLLOW-UP; CEREBROVASCULAR DISEASES; LUNG-CANCER AB High-dose ionising radiation is associated with circulatory disease. Risks associated with lower-dose (< 0.5 Gy) exposures remain unclear, with little information on risk modification by age at exposure, years since exposure or dose-rate. Tuberculosis patients in Canada and Massachusetts received multiple diagnostic x-ray fluoroscopic exposures, over a wide range of ages, many at doses < 0.5 Gy. We evaluated risks of circulatory-disease mortality associated with < 0.5 Gy radiation exposure in a pooled cohort of 63,707 patients in Canada and 13,568 patients in Massachusetts. Under 0.5 Gy there are increasing trends for all circulatory disease (n = 10,209; excess relative risk/Gy = 0.246; 95% CI 0.036, 0.469; p = 0.021) and for ischaemic heart disease (n = 6410; excess relative risk/Gy = 0.267; 95% CI 0.003, 0.552; p = 0.048). All circulatory-disease and ischaemic-heart-disease risk reduces with increasing time since exposure (p < 0.005). Over the entire dose range, there are negative mortality dose trends for all circulatory disease (p = 0.014) and ischaemic heart disease (p = 0.003), possibly due to competing causes of death over this dose interval. These results confirm and extend earlier findings and strengthen the evidence for circulatory-disease mortality radiation risk at doses < 0.5 Gy. The limited information on well-known lifestyle/medical risk factors for circulatory disease implies that confounding of the dose trend cannot be entirely excluded. C1 [Van Tran; Zablotska, Lydia B.; Brenner, Alina V.; Little, Mark P.] NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. [Zablotska, Lydia B.] Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA USA. RP Little, MP (reprint author), NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. EM mark.little@nih.gov FU Intramural Research Program of the National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics; National Institutes of Health, the National Cancer Institute [R03CA188614, R01CA197422] FX V.T., M.P.L. and A.V.B. were supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics. L.B.Z. was supported by the National Institutes of Health, the National Cancer Institute (grants R03CA188614 and R01CA197422). The authors are grateful for the detailed and helpful comments of the two referees. NR 62 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 13 PY 2017 VL 7 AR 44147 DI 10.1038/srep44147 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EO0XY UT WOS:000396423100001 PM 28287147 ER PT J AU Weinberg, A Mussi-Pinhata, MM Yu, QL Cohen, RA Almeida, VC Amaral, F Pinto, J Teixeira, MLB Succi, RCM Freimanis, L Read, JS Siberry, G AF Weinberg, Adriana Mussi-Pinhata, Marisa M. Yu, Qilu Cohen, Rachel A. Almeida, Volia C. Amaral, Fabiana Pinto, Jorge Teixeira, Maria L. B. Succi, Regina C. M. Freimanis, Laura Read, Jennifer S. Siberry, George CA NISDI Perinatal LILAC CIRAI Protocols TI Excess respiratory viral infections and low antibody responses among HIV-exposed, uninfected infants SO AIDS LA English DT Article DE antibody responses; childhood vaccines; HIV-exposed uninfected infants; immunogenicity; respiratory infections; respiratory viruses; tetanus vaccine ID NEGATIVE INFANTS; INCREASED RISK; IN-UTERO; PNEUMOCOCCAL DISEASE; IMMUNE-RESPONSES; PREGNANT-WOMEN; CHILDREN BORN; T-LYMPHOCYTES; CORD BLOOD; IMMUNODEFICIENCY AB Objective: HIV-exposed uninfected (HEUs) infants have frequent severe infection, hospitalization, and death. We performed a serologic investigation to determine the role of common childhood respiratory pathogens in the excess incidence of infections in HEUs. Design: Prospective cohort study of mother-infant pairs. Methods: Among 247 HEUs and 88 HIV-unexposed uninfected (HUU) infant-mother pairs, we measured maternal antibodies to respiratory syncytial virus (RSV) and pneumococcus (PNC 1, 5, 6B, 14); infant antibodies to RSV, influenza A (flu), parainfluenza viruses (1, 2, 3), and PNC 1, 5, 6B, and 14 were measured at 0 and 6 months, and antitetanus antibodies at 6 months. Results: HIV-infected mothers had higher RSV and lower PNC antibody concentrations at delivery than uninfected mothers. Transplacental transfer of maternal antibodies, particularly for RSV, was lower in HEUs compared with HUUs. At birth, HEUs had higher concentrations of anti-RSV antibodies than HUUs, but lower antibodies to the other respiratory agents. At 6 months, HEUs had significantly higher proportions of seroconversions and higher antibody concentrations against parainfluenza viruses 1, 2, and 3. There were no significant differences in seroconversions to flu and RSV, but antibody concentrations to RSV were six-fold lower in HEUs versus HUUs at 6 months. Antibody responses to at least two doses of tetanus vaccine were also six-fold lower in HEUs compared with HUUs. Conclusion: Six-month-old HEUs had a higher incidence of respiratory viral infections than HUUs. In addition to the low passive protection from maternal antibodies, low antibody responses of HEUs may contribute to increased morbidity and mortality. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved. C1 [Weinberg, Adriana] Univ Colorado Denver, Anschutz Med Ctr, Mail Stop 8604,12700 E 19th Ave,Room 11126, Aurora, CO 80045 USA. [Mussi-Pinhata, Marisa M.; Amaral, Fabiana] Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Pediat, Sao Paulo, Brazil. [Yu, Qilu; Cohen, Rachel A.; Freimanis, Laura] Westat Corp, Rockville, MD USA. [Almeida, Volia C.] Univ Fed Sao Carlos, Dept Med, Sao Paulo, Brazil. [Pinto, Jorge] Univ Minas Gerais, Escola Med, Belo Horizonte, MG, Brazil. [Teixeira, Maria L. B.] HFSE, Rio De Janeiro, Brazil. [Succi, Regina C. M.] Univ Fed Sao Paulo, Escola Paulista Med, Sao Paulo, Brazil. [Read, Jennifer S.; Siberry, George] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Read, Jennifer S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Weinberg, A (reprint author), Univ Colorado Denver, Anschutz Med Ctr, Mail Stop 8604,12700 E 19th Ave,Room 11126, Aurora, CO 80045 USA. EM adriana.weinberg@ucdenver.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [N01-HD-3-3345, HHSN267200800001C, HHSN275201300003C]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2010/19539-9] FX This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Contracts N01-HD-3-3345 (2002-2007), HHSN267200800001C (2007-2012) and HHSN275201300003C (2012-2017), and Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) 2010/19539-9 (to MMMP). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or of the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo. NR 57 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 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD MAR 13 PY 2017 VL 31 IS 5 BP 669 EP 679 DI 10.1097/QAD.0000000000001393 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EN4TT UT WOS:000396000500008 PM 28060016 ER PT J AU Minegishi, K Hashimoto, M Ajima, R Takaoka, K Shinohara, K Ikawa, Y Nishimura, H McMahon, AP Willert, K Okada, Y Sasaki, H Shi, D Fujimori, T Ohtsuka, T Igarashl, Y Yamaguchi, TP Shimono, A Shiratori, H Hamada, H AF Minegishi, Katsura Hashimoto, Masakazu Ajima, Rieko Takaoka, Katsuyoshi Shinohara, Kyosuke Ikawa, Yayoi Nishimura, Hiromi McMahon, Andrew P. Willert, Karl Okada, Yasushi Sasaki, Hiroshi Shi, Dongbo Fujimori, Toshihiko Ohtsuka, Toshihisa Igarashl, Yasunobu Yamaguchi, Terry P. Shimono, Akihiko Shiratori, Hidetaka Hamada, Hiroshi TI A Wnt5 Activity Asymmetry and Intercellular Signaling via PCP Proteins Polarize Node ells for Left-Right Symmetry Breaking SO DEVELOPMENTAL CELL LA English DT Article ID PLANAR CELL POLARITY; LEFT-RIGHT AXIS; MOUSE; CILIA; FLOW; ORIENTATION; ELONGATION; DROSOPHILA; PRICKLE; EMBRYOGENESIS AB Polarization of node cells along the anterior-posterior axis of mouse embryos is responsible for left-right symmetry breaking. How node cells become polarized has remained unknown, however. Wnt5a and Wnt5b are expressed posteriorly relative to the node, whereas genes for Sfrp inhibitors of Wnt signaling are expressed anteriorly. Here we show that polarization of node cells is impaired in Wnt5a(-/-)Wnt5b(-/-) and Sfrp mutant embryos, and also in the presence of a uniform distribution of Wnt5a or Sfrp1, suggesting that Wnt5 and Sfrp proteins act as instructive signals in this process. The absence of planar cell polarity (PCP) core proteins Prickle1 and Prickle2 in individual cells or local forced expression of Wnt5a perturbed polarization of neighboring wild-type cells. Our results suggest that opposing gradients of Wnt5a and Wnt5b and of their Sfrp inhibitors, together with intercellular signaling via PCP proteins, polarize node cells along the anterior-posterior axis for breaking of left-right symmetry. C1 [Minegishi, Katsura; Hashimoto, Masakazu; Ajima, Rieko; Takaoka, Katsuyoshi; Shinohara, Kyosuke; Ikawa, Yayoi; Nishimura, Hiromi; Shiratori, Hidetaka; Hamada, Hiroshi] Osaka Univ, Grad Sch Frontier Biosci, Dev Genet Grp, 1-3 Yamada Oka, Suita, Osaka 5650871, Japan. [Minegishi, Katsura; Ikawa, Yayoi; Nishimura, Hiromi; Hamada, Hiroshi] RIKEN, Ctr Dev Biol, Lab Organismal Patterning, Chuo Ku, 2-2-3 Minatojima Minamimachi, Kobe, Hyogo 6500047, Japan. [Ajima, Rieko; Yamaguchi, Terry P.] NCI, Canc & Dev Biol Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [McMahon, Andrew P.] Univ Southern Calif, Keck Sch Med, Dept Stem Cell Biol & Regenerat Med, Los Angeles, CA 90033 USA. [Willert, Karl] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Okada, Yasushi] RIKEN, Quantitat Biol Ctr, Lab Cell Polar Regulat, 6-2-3 Furuedai, Suita, Osaka 5650874, Japan. [Sasaki, Hiroshi] Osaka Univ, Grad Sch Frontier Biosci, Lab Embryogenesis, 1-3 Yamada Oka, Suita, Osaka 5650871, Japan. [Shi, Dongbo; Fujimori, Toshihiko] Natl Inst Basic Biol, Div Embryol, 5-1 Higashiyama, Okazaki, Aichi 4448787, Japan. [Ohtsuka, Toshihisa] Univ Yamanashi, Grad Sch Med, Dept Biochem, Fac Med, 1110 Shimo Kato, Chuo, Yamanashi 4093898, Japan. [Igarashl, Yasunobu] OLYMPUS Software Technol Corp, Adv Software Dev Dept, 2-3 Kuboyama Cho, Hachioji, Tokyo 1928512, Japan. [Shimono, Akihiko] RIKEN, Ctr Dev Biol, Vertebrate Body Plan Grp, Chuo Ku, 2-2-3 Minatojima Minamimachi, Kobe, Hyogo 6500047, Japan. [Ajima, Rieko] Natl Inst Genet, Yata 1111, Mishima, Shizuoka 4118540, Japan. [Takaoka, Katsuyoshi] Max Planck Inst Biophys Chem, Fassberg 11, D-37077 Gottingen, Germany. [Shinohara, Kyosuke] Tokyo Univ Agr & Technol, Inst Engn, Koganei, Tokyo 1848588, Japan. [Shi, Dongbo] Heidelberg Univ, Ctr Organismal Studies, D-89120 Heidelberg, Germany. [Shimono, Akihiko] Bristol Myers Squibb, Shinji Ku, 6-5-1 Nishi Shinjiku, Tokyo 1631328, Japan. [Shiratori, Hidetaka] Kyoto Sangyo Univ, Fac Life Sci, Kita Ku, Kyoto 6038555, Japan. RP Minegishi, K; Hamada, H (reprint author), Osaka Univ, Grad Sch Frontier Biosci, Dev Genet Grp, 1-3 Yamada Oka, Suita, Osaka 5650871, Japan.; Hamada, H (reprint author), RIKEN, Ctr Dev Biol, Lab Organismal Patterning, Chuo Ku, 2-2-3 Minatojima Minamimachi, Kobe, Hyogo 6500047, Japan. EM katsura.minegishi@riken.jp; hiroshi.hamada@riken.jp RI Shinohara, Kyosuke/I-1470-2016 FU Ministry of Education, Culture, Sports, Science, and Technology of Japan [24113001, 24113004]; Core Research for Evolutional Science and Technology of the Japan Science and Technology Corporation FX We thank J. Miyazaki (Osaka University) for the CAG-CAT-EGFP mouse; K. Okamoto (University of Tokyo) for Software of particle image velocimetry analysis; A. Fukumoto for technical assistance; and K. Mizuno (RIKEN CDB) for his help in statistical analysis. This study was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (nos. 24113001 and 24113004) and by Core Research for Evolutional Science and Technology of the Japan Science and Technology Corporation. NR 46 TC 1 Z9 1 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 EI 1878-1551 J9 DEV CELL JI Dev. Cell PD MAR 13 PY 2017 VL 40 IS 5 BP 439 EP 452 DI 10.1016/j.devcel.2017.02.010 PG 14 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA EO8UM UT WOS:000396966000005 PM 28292423 ER PT J AU Zhou, LQ Canagarajah, B Zhao, YG Baibakov, B Tokuhiro, K Maric, D Dean, J AF Zhou, Liquan Canagarajah, Bertram Zhao, Yangu Baibakov, Boris Tokuhiro, Keizo Maric, Dragan Dean, Jurrien TI BTBD18 Regulates a Subset of piRNA-Generating Loci through Transcription Elongation in Mice SO DEVELOPMENTAL CELL LA English DT Article ID CHIP-SEQ; PIWI PROTEINS; MOUSE TESTES; SPERMATOGENIC CELLS; RNA ELEMENTS; STEM-CELLS; CHROMATIN; GERMLINE; BIOGENESIS; MEIOSIS AB PIWI-interacting RNAs (piRNAs) are small non-coding RNAs essential for animal germ cell development. Despite intense investigation of post-transcriptional processing, chromatin regulators for piRNA biogenesis in mammals remain largely unexplored. Here we document that BTBD18 is a pachytene nuclear protein in mouse testes that occupies a subset of pachytene piRNA-producing loci. Ablation of Btbd18 in mice disrupts piRNA biogenesis, prevents spermiogenesis, and results in male sterility. Transcriptome profiling, chromatin accessibility, and RNA polymerase II occupancy demonstrate that BTBD18 facilitates expression of pachytene piRNA precursors by promoting transcription elongation. Thus, our study identifies BTBD18 as a specific controller for transcription activation through RNA polymerase II elongation at a subset of genomic piRNA loci. C1 [Zhou, Liquan; Canagarajah, Bertram; Zhao, Yangu; Baibakov, Boris; Tokuhiro, Keizo; Dean, Jurrien] NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Maric, Dragan] NINDS, Flow Cytometry Core Facil, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Zhou, LQ; Dean, J (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. EM li-quan.zhou@nih.gov; jurrien.dean@nih.gov FU NIH, The National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) FX We thank all members of J.D.'s laboratory for helpful suggestions on the project. We thank Dr. R. Daniel Camerini-Otero's laboratory (NIDDK) for advice on meiosis and morphology. We thank Dr. Astrid D. Haase (NIDDK) and her laboratory member Dr. Pavol Genzor for helpful discussion on the project. We thank Dr. Alex Bortvin (Carnegie Institution for Science) for providing anti-ORF1 p antibody. We thank Dr. Chul Min Yang (NIDDK) for help with the ATAC-seq experiment. We thank Dr. Chengyu Liu's laboratory (NHLBI) for technical advice and assistance with mouse genetics. We thank the NIDDK Genomics Core for deep sequencing, and the NIH HPC Biowuif cluster for high-performance computing. This research was supported by the Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Disease (NIDDK). NR 58 TC 0 Z9 0 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 EI 1878-1551 J9 DEV CELL JI Dev. Cell PD MAR 13 PY 2017 VL 40 IS 5 BP 453 EP 466 DI 10.1016/j.devcel.2017.02.007 PG 14 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA EO8UM UT WOS:000396966000006 PM 28292424 ER PT J AU Cherniack, AD Shen, H Walter, V Stewart, C Murray, BA Bowlby, R Hu, X Ling, SY Soslow, RA Broaddus, RR Zuna, RE Robertson, G Laird, PW Kucherlapati, R Mills, GB Weinstein, JN Zhang, JS Akbani, R Levine, DA AF Cherniack, Andrew D. Shen, Hui Walter, Vonn Stewart, Chip Murray, Bradley A. Bowlby, Reanne Hu, Xin Ling, Shiyun Soslow, Robert A. Broaddus, Russell R. Zuna, Rosemary E. Robertson, Gordon Laird, Peter W. Kucherlapati, Raju Mills, Gordon B. Weinstein, John N. Zhang, Jiashan Akbani, Rehan Levine, Douglas A. CA Canc Genome Atlas Res Network TI Integrated Molecular Characterization of Uterine Carcinosarcoma SO CANCER CELL LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; MIXED MULLERIAN TUMORS; COPY-NUMBER ALTERATION; ENDOMETRIAL CARCINOMAS; SENSITIZES CELLS; CANCER; HETEROGENEITY; ARID1A; GENES; RESISTANCE AB We performed genomic, epigenomic, transcriptomic, and proteomic characterizations of uterine carcinosarcomas (UCSs). Cohort samples had extensive copy-number alterations and highly recurrent somatic mutations. Frequent mutations were found in TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS, similar to endometrioid and serous uterine carcinomas. Transcriptome sequencing identified a strong epithelial-to-mesenchymal transition (EMT) gene signature in a subset of cases that was attributable to epigenetic alterations at microRNA promoters. The range of EMT scores in UCS was the largest among all tumor types studied via The Cancer Genome Atlas. UCSs shared proteomic features with gynecologic carcinomas and sarcomas with intermediate EMT features. Multiple somatic mutations and copy-number alterations in genes that are therapeutic targets were identified. C1 [Cherniack, Andrew D.; Stewart, Chip; Murray, Bradley A.] MIT, Eli & Edythe L Broad Inst, Cambridge, MA 02142 USA. [Cherniack, Andrew D.; Stewart, Chip; Murray, Bradley A.] Harvard Univ, Cambridge, MA 02142 USA. [Shen, Hui; Laird, Peter W.] Van Andel Res Inst, Ctr Epigenet, Grand Rapids, MI 49503 USA. [Walter, Vonn] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Bowlby, Reanne; Robertson, Gordon] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada. [Hu, Xin; Ling, Shiyun; Broaddus, Russell R.; Mills, Gordon B.; Weinstein, John N.; Akbani, Rehan] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Soslow, Robert A.] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Zuna, Rosemary E.] Univ Oklahoma, Hlth Sci Ctr, Stephenson Canc Ctr, Oklahoma City, OK 73104 USA. [Kucherlapati, Raju] Harvard Med Sch, Boston, MA 02115 USA. [Zhang, Jiashan] NCI, Bethesda, MD 20892 USA. [Levine, Douglas A.] NYU, Langone Med Ctr, Laura & Isaac Perlmutter Canc Ctr, 550 1St Ave, New York, NY 10016 USA. RP Akbani, R (reprint author), Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA.; Levine, DA (reprint author), NYU, Langone Med Ctr, Laura & Isaac Perlmutter Canc Ctr, 550 1St Ave, New York, NY 10016 USA. EM rakbani@mdanderson.org; douglas.levine@nyumc.org RI Marra, Marco/B-5987-2008; OI Gehlenborg, Nils/0000-0003-0327-8297 FU US NIH [U54 HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24 CA143835, U24 CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA143858, U24 CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025, P30 CA016672]; Bayer AG FX We wish to thank all patients and families who contributed to this study. This work was supported by the following grants from the US NIH: U54 HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24 CA143835, U24 CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA143858, U24 CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025, and P30 CA016672. Andrew D. Cherniack and Matthew Meyerson declare research funding from Bayer AG. NR 42 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD MAR 13 PY 2017 VL 31 IS 3 BP 411 EP 423 DI 10.1016/j.ccell.2017.02.010 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EN8VA UT WOS:000396276700013 PM 28292439 ER PT J AU Courtney, CR Mayr, L Nanfack, AJ Banin, AN Tuen, M Pan, RM Jiang, XQ Kong, XP Kirkpatrick, AR Bruno, D Martens, CA Sykora, L Porcella, SF Redd, AD Quinn, TC Nyambi, PN Durr, R AF Courtney, Colleen R. Mayr, Luzia Nanfack, Aubin J. Banin, Andrew N. Tuen, Michael Pan, Ruimin Jiang, Xunqing Kong, Xiang-Peng Kirkpatrick, Allison R. Bruno, Daniel Martens, Craig A. Sykora, Lydia Porcella, Stephen F. Redd, Andrew D. Quinn, Thomas C. Nyambi, Phillipe N. Duerr, Ralf TI Contrasting antibody responses to intrasubtype superinfection with CRF02_AG SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; BROADLY NEUTRALIZING ANTIBODIES; HIV SUPERINFECTION; PRIMARY INFECTION; DUAL INFECTIONS; GP120; IDENTIFICATION; FREQUENCY; UGANDA; ENV AB HIV superinfection describes the sequential infection of an individual with two or more unrelated HIV strains. Intersubtype superinfection has been shown to cause a broader and more potent heterologous neutralizing antibody response when compared to singly infected controls, yet the effects of intrasubtype superinfection remain controversial. Longitudinal samples were analyzed phylogenetically for pol and env regions using Next-Generation Sequencing and envelope cloning. The impact of CRF02_AG intrasubtype superinfection was assessed for heterologous neutralization and antibody binding responses. We compared two cases of CRF02_AG intrasubtype superinfection that revealed complete replacement of the initial virus by superinfecting CRF02_AG variants with signs of recombination. NYU6564, who became superinfected at an early time point, exhibited greater changes in antibody binding profiles and generated a more potent neutralizing antibody response post-superinfection compared to NYU6501. In contrast, superinfection occurred at a later time point in NYU6501 with strains harboring significantly longer V1V2 regions with no observable changes in neutralization patterns. Here we show that CRF02_AG intrasubtype superinfection can induce a cross-subtype neutralizing antibody response, and our data suggest timing and/or superinfecting viral envelope characteristics as contributing factors. These results highlight differential outcomes in intrasubtype superinfection and provide the first insight into cases with CRF02_AG, the fourth most prevalent HIV-1 strain worldwide. C1 [Courtney, Colleen R.] NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA. [Mayr, Luzia; Nanfack, Aubin J.; Banin, Andrew N.; Tuen, Michael; Nyambi, Phillipe N.; Duerr, Ralf] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [Banin, Andrew N.] Univ Yaounde, Fac Med & Biomed Sci, Yaounde, Cameroon. [Pan, Ruimin; Jiang, Xunqing; Kong, Xiang-Peng] NYU, Sch Med, Dept Biochem & Mol Pharmacol, New York, NY USA. [Kirkpatrick, Allison R.; Quinn, Thomas C.] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Bruno, Daniel; Martens, Craig A.; Sykora, Lydia; Porcella, Stephen F.] NIAID, Genom Unit, Res Technol Branch, Rocky Mt Labs,Div Intramural Res,NIH, Hamilton, MT USA. [Redd, Andrew D.; Quinn, Thomas C.] Johns Hopkins Sch Med, Dept Pathol, Baltimore, MD USA. [Nyambi, Phillipe N.] Vet Affairs New York Harbor Healthcare Syst, New York, NY USA. [Mayr, Luzia] Univ Strasbourg, Strasbourg, France. [Mayr, Luzia] Dept Virol, 4 Rue Blaise Pascal, Strasbourg, France. RP Durr, R (reprint author), NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. EM ralf.duerr@nyumc.org FU National Institutes of Health [R01 AI083142, D43 TW009604, AI100151]; Division of Intramural Research, NIAID, NIH FX This work was supported by the National Institutes of Health (R01 AI083142, D43 TW009604; PNN) to PNN, RD, CRC, LM, AJN and ANB; (AI100151; XK) to XK, XJ, RP; and in part by the Division of Intramural Research, NIAID, NIH (TCQ) to TCQ, ADR, ARK, DB, CAM, LS, SFP. NR 53 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 13 PY 2017 VL 12 IS 3 AR e0173705 DI 10.1371/journal.pone.0173705 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6CP UT WOS:000396092400030 PM 28288209 ER PT J AU Nelson, SM Gao, YT Nogueira, LM Shen, MC Wang, BS Rashid, A Hsing, AW Koshiol, J AF Nelson, Shakira M. Gao, Yu-Tang Nogueira, Leticia M. Shen, Ming-Chang Wang, Bingsheng Rashid, Asif Hsing, Ann W. Koshiol, Jill TI Diet and biliary tract cancer risk in Shanghai, China SO PLOS ONE LA English DT Article ID C-REACTIVE PROTEIN; GALLBLADDER CANCER; GASTRIC-CANCER; INFLAMMATION; GALLSTONES; MARKERS; METAANALYSIS; ASSOCIATION; PATTERNS; BIOMARKERS AB Trends in biliary tract cancer incidence rates have increased in Shanghai, China. These trends have coincided with economic and developmental growth, as well as a shift in dietary patterns to a more Westernized diet. To examine the effect of dietary changes on incident disease, we evaluated associations between diet and biliary tract cancers amongst men and women from a population-based case-control study in Shanghai, China. Biliary tract cancer cases were recruited from 42 collaborating hospitals in urban Shanghai, and population -based controls were randomly selected from the Shanghai Household Registry. Food frequency questionnaire data were available for 225 gallbladder, 190 extrahepatic bile duct, and 68 ampulla of Vater cancer cases. A total of 39 food groups were created and examined for associations with biliary tract cancer. Interestingly, only four food groups demonstrated a suggested association with gallbladder, extrahepatic bile duct, or ampulla of Vater cancers. The allium food group, consisting of onions, garlic, and shallots showed an inverse association with gallbladder cancer (OR: 0.81, 95% CI: 0.68-0.97). Similar trends were seen in the food group containing seaweed and kelp (OR: 0.79, 95% CI: 0.67-0.96). In contrast, both preserved vegetables and salted meats food groups showed positive associations with gallbladder cancer (OR:1.27, 95% CI: 1.06-1.52; OR: 1.18, 95% CI: 1.02-1.37, respectively). Each of these four food groups showed similar trends for extrahepatic bile duct and ampulla of Vater cancers. The results of our analysis suggest intake of foods with greater anti-inflammatory properties may play a role in decreasing the risk of biliary tract cancers. Future studies should be done to better understand effects of cultural changes on diet, and to further examine the impact diet and inflammation have on biliary tract cancer incidence. C1 [Nelson, Shakira M.; Nogueira, Leticia M.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Rockville, MD 20892 USA. [Nelson, Shakira M.] NCI, Metab Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. [Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Nogueira, Leticia M.] Texas Dept State Hlth Serv, Texas Canc Registry, Canc Epidemiol & Surveillance Branch, Austin, TX USA. [Shen, Ming-Chang] Fudan Univ, Shanghai Canc Ctr, Dept Pathol, Shanghai, Peoples R China. [Wang, Bingsheng] Fudan Univ, Sch Med, Zhongshan Hosp, Dept Gen Surg, Shanghai, Peoples R China. [Rashid, Asif] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Hsing, Ann W.] Stanford Canc Inst, Palo Alto, CA USA. [Hsing, Ann W.] Stanford Sch Med, Stanford Prevent Res Ctr, Palo Alto, CA USA. [Koshiol, Jill] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Nelson, SM (reprint author), NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Rockville, MD 20892 USA.; Nelson, SM (reprint author), NCI, Metab Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. EM shakira.nelson@nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics (DCEG) FX This work was supported by general funds from the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics (DCEG). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 0 Z9 0 U1 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 13 PY 2017 VL 12 IS 3 AR e0173935 DI 10.1371/journal.pone.0173935 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6CP UT WOS:000396092400043 PM 28288186 ER PT J AU Oh, H Coburn, SB Matthews, CE Falk, RT LeBlanc, ES Wactawski-Wende, J Sampson, J Pfeiffer, RM Brinton, LA Wentzensen, N Anderson, GL Manson, JE Chen, C Zaslavsky, O Xu, X Trabert, B AF Oh, Hannah Coburn, Sally B. Matthews, Charles E. Falk, Roni T. LeBlanc, Erin S. Wactawski-Wende, Jean Sampson, Joshua Pfeiffer, Ruth M. Brinton, Louise A. Wentzensen, Nicolas Anderson, Garnet L. Manson, Joann E. Chen, Chu Zaslavsky, Oleg Xu, Xia Trabert, Britton TI Anthropometric measures and serum estrogen metabolism in postmenopausal women: the Women's Health Initiative Observational Study SO BREAST CANCER RESEARCH LA English DT Article DE BMI; WHR; Height; Estrogen; Estrogen metabolites; Sex hormones; Postmenopausal ID BREAST-CANCER RISK; BODY-MASS INDEX; ENDOMETRIAL CANCER; ESTRADIOL METABOLISM; DOWN-REGULATION; SEX-HORMONES; OBESITY; WEIGHT; SIZE; METAANALYSIS AB Background: Several anthropometric measures have been associated with hormone-related cancers. However, it is unknown whether estrogen metabolism plays an important role in these relationships. We examined whether measured current body mass index (BMI), waist-to-hip ratio (WHR), height, and self-reported BMI at age 18 years were associated with serum estrogens/estrogen metabolites using baseline, cross-sectional data from 1835 postmenopausal women enrolled in the Women's Health Initiative Observational Study. Methods: Fifteen estrogens/estrogen metabolites were quantified using liquid chromatography-tandem mass spectrometry. Geometric means (GMs) of estrogens/estrogen metabolites (in picomoles per liter) were estimated using inverse probability weighted linear regression, adjusting for potential confounders and stratified on menopausal hormone therapy (MHT) use. Results: Among never or former MHT users, current BMI (>= 30 vs. <25 kg/m(2)) was positively associated with parent estrogens (multivariable adjusted GM 432 vs. 239 pmol/L for estrone, 74 vs. 46 pmol/L for estradiol; p-trend <0.001 for both) and all of the 2-, 4-, and 16-pathway estrogen metabolites evaluated (all p-trend <= 0.02). After additional adjustment for estradiol, unconjugated methylated 2-catechols were inversely associated (e.g., 2-methoxyestrone multivariable GM 9.3 vs. 12.0 pmol/L; p-trend < 0.001). Among current MHT users, current BMI was not associated with parent estrogens but was inversely associated with methylated catechols (e.g., 2-methoxyestrone multivariable GM 216 vs. 280 pmol/L; p-trend = 0.008). Similar patterns of association were found with WHR; however, the associations were not independent of BMI. Height and BMI at age 18 years were not associated with postmenopausal estrogens/estrogen metabolite levels. Conclusions: Our data suggest that postmenopausal BMI is associated with increased circulating levels of parent estrogens and reduced methylation of catechol estrogen metabolites, the estrogen metabolism patterns that have previously been associated with higher breast cancer risk. C1 [Oh, Hannah; Coburn, Sally B.; Matthews, Charles E.; Falk, Roni T.; Sampson, Joshua; Pfeiffer, Ruth M.; Brinton, Louise A.; Wentzensen, Nicolas; Trabert, Britton] NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,6E332, Bethesda, MD 20892 USA. [LeBlanc, Erin S.] Kaiser Permanente NW, Ctr Hlth Res, Portland, OR USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Epidemiol & Environm Hlth, Buffalo, NY USA. [Anderson, Garnet L.; Chen, Chu] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, 1124 Columbia St, Seattle, WA 98104 USA. [Manson, Joann E.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA USA. [Zaslavsky, Oleg] Univ Washington, Sch Nursing, Seattle, WA 98195 USA. [Xu, Xia] Leidos Biomedical Res Inc, Frederick Natl Lab Canc Res, Canc Res Technol Program, Frederick, MD USA. RP Oh, H (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,6E332, Bethesda, MD 20892 USA. EM hannah.oh@nih.gov FU National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; Intramural Research Program of the Division of Cancer Epidemiology; Genetics of the National Cancer Institute FX The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services, through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. This study was also supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute. NR 53 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X EI 1465-5411 J9 BREAST CANCER RES JI Breast Cancer Res. PD MAR 11 PY 2017 VL 19 AR 28 DI 10.1186/s13058-017-0810-0 PG 17 WC Oncology SC Oncology GA EO8EN UT WOS:000396922000001 PM 28284224 ER PT J AU Xu, AZ Wang, R Freywald, A Stewart, K Tikoo, S Xu, JQ Zheng, CY Xiang, J AF Xu, Aizhang Wang, Rong Freywald, Andrew Stewart, Kristoffor Tikoo, Suresh Xu, Jianqing Zheng, Changyu Xiang, Jim TI CD40 agonist converting CTL exhaustion via the activation of the mTORC1 pathway enhances PD-1 antagonist action in rescuing exhausted CTLs in chronic infection SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE CD40 agonist; PD-1 antagonist; Chronic infection; CTL exhaustion; mTORC1 pathway ID CHRONIC VIRAL-INFECTION; T-CELL EXHAUSTION; MEMORY; MECHANISMS; SYNERGIZES; RECEPTORS; RESPONSES; BLOCKADE; FAMILY AB Expansion of PD-1-expressing CD8+ cytotoxic T lymphocytes (CTLs) and associated CTL exhaustion are chief issues for ineffective virus-elimination in chronic infectious diseases. PD-1 blockade using antagonistic anti-PD-L1 antibodies results in a moderate conversion of CTL exhaustion. We previously demonstrated that CD40L signaling of ovalbumin (OVA)-specific vaccine, OVA-Texo, converts CTL exhaustion via the activation of the mTORC1 pathway in OVA-expressing adenovirus (AdVova)-infected B6 mice showing CTL inflation and exhaustion. Here, we developed AdVova-infected B6 and transgenic CD11c-DTR (termed AdVova-B6 and AdVova-CD11c-DTR) mice with chronic infection, and assessed a potential effect of CD40 agonist on the conversion of CTL exhaustion and on a potential enhancement of PD-1 antagonist action in rescuing exhausted CTLs in our chronic infection models. We demonstrate that a single dose of anti-CD40 alone can effectively convert CTL exhaustion by activating the mTORC1 pathway, leading to CTL proliferation, up-regulation of an effector-cytokine IFN-gamma and the cytolytic effect in AdVova-B6 mice. Using anti-CD4 antibody and diphtheria toxin (DT) to deplete CD4+ T-cells and dendritic cells (DCs), we discovered that the CD40 agonist-induced conversion in AdVova-B6 and AdVova-CD11c-DTR mice is dependent upon host CD4+ T-cell and DC involvements. Moreover, CD40 agonist significantly enhances PD-1 antagonist effectiveness in rescuing exhausted CTLs in chronic infection. Taken together, our data demonstrate the importance of CD40 signaling in the conversion of CTL exhaustion and its ability to enhance PD-1 antagonist action in rescuing exhausted CTLs in chronic infection. Therefore, our findings may positively impact the design of new therapeutic strategies for chronic infectious diseases. (C) 2017 Elsevier Inc. All rights reserved. C1 [Xu, Aizhang; Wang, Rong; Xiang, Jim] Saskatchewan Canc Agcy, Canc Res, Saskatoon, SK, Canada. [Xu, Aizhang; Wang, Rong; Xiang, Jim] Univ Saskatchewan, Coll Med, Dept Oncol, Saskatoon, SK, Canada. [Freywald, Andrew] Univ Saskatchewan, Dept Pathol, Coll Med, Saskatoon, SK, Canada. [Stewart, Kristoffor] Univ Saskatchewan, Dept Internal Med, Coll Med, Saskatoon, SK, Canada. [Tikoo, Suresh] Univ Saskatchewan, Sch Publ Hlth, Saskatoon, SK S7N 0W0, Canada. [Xu, Jianqing] Fudan Univ, Shanghai Publ Hlth Clin Ctr, Shanghai, Peoples R China. [Zheng, Changyu] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. RP Xiang, J (reprint author), Univ Saskatchewan, 4D30-1,Hlth Sci Bldg,107 Wiggins Rd, Saskatoon, SK S7N 5E5, Canada. EM jim.xiang@usask.ca FU Canadian Institute of Health Research (CIHR) [OCH 126276] FX We thank Mark Boyd for help in flow cytometric analyses and Linda Chelico for useful comments. This work was supported by Canadian Institute of Health Research (CIHR) Grant OCH 126276. NR 22 TC 0 Z9 0 U1 2 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 11 PY 2017 VL 484 IS 3 BP 662 EP 667 DI 10.1016/j.bbrc.2017.01.172 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA EN4FR UT WOS:000395963900030 PM 28153727 ER PT J AU Shiels, MS Chernyavskiy, P Anderson, WF Best, AF Haozous, EA Hartge, P Rosenberg, PS Thomas, D Freedman, ND de Gonzalez, AB AF Shiels, Meredith S. Chernyavskiy, Pavel Anderson, William F. Best, Ana F. Haozous, Emily A. Hartge, Patricia Rosenberg, Philip S. Thomas, David Freedman, Neal D. de Gonzalez, Amy Berrington TI Trends in premature mortality in the USA by sex, race, and ethnicity from 1999 to 2014: an analysis of death certificate data SO LANCET LA English DT Article ID UNITED-STATES; AMERICAN-INDIANS; CIGARETTE-SMOKING; ALASKA NATIVES; RISK-FACTORS; HEALTH; RATES; INDIVIDUALS; PATTERNS; SERVICES AB Background Reduction of premature mortality is a UN Sustainable Development Goal. Unlike other high-income countries, age-adjusted mortality in the USA plateaued in 2010 and increased slightly in 2015, possibly because of rising premature mortality. We aimed to analyse trends in mortality in the USA between 1999 and 2014 in people aged 25-64 years by age group, sex, and race and ethnicity, and to identify specific causes of death underlying the temporal trends. Methods For this analysis, we used cause-of-death and demographic data from death certificates from the US National Center for Health Statistics, and population estimates from the US Census Bureau. We estimated annual percentage changes in mortality using age-period-cohort models. Age-standardised excess deaths were estimated for 2000 to 2014 as observed deaths minus expected deaths (estimated from 1999 mortality rates). Findings Between 1999 and 2014, premature mortality increased in white individuals and in American Indians and Alaska Natives. Increases were highest in women and those aged 25-30 years. Among 30-year-olds, annual mortality increases were 2.3% (95% CI 2.1-2.4) for white women, 0.6% (0.5-0.7) for white men, and 4.3% (3.5-5.0) and 1.9% (1.3-2.5), respectively, for American Indian and Alaska Native women and men. These increases were mainly attributable to accidental deaths (primarily drug poisonings), chronic liver disease and cirrhosis, and suicide. Among individuals aged 25-49 years, an estimated 111 000 excess premature deaths occurred in white individuals and 6600 in American Indians and Alaska Natives during 2000-14. By contrast, premature mortality decreased substantially across all age groups in Hispanic individuals (up to 3.2% per year), black individuals (up to 3.9% per year), and Asians and Pacific Islanders (up to 2.6% per year), mainly because of declines in HIV, cancer, and heart disease deaths, resulting in an estimated 112 000 fewer deaths in Hispanic individuals, 311 000 fewer deaths in black individuals, and 34 000 fewer deaths in Asians and Pacific Islanders aged 25-64 years. During 2011-14, American Indians and Alaska Natives had the highest premature mortality, followed by black individuals. Interpretation Important public health successes, including HIV treatment and smoking cessation, have contributed to declining premature mortality in Hispanic individuals, black individuals, and Asians and Pacific Islanders. However, this progress has largely been negated in young and middle-aged (25-49 years) white individuals, and American Indians and Alaska Natives, primarily because of potentially avoidable causes such as drug poisonings, suicide, and chronic liver disease and cirrhosis. The magnitude of annual mortality increases in the USA is extremely unusual in high-income countries, and a rapid public health response is needed to avert further premature deaths. C1 [Shiels, Meredith S.; Chernyavskiy, Pavel; Anderson, William F.; Best, Ana F.; Hartge, Patricia; Rosenberg, Philip S.; Freedman, Neal D.; de Gonzalez, Amy Berrington] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Haozous, Emily A.] Univ New Mexico, Coll Nursing, Albuquerque, NM 87131 USA. [Thomas, David] NIDA, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. RP Shiels, MS (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM shielsms@mail.nih.gov FU US National Cancer Institute FX US National Cancer Institute Intramural Research Program. NR 46 TC 1 Z9 1 U1 12 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD MAR 11 PY 2017 VL 389 IS 10073 BP 1043 EP 1054 DI 10.1016/S0140-6736(17)30187-3 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA EN9UN UT WOS:000396345200026 PM 28131493 ER PT J AU Curado, TF Fishbein, K Pho, H Brennick, M Dergacheva, O Sennes, LU Pham, LV Ladenheim, EE Spencer, R Mendelowitz, D Schwartz, AR Polotsky, VY AF Curado, Thomaz Fleury Fishbein, Kenneth Huy Pho Brennick, Michael Dergacheva, Olga Sennes, Luiz U. Pham, Luu V. Ladenheim, Ellen E. Spencer, Richard Mendelowitz, David Schwartz, Alan R. Polotsky, Vsevolod Y. TI Chemogenetic stimulation of the hypoglossal neurons improves upper airway patency SO SCIENTIFIC REPORTS LA English DT Article ID OBSTRUCTIVE SLEEP-APNEA; REM-SLEEP; ENERGY-EXPENDITURE; IN-VITRO; CIRCUIT; WEIGHT; SYSTEM; NERVE; MOUSE; MODEL AB Obstructive sleep apnea (OSA) is characterized by recurrent upper airway obstruction during sleep. OSA leads to high cardiovascular morbidity and mortality. The pathogenesis of OSA has been linked to a defect in neuromuscular control of the pharynx. There is no effective pharmacotherapy for OSA. The objective of this study was to determine whether upper airway patency can be improved using chemogenetic approach by deploying designer receptors exclusively activated by designer drug (DREADD) in the hypoglossal motorneurons. DREADD (rAAV5-hSyn-hM3(Gq)-mCherry) and control virus (rAAV5-hSyn-EGFP) were stereotactically administered to the hypoglossal nucleus of C57BL/6J mice. In 6-8 weeks genioglossus EMG and dynamic MRI of the upper airway were performed before and after administration of the DREADD ligand clozapine-N-oxide (CNO) or vehicle (saline). In DREADD-treated mice, CNO activated the genioglossus muscle and markedly dilated the pharynx, whereas saline had no effect. Control virus treated mice showed no effect of CNO. Our results suggest that chemogenetic approach can be considered as a treatment option for OSA and other motorneuron disorders. C1 [Curado, Thomaz Fleury; Huy Pho; Brennick, Michael; Pham, Luu V.; Schwartz, Alan R.; Polotsky, Vsevolod Y.] Johns Hopkins Univ, Sch Med, Div Pulm & Crit Care Med, Dept Med, Baltimore, MD 21218 USA. [Curado, Thomaz Fleury; Sennes, Luiz U.] Univ Sao Paulo, Dept Otolaryngol, Sao Paulo, Brazil. [Fishbein, Kenneth; Spencer, Richard] NIA, NIH, Baltimore, MD 21224 USA. [Dergacheva, Olga; Mendelowitz, David] George Washington Univ, Dept Pharmacol & Physiol, Washington, DC USA. [Ladenheim, Ellen E.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD USA. RP Polotsky, VY (reprint author), Johns Hopkins Univ, Sch Med, Div Pulm & Crit Care Med, Dept Med, Baltimore, MD 21218 USA. FU NIH [R01 HL128970, R01 HL133100, P50 ES018176]; American Heart Association [16POST31000017] FX This work has been supported by NIH grants R01 HL128970, R01 HL133100, P50 ES018176 (all to VYP) and by the American Heart Association Post-doctoral Fellowship 16POST31000017 (to TFC). NR 35 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 10 PY 2017 VL 7 AR 44392 DI 10.1038/srep44392 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EO2FW UT WOS:000396513000001 ER PT J AU Vogtmann, E Corley, DA Almers, LM Cardwell, CR Murray, LJ Abnet, CC AF Vogtmann, Emily Corley, Douglas A. Almers, Lucy M. Cardwell, Chris R. Murray, Liam J. Abnet, Christian C. TI Oral bisphosphonates and colorectal cancer SO SCIENTIFIC REPORTS LA English DT Article ID REDUCED RISK; METAANALYSIS; EXPOSURE; OSTEOPOROSIS; VALIDATION AB Use of oral bisphosphonates has been associated with a decreased risk of colorectal cancer (CRC), but the association may be related to residual confounding by healthy lifestyle or body mass index (BMI). Therefore, we conducted a prospective nested case-control study within the Kaiser Permanente, Northern California health system cohort. In total, 12,505 CRC cases were individually matched to 599,534 controls. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression models with adjustment for important covariates extracted from the database. Participants who had ever used oral bisphosphonates were less likely than non-users to be diagnosed with CRC (OR 0.82; 95% CI: 0.74, 0.89). Colon and rectum site-specific associations were similar to the overall association. A stronger inverse association for ever use of bisphosphonates was observed for men (OR 0.63; 95% CI: 0.47, 0.85), however when stratified by previous lower endoscopy, the association was only observed in the participants who did not have a previous lower endoscopy (OR 0.73 (0.64, 0.83)). In conclusion, we found that oral bisphosphonate use was associated with a decreased odds of CRC, however this association may be due to residual confounding by BMI or another confounder. C1 [Vogtmann, Emily; Abnet, Christian C.] NCI, Metab Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Corley, Douglas A.; Almers, Lucy M.] Kaiser Permanente, San Francisco Med Ctr, San Francisco, CA USA. [Cardwell, Chris R.; Murray, Liam J.] Queens Univ Belfast, Ctr Publ Hlth, Belfast, Antrim, North Ireland. RP Vogtmann, E (reprint author), NCI, Metab Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM emily.vogtmann@nih.gov FU Intramural Research Program of the National Institutes of Health; Cancer Prevention Fellowship Program of the National Institutes of Health; National Cancer Institute FX This work was supported by the Intramural Research Program and the Cancer Prevention Fellowship Program of the National Institutes of Health and the National Cancer Institute. NR 27 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 10 PY 2017 VL 7 AR 44177 DI 10.1038/srep44177 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN3EI UT WOS:000395891400002 PM 28281559 ER PT J AU Jongbloets, BC Lemstra, S Schellino, R Broekhoven, MH Parkash, J Hellemons, AJCGM Mao, TY Giacobini, P van Praag, H De Marchis, S Ramakers, GMJ Pasterkamp, RJ AF Jongbloets, Bart C. Lemstra, Suzanne Schellino, Roberta Broekhoven, Mark H. Parkash, Jyoti Hellemons, Anita J. C. G. M. Mao, Tianyi Giacobini, Paolo van Praag, Henriette De Marchis, Silvia Ramakers, Geert M. J. Pasterkamp, R. Jeroen TI Stage-specific functions of Semaphorin7A during adult hippocampal neurogenesis rely on distinct receptors SO NATURE COMMUNICATIONS LA English DT Article ID DENTATE GYRUS; NEURAL STEM; MELANOMA PROGRESSION; SUBVENTRICULAR ZONE; AXON GUIDANCE; PLEXIN C1; 7A; BRAIN; MIGRATION; INTEGRIN AB The guidance protein Semaphorin7A (Sema7A) is required for the proper development of the immune and nervous systems. Despite strong expression in the mature brain, the role of Sema7A in the adult remains poorly defined. Here we show that Sema7A utilizes different cell surface receptors to control the proliferation and differentiation of neural progenitors in the adult hippocampal dentate gyrus (DG), one of the select regions of the mature brain where neurogenesis occurs. PlexinC1 is selectively expressed in early neural progenitors in the adult mouse DG and mediates the inhibitory effects of Sema7A on progenitor proliferation. Subsequently, during differentiation of adult-born DG granule cells, Sema7A promotes dendrite growth, complexity and spine development through beta 1-subunit-containing integrin receptors. Our data identify Sema7A as a key regulator of adult hippocampal neurogenesis, providing an example of how differential receptor usage spatiotemporally controls and diversifies the effects of guidance cues in the adult brain. C1 [Jongbloets, Bart C.; Lemstra, Suzanne; Broekhoven, Mark H.; Hellemons, Anita J. C. G. M.; Ramakers, Geert M. J.; Pasterkamp, R. Jeroen] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Translat Neurosci, NL-3584 CG Utrecht, Netherlands. [Schellino, Roberta; De Marchis, Silvia] Univ Torino, Dipartimento Sci Vita & Biol Sistemi, I-10100 Turin, Italy. [Schellino, Roberta; De Marchis, Silvia] Univ Torino, Neurosci Inst Cavalieri Ottolenghi, I-10100 Turin, Italy. [Parkash, Jyoti] Cent Univ Punjab, Sch Basic & Appl Sci, Ctr Anim Sci, City Campus,Mansa Rd, Bathinda 151001, India. [Jongbloets, Bart C.; Mao, Tianyi] Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97239 USA. [Giacobini, Paolo] Jean Pierre Aubert Res Ctr, Lab Dev & Plast Neuroendocrine Brain, INSERM, U1172, F-59045 Lille, France. [Giacobini, Paolo] Univ Lille, F-59045 Lille, France. [van Praag, Henriette] NIA, Neuroplast & Behav Unit, Lab Neurosci, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Pasterkamp, RJ (reprint author), Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Translat Neurosci, NL-3584 CG Utrecht, Netherlands. EM r.j.pasterkamp@umcutrecht.nl OI Mao, Tianyi/0000-0002-3532-8319 FU Netherlands Organization for Health Research and Development (VIDI); Netherlands Organization for Health Research and Development (ZonMW-TOP); Netherlands Organization for Health Research and Development (ALW-VICI); Epilepsiefonds [NEF 17-10]; Neuroscience and Cognition Utrecht (NCU); Stichting ParkinsonFonds; National Institute on Aging, Intramural Research Program FX We thank members of the Pasterkamp laboratory for assistance and helpful discussions throughout the course of this project, and Alex Kolodkin and Guo-li Ming for comments on the manuscript. We thank Luca Tamagone for kindly providing plexinC1-/- mice, Onur Basak and Tamar Smit for assistance with setting up aNPC cultures, Haining Zhong for providing custom-written Matlab routines for mEPSC analysis, Wouter Beenker for assisting with immunohistochemistry, Emmeke Aarts for statistical advice, and Matthijs Verhage and Joke Wortel for help with mouse breeding. This work was supported by the Netherlands Organization for Health Research and Development (VIDI, ZonMW-TOP, ALW-VICI), Epilepsiefonds (NEF 17-10), Neuroscience and Cognition Utrecht (NCU), Stichting ParkinsonFonds to R.J.P., and in part by the National Institute on Aging, Intramural Research Program (to H.v.P.). NR 72 TC 0 Z9 0 U1 0 U2 0 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 10 PY 2017 VL 8 AR 14666 DI 10.1038/ncomms14666 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN3BG UT WOS:000395883400001 PM 28281529 ER PT J AU Celiku, O Tandle, A Chung, JY Hewitt, SM Camphausen, K Shankavaram, U AF Celiku, Orieta Tandle, Anita Chung, Joon-Yong Hewitt, Stephen M. Camphausen, Kevin Shankavaram, Uma TI Computational analysis of the mesenchymal signature landscape in gliomas SO BMC MEDICAL GENOMICS LA English DT Article DE Glioma; Computational modeling; Epithelial to mesenchymal transition; CD44 ID EPITHELIAL OVARIAN-CARCINOMA; CANCER STEM-CELLS; TRANSCRIPTION FACTOR; GENOMIC ANALYSIS; BREAST-CANCER; GLIOBLASTOMA; TRANSITION; CD44; GRADE; RESISTANCE AB Background: Epithelial to mesenchymal transition, and mimicking processes, contribute to cancer invasion and metastasis, and are known to be responsible for resistance to various therapeutic agents in many cancers. While a number of studies have proposed molecular signatures that characterize the spectrum of such transition, more work is needed to understand how the mesenchymal signature (MS) is regulated in non-epithelial cancers like gliomas, to identify markers with the most prognostic significance, and potential for therapeutic targeting. Results: Computational analysis of 275 glioma samples from "The Cancer Genome Atlas" was used to identify the regulatory changes between low grade gliomas with little expression of MS, and high grade glioblastomas with high expression of MS. TF (transcription factor)-gene regulatory networks were constructed for each of the cohorts, and 5 major pathways and 118 transcription factors were identified as involved in the differential regulation of the networks. The most significant pathway -Extracellular matrix organization -was further analyzed for prognostic relevance. A 20-gene signature was identified as having prognostic significance (HR (hazard ratio) 3.2, 95% CI (confidence interval) = 1.53-8.33), after controlling for known prognostic factors (age, and glioma grade). The signature's significance was validated in an independent data set. The putative stem cell marker CD44 was biologically validated in glioma cell lines and brain tissue samples. Conclusions: Our results suggest that the differences between low grade gliomas and high grade glioblastoma are associated with differential expression of the signature genes, raising the possibility that targeting these genes might prolong survival in glioma patients. C1 [Celiku, Orieta; Tandle, Anita; Camphausen, Kevin; Shankavaram, Uma] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Bldg 10,Rm B3B70, Bethesda, MD 20892 USA. [Chung, Joon-Yong; Hewitt, Stephen M.] NCI, Expt Pathol Lab, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Shankavaram, U (reprint author), NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Bldg 10,Rm B3B70, Bethesda, MD 20892 USA. EM uma@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 58 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1755-8794 J9 BMC MED GENOMICS JI BMC Med. Genomics PD MAR 9 PY 2017 VL 10 AR 13 DI 10.1186/s12920-017-0252-7 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA EN8XK UT WOS:000396283000001 PM 28279210 ER PT J AU Zhang, S Zhou, B Wang, L Li, P Bennett, B Snyder, R Garantziotis, S Fargo, D Cox, A Chen, L Hu, G AF Zhang, S. Zhou, B. Wang, L. Li, P. Bennett, Bd Snyder, R. Garantziotis, S. Fargo, Dc Cox, Ad Chen, L. Hu, G. TI INO80 is required for oncogenic transcription and tumor growth in non-small cell lung cancer SO ONCOGENE LA English DT Article ID CHROMATIN REMODELING COMPLEX; AMPLIFICATION; PLURIPOTENCY; REPLICATION; MECHANISMS; LANDSCAPE; BIOLOGY; ENZYME; GENES AB Epigenetic regulators are attractive targets for the development of new cancer therapies. Among them, the ATP-dependent chromatin remodeling complexes control the chromatin architecture and have important roles in gene regulation. They are often found to be mutated and de-regulated in cancers, but how they influence the cancer gene expression program during cancer initiation and progression is not fully understood. Here we show that the INO80 chromatin remodeling complex is required for oncogenic transcription and tumor growth in non-small-cell lung cancer (NSCLC). Ino80, the SWI/SNF ATPase in the complex, is highly expressed in NSCLC cells compared with normal lung epithelia cells. Further, its expression, as well as that of another subunit Ino80B, negatively correlates with disease prognosis in lung cancer patients. Functionally, INO80 silencing inhibits NSCLC cell proliferation and anchorage-independent growth in vitro and tumor formation in mouse xenografts. It occupies enhancer regions near lung cancer-associated genes, and its occupancy correlates with increased genome accessibility and enhanced expression of downstream genes. Together, our study defines a critical role of INO80 in promoting oncogenic transcription and NSCLC tumorigenesis, and reveals a potential treatment strategy for inhibiting the cancer transcription network by targeting the INO80 chromatin remodeling complex. C1 [Zhang, S.; Chen, L.] Chinese Peoples Liberat Army Gen Hosp, Dept Pulm & Crit Care Med, Beijing 100853, Peoples R China. [Zhou, B.; Cox, Ad] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Zhou, B.; Wang, L.] Fuwai Hosp, Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, State Key Lab Cardiovasc Dis, Beijing, Peoples R China. [Zhou, B.; Wang, L.] Fuwai Hosp, Chinese Acad Med Sci, Peking Union Med Coll, Natl Ctr Cardiovasc Dis, Beijing, Peoples R China. [Wang, L.; Li, P.; Hu, G.] Natl Inst Environm Hlth Sci, Epigenet & Stem Cell Biol Lab, 111 TW Alexander Dr,Bldg 101,Room A314, Res Triangle Pk, NC 27709 USA. [Bennett, Bd; Fargo, Dc] Natl Inst Environm Hlth Sci, Integrat Bioinformat, Res Triangle Pk, NC USA. [Snyder, R.; Garantziotis, S.] Natl Inst Environm Hlth Sci, Clin Res Branch, Res Triangle Pk, NC USA. RP Chen, L (reprint author), Chinese Peoples Liberat Army Gen Hosp, Dept Pulm & Crit Care Med, Beijing 100853, Peoples R China.; Hu, G (reprint author), Natl Inst Environm Hlth Sci, Epigenet & Stem Cell Biol Lab, 111 TW Alexander Dr,Bldg 101,Room A314, Res Triangle Pk, NC 27709 USA. EM CLA_301@163.com; hug4@niehs.nih.gov FU Intramural Research Program of the NIH; National Institute of Environmental Health Sciences [Z01ES102745]; National Institutes of Health Grants [CA042978, CA161494] FX We thank the NIEHS Animal, Epigenomics and Bioinformatics core facilities for assistance with various techniques and experiments. This study was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences Z01ES102745 (to GH) and by National Institutes of Health Grants CA042978 and CA161494 (to ADC). NR 35 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD MAR 9 PY 2017 VL 36 IS 10 BP 1430 EP 1439 DI 10.1038/onc.2016.311 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA EN2TG UT WOS:000395862500011 PM 27641337 ER PT J AU Bowers, JS Nelson, MH Majchrzak, K Bailey, SR Rohrer, B Kaiser, ADM Atkinson, C Gattinoni, L Paulos, CM AF Bowers, Jacob S. Nelson, Michelle H. Majchrzak, Kinga Bailey, Stefanie R. Rohrer, Baerbel Kaiser, Andrew D. M. Atkinson, Carl Gattinoni, Luca Paulos, Chrystal M. TI Th17 cells are refractory to senescence and retain robust antitumor activity after long-term ex vivo expansion SO JCI INSIGHT LA English DT Article ID CD8(+) T-CELLS; TUMOR-INFILTRATING LYMPHOCYTES; ADOPTIVE IMMUNOTHERAPY; METASTATIC MELANOMA; ESTABLISHED MELANOMA; CANCER-IMMUNOTHERAPY; TRANSFER THERAPY; TELOMERE LENGTH; HUMAN EFFECTOR; MEMORY CELLS AB Adoptive immunotherapy for solid tumors relies on infusing large numbers of T cells to mediate successful antitumor responses in patients. While long-term rapid-expansion protocols (REPs) produce sufficient numbers of CD8(+) T cells for treatment, they also cause decline in the cell's therapeutic fitness. In contrast, we discovered that IL-17-producing CD4(+) T cells (Th17 cells) do not require REPs to expand 5,000-fold over 3 weeks. Also, unlike Th1 cells, Th17 cells do not exhibit hallmarks of senescence or apoptosis, retaining robust antitumor efficacy in vivo. Three-week-expanded Th17 cells eliminated melanoma as effectively as Th17 cells expanded for 1 week when infused in equal numbers into mice. However, treating mice with large recalcitrant tumors required the infusion of all cells generated after 2 or 3 weeks of expansion, while the cell yield obtained after 1-week expansion was insufficient. Long-term-expanded Th17 cells also protected mice from tumor rechallenge including lung metastasis. Importantly, 2-week-expanded human chimeric antigen receptor-positive (CAR(+)) Th17 cells also retained their ability to regress human mesothelioma, while CAR(+) Th1 cells did not. Our results indicate that tumor-reactive Th17 cells are an effective cell therapy for cancer, remaining uncompromised when expanded for a long duration owing to their resistance to senescence. C1 [Bowers, Jacob S.; Nelson, Michelle H.; Majchrzak, Kinga; Bailey, Stefanie R.; Atkinson, Carl; Paulos, Chrystal M.] Med Univ South Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. [Bowers, Jacob S.; Nelson, Michelle H.; Majchrzak, Kinga; Bailey, Stefanie R.; Paulos, Chrystal M.] Med Univ South Carolina, Dept Dermatol, Charleston, SC 29425 USA. [Bowers, Jacob S.; Nelson, Michelle H.; Majchrzak, Kinga; Bailey, Stefanie R.; Paulos, Chrystal M.] Med Univ South Carolina, Dept Surg, Charleston, SC 29425 USA. [Majchrzak, Kinga] Warsaw Univ Life Sci, Dept Physiol Sci, Fac Vet Med, Warsaw, Poland. [Rohrer, Baerbel] Med Univ South Carolina, Dept Ophthalmol, Charleston, SC 29425 USA. [Rohrer, Baerbel] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Kaiser, Andrew D. M.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gattinoni, Luca] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Kaiser, Andrew D. M.] Miltenyi Biotec, Bergisch Gladbach, Germany. RP Bowers, JS; Paulos, CM (reprint author), Med Univ South Carolina, Hollings Canc Ctr, 86 Jonathan Lucas St,Room 606B MSC509, Charleston, SC 29425 USA. EM bowersjs@musc.edu; paulos@musc.edu FU Hollings Cell Evaluation Therapy; Hollings Cell Evaluation & Therapy, and Hollings Biostatistics Shared Resources, Hollings Cancer Center, MUSC [P30 CA138313]; NIH [F30 CA200272, T32 GM008716, F31 CA192787]; Jeane B. Kempner Foundation; ACS [122704-PF-13-084-01-LIB]; NCI [R01 CA175061, R01 CA208514]; KL2 South Carolina Clinical & Translational Research grant [UL1 TR000062]; ACS-IRG grant [016623-004]; MUSC start-up funds FX We thank Logan Huff and Hannah Knochelmann for experimental support and Kent Armeson for help in statistical analysis of this work. This research was supported in part by the Hollings Cell Evaluation & Therapy, and Hollings Biostatistics Shared Resources, Hollings Cancer Center, MUSC (P30 CA138313).; This work was supported by NIH fellowship grant F30 CA200272 and NIH training grant T32 GM008716 to J.S. Bowers, a Jeane B. Kempner Foundation grant and ACS Postdoctoral fellowship (122704-PF-13-084-01-LIB) grant to M.H. Nelson, an NIH fellowship grant F31 CA192787 to S.R. Bailey, and NCI grants R01 CA175061 and R01 CA208514, KL2 South Carolina Clinical & Translational Research grant UL1 TR000062, ACS-IRG grant 016623-004, and MUSC start-up funds to C.M. Paulos. NR 57 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD MAR 9 PY 2017 VL 2 IS 5 AR e90772 DI 10.1172/jci.insight.90772 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EN5FA UT WOS:000396029800010 PM 28289713 ER PT J AU You, J Volkow, ND Park, K Zhang, QJ Clare, K Du, CW Pan, YT AF You, Jiang Volkow, Nora D. Park, Kicheon Zhang, Qiujia Clare, Kevin Du, Congwu Pan, Yingtian TI Cerebrovascular adaptations to cocaine-induced transient ischemic attacks in the rodent brain SO JCI INSIGHT LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; BLOOD-FLOW; STROKE; USERS; CORTEX; LAYERS; NOREPINEPHRINE; ANGIOGENESIS; THROMBOSIS; VESSELS AB Occurrence of transient ischemic attacks (TIA) and cerebral strokes is a recognized risk associated with cocaine abuse. Here, we use a rodent model along with optical imaging to study cocaine-induced TIA and the associated dynamic changes in cerebral blood flow velocity (CBFv) and cerebrovasculature. We show that chronic cocaine exposure in mice resulted in marked cortical hypoperfusion, in significant arterial and venous vasoconstriction, and in a sensitized vascular response to an acute cocaine injection. Starting after 10 days of exposure, an acute cocaine challenge to these mice resulted in a TIA, which presented as hemiparalysis and was associated with an abrupt exacerbation of CBFv. The severity of the TIA correlated with the decreases in cortical CBFv such that the greater the decreases in flow, the longer the TIA duration. The severity of TIA peaked around 17-22 days of cocaine exposure and decreased thereafter in parallel to a reorganization of CBFv from superficial to deep cortical layers, along with an increase in vessel density into these layers. Here, we document for the first time to our knowledge evidence of a TIA in an animal model of chronic cocaine exposure that was associated with profound decreases in CBFv, and we revealed that while the severity of the TIA initially increased with repeated exposures, it subsequently improved in parallel to an increase in the vessel density. This suggests that strategies to accelerate cerebrovascular recovery might be therapeutically beneficial in cocaine abusers. C1 [You, Jiang; Park, Kicheon; Zhang, Qiujia; Clare, Kevin; Du, Congwu; Pan, Yingtian] SUNY Stony Brook, Dept Biomed Engn, 002 Life Sci Bldg, Stony Brook, NY 11794 USA. [Volkow, Nora D.] NIAAA, NIH, Bethesda, MD USA. RP Du, CW (reprint author), SUNY Stony Brook, Dept Biomed Engn, 002 Life Sci Bldg, Stony Brook, NY 11794 USA.; Pan, YT (reprint author), SUNY Stony Brook, G17 Bioengn Bldg, Stony Brook, NY 11794 USA.; Volkow, ND (reprint author), NIDA, Room 5274,6001 Execut Blvd, Rockville, MD 20852 USA. EM nvolkow@nida.nih.gov; congwu.du@stonybrook.edu; yingtian.pan@stonybrook.edu FU NIH [1R01DA029718, R21DA042597]; NIH's Intramural Program of NIAAA FX This work was supported in part by NIH grants 1R01DA029718 (CD and YP), R21DA042597 (YP and CD), and NIH's Intramural Program of NIAAA (NDV). NR 42 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD MAR 9 PY 2017 VL 2 IS 5 AR e90809 DI 10.1172/jci.insight.90809 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EN5FA UT WOS:000396029800018 PM 28289715 ER PT J AU Lin, JC Lee, YC Liang, YC Fann, YC Johnson, KR Lin, YJ AF Lin, Jung-Chun Lee, Yuan-Chii Liang, Yu-Chih Fann, Yang C. Johnson, Kory R. Lin, Ying-Ju TI The impact of the RBM4-initiated splicing cascade on modulating the carcinogenic signature of colorectal cancer cells SO SCIENTIFIC REPORTS LA English DT Article ID BROWN ADIPOCYTES; DOWN-REGULATION; GASTRIC-CANCER; BREAST-CANCER; COLON-CANCER; EXPRESSION; PROTEIN; RBM4; REGULATOR; GROWTH AB A growing body of studies has demonstrated that dysregulated splicing profiles constitute pivotal mechanisms for carcinogenesis. In this study, we identified discriminative splicing profiles of colorectal cancer (CRC) cells compared to adjacent normal tissues using deep RNA-sequencing (RNA-seq). The RNA-seq results and cohort studies indicated a relatively high ratio of exon 4-excluded neurooncological ventral antigen 1 (Nova1(-4)) and intron 2-retained SRSF6 (SRSF6+(intron2)) transcripts in CRC tissues and cell lines. Nova1 variants exhibited differential effects on eliminating SRSF6 expression in CRC cells by inducing SRSF6+(intron2) transcripts which were considered to be the putative target of alternative splicing-coupled nonsense-mediated decay mechanism. Moreover, the splicing profile of vascular endothelial growth factor (VEGF) 165/VEGF165b transcripts was relevant to SRSF6 expression, which manipulates the progression of CRC calls. These results highlight the novel and hierarchical role of an alternative splicing cascade that is involved in the development of CRC. C1 [Lin, Jung-Chun; Liang, Yu-Chih] Taipei Med Univ, Sch Med Lab Sci & Biotechnol, Coll Med Sci & Technol, Taipei, Taiwan. [Lee, Yuan-Chii] Taipei Med Univ, Grad Inst Biomed Informat, Taipei, Taiwan. [Fann, Yang C.; Johnson, Kory R.] NINDS, Informat Technol & Bioinformat Program, Div Intramural Res, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Lin, Ying-Ju] China Med Univ, Sch Chinese Med, Taichung, Taiwan. RP Lin, JC (reprint author), Taipei Med Univ, Sch Med Lab Sci & Biotechnol, Coll Med Sci & Technol, Taipei, Taiwan. EM lin2511@tmu.edu.tw FU Ministry of Science and Technology of Taiwan [MOST 105-2311-B-038-003] FX We greatly appreciate Prof. Wen-Sen Lee (Taipei Medical University, Taiwan) for providing HUVECs. This work was supported by a grant (MOST 105-2311-B-038-003) from the Ministry of Science and Technology of Taiwan. NR 42 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 9 PY 2017 VL 7 AR 44204 DI 10.1038/srep44204 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN4NP UT WOS:000395984500001 PM 28276498 ER PT J AU Gerlits, O Keen, DA Blakeley, MP Louis, JM Weber, IT Kovalevskyk, A AF Gerlits, Oksana Keen, David A. Blakeley, Matthew P. Louis, John M. Weber, Irene T. Kovalevskyk, Andrey TI Room Temperature Neutron Crystallography of Drug Resistant HIV-1 Protease Uncovers Limitations of X-ray Structural Analysis at 100 K SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID VIRUS TYPE-1 PROTEASE; CRYSTAL-STRUCTURE; CLINICAL INHIBITORS; MOLECULAR-DYNAMICS; HYDROGEN-BOND; MECHANISM; MUTATIONS; COMPLEX; MUTANT; SIMULATIONS AB HIV-1 protease inhibitors are crucial for treatment of HIV-1/AIDS, but their effectiveness is thwarted by rapid emergence of drug resistance. To better understand binding of clinical inhibitors to resistant HIV-1 protease, we used room -temperature joint X-ray/neutron (XN) crystallography to obtain an atomic-resolution structure of the protease triple mutant (V321/147V/V821) in complex with amprenavir. The XN structure reveals a D+ ion located midway between the inner 061 oxygen atoms of the catalytic aspartic acid residues. Comparison of the current XN structure with our previous XN structure of the wild-type HIV-1 proteaseamprenavir complex suggests that the three mutations do not significantly alter the drug enzyme interactions. This is in contrast to the observations in previous 100 K X-ray structures of these complexes that indicated loss of interactions by the drug with the triple mutant protease. These findings, thus, uncover limitations of structural analysis of drug binding using X-ray structures obtained at 100 K. C1 [Gerlits, Oksana] Univ Tennessee, UT ORNL Joint Inst Biol Sci, Knoxville, TN 37996 USA. [Keen, David A.] ISIS Facil, Rutherford Appleton Lab, Harwell Campus, Didcot OX11 0QX, Oxon, England. [Blakeley, Matthew P.] Inst Laue Langevin, Large Scale Struct Grp, 71 Ave Martyrs, F-38000 Grenoble, France. [Louis, John M.] Natl Inst Hlth, Natl Inst Diabet & Digest & Kidney Dis, DHHS, Lab Chem Phys, Bethesda, MD 20892 USA. [Weber, Irene T.] Georgia State Univ, Dept Biol & Chem, Atlanta, GA 30302 USA. [Kovalevskyk, Andrey] Oak Ridge Natl Lab, Biol & Soft Matter Div, Oak Ridge, TN 37831 USA. RP Kovalevskyk, A (reprint author), Oak Ridge Natl Lab, Biol & Soft Matter Div, Oak Ridge, TN 37831 USA. EM kovalevskyay@ornl.gov OI Blakeley, Matthew/0000-0002-6412-4358 FU Scientific User Facilities Division, Office of Basic Energy Sciences, U.S. Department of Energy; Office of Biological and Environmental Research; NIH [R01GM02920]; NIDDK, National Institutes of Health; Intramural AIDS-Targeted Program of the Office of the Director, NIH; DOE [DE-AC05-00OR22725] FX This research at ORNL's Spallation Neutron Source was sponsored by the Scientific User Facilities Division, Office of Basic Energy Sciences, U.S. Department of Energy. The Office of Biological and Environmental Research supported research at Oak Ridge National Laboratory's Center for Structural Molecular Biology (CSMB), using facilities supported by the Scientific User Facilities Division, Office of Basic Energy Sciences, U.S. Department of Energy. The authors thank Institut Laue Langevin (beamline LADI-III) for awarded neutron beamtime. I.T.W. was partly supported by NIH grant R01GM02920. J.M.L. was supported by the Intramural Research Program of the NIDDK, National Institutes of Health and the Intramural AIDS-Targeted Program of the Office of the Director, NIH. Notice: This manuscript has been authored by UT-Battelle LLC under DOE Contract No. DE-AC05-00OR22725. NR 53 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD MAR 9 PY 2017 VL 60 IS 5 BP 2018 EP 2025 DI 10.1021/acs.jmedchem.6b01767 PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA EN9BQ UT WOS:000396296100027 PM 28195728 ER PT J AU Richner, JM Himansu, S Dowd, KA Butler, SL Salazar, V Fox, JM Julander, JG Tang, WW Shresta, S Pierson, TC Ciaramella, G Diamond, MS AF Richner, Justin M. Himansu, Sunny Dowd, Kimberly A. Butler, Scott L. Salazar, Vanessa Fox, Julie M. Julander, Justin G. Tang, William W. Shresta, Sujan Pierson, Theodore C. Ciaramella, Giuseppe Diamond, Michael S. TI Modified mRNA Vaccines Protect against Zika Virus Infection SO CELL LA English DT Article ID WEST-NILE-VIRUS; ANTIBODY-DEPENDENT ENHANCEMENT; CROSS-REACTIVE ANTIBODIES; MALE SEXUAL TRANSMISSION; DENGUE VIRUS; ENVELOPE PROTEIN; DNA VACCINE; IN-VITRO; IMMUNE-RESPONSES; STRUCTURAL BASIS AB The emergence of ZIKV infection has prompted a global effort to develop safe and effective vaccines. We engineered a lipid nanoparticle (LNP) encapsulated modified mRNA vaccine encoding wild-type or variant ZIKV structural genes and tested immunogenicity and protection in mice. Two doses of modified mRNA LNPs encoding prM-E genes that produced virus-like particles resulted in high neutralizing antibody titers (similar to 1/100,000) that protected against ZIKV infection and conferred sterilizing immunity. To offset a theoretical concern of ZIKV vaccines inducing antibodies that cross-react with the related dengue virus (DENV), we designed modified prM-E RNA encoding mutations destroying the conserved fusion-loop epitope in the E protein. This variant protected against ZIKV and diminished production of antibodies enhancing DENV infection in cells or mice. A modified mRNA vaccine can prevent ZIKV disease and be adapted to reduce the risk of sensitizing individuals to subsequent exposure to DENV, should this become a clinically relevant concern. C1 [Richner, Justin M.; Salazar, Vanessa; Fox, Julie M.; Diamond, Michael S.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Himansu, Sunny; Butler, Scott L.; Ciaramella, Giuseppe] Valera LLC, 500 Technol Sq, Cambridge, MA 02139 USA. [Dowd, Kimberly A.; Pierson, Theodore C.] NIH, Viral Pathogenesis Sect, Bldg 10, Bethesda, MD 20892 USA. [Julander, Justin G.] Utah State Univ, Inst Antiviral Res, Logan, UT 84335 USA. [Tang, William W.; Shresta, Sujan] La Jolla Inst Allergy & Immunol, Div Inflammat Biol, La Jolla, CA 92037 USA. [Diamond, Michael S.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Diamond, Michael S.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Diamond, Michael S.] Washington Univ, Sch Med, Andrew M & Jane M Bursky Ctr Human Immunol & Immu, St Louis, MO 63110 USA. RP Diamond, MS (reprint author), Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA.; Ciaramella, G (reprint author), Valera LLC, 500 Technol Sq, Cambridge, MA 02139 USA.; Diamond, MS (reprint author), Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA.; Diamond, MS (reprint author), Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA.; Diamond, MS (reprint author), Washington Univ, Sch Med, Andrew M & Jane M Bursky Ctr Human Immunol & Immu, St Louis, MO 63110 USA. EM Giuseppe.Ciaramella@Valeratx.com; diamond@wusm.wustl.edu FU NIH-NIAID [R01 AI073755, R01 AI104972, P01 AI106695, R01 AI116813]; DARPA [W911NF-13-1-0417]; Moderna FX This work was supported by grants from the NIH-NIAID (R01 AI073755, R01 AI104972, and P01 AI106695 to M.S.D; R01 AI116813 to S.S), the intramural program of NIH-NIAID (T.C.P), a research grant from DARPA (agreement #W911NF-13-1-0417), and by a research grant from Moderna. We thank W. H. Hui (University of California, Los Angeles) for performing the negative stain imaging of the SVPs. M.S.D. is a consultant for Inbios, Visterra, and Takeda Pharmaceuticals and on the Scientific Advisory Boards of Moderna and OvaGene. S.H., S.L.B., and G.C. are employees of Valera LLC, a Moderna Venture focusing on the development of therapeutic approaches for infectious diseases, including ZIKV mRNA vaccines. NR 72 TC 0 Z9 0 U1 22 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD MAR 9 PY 2017 VL 168 IS 6 BP 1114 EP + DI 10.1016/j.cell.2017.02.017 PG 22 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EN8ZF UT WOS:000396287900018 PM 28222903 ER PT J AU Hon, CC Ramilowski, JA Harshbarger, J Bertin, N Rackham, OJL Gough, J Denisenko, E Schmeier, S Poulsen, TM Severin, J Lizio, M Kawaji, H Kasukawa, T Itoh, M Burroughs, AM Noma, S Djebali, S Alam, T Medvedeva, YA Testa, AC Lipovich, L Yip, CW Abugessaisa, I Mendez, M Hasegawa, A Tang, D Lassmann, T Heutink, P Babina, M Wells, CA Kojima, S Nakamura, Y Suzuki, H Daub, CO de Hoon, MJL Arner, E Hayashizaki, Y Carninci, P Forrest, ARR AF Hon, Chung-Chau Ramilowski, Jordan A. Harshbarger, Jayson Bertin, Nicolas Rackham, Owen J. L. Gough, Julian Denisenko, Elena Schmeier, Sebastian Poulsen, Thomas M. Severin, Jessica Lizio, Marina Kawaji, Hideya Kasukawa, Takeya Itoh, Masayoshi Burroughs, A. Maxwell Noma, Shohei Djebali, Sarah Alam, Tanvir Medvedeva, Yulia A. Testa, Alison C. Lipovich, Leonard Yip, Chi-Wai Abugessaisa, Imad Mendez, Mickael Hasegawa, Akira Tang, Dave Lassmann, Timo Heutink, Peter Babina, Magda Wells, Christine A. Kojima, Soichi Nakamura, Yukio Suzuki, Harukazu Daub, Carsten O. de Hoon, Michiel J. L. Arner, Erik Hayashizaki, Yoshihide Carninci, Piero Forrest, Alistair R. R. TI An atlas of human long non-coding RNAs with accurate 5 ' ends SO NATURE LA English DT Article ID GENOME-WIDE ASSOCIATION; GENE-EXPRESSION; PROMOTER USAGE; PR INTERVAL; TRANSCRIPTION; EVOLUTION; SEQ; ARCHITECTURE; ANNOTATION; LANDSCAPE AB Long non-coding RNAs (lncRNAs) are largely heterogeneous and functionally uncharacterized. Here, using FANTOM5 cap analysis of gene expression (CAGE) data, we integrate multiple transcript collections to generate a comprehensive atlas of 27,919 human lncRNA genes with high-confidence 5' ends and expression profiles across 1,829 samples from the major human primary cell types and tissues. Genomic and epigenomic classification of these lncRNAs reveals that most intergenic lncRNAs originate from enhancers rather than from promoters. Incorporating genetic and expression data, we show that lncRNAs overlapping trait-associated single nucleotide polymorphisms are specifically expressed in cell types relevant to the traits, implicating these lncRNAs in multiple diseases. We further demonstrate that lncRNAs overlapping expression quantitative trait loci (eQTL)-associated single nucleotide polymorphisms of messenger RNAs are co-expressed with the corresponding messenger RNAs, suggesting their potential roles in transcriptional regulation. Combining these findings with conservation data, we identify 19,175 potentially functional lncRNAs in the human genome. C1 [Hon, Chung-Chau; Ramilowski, Jordan A.; Harshbarger, Jayson; Severin, Jessica; Lizio, Marina; Kawaji, Hideya; Kasukawa, Takeya; Itoh, Masayoshi; Burroughs, A. Maxwell; Noma, Shohei; Yip, Chi-Wai; Abugessaisa, Imad; Mendez, Mickael; Hasegawa, Akira; Tang, Dave; Lassmann, Timo; Heutink, Peter; Suzuki, Harukazu; Daub, Carsten O.; de Hoon, Michiel J. L.; Arner, Erik; Carninci, Piero; Forrest, Alistair R. R.] RIKEN, Ctr Life Sci Technol, Div Gen Technol, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan. [Ramilowski, Jordan A.; Harshbarger, Jayson; Bertin, Nicolas; Severin, Jessica; Lizio, Marina; Kawaji, Hideya; Itoh, Masayoshi; Burroughs, A. Maxwell; Noma, Shohei; Mendez, Mickael; Hasegawa, Akira; Tang, Dave; Lassmann, Timo; Suzuki, Harukazu; Daub, Carsten O.; de Hoon, Michiel J. L.; Arner, Erik; Hayashizaki, Yoshihide; Carninci, Piero; Forrest, Alistair R. R.] RIKEN, Omics Sci Ctr, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan. [Bertin, Nicolas] Natl Univ Singapore, Ctr Translat Med, Canc Sci Inst Singapore, 14 Med Dr 12-01, Singapore 117599, Singapore. [Rackham, Owen J. L.; Gough, Julian] Univ Bristol, Dept Comp Sci, Life Sci Bldg,24 Tyndall Ave, Bristol BS8 1TQ, Avon, England. [Rackham, Owen J. L.] Duke NUS Med Sch, Program Cardiovasc & Metab Disorders, 8 Coll Rd, Singapore 169857, Singapore. [Denisenko, Elena; Schmeier, Sebastian] Massey Univ Auckland, Inst Nat & Math Sci, Albany 0632, New Zealand. [Poulsen, Thomas M.] Natl Inst Adv Ind Sci & Technol, Biotechnol Res Inst Drug Discovery BRD, Tsukuba Cent 2,1-1-1 Umezono, Tsukuba, Ibaraki 3058568, Japan. [Kawaji, Hideya; Itoh, Masayoshi; Hayashizaki, Yoshihide] RIKEN, Prevent Med & Diag Innovat Program, 2-1 Hirosawa, Wako, Saitama 3510198, Japan. [Burroughs, A. Maxwell] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Djebali, Sarah] Barcelona Inst Sci & Technol, Ctr Gen Regulat CRG, Dr Aiguader 88, Barcelona 08003, Spain. [Djebali, Sarah] UPF, Barcelona Biomed Res Pk PRBB, Dr Aiguader 88, Barcelona 08003, Spain. [Alam, Tanvir] KAUST, Computat Biosci Res Ctr, Comp Elect & Math Sci & Engn Div, Thuwal 239556900, Saudi Arabia. [Medvedeva, Yulia A.] RAS, Biotechnol Res Ctr, Inst Bioengn, Moscow 119071, Russia. [Medvedeva, Yulia A.] RAS, Vavilov Inst Gen Genet, Moscow 119991, Russia. [Testa, Alison C.; Forrest, Alistair R. R.] Univ Western Australia, QEII Med Ctr, Harry Perkins Inst Med Res, Nedlands, WA 6009, Australia. [Testa, Alison C.; Forrest, Alistair R. R.] Univ Western Australia, Med Res Ctr, Nedlands, WA 6009, Australia. [Lipovich, Leonard] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Lipovich, Leonard] Wayne State Univ, Sch Med, Dept Neurol, Detroit, MI 48201 USA. [Tang, Dave; Lassmann, Timo] Univ Western Australia, Telethon Kids Inst, 100 Roberts Rd, Subiaco, WA 6008, Australia. [Heutink, Peter] German Ctr Neurodegenerat Dis DZNE, D-72076 Tubingen, Germany. [Babina, Magda] Charite, Dept Dermatol & Allergy, D-10117 Berlin, Germany. [Wells, Christine A.] Univ Queensland, Australian Inst Bioengn & Nanotechnol, Brisbane, Qld 4072, Australia. [Wells, Christine A.] Univ Melbourne, Fac Med, Dept Anat & Neurosci, Melbourne, Vic 3010, Australia. [Kojima, Soichi] RIKEN, CLST Div Biofunct Dynam Imaging, Wako, Saitama 3510198, Japan. [Nakamura, Yukio] RIKEN, BioResource Ctr, Cell Engn Div, Tsukuba, Ibaraki 3050074, Japan. [Nakamura, Yukio] Univ Tsukuba, Fac Med, Tsukuba, Ibaraki 3058577, Japan. [Daub, Carsten O.] Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden. [Bertin, Nicolas] Human Longev Singapore Pte Ltd, Singapore, Singapore. [Djebali, Sarah] Univ Toulouse, INRA, INPT, ENVT,GenPhySE, Castanet Tolosan, France. [Mendez, Mickael] Univ Toronto, Dept Comp Sci, Toronto, ON, Canada. RP Carninci, P; Forrest, ARR (reprint author), RIKEN, Ctr Life Sci Technol, Div Gen Technol, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan.; Carninci, P; Forrest, ARR (reprint author), RIKEN, Omics Sci Ctr, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan.; Forrest, ARR (reprint author), Univ Western Australia, QEII Med Ctr, Harry Perkins Inst Med Res, Nedlands, WA 6009, Australia.; Forrest, ARR (reprint author), Univ Western Australia, Med Res Ctr, Nedlands, WA 6009, Australia. EM carninci@riken.jp; alistair.forrest@gmail.com OI Abugessaisa, Imad/0000-0001-7458-801X; Wells, Christine/0000-0003-3133-3628 FU MEXT; MEXT, Japan; Cancer Research Trust; MACA Ride to Conquer Cancer; Australian Research Council [DP160101960]; National Human Genome Research Institute of the National Institutes of Health [U54HG007004]; Ministry of Economy and Competitiveness (MINECO) [BIO2011-26205]; Spanish Ministry of Economy and Competitiveness [SEV-2012-0208]; Russian Science Foundation [15-14-30002] FX FANTOM5 was made possible by research grants for the RIKEN Omics Science Center and the Innovative Cell Biology by Innovative Technology (Cell Innovation Program) from the MEXT to Y.H. It was also supported by research grants for the RIKEN Preventive Medicine and Diagnosis Innovation Program (RIKEN PMI) to Y.H. and the RIKEN Centre for Life Science Technologies, Division of Genomic Technologies (RIKEN CLST (DGT)) from the MEXT, Japan. A.R.R.F. is supported by a Senior Cancer Research Fellowship from the Cancer Research Trust, the MACA Ride to Conquer Cancer and the Australian Research Council's Discovery Projects funding scheme (DP160101960). S.D. is supported by award number U54HG007004 from the National Human Genome Research Institute of the National Institutes of Health, funding from the Ministry of Economy and Competitiveness (MINECO) under grant number BIO2011-26205, and SEV-2012-0208 from the Spanish Ministry of Economy and Competitiveness. Y.A.M. is supported by the Russian Science Foundation, grant 15-14-30002. We thank RIKEN GeNAS for generation of the CAGE and RNA-seq libraries, the Netherlands Brain Bank for brain materials, the RIKEN BioResource Centre for providing cell lines and all members of the FANTOM5 consortium for discussions, in particular H. Ashoor, M. Frith, R. Guigo, A. Tanzer, E. Wood, H. Jia, K. Bailie, J. Harrow, E. Valen, R. Andersson, K. Vitting-Seerup, A. Sandelin, M. Taylor, J. Shin, R. Mori, C. Mungall and T. Meehan. NR 68 TC 0 Z9 0 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAR 9 PY 2017 VL 543 IS 7644 BP 199 EP + DI 10.1038/nature21374 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN0GQ UT WOS:000395688700030 PM 28241135 ER PT J AU Pardi, N Hogan, MJ Pelc, RS Muramatsu, H Andersen, H DeMaso, CR Dowd, KA Sutherland, LL Scearce, RM Parks, R Wagner, W Granados, A Greenhouse, J Walker, M Willis, E Yu, JS Mcgee, CE Sempowski, GD Mui, BL Tam, YK Huang, YJ Vanlandingham, D Holmes, VM Balachandran, H Sahu, S Lifton, M Higgs, S Hensley, SE Madden, TD Hope, MJ Kariko, K Santra, S Graham, BS Lewis, MG Pierson, TC Haynes, BF Weissman, D AF Pardi, Norbert Hogan, Michael J. Pelc, Rebecca S. Muramatsu, Hiromi Andersen, Hanne DeMaso, Christina R. Dowd, Kimberly A. Sutherland, Laura L. Scearce, Richard M. Parks, Robert Wagner, Wendeline Granados, Alex Greenhouse, Jack Walker, Michelle Willis, Elinor Yu, Jae-Sung McGee, Charles E. Sempowski, Gregory D. Mui, Barbara L. Tam, Ying K. Huang, Yan-Jang Vanlandingham, Dana Holmes, Veronica M. Balachandran, Harikrishnan Sahu, Sujata Lifton, Michelle Higgs, Stephen Hensley, Scott E. Madden, Thomas D. Hope, Michael J. Kariko, Katalin Santra, Sampa Graham, Barney S. Lewis, Mark G. Pierson, Theodore C. Haynes, Barton F. Weissman, Drew TI Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination SO NATURE LA English DT Article ID LIPID NANOPARTICLES; INFECTION; VACCINES; PSEUDOURIDINE; THERAPEUTICS; SPECIFICITY; EXPRESSION; IMMUNITY; VECTORS; THERAPY AB Zika virus (ZIKV) has recently emerged as a pandemic associated with severe neuropathology in newborns and adults(1). There are no ZIKV-specific treatments or preventatives. Therefore, the development of a safe and effective vaccine is a high priority. Messenger RNA (mRNA) has emerged as a versatile and highly effective platform to deliver vaccine antigens and therapeutic proteins(2,3). Here we demonstrate that a single low-dose intradermal immunization with lipid-nanoparticle-encapsulated nucleoside-modified mRNA (mRNA-LNP) encoding the pre-membrane and envelope glycoproteins of a strain from the ZIKV outbreak in 2013 elicited potent and durable neutralizing antibody responses in mice and non-human primates. Immunization with 30 mu g of nucleoside-modified ZIKV mRNA-LNP protected mice against ZIKV challenges at 2 weeks or 5 months after vaccination, and a single dose of 50 mu g was sufficient to protect non-human primates against a challenge at 5 weeks after vaccination. These data demonstrate that nucleoside-modified mRNA-LNP elicits rapid and durable protective immunity and therefore represents a new and promising vaccine candidate for the global fight against ZIKV. C1 [Pardi, Norbert; Hogan, Michael J.; Muramatsu, Hiromi; Holmes, Veronica M.; Weissman, Drew] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Pelc, Rebecca S.; DeMaso, Christina R.; Dowd, Kimberly A.; Pierson, Theodore C.] NIAID, Viral Pathogenesis Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Andersen, Hanne; Wagner, Wendeline; Granados, Alex; Greenhouse, Jack; Walker, Michelle; Lewis, Mark G.] Bioqual Inc, Rockville, MD 20850 USA. [Sutherland, Laura L.; Scearce, Richard M.; Parks, Robert; Yu, Jae-Sung; McGee, Charles E.; Sempowski, Gregory D.; Haynes, Barton F.] Duke Univ, Sch Med, Duke Human Vaccine Inst, Durham, NC 27710 USA. [Hensley, Scott E.] Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Mui, Barbara L.; Tam, Ying K.; Madden, Thomas D.; Hope, Michael J.] Acuitas Therapeut, Vancouver, BC V6T 1Z3, Canada. [Huang, Yan-Jang; Vanlandingham, Dana; Higgs, Stephen] Kansas State Univ, Coll Vet Med, Diagnost Med & Pathobiol, Manhattan, KS 66506 USA. [Huang, Yan-Jang; Vanlandingham, Dana; Higgs, Stephen] Kansas State Univ, Biosecur Res Inst, Manhattan, KS 66506 USA. [Balachandran, Harikrishnan; Sahu, Sujata; Lifton, Michelle; Santra, Sampa] Harvard Med Sch, Ctr Virol & Vaccine Res, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Kariko, Katalin] BioNTech RNA Pharmaceut, Goldgrube 12, D-55131 Mainz, Germany. [Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Weissman, D (reprint author), Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. EM dreww@upenn.edu FU NIH [UC6-AI058607, AI100645, U19-AI057229, T32 AI007632-14, R01-AI050484, R01-AI124429, R01-AI084860]; Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University; NIAID Division of Intramural Research; Vaccine Research Center; Takeda Pharmaceuticals, New Frontier Science FX We thank R. Tesh at the UTMB World Reference Center for Emerging Viruses and Arboviruses for providing ZIKV stocks. We gratefully acknowledge the technical or administrative support of M. Bertrand, L. Arwood, C. Sample, M. J. Barr, C. Vivian, T. Gurley and M. A. Moody, E. E. Ooi, S. Lok, H.-X. Liao, S. Awasthi, L. Hook, F. Shaheen, and the UPenn CFAR. The Virology Unit of the Duke Regional Biocontainment Laboratory (Duke Human Vaccine Institute) received support from the NIH, UC6-AI058607. The Duke Center for HIV/AIDS Vaccine Immunology received support from NIH AI100645. D.V. received funding from the Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University. R.S.P., C.R.D., K.A.D., T.C.P. and B.S.G. were funded by the NIAID Division of Intramural Research and the Vaccine Research Center. S.E.H. received funding through NIH U19-AI057229. M. J. Hog. received funding from NIH T32 AI007632-14. D.W. received funding from NIH R01-AI050484, R01-AI124429 and R01-AI084860, and Takeda Pharmaceuticals, New Frontier Science. NR 31 TC 0 Z9 0 U1 17 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAR 9 PY 2017 VL 543 IS 7644 BP 248 EP + DI 10.1038/nature21428 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN0GQ UT WOS:000395688700040 PM 28151488 ER PT J AU Ledgerwood, JE DeZure, AD Stanley, DA Coates, EE Novik, L Enama, ME Berkowitz, NM Hu, ZH Joshi, G Ploquin, A Sitar, S Gordon, IJ Plummer, SA Holman, LA Hendel, CS Yamshchikov, G Roman, F Nicosia, A Colloca, S Cortese, R Bailer, RT Schwartz, RM Roederer, M Mascola, JR Koup, RA Sullivan, NJ Graham, BS AF Ledgerwood, Julie E. DeZure, Adam D. Stanley, Daphne A. Coates, Emily E. Novik, Laura Enama, Mary E. Berkowitz, Nina M. Hu, Zonghui Joshi, Gyan Ploquin, Aurelie Sitar, Sandra Gordon, Ingelise J. Plummer, Sarah A. Holman, LaSonji A. Hendel, Cynthia S. Yamshchikov, Galina Roman, Francois Nicosia, Alfredo Colloca, Stefano Cortese, Riccardo Bailer, Robert T. Schwartz, Richard M. Roederer, Mario Mascola, John R. Koup, Richard A. Sullivan, Nancy J. Graham, Barney S. CA VRC 207 Study Team TI Chimpanzee Adenovirus Vector Ebola Vaccine SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID I CLINICAL-TRIAL; NONHUMAN-PRIMATES; PROTECTIVE IMMUNITY; VIRUS INFECTION; HEALTHY-ADULTS; IMMUNOGENICITY; SAFETY AB BACKGROUND The unprecedented 2014 epidemic of Ebola virus disease (EVD) prompted an international response to accelerate the availability of a preventive vaccine. A replication-defective recombinant chimpanzee adenovirus type 3-vectored ebolavirus vaccine (cAd3-EBO), encoding the glycoprotein from Zaire and Sudan species, that offers protection in the nonhuman primate model, was rapidly advanced into phase 1 clinical evaluation. METHODS We conducted a phase 1, dose-escalation, open-label trial of cAd3-EBO. Twenty healthy adults, in sequentially enrolled groups of 10 each, received vaccination intramuscularly in doses of 2x10(10) particle units or 2x10(11) particle units. Primary and secondary end points related to safety and immunogenicity were assessed throughout the first 8 weeks after vaccination; in addition, longer-term vaccine durability was assessed at 48 weeks after vaccination. RESULTS In this small study, no safety concerns were identified; however, transient fever developed within 1 day after vaccination in two participants who had received the 2x10(11) particle-unit dose. Glycoprotein-specific antibodies were induced in all 20 participants; the titers were of greater magnitude in the group that received the 2x10(11) particle-unit dose than in the group that received the 2x10(10) particle-unit dose (geometric mean titer against the Zaire antigen at week 4, 2037 vs. 331; P = 0.001). Glycoprotein-specific T-cell responses were more frequent among those who received the 2x10(11) particle-unit dose than among those who received the 2x10(10) particle-unit dose, with a CD4 response in 10 of 10 participants versus 3 of 10 participants (P = 0.004) and a CD8 response in 7 of 10 participants versus 2 of 10 participants (P = 0.07) at week 4. Assessment of the durability of the antibody response showed that titers remained high at week 48, with the highest titers in those who received the 2x10(11) particle-unit dose. CONCLUSIONS Reactogenicity and immune responses to cAd3-EBO vaccine were dose-dependent. At the 2x10(11) particle-unit dose, glycoprotein Zaire-specific antibody responses were in the range reported to be associated with vaccine-induced protective immunity in challenge studies involving nonhuman primates, and responses were sustained to week 48. Phase 2 studies and efficacy trials assessing cAd3-EBO are in progress. (Funded by the Intramural Research Program of the National Institutes of Health; VRC 207 ClinicalTrials.gov number, NCT02231866.) C1 [Ledgerwood, Julie E.; DeZure, Adam D.; Stanley, Daphne A.; Coates, Emily E.; Novik, Laura; Enama, Mary E.; Berkowitz, Nina M.; Ploquin, Aurelie; Sitar, Sandra; Gordon, Ingelise J.; Plummer, Sarah A.; Holman, LaSonji A.; Hendel, Cynthia S.; Yamshchikov, Galina; Bailer, Robert T.; Schwartz, Richard M.; Roederer, Mario; Mascola, John R.; Koup, Richard A.; Sullivan, Nancy J.; Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hu, Zonghui; Joshi, Gyan] NIAID, Biostat Res Branch, Div Clin Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Roman, Francois] GlaxoSmithKline Vaccines, Rixensart, Belgium. [Nicosia, Alfredo; Colloca, Stefano] ReiThera, Rome, Italy. [Nicosia, Alfredo] Univ Naples Federico II, CEINGE, Naples, Italy. [Nicosia, Alfredo] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, Naples, Italy. [Cortese, Riccardo] Keires, Basel, Switzerland. RP Ledgerwood, JE (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ledgerwood@mail.nih.gov FU National Institutes of Health FX Funded by the Intramural Research Program of the National Institutes of Health; VRC 207 ClinicalTrials.gov number, NCT02231866. NR 31 TC 45 Z9 45 U1 7 U2 7 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 9 PY 2017 VL 376 IS 10 BP 928 EP 938 DI 10.1056/NEJMoa1410863 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EM9JA UT WOS:000395626500009 PM 25426834 ER PT J AU Ritchlin, CT Colbert, RA Gladman, DD AF Ritchlin, Christopher T. Colbert, Robert A. Gladman, Dafna D. TI Psoriatic Arthritis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID JUVENILE IDIOPATHIC ARTHRITIS; PLACEBO-CONTROLLED TRIAL; AXIAL SPONDYLOARTHRITIS; ANKYLOSING-SPONDYLITIS; RHEUMATOID-ARTHRITIS; RISK-FACTORS; MONOCLONAL-ANTIBODY; DISEASE-ACTIVITY; DOUBLE-BLIND; T-CELLS C1 [Ritchlin, Christopher T.] Univ Rochester, Sch Med, Div Rheumatol Allergy & Immunol, 601 Elmwood Ave,Box 695, Rochester, NY 14642 USA. [Colbert, Robert A.] NIAMSD, Pediat Translat Res Branch, Bethesda, MD 20892 USA. [Gladman, Dafna D.] Toronto Western Hosp, Krembil Res Inst, Psoriat Arthrit Program, Univ Hlth Network, Toronto, ON, Canada. [Gladman, Dafna D.] Toronto Western Hosp, Ctr Prognosis Studies Rheumat Dis, Toronto, ON, Canada. RP Ritchlin, CT (reprint author), Univ Rochester, Sch Med, Div Rheumatol Allergy & Immunol, 601 Elmwood Ave,Box 695, Rochester, NY 14642 USA. EM christopher_ritchlin@urmc.rochester.edu FU AbbVie; Novartis Pharmaceuticals; Sun Pharmaceutical Industries; Pfizer; UCB Pharmaceuticals; Amgen; Janssen Pharmaceuticals; Eli Lilly; Celgene FX Dr. Ritchlin reports receiving consulting fees from AbbVie, Novartis Pharmaceuticals, Sun Pharmaceutical Industries, and Pfizer and grant support from UCB Pharmaceuticals, Amgen, Janssen Pharmaceuticals, and AbbVie; Dr. Colbert, being a principal investigator on a Cooperative Research and Development Agreement (CRADA) between his institute and Eli Lilly; and Dr. Gladman, receiving honoraria from AbbVie, Amgen, Celgene, Janssen Pharmaceuticals, Novartis Pharmaceuticals, UCB Pharmaceuticals, and Bristol-Myers Squibb, consulting fees from Eli Lilly, and grant support from Pfizer, AbbVie, Celgene, Janssen Pharmaceuticals, Novartis Pharmaceuticals, and UCB Pharmaceuticals. No other potential conflict of interest relevant to this article was reported. NR 82 TC 0 Z9 0 U1 2 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 9 PY 2017 VL 376 IS 10 BP 957 EP 970 DI 10.1056/NEJMra1505557 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA EM9JA UT WOS:000395626500012 PM 28273019 ER PT J AU Cockrell, DC Long, CM Robertson, SJ Shannon, JG Miller, HE Myers, L Larson, CL Starr, T Beare, PA Heinzen, RA AF Cockrell, Diane C. Long, Carrie M. Robertson, Shelly J. Shannon, Jeffrey G. Miller, Heather E. Myers, Lara Larson, Charles L. Starr, Tregei Beare, Paul A. Heinzen, Robert A. TI Robust growth of avirulent phase II Coxiella burnetii in bone marrow-derived murine macrophages SO PLOS ONE LA English DT Article ID PARASITOPHOROUS VACUOLE MATURATION; Q-FEVER; IN-VITRO; ALVEOLAR MACROPHAGES; NATURAL-RESISTANCE; EFFECTOR PROTEINS; MOUSE MACROPHAGES; HOST-CELL; INFECTION; LIPOPOLYSACCHARIDE AB Published data show that murine bone marrow-derived macrophages (BMDM) restrict growth of avirulent phase II, but not virulent phase I, Coxiella burnetii. Growth restriction of phase II bacteria is thought to result from potentiated recognition of pathogen-associated molecular patterns, which leads to production of inhibitory effector molecules. Past studies have used conditioned medium from L-929 murine fibroblasts as a source of macrophagecolony stimulating factor (M-CSF) to promote differentiation of bone marrow-derived myeloid precursors into macrophages. However, uncharacterized components of conditioned medium, such as variable amounts of type I interferons, can affect macrophage activation status and their permissiveness for infection. In the current study, we show that the C. burnetii Nine Mile phase II (NMII) strain grows robustly in primary macrophages from C57BL/6J mice when bone marrow cells are differentiated with recombinant murine M-CSF (rmMCSF). Bacteria were readily internalized by BMDM, and replicated within degradative, LAMP1-positive vacuoles to achieve roughly 3 logs of growth over 6 days. Uninfected BMDM did not appreciably express CD38 or Egr2, markers of classically (M1) and alternatively (M2) activated macrophages, respectively, nor did infection change the lack of polarization. In accordance with an M0 phenotype, infected BMDM produced moderate amounts of TNF and nitric oxide. Similar NMII growth results were obtained using C57BL/6J myeloid progenitors immortalized with an estrogen-regulated Hoxb8 (ER-Hoxb8) oncogene. To demonstrate the utility of the ER-Hoxb8 system, myeloid progenitors from natural resistance-associated macrophage protein 1 (Nramp1) C57BL/6J knock-in mice were transduced with ER-Hoxb8, and macrophages were derived from immortalized progenitors using rmM-CSF and infected with NMII. No difference in growth was observed when compared to macrophages from wild type mice, indicating depletion of metal ions by the Nramp1 transporter does not negatively impact NMII growth. Results with NMII were recapitulated in primary macrophages where C57BL/6J Nramp1+ BMDM efficiently killed Salmonella enterica serovar Typhimurium. M-CSF differentiated murine macrophages from bone marrow and conditional ER-Hoxb8 myeloid progenitors will be useful ex vivo models for studying Coxiella-macrophage interactions. C1 [Cockrell, Diane C.; Long, Carrie M.; Miller, Heather E.; Larson, Charles L.; Beare, Paul A.; Heinzen, Robert A.] NIAID, Coxiella Pathogenesis Sect, Bacteriol Lab, Rocky Mt Labs,NIH, Hamilton, MT USA. [Robertson, Shelly J.] NIAID, Innate Immun & Pathogenesis Unit, Virol Lab, Rocky Mt Labs,NIH, Hamilton, MT USA. [Shannon, Jeffrey G.] NIAID, Plague Sect, Lab Zoonot Pathogens, Rocky Mt Labs,NIH, Hamilton, MT USA. [Myers, Lara] NIAID, Retroviral Immunol Sect, Persistent Viral Dis Lab, Rocky Mt Labs,NIH, Hamilton, MT USA. [Starr, Tregei] NIAID, Salmonella Host Cell Interact Sect, Bacteriol Lab, Rocky Mt Labs,NIH, Hamilton, MT USA. RP Heinzen, RA (reprint author), NIAID, Coxiella Pathogenesis Sect, Bacteriol Lab, Rocky Mt Labs,NIH, Hamilton, MT USA. EM rheinzen@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health [1 Z1A A100931]; Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (grant number 1 Z1A A100931).; This work was supported by funding from the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases (RAH) NR 67 TC 0 Z9 0 U1 0 U2 0 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 9 PY 2017 VL 12 IS 3 AR e0173528 DI 10.1371/journal.pone.0173528 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6AW UT WOS:000396087900007 PM 28278296 ER PT J AU Raihan, MJ Farzana, FD Sultana, S Haque, MA Rahman, AS Waid, JL McCormick, B Choudhury, N Ahmed, T AF Raihan, Mohammad Jyoti Farzana, Fahmida Dil Sultana, Sabiha Haque, Md Ahshanul Rahman, Ahmed Shafiqur Waid, Jillian L. McCormick, Ben Choudhury, Nuzhat Ahmed, Tahmeed TI Examining the relationship between socio-economic status, WASH practices and wasting SO PLOS ONE LA English DT Article ID ACUTE MALNUTRITION; RURAL BANGLADESH; CHILD UNDERNUTRITION; WATER; INTERVENTION; ENTEROPATHY; PREVENTION; DIARRHEA; DISINFECTION; INFECTIONS AB Childhood wasting is a global problem and is significantly more pronounced in low and middle income countries like Bangladesh. Socio Economic Status (SES) and Water, Sanitation and Hygiene (WASH) practices may be significantly associated with wasting. Most previous research is consistent about the role of SES, but the significance of WASH in the context of wasting remains ambiguous. The effect of SES and WASH on weight for length (WHZ) is examined using a Structural Equation Model (SEM) to explicitly describe the direct and indirect role of WASH in the context of SES. A nationally representative survey of 10,478 Bangladeshi children under 5 were examined. An expert defined SEM was used to construct latent variables for SES and WASH. The SEM included a direct pathway from SES to WHZ and an indirect pathway from SES to WHZ via WASH along with regression of relevant covariates on the outcome WHZ and the latent variables. Both SES (p<0.01) and WASH (p<0.05) significantly affect WHZ. SES (p<0.01) also significantly affects WASH. Other structural components showed that child's age (p<0.01) affects WHZ and types of residence (p<0.01) affects SES. WASH practices at least partially mediate the association between SES and wasting status. WASH and SES are both significantly associated with WHZ. C1 [Raihan, Mohammad Jyoti; Farzana, Fahmida Dil; Haque, Md Ahshanul; Rahman, Ahmed Shafiqur; Choudhury, Nuzhat; Ahmed, Tahmeed] Int Ctr Diarrhoeal Dis Res, Nutr & Clin Serv Div, Dhaka, Bangladesh. [Sultana, Sabiha; Ahmed, Tahmeed] BRAC Univ, James P Grant Sch Publ Hlth, Dhaka, Bangladesh. [Waid, Jillian L.] Helen Keller Int, Dhaka, Bangladesh. [McCormick, Ben] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Ahmed, T (reprint author), Int Ctr Diarrhoeal Dis Res, Nutr & Clin Serv Div, Dhaka, Bangladesh.; Ahmed, T (reprint author), BRAC Univ, James P Grant Sch Publ Hlth, Dhaka, Bangladesh. EM tahmeed@icddrb.org FU European Commission; EU FX This study was made possible by the committed contribution and partnership of James P Grant School of Public Health (JPGSPH), BRAC University and icddr,b. This project itself is a joint partnership between JPGSPH, BRAC University, Bangladesh Bureau of Statistics and Helen Keller International (HKI), Bangladesh and funded by European Commission.; This manuscript was made possible by the committed contribution and partnership of James P Grant School of Public Health (JPGSPH), BRAG University (BU) and icddr,b. The manuscript is based on data collected and shared by FSNSP, implemented by JPGSPH, BU, Helen Keller International, Bangladesh and Bangladesh Bureau of Statistics and funded by EU. This manuscript has been reviewed by FSNSP technical reviewers for scientific content and consistency of data interpretation with previous FSNSP publications and significant comments have been incorporated prior to submission for publication. We acknowledge the following donors for providing unrestricted support to icddr,b's effort and advancement to its strategic plan: Government of the People's Republic of Bangladesh; Canada (Global Affairs, Canada-GAC), Sweden (Sida), and the United Kingdom (DFID). NR 49 TC 0 Z9 0 U1 0 U2 0 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 9 PY 2017 VL 12 IS 3 AR e0172134 DI 10.1371/journal.pone.0172134 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6AW UT WOS:000396087900115 PM 28278161 ER PT J AU Vermeersch, E Denorme, F Maes, W De Meyer, SF Vanhoorelbeke, K Edwards, J Shevach, EM Unutmaz, D Fujii, H Deckmyn, H Tersteeg, C AF Vermeersch, Elien Denorme, Frederik Maes, Wim De Meyer, Simon F. Vanhoorelbeke, Karen Edwards, Justin Shevach, Ethan M. Unutmaz, Derya Fujii, Hodaka Deckmyn, Hans Tersteeg, Claudia TI The role of platelet and endothelial GARP in thrombosis and hemostasis SO PLOS ONE LA English DT Article ID LATENT TGF-BETA; MESSENGER-RNA EXPRESSION; REGULATORY T-CELL; IN-VIVO; GENE-EXPRESSION; TRANSGENIC MICE; MODEL; SURFACE; ACTIVATION; TGF-BETA-1 AB Background Glycoprotein-A Repetitions Predominant protein (GARP or LRRC32) is present on among others human platelets and endothelial cells. Evidence for its involvement in thrombus formation was suggested by full knockout of GARP in zebrafish. Objectives To evaluate the role of GARP in platelet physiology and in thrombus formation using platelet and endothelial conditional GARP knock out mice. Methods Platelet and endothelial specific GARP knockout mice were generated using the Cre-loxP recombination system. The function of platelets without GARP was measured by flow cytometry, spreading analysis and aggregometry using PAR4-activating peptide and collagen related peptide. Additionally, clot retraction and collagen-induced platelet adhesion and aggregation under flow were analyzed. Finally, in vivo tail bleeding time, occlusion time of the mesenteric and carotid artery after FeCI3-induced thrombosis were determined in platelet and endothelial specific GARP knock out mice. Results Platelet specific GARP knockout mice had normal surface GPIb, GPVI and integrin al lb glycoprotein expression. Although GARP expression was increased upon platelet activation, platelets without GARP displayed normal agonist induced activation, spreading on fibrinogen and aggregation responses. Furthermore, absence of GARP on platelets did not influence clot retraction and had no impact on thrombus formation on collagen-coated surfaces under flow. In line with this, neither the tail bleeding time nor the occlusion time in the carotidand mesenteric artery after FeCI3-induced thrombus formation in platelet or endothelial specific GARP knock out mice were affected. Conclusions Evidence is provided that platelet and endothelial GARP are not important in hemostasis and thrombosis in mice. C1 [Vermeersch, Elien; Denorme, Frederik; Maes, Wim; De Meyer, Simon F.; Vanhoorelbeke, Karen; Deckmyn, Hans; Tersteeg, Claudia] Katholieke Univ Leuven, IRF Life Sci, Lab Thrombosis Res, Campus Kulak Kortrijk, Kortrijk, Belgium. [Edwards, Justin; Shevach, Ethan M.] NIAID, Immunol Lab, Bldg 10, Bethesda, MD 20892 USA. [Unutmaz, Derya] Jackson Lab Genom Med, Farmington, CT USA. [Fujii, Hodaka] Osaka Univ, Chromatin Biochem Res Grp, Combined Program Microbiol & Immunol, Microbial Dis Res Inst, Osaka, Japan. RP Deckmyn, H (reprint author), Katholieke Univ Leuven, IRF Life Sci, Lab Thrombosis Res, Campus Kulak Kortrijk, Kortrijk, Belgium. EM Hans.Deckmyn@kuleuven.be RI Fujii, Hodaka/A-2420-2008 OI Fujii, Hodaka/0000-0003-1296-4256 FU Research Foundation Flanders (FWO), Belgium [G.0628.13]; FWO, Belgium [12N0715N]; Division of Intramural Research, NIAID FX HD received funding from the Research Foundation Flanders (FWO, http://www.fwo.be), Belgium (FWO grant G.0628.13). CT is a Postdoctoral Fellow also supported by the FWO, Belgium (12N0715N). JE and EMS are supported by funds from the Division of Intramural Research, NIAID (http://www.niaid.niti.gov/about/dir). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 0 Z9 0 U1 6 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 9 PY 2017 VL 12 IS 3 AR e0173329 DI 10.1371/journal.pone.0173329 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN6AW UT WOS:000396087900073 PM 28278197 ER PT J AU Park, JY Chung, H Choi, Y Park, JH AF Park, Joo-Young Chung, Hyunsoo Choi, Youngnim Park, Jung-Hyun TI Phenotype and Tissue residency of lymphocytes in the Murine Oral Mucosa SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE cellular immunity; maxillofacial; collagenases; flow cytometry; monocytes; cell isolation ID MEMORY T-CELLS; DENDRITIC CELLS; NONLYMPHOID TISSUE; LYMPHOID ORGANS; MONOCYTES; IMMUNITY; EGRESS; EPITHELIUM; TOLERANCE; PEPTIDES AB The oral mucosa is a critical barrier tissue that harbors a series of distinct immune cell subsets. Immune surveillance in the oral mucosa is important for both local and systemic immunity because the oral cavity is a heavily utilized route of pathogen entry and also serves as site of pathogen propagation. Nonetheless, composition and phenotype of the lymphocyte pool in the oral mucosa have remained poorly characterized. Utilizing a newly established protocol for mucosal immune cell isolation, here, we report that the oral mucosa features a unique cellular composition of immune cells, which differed not only from secondary lymphoid organs but also from mucosal tissues in the gut and lung. We observed profound accumulation of CD11b(+)Ly6C(lo) monocytes in the oral mucosa that were maintained independently of T-and B-lymphocytes. Unlike the gut mucosa, the oral mucosa neither contained CD8aa T cells nor was it enriched for CD103(+)CD69(+) tissue-resident memory CD8 T cells. In fact, a major fraction of T cells circulated and trafficked through the mucosa as revealed by treatment with the S1P1 receptor antagonist, FTY720, a potent inhibitor of lymphocyte migration. Collectively, these results provide a comprehensive picture of immune cells in the oral mucosa as an active site of lymphocyte recruitment and surveillance. C1 [Park, Joo-Young; Chung, Hyunsoo; Park, Jung-Hyun] NCI, NIH, Expt Immunol Branch, Bethesda, MD 20892 USA. [Choi, Youngnim] Seoul Natl Univ, Sch Dent, Dent Res Inst, Dept Oral Microbiol & Immunol, Seoul 151, South Korea. RP Park, JH (reprint author), NCI, NIH, Expt Immunol Branch, Bethesda, MD 20892 USA.; Choi, Y (reprint author), Seoul Natl Univ, Sch Dent, Dent Res Inst, Dept Oral Microbiol & Immunol, Seoul 151, South Korea. EM youngnim@snu.ac.kr; parkhy@mail.nih.gov FU US National Institutes of Health, National Cancer Institute, Center for Cancer Research [2015048003]; National Research Foundation of Korea (Daejon, Korea) - Korean Government FX The authors thank Dr. A. Singer for discussion and review of this manuscript. The authors thank Susan Sharrow and Tony Adams for expert flow cytometry. This study was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research, and by a grant, 2015048003, of the National Research Foundation of Korea (Daejon, Korea), funded by the Korean Government. NR 46 TC 0 Z9 0 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD MAR 8 PY 2017 VL 8 AR 250 DI 10.3389/fimmu.2017.00250 PG 10 WC Immunology SC Immunology GA EN0HP UT WOS:000395691200001 PM 28337201 ER PT J AU Jain, V Garg, A Parascandola, M Chaturvedi, P Khariwala, SS Stepanov, I AF Jain, Vipin Garg, Apurva Parascandola, Mark Chaturvedi, Pankaj Khariwala, Samir S. Stepanov, Irina TI Analysis of Alkaloids in Areca Nut-Containing Products by Liquid Chromatography-Tandem Mass Spectrometry SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE areca nut; arecaidine; arecoline; guvacine; guvacoline; LC MS/MS ID BETEL QUID CHEWERS; EPITHELIAL-CELLS; ORAL-CANCER; ARECOLINE; TOBACCO; SALIVA; CARCINOGENICITY; CATECHU; INVITRO AB Chewing of areca nut in different forms such as betel quid or commercially produced pan masala and gutkha is common practice in the Indian subcontinent and many parts of Asia and is associated with a variety of negative health outcomes, particularly oral and esophageal cancers. Areca nut-specific alkaloids arecoline, arecaidine, guvacoline, and guvacine have been implicated in both the abuse liability and the carcinogenicity of the areca nut. Therefore, variations in the levels of areca alkaloids could potentially contribute to variations in addictive and carcinogenic potential across areca nut-containing products. Here, we developed an accurate and robust liquid chromatography tandem mass-spectrometry (LC-MS/MS) method for simultaneous quantitation of all four areca alkaloids and applied this method to the analysis of a range of products obtained from India, China, and the United States. The results of the analyses revealed substantial variations in the levels of alkaloids across the tested products, with guvacine being the most abundant (1.39-8.16 mg/g), followed by arecoline (0.64-2.22 mg/g), arecaidine (0.14-1.70 mg/g), and guvacoline (0.17-0.99 mg/g). Substantial differences in the relative contribution of individual alkaloids to the total alkaloid content were also observed among the different products. Our results highlight the need for systematic surveillance of constituent levels in areca nut-containing products and a better understanding of the relationship between the chemical profile and the harmful potential of these products. C1 [Jain, Vipin; Stepanov, Irina] Univ Minnesota, Masonic Canc Ctr, 2231 Sixth St SE, Minneapolis, MN 55455 USA. [Garg, Apurva; Chaturvedi, Pankaj] Tata Mem Hosp, Dept Head & Neck Oncosurg, Mumbai 400012, Maharashtra, India. [Parascandola, Mark] NCI, Tobacco Control Res Branch, Bethesda, MD 20892 USA. [Khariwala, Samir S.] Univ Minnesota, Dept Otolaryngol Head & Neck Surg, 420 Delaware St SE, Minneapolis, MN 55455 USA. [Stepanov, Irina] Univ Minnesota, Div Environm Hlth Sci, 2231 Sixth St SE, Minneapolis, MN 55455 USA. RP Stepanov, I (reprint author), Univ Minnesota, Masonic Canc Ctr, 2231 Sixth St SE, Minneapolis, MN 55455 USA. EM stepa011@umn.edu FU National Cancer Institute [HHSN261201200392P, CA180880]; National Institute of Dental and Craniofacial Research [K23DE023572]; Masonic Cancer Center [CA-77598] FX This study was supported by Contract HHSN261201200392P and Grant CA180880 from the National Cancer Institute, Grant K23DE023572 from the National Institute of Dental and Craniofacial Research, and by startup funds to I.S. from the Masonic Cancer Center. LC MS/MS was carried out in the Analytical Biochemistry Shared Resource of the Masonic Cancer Center, supported in part by Grant CA-77598 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 31 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 EI 1520-5118 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD MAR 8 PY 2017 VL 65 IS 9 BP 1977 EP 1983 DI 10.1021/acs.jafc.6b05140 PG 7 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA EN7ME UT WOS:000396186100016 PM 28190359 ER PT J AU Rosenberger, A Sohns, M Friedrichs, S Hung, RJ Fehringer, G McLaughlin, J Amos, CI Brennan, P Risch, A Bruske, I Caporaso, NE Landi, MT Christiani, DC Wei, YY Bickeboller, H AF Rosenberger, Albert Sohns, Melanie Friedrichs, Stefanie Hung, Rayjean J. Fehringer, Gord McLaughlin, John Amos, Christopher I. Brennan, Paul Risch, Angela Brueske, Irene Caporaso, Neil E. Landi, Maria Teresa Christiani, David C. Wei, Yongyue Bickeboeller, Heike TI Gene-set meta-analysis of lung cancer identifies pathway related to systemic lupus erythematosus SO PLOS ONE LA English DT Article ID RISK-FACTORS; SUSCEPTIBILITY LOCUS; ASSOCIATION ANALYSIS; POOLED ANALYSIS; NEVER-SMOKERS; DNA-REPAIR; CONSORTIUM; VARIANTS; POLYMORPHISMS; INFLAMMATION AB Introduction Gene-set analysis (GSA) is an approach using the results of single-marker genome-wide association studies when investigating pathways as a whole with respect to the genetic basis of a disease. Methods We performed a meta-analysis of seven GSAs for lung cancer, applying the method METAGSA. Overall, the information taken from 11,365 cases and 22,505 controls from within the TRICL/ILCCO consortia was used to investigate a total of 234 pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Results META-GSA reveals the systemic lupus erythematosus KEGG pathway hsa05322, driven by the gene region 6p21-22, as also implicated in lung cancer (p = 0.0306). This gene region is known to be associated with squamous cell lung carcinoma. The most important genes driving the significance of this pathway belong to the genomic areas HIST1-H4L,- 1BN, -2BN, -H2AK, -H4K and C2/C4A/C4B. Within these areas, the markers most significantly associated with LC are rs13194781 (located within HIST12BN) and rs1270942 (located between C2 and C4A). Conclusions We have discovered a pathway currently marked as specific to systemic lupus erythematosus as being significantly implicated in lung cancer. The gene region 6p21-22 in this pathway appears to be more extensively associated with lung cancer than previously assumed. Given wide-stretched linkage disequilibrium to the area APOM/BAG6/MSH5, there is currently simply not enough information or evidence to conclude whether the potential pleiotropy of lung cancer and systemic lupus erythematosus is spurious, biological, or mediated. Further research into this pathway and gene region will be necessary. C1 [Rosenberger, Albert; Sohns, Melanie; Friedrichs, Stefanie; Bickeboeller, Heike] Georg August Univ Gottingen, Univ Med Ctr, Dept Genet Epidemiol, Gottingen, Germany. [Hung, Rayjean J.; Fehringer, Gord] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [Hung, Rayjean J.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [McLaughlin, John] Publ Hlth Ontario, Toronto, ON, Canada. [Amos, Christopher I.] Geisel Sch Med Dartmouth, Dept Biomed Data Sci, Hanover, NH USA. [Brennan, Paul] Int Agcy Res Canc, Lyon, France. [Risch, Angela] Salzburg Univ, Div Mol Biol, Salzburg, Austria. [Brueske, Irene] Helmholtz Ctr Munich, Inst Epidemiol 1, Munich, Germany. [Caporaso, Neil E.; Landi, Maria Teresa] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Christiani, David C.; Wei, Yongyue] Harvard Univ, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. RP Rosenberger, A (reprint author), Georg August Univ Gottingen, Univ Med Ctr, Dept Genet Epidemiol, Gottingen, Germany. EM arosenb@gwdg.de FU National Institute of Health (NIH) [U19CA148127]; Canadian Cancer Society Research Institute [020214]; Cancer Care Ontario Chair Award; Deutsche Krebshilfe [70-2919]; Helmholtz-Gemeinschaft (HGF) Munich; National Genome Research Network (NGFN); Deutsche Forschungsgemeinschaft DFG [BI 576/2-1, BI 576/2-2]; Federal Office for Radiation Protection [BfS: STSch4454]; European Community [LSHG-CT-2005-512113]; Norwegian Cancer Association; Functional Genomics Programme of Research Council of Norway; European Regional Development Fund; State Budget of the Czech Republic (RECAMO) [CZ.1.05/2.1.00/03.0101]; FP7 [REGPOT 245536]; Estonian Government [SF0180142s08]; EU RDF in the frame of Centre of Excellence in Genomics and Estoinian Research Infrastructure's Roadmap; University of Tartu (SP1GVARENG); Intramural Research Program of National Institute of Health (NIH), National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics; U.S. Public Health Service from the NCI [N01-CN-45165, N01-RC-45035, N01-RC 37004]; NCI [N01-CN-25514]; Georgetown University [N01-CN-25522]; Pacific Health Research Institute [N01-CN-25515]; Henry Ford Health System [N01-CN-25512]; University of Minnesota [N01-CN-25513]; Washington University [N01-CN-25516]; University of Pittsburgh [N01-CN-25511]; University of Utah [N01-CN-25524]; Marshfield Clinic Research Foundation [N01-CN-25518]; University of Alabama at Birmingham (Westat, Inc.) [N01-CN-75022, NO1-CN-25476]; University of California, Los Angeles [N01-CN-25404]; American Cancer Society; NIH Genes, Environment and Health Initiative [HG-06-033-NCI-01, RO1HL091172-01]; NIH grants [P50 CA70907, RO1CA121197, RO1 CA127219, U19 CA148127, RO1 CA55769]; CPRIT [RP100443]; NIH [HHSN2682007820 96C]; NHI [CA074386, CA092824, CA090578]; HGF; Institut National du Cancer, France FX This study was supported by a grant from the National Institute of Health (NIH) (U19CA148127). The Toronto study was supported by Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and ILCCO data management was supported by the Cancer Care Ontario Chair Award to R.H. The German Lung Cancer Study (GLC) consists of three data sets. The Heidelberg Lung Cancer Study was in part supported by a grant (70-2919) from the Deutsche Krebshilfe. The KORA Surveys were financed by the Helmholtz-Gemeinschaft (HGF) Munich. The LUng Cancer in the Young (LUCY) study was funded in part by the National Genome Research Network (NGFN), the Deutsche Forschungsgemeinschaft DFG (BI 576/2-1; BI 576/2-2), the HGF and the Federal Office for Radiation Protection (BfS: STSch4454). Genotyping was performed in the Genome-Analysis-Center (GAC) of the Helmholtz Zentrum MOnchen (HMGU). Support for the Central Europe, HUNT2/Tromso and CARET genome-wide studies was provided by Institut National du Cancer, France. Support for the HUNT2/Tromso genome-wide study was also provided by the European Community (Integrated Project DNA repair, LSHG-CT-2005-512113), the Norwegian Cancer Association and the Functional Genomics Programme of Research Council of Norway. Support for the Central Europe study, Czech Republic, was also provided by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101). The lung cancer GWAS from Estonia was partly supported by a FP7 grant (REGPOT 245536), by the Estonian Government (SF0180142s08), by EU RDF in the frame of Centre of Excellence in Genomics and Estoinian Research Infrastructure's Roadmap and by University of Tartu (SP1GVARENG). The Environment and Genetics in Lung Cancer Etiology (EAGLE), the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC) and the Prostate, Lung, Colon, Ovary Screening Trial (PLCO) studies and the genotyping of ATBC, the Cancer Prevention Study II Nutrition Cohort (CPS-II) and part of PLCO were supported by the Intramural Research Program of National Institute of Health (NIH), National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics. ATBC was also supported by U.S. Public Health Service contracts (N01-CN-45165, N01-RC-45035 and N01-RC 37004) from the NCI. PLCO was also supported by individual contracts from the NCI to the University of Colorado Denver (N01-CN-25514), Georgetown University (N01-CN-25522), Pacific Health Research Institute (N01-CN-25515), Henry Ford Health System (N01-CN-25512), University of Minnesota (N01-CN-25513), Washington University (N01-CN-25516), University of Pittsburgh (N01-CN-25511), University of Utah (N01-CN-25524), Marshfield Clinic Research Foundation (N01-CN-25518), University of Alabama at Birmingham (N01-CN-75022, Westat, Inc. NO1-CN-25476), University of California, Los Angeles (N01-CN-25404). The Cancer Prevention Study II Nutrition Cohort was supported by the American Cancer Society. The NIH Genes, Environment and Health Initiative (GED partly funded DNA extraction and statistical analyses (HG-06-033-NCI-01 and RO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C) and study coordination at the GENEVA Coordination Center (U01 HG004446) for EAGLE and part of PLCO studies. Funding for the MD Anderson Cancer Study was provided by NIH grants (P50 CA70907, RO1CA121197, RO1 CA127219, U19 CA148127, RO1 CA55769) and CPRIT grant (RP100443).; Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is funded through a federal contract from the NIH to The Johns Hopkins University (HHSN2682007820 96C). The Harvard Lung Cancer Study was funded by Funded by NHI (CA074386, CA092824, CA090578). NR 51 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 8 PY 2017 VL 12 IS 3 AR e0173339 DI 10.1371/journal.pone.0173339 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN5VL UT WOS:000396073700053 PM 28273134 ER PT J AU Takeda, T Hao, M Cheng, TJ Bryant, SH Wang, YL AF Takeda, Takako Hao, Ming Cheng, Tiejun Bryant, Stephen H. Wang, Yanli TI Predicting drug-drug interactions through drug structural similarities and interaction networks incorporating pharmacokinetics and pharmacodynamics knowledge SO JOURNAL OF CHEMINFORMATICS LA English DT Article DE Drug-drug interaction (DDI); Structural similarity; Interaction networks; Enzymes; Transporters; Target proteins; Pharmacokinetics (PK); Pharmacodynamics (PD); Protein-protein interaction (PPI) ID PHARMACOGENOMICS; SIMVASTATIN; ALBUMIN AB Drug-drug interactions (DDIs) may lead to adverse effects and potentially result in drug withdrawal from the market. Predicting DDIs during drug development would help reduce development costs and time by rigorous evaluation of drug candidates. The primary mechanisms of DDIs are based on pharmacokinetics (PK) and pharmacodynamics (PD). This study examines the effects of 2D structural similarities of drugs on DDI prediction through interaction networks including both PD and PK knowledge. Our assumption was that a query drug (Dq) and a drug to be examined (De) likely have DDI if the drugs in the interaction network of De are structurally similar to Dq. A network of De describes the associations between the drugs and the proteins relating to PK and PD for De. These include target proteins, proteins interacting with target proteins, enzymes, and transporters for De. We constructed logistic regression models for DDI prediction using only 2D structural similarities between each Dq and the drugs in the network of De. The results indicated that our models could effectively predict DDIs. It was found that integrating structural similarity scores of the drugs relating to both PK and PD of De was crucial for model performance. In particular, the combination of the target-and enzyme-related scores provided the largest increase of the predictive power. C1 [Takeda, Takako; Hao, Ming; Cheng, Tiejun; Bryant, Stephen H.; Wang, Yanli] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Wang, YL (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM ywang@ncbi.nlm.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH) National Library of Medicine (NLM) FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH) National Library of Medicine (NLM). This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD. (http://biowulf.nih.gov). We thank Douglas Joubert, NIH Library Writing Center, for manuscript editing assistance. NR 32 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-2946 J9 J CHEMINFORMATICS JI J. Cheminformatics PD MAR 7 PY 2017 VL 9 AR 16 DI 10.1186/s13321-017-0200-8 PG 9 WC Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Chemistry; Computer Science GA EO6VL UT WOS:000396830500001 PM 28316654 ER PT J AU Liao, TJ Jang, HB Tsai, CJ Fushman, D Nussinov, R AF Liao, Tsung-Jen Jang, Hyunbum Tsai, Chung-Jung Fushman, David Nussinov, Ruth TI The dynamic mechanism of RASSF5 and MST kinase activation by Ras SO PHYSICAL CHEMISTRY CHEMICAL PHYSICS LA English DT Article ID SMALL GTPASE K-RAS4B; PROTEIN-PROTEIN INTERACTIONS; HYPERVARIABLE REGION; STRUCTURAL BASIS; SARAH DOMAINS; ONCOGENIC MUTATIONS; LIGAND-BINDING; K-RAS; KRAS; CANCER AB As a tumor suppressor, RASSF5 (NORE1A) activates MST1/2 thereby modulating the Hippo pathway. Structurally, activation involves RASSF5 and MST1/2 swapping their SARAH domains to form a SARAH heterodimer. This exposes the MST1/2 kinase domain which homodimerizes, leading to trans-autophosphorylation. The SARAH-SARAH interaction shifts RASSF5 away from its autoinhibited state and relieves MST1/2 autoinhibition. Separate crystal structures are available for the RA (Ras association) domain and SARAH dimer, where SARAH is a long straight a-helix. Using all-atom molecular dynamics simulations, we modeled the RASSF5 RA with a covalently connected SARAH to elucidate the dynamic mechanism of how SARAH mediates between autoinhibition and Ras triggered- activation. Our results show that in inactive RASSF5 the RA domain retains SARAH, yielding a self-associated conformation in which SARAH is in a kinked a-helical motif that increases the binding interface. When RASSF5 binds K-Ras4B-GTP, the equilibrium shifts toward SARAH's interacting with MST. Since the RA/SARAH affinity is relatively low, whereas that of the SARAH heterodimer is in the nM range, we suggest that RASSF5 exerts its tumor suppressor action through competition with other Ras effectors for Ras effector binding site, as well as coincidentally its recruitment to the membrane to help MST activation. Thus, SARAH plays a key role in RASSF5's tumor suppression action by linking the two major pathways in tumor cell proliferation: Ras and the MAPK ( tumor cell proliferation-promoting) pathway, and the Hippo ( tumor cell proliferation-suppressing) pathway. C1 [Liao, Tsung-Jen; Jang, Hyunbum; Tsai, Chung-Jung; Nussinov, Ruth] NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Liao, Tsung-Jen; Fushman, David] Univ Maryland, Ctr Biomol Struct & Org, Biophys Program, College Pk, MD 20742 USA. [Fushman, David] Univ Maryland, Dept Chem & Biochem, Ctr Biomol Struct & Org, College Pk, MD 20742 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Canc & Inflammat Program, Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA.; Nussinov, R (reprint author), Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel. EM nussinor@helix.nih.gov FU Frederick National Laboratory for Cancer Research; National Institutes of Health [HHSN261200800001E]; Intramural Research Program of NIH; Frederick National Lab; Center for Cancer Research FX This project 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 HHSN261200800001E. This research was supported ( in part) by the Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of theDepartment of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. All simulations had been performed using the high-performance computational facilities of the Biowulf PC/Linux cluster at the National Institutes of Health, Bethesda, MD (http:// biowulf. nih. gov). NR 52 TC 0 Z9 0 U1 0 U2 0 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1463-9076 EI 1463-9084 J9 PHYS CHEM CHEM PHYS JI Phys. Chem. Chem. Phys. PD MAR 7 PY 2017 VL 19 IS 9 BP 6470 EP 6480 DI 10.1039/c6cp08596b PG 11 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA EN5FO UT WOS:000396031200016 PM 28197608 ER PT J AU Panyutin, IV Holar, SA Neumann, RD Panyutin, IG AF Panyutin, Irina V. Holar, Sonia A. Neumann, Ronald D. Panyutin, Igor G. TI Effect of ionizing radiation on the proliferation of human embryonic stem cells SO SCIENTIFIC REPORTS LA English DT Article ID HOMOLOGOUS RECOMBINATION; HUMAN BLASTOCYSTS; SOMATIC-CELLS; SELF-RENEWAL; DNA-DAMAGE; IN-VITRO; PLURIPOTENCY; SURVIVAL; CULTURE; LINES AB We studied the effect of ionizing radiation (IR) on continuous growth of seven hESC lines. Cells were exposed to 0, 0.2, or 1 Gy of X-rays, and the growth rates of cell populations were assessed by measuring areas of the same individual colonies versus time. The population doubling times (DT) of sham-irradiated cells varied from 18.9 to 28.7 hours for different cell lines. All cell lines showed similar reaction to IR, i.e. cell populations dropped within 24-48 hours post IR; after that they recovered and grew with the same rate as the sham-irradiated cells. The relative cell survival (RCS), i.e. the ratio of normalized cell population in the irradiated samples to that of the sham-irradiated ones varied from 0.6 to 0.8 after 0.2 Gy, and from 0.1 to 0.2 after 1 Gy IR for different cell lines. We found that the RCS values of hESC lines correlated directly with their DT, i.e. the faster cells grow the more radiosensitive they are. We also found that DT and RCS values of individual colonies varied significantly within all hESC lines. We believe that the method developed herein can be useful for assessing other cytotoxic insults on cultures of hESC. C1 [Panyutin, Irina V.; Holar, Sonia A.; Neumann, Ronald D.; Panyutin, Igor G.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Holar, Sonia A.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. RP Panyutin, IG (reprint author), NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM ipanyuting@helix.nih.gov FU Intramural Research Program of the National Institutes of Health, Clinical Center FX We thank William DeGraff for his valuable help with irradiation of cells. This research was supported by the Intramural Research Program of the National Institutes of Health, Clinical Center. NR 31 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 7 PY 2017 VL 7 AR 43995 DI 10.1038/srep43995 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN3MO UT WOS:000395912800002 PM 28266624 ER PT J AU Raciti, GA Spinelli, R Desiderio, A Longo, M Parrillo, L Nigro, C D'Esposito, V Mirra, P Fiory, F Pilone, V Forestieri, P Formisano, P Pastan, I Miele, C Beguinot, F AF Raciti, Gregory A. Spinelli, Rosa Desiderio, Antonella Longo, Michele Parrillo, Luca Nigro, Cecilia D'Esposito, Vittoria Mirra, Paola Fiory, Francesca Pilone, Vincenzo Forestieri, Pietro Formisano, Pietro Pastan, Ira Miele, Claudia Beguinot, Francesco TI Specific CpG hyper-methylation leads to Ankrd26 gene downregulation in white adipose tissue of a mouse model of diet-induced obesity SO SCIENTIFIC REPORTS LA English DT Article ID IMPAIRED GLUCOSE-TOLERANCE; WIDE DNA METHYLATION; HIGH-FAT DIET; VISCERAL ADIPOSITY; JAPANESE-AMERICANS; WEIGHT-LOSS; MICE; EXPRESSION; RISK; EPIGENETICS AB the individual risk of obesity and Type 2 Diabetes (T2D). Here, we have estimated the in vivo effect of a fat-enriched diet (HFD) on the expression and the epigenetic regulation of the Ankyrin repeat domain 26 (Ankrd26) gene, which is associated with the onset of these disorders. In visceral adipose tissue (VAT), HFD exposure determined a specific hyper-methylation of Ankrd26 promoter at the -436 and -431 bp CpG sites (CpGs) and impaired its expression. Methylation of these 2 CpGs impaired binding of the histone acetyltransferase/transcriptional coactivator p300 to this same region, causing hypoacetylation of histone H4 at the Ankrd26 promoter and loss of binding of RNA Pol II at the Ankrd26 Transcription Start Site (TSS). In addition, HFD increased binding of DNA methyl-transferases (DNMTs) 3a and 3b and methyl-CpG-binding domain protein 2 (MBD2) to the Ankrd26 promoter. More importantly, Ankrd26 down-regulation enhanced secretion of pro-inflammatory mediators by 3T3-L1 adipocytes as well as in human sera. Thus, in mice, the exposure to HFD induces epigenetic silencing of the Ankrd26 gene, which contributes to the adipose tissue inflammatory secretion profile induced by high-fat regimens. C1 [Raciti, Gregory A.; Spinelli, Rosa; Desiderio, Antonella; Longo, Michele; Parrillo, Luca; Nigro, Cecilia; D'Esposito, Vittoria; Mirra, Paola; Fiory, Francesca; Formisano, Pietro; Miele, Claudia; Beguinot, Francesco] CNR, Inst Expt Endocrinol & Oncol G Salvatore, IURT, I-80131 Naples, Italy. [Raciti, Gregory A.; Spinelli, Rosa; Desiderio, Antonella; Longo, Michele; Parrillo, Luca; Nigro, Cecilia; D'Esposito, Vittoria; Mirra, Paola; Fiory, Francesca; Formisano, Pietro; Miele, Claudia; Beguinot, Francesco] Univ Naples Federico II, Dept Translat Med Sci, I-80131 Naples, Italy. [Pilone, Vincenzo] Univ Salerno, Bariatr & Metab Surg Unit, I-84084 Salerno, Italy. [Forestieri, Pietro] Univ Naples Federico II, Dept Clin Med & Surg, I-80131 Naples, Italy. [Pastan, Ira] Natl Inst Hlth, Natl Canc Inst, Mol Biol Lab, Bethesda, MD 20892 USA. RP Miele, C; Beguinot, F (reprint author), CNR, Inst Expt Endocrinol & Oncol G Salvatore, IURT, I-80131 Naples, Italy.; Miele, C; Beguinot, F (reprint author), Univ Naples Federico II, Dept Translat Med Sci, I-80131 Naples, Italy. EM c.miele@ieos.cnr.it; beguino@unina.it FU European Foundation for the Study of Diabetes (EFSD); Ministero dell'Istruzione, Universita e della Ricerca Scientifica [PON 01_02460]; Societa Italiana di Diabetologia (SID-FO.DI.RI); P.O.R. Campania FSE, Project CREMe; Ministero dell'Istruzione, Universita e della Ricerca Scientifica (grant PRIN); Ministero dell'Istruzione, Universita e della Ricerca Scientifica (grant FIRB-MERIT) FX This study was funded by the European Foundation for the Study of Diabetes (EFSD), by the Ministero dell'Istruzione, Universita e della Ricerca Scientifica (grants PRIN and FIRB-MERIT, and PON 01_02460) and by the Societa Italiana di Diabetologia (SID-FO.DI.RI). This work was further supported by the P.O.R. Campania FSE 2007-2013, Project CREMe. NR 57 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 7 PY 2017 VL 7 AR 43526 DI 10.1038/srep43526 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EM9NL UT WOS:000395638300001 PM 28266632 ER PT J AU Kreisl, WC Lawrence, R Page, E Teich, AF Subramaniam, DS Innis, RB Turner, RS AF Kreisl, William C. Lawrence, Robin Page, Emily Teich, Andrew F. Subramaniam, Deepa S. Innis, Robert B. Turner, R. Scott TI C-11-PBR28 PET DETECTS TRANSLOCATOR PROTEIN IN A PATIENT WITH ASTROCYTOMA AND ALZHEIMER DISEASE SO NEUROLOGY LA English DT Letter C1 [Kreisl, William C.; Page, Emily; Innis, Robert B.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Kreisl, William C.] Taub Inst, New York, NY 10032 USA. [Teich, Andrew F.] Columbia Univ, Med Ctr, New York, NY USA. [Lawrence, Robin; Turner, R. Scott] Georgetown Univ, Mem Disorders Program, Washington, DC USA. [Subramaniam, Deepa S.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. RP Kreisl, WC (reprint author), NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA.; Kreisl, WC (reprint author), Taub Inst, New York, NY 10032 USA. EM wck2107@cumc.columbia.edu FU NIMH NIH HHS [ZIA MH002852] 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 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAR 7 PY 2017 VL 88 IS 10 BP 1001 EP 1004 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA EP4ID UT WOS:000397343300023 PM 28179461 ER PT J AU Hachmo, Y Kalechman, Y Skornick, I Gafter, U Caspi, RR Sredni, B AF Hachmo, Yafit Kalechman, Yona Skornick, Itai Gafter, Uzi Caspi, Rachel R. Sredni, Benjamin TI The Small Tellurium Compound AS101 Ameliorates Rat Crescentic Glomerulonephritis: Association with Inhibition of Macrophage Caspase-1 Activity via Very Late Antigen-4 Inactivation SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE glomerulonephritis; cytokines; integrin; caspase-1; AS101; inflammation ID IMMUNOMODULATOR AS101; BASEMENT-MEMBRANE; MESANGIAL CELLS; TNF-ALPHA; INDUCED DEATH; VLA-4; INFILTRATION; INFLAMMATION; FIBRONECTIN; EXPRESSION AB Crescentic glomerulonephritis (CGN) is the most aggressive form of GN and, if untreated, patients can progress to end-stage renal failure within weeks of presentation. The alpha 4 beta 1 integrin very late antigen-4 (VLA-4) is an adhesion molecule of fundamental importance to the recruitment of leukocytes in inflammation. We addressed the role of VLA-4 in mediating progressive renal injury in a rat model of CGN using a small tellurium compound. AS101 [ ammonium trichloro(dioxoethylene-o, o') tellurate]. This compound has been previously shown to uniquely inhibit VLA-4 activity by redox inactivation of adjacent thiols in the exofacial domain of VLA-4. The study shows that administration of AS101 either before or after glomerular basement membrane antiserum injection ameliorates crescent formation or preserves renal function. This was associated with profound inhibition of critical inflammatory mediators, accompanied by decreased glomerular infiltration of macrophages. Mechanistic studies demonstrated vla-4 inactivation on glomerular macrophages both in vitro and in vivo as well as inhibition of caspase-1 activity. Importantly, this cysteine protease activity modification was dependent on VLA-4 inactivation and was associated with the anti-inflammatory activity of AS101. We propose that inactivation of macrophage VLA-4 by AS101 in vivo results in a decrease of inflammatory cytokines and chemokines produced in the glomeruli of diseased rats, resulting in decreased further macrophage recruitment and decreased extracellular matrix expansion. Thus, AS101, which is currently in clinical trials for other indications, might be beneficial for treatment of CGN. C1 [Hachmo, Yafit; Kalechman, Yona; Skornick, Itai; Sredni, Benjamin] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Safdie AIDS & Immunol Res Ctr, CAIR Inst, Ramat Gan, Israel. [Gafter, Uzi] Rabin Med Ctr, Lab Nephrol & Transplant Immunol, Petah Tiqwa, Israel. [Gafter, Uzi] Tel Aviv Univ, Tel Aviv, Israel. [Caspi, Rachel R.] NEI, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Sredni, B (reprint author), Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Safdie AIDS & Immunol Res Ctr, CAIR Inst, Ramat Gan, Israel. EM srednib@mail.biu.ac.il FU U.S.-Israel Binational Science Foundation (BSF) [2013481]; Safdie' Institute for AIDS and Immunology Research; Dr. Tovi Comet-Walerstein Cancer Research Chair FX This work was supported by grants from the U.S.-Israel Binational Science Foundation (BSF), 2013-2014, no. 2013481 and by The Safdie' Institute for AIDS and Immunology Research and The Dr. Tovi Comet-Walerstein Cancer Research Chair. NR 47 TC 0 Z9 0 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD MAR 7 PY 2017 VL 8 AR UNSP 240 DI 10.3389/fimmu.2017.00240 PG 13 WC Immunology SC Immunology GA EM8FY UT WOS:000395548100001 PM 28326083 ER PT J AU Lindberg, DAB AF Lindberg, Donald A. B. TI Praise for an Obituary SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Lindberg, Donald A. B.] NIH, Natl Lib Med, Germantown, MD 20874 USA. RP Lindberg, DAB (reprint author), NIH, Natl Lib Med, Germantown, MD 20874 USA. EM donald.lindberg@gmail.com NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 7 PY 2017 VL 317 IS 9 BP 907 EP 907 DI 10.1001/jama.2016.11556 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA EM8DM UT WOS:000395541500008 PM 28267859 ER PT J AU Clayton, JA Tannenbaum, C AF Clayton, Janine Austin Tannenbaum, Cara TI Sex and Gender Reporting in Research In Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Clayton, Janine Austin] NIH, Off Res Womens Hlth, 6707 Democracy Blvd,400, Bethesda, MD 20892 USA. [Tannenbaum, Cara] Canadian Inst Hlth Res, Inst Gender & Hlth, Montreal, PQ, Canada. RP Clayton, JA (reprint author), NIH, Off Res Womens Hlth, 6707 Democracy Blvd,400, Bethesda, MD 20892 USA. EM janine.clayton@nih.gov NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 7 PY 2017 VL 317 IS 9 BP 975 EP 975 DI 10.1001/jama.2017.0151 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA EM8DM UT WOS:000395541500022 PM 28267852 ER PT J AU Ahuja, M Schwartz, DM Tandon, M Son, A Zeng, M Swaim, W Eckhaus, M Hoffman, V Cui, YY Xiao, B Worley, PF Muallem, S AF Ahuja, Malini Schwartz, Daniella M. Tandon, Mayank Son, Aran Zeng, Mei Swaim, William Eckhaus, Michael Hoffman, Victoria Cui, Yiyuan Xiao, Bo Worley, Paul F. Muallem, Shmuel TI Orai1-Mediated Antimicrobial Secretion from Pancreatic Acini Shapes the Gut Microbiome and Regulates Gut Innate Immunity SO CELL METABOLISM LA English DT Article ID CROHNS-DISEASE; BACTERIAL OVERGROWTH; ENTERAL NUTRITION; CALCIUM-CHANNELS; MICE LACKING; CELLS; ORAI1; DYSBIOSIS; DIET; MICRODOMAIN AB The gut microbiome participates in numerous physiologic functions and communicates intimately with the host immune system. Antimicrobial peptides are critical components of intestinal innate immunity. We report a prominent role for antimicrobials secreted by pancreatic acini in shaping the gut microbiome that is essential for intestinal innate immunity, barrier function, and survival. Deletion of the Ca2+ channel Orai1 in pancreatic acini of adult mice resulted in 60%-70% mortality within 3 weeks. Despite robust activation of the intestinal innate immune response, mice lacking acinar Orai1 exhibited intestinal bacterial outgrowth and dysbiosis, ultimately causing systemic translocation, inflammation, and death. While digestive enzyme supplementation was ineffective, treatments constraining bacterial outgrowth (purified liquid diet, broad-spectrum antibiotics) rescued survival, feeding, and weight gain. Pancreatic levels of cathelicidin-related antimicrobial peptide (CRAMP) were reduced, and supplement of synthetic CRAMP prevented intestinal disease. These findings reveal a critical role for antimicrobial pancreatic secretion in gut innate immunity. C1 [Ahuja, Malini; Tandon, Mayank; Son, Aran; Zeng, Mei; Swaim, William; Muallem, Shmuel] Nat Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Schwartz, Daniella M.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Eckhaus, Michael; Hoffman, Victoria] NIH, Off Res Serv, Bldg 10, Bethesda, MD 20892 USA. [Cui, Yiyuan; Xiao, Bo] Sichuan Univ, Dept Neurosci, Chengdu 610041, Peoples R China. [Worley, Paul F.] Johns Hopkins Univ, Dept Neurosci, Baltimore, MD 21205 USA. RP Muallem, S (reprint author), Nat Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. EM shmuel.muallem@nih.gov FU NIH [R01 DA010309]; [DE000735] FX We thank Drs. Craig Logsdon (University of Texas, M.D. Anderson Cancer Center, Houston) and Baoan Ji (Mayo Clinic, Rochester) for providing the Cre mice and Dr. Owen G. Schwartz (Washington Hospital center) for help in reviewing and editing. This work was supported by intramural grant DE000735 to S.M. and NIH grant R01 DA010309 to P.F.W. The microbiome analysis was done by University of California Davis Mouse biology core, and the SCFAs analysis was done by the Metabolomics at University of Michigan. NR 50 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD MAR 7 PY 2017 VL 25 IS 3 BP 635 EP 646 DI 10.1016/j.cmet.2017.02.007 PG 12 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA EN9YO UT WOS:000396355700020 PM 28273482 ER PT J AU Roatt, BM Aguiar-Soares, RDD Reis, LES Cardoso, JMD Mathias, FAS de Brito, RCF da Silva, SM Gontijo, ND Ferreira, SD Valenzuela, JG Correa-Oliveira, R Giunchetti, RC Reis, AB AF Roatt, Bruno Mendes de Oliveira Aguiar-Soares, Rodrigo Dian Soares Reis, Levi Eduardo de Oliveira Cardoso, Jamille Mirelle Siqueira Mathias, Fernando Augusto Fortes de Brito, Rory Cristiane da Silva, Sydnei Magno Gontijo, Nelder De Figueiredo Ferreira, Sidney de Almeida Valenzuela, Jesus G. Correa-Oliveira, Rodrigo Giunchetti, Rodolfo Cordeiro Reis, Alexandre Barbosa TI A Vaccine Therapy for Canine Visceral Leishmaniasis Promoted Significant Improvement of Clinical ans Immune Status with Reduction in Parasite Burden SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE heterologous vaccine therapy; immunotherapy; canine visceral leishmaniasis; L. infantum; immune response ID REAL-TIME PCR; AMERICAN CUTANEOUS LEISHMANIASIS; NATURALLY INFECTED-DOGS; LUTZOMYIA-LONGIPALPIS; MEGLUMINE ANTIMONIATE; INTERFERON-GAMMA; PROTECTIVE IMMUNITY; SAPONIN ADJUVANT; CELL-MIGRATION; IMMUNOTHERAPY AB Herein, we evaluated the treatment strategy employing a therapeutic heterologous vaccine composed of antigens of Leishmania braziliensis associated with MPL adjuvant (LBMPL vaccine) for visceral leishmaniasis (VL) in symptomatic dogs naturally infected by Leishmania infantum. Sixteen dogs received immunotherapy with MPL adjuvant (n=6) or with a vaccine composed of antigens of L. braziliensis associated with MPL (LBMPL vaccine therapy, n = 10). Dogs were submitted to an immunotherapeutic scheme consisting of 3 series composed of 10 subcutaneous doses with 10-day interval between each series. The animals were evaluated before (T0) and 90 days after treatment (T90) for their biochemical/hematological, immunological, clinical, and parasitological variables. Our major results showed that the vaccine therapy with LBMPL was able to restore and normalize main biochemical (urea, AST, ALP, and bilirubin) and hematological (erythrocytes, hemoglobin, hematocrit, and platelets) parameters. In addition, in an ex vivo analysis using flow cytometry, dogs treated with LBMPL vaccine showed increased CD3+ T lymphocytes and their subpopulations (TCD4+ and TCD8(+)), reduction of CD21(+) B lymphocytes, increased NK cells (CD5- CD16(+)) and CD14(+) monocytes. Under in vitro conditions, the animals developed a strong antigen-specific lymphoproliferation mainly by TCD4(+) and TCD8(+) cells; increasing in both TCD4(+)IFN-gamma(+) and TCD8(+) IFN-gamma(+) as well as reduction of TCD4(+) IL-4(+) and TCD8(+)IL- 4(+) lymphocytes with an increased production of TNF-alpha and reduced levels of IL-10. Concerning the clinical signs of canine visceral leishmaniasis, the animals showed an important reduction in the number and intensity of the disease signs; increase body weight as well as reduction of splenomegaly. In addition, the LBMPL immunotherapy also promoted a reduction in parasite burden assessed by real-time PCR. In the bone marrow, we observed seven times less parasites in LBMPL animals compared with MPL group. The skin tissue showed a reduction in parasite burden in LBMPL dogs 127.5 times higher than MPL. As expected, with skin parasite reduction promoted by immunotherapy, we observed a blocking transmission to sand flies in LBMPL dogs with only three positive dogs after xenodiagnosis. The results obtained in this study highlighted the strong potential for the use of this heterologous vaccine therapy as an important strategy for VL treatment. C1 [Roatt, Bruno Mendes; de Oliveira Aguiar-Soares, Rodrigo Dian; Soares Reis, Levi Eduardo; de Oliveira Cardoso, Jamille Mirelle; Siqueira Mathias, Fernando Augusto; Fortes de Brito, Rory Cristiane; Ferreira, Sidney de Almeida; Correa-Oliveira, Rodrigo; Reis, Alexandre Barbosa] Univ Fed Ouro Preto, Nucleo Pesquisas Ciencias Biol, Lab Imunopatol, Ouro Preto, MG, Brazil. [Roatt, Bruno Mendes] Univ Fed Minas Gerais, COLTEC, Dept Patol Clin, Belo Horizonte, MG, Brazil. [Roatt, Bruno Mendes; Correa-Oliveira, Rodrigo; Reis, Alexandre Barbosa] INCT DT, Salvador, BA, Brazil. [da Silva, Sydnei Magno] Univ Fed Uberlandia, Inst Ciencias Biomed, Lab Bioensaios Leishmania, Uberlandia, MG, Brazil. [Gontijo, Nelder De Figueiredo] Univ Fed Minas Gerais, Dept Parasitol, Lab Fisiol Insetos Hematofagos, Belo Horizonte, MG, Brazil. [Valenzuela, Jesus G.] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Giunchetti, Rodolfo Cordeiro] Univ Fed Minas Gerais, Dept Morfol, Lab Biol Interacoes Celulares, Belo Horizonte, MG, Brazil. RP Roatt, BM; Reis, AB (reprint author), Univ Fed Ouro Preto, Nucleo Pesquisas Ciencias Biol, Lab Imunopatol, Ouro Preto, MG, Brazil.; Roatt, BM (reprint author), Univ Fed Minas Gerais, COLTEC, Dept Patol Clin, Belo Horizonte, MG, Brazil.; Roatt, BM; Reis, AB (reprint author), INCT DT, Salvador, BA, Brazil. EM bmroatt@gmail.com; alexreis@nupeb.ufop.br RI Roatt, Bruno/R-5502-2016 OI Roatt, Bruno/0000-0001-5281-3263 FU Brazilian agency CNPq [476951/2013-5]; Brazilian agency FAPEMIG [APQ-01358-12, APQ-01008-14, PRONEX APQ-01373-14]; Brazilian agency INCT-DT; Brazilian agency CAPES; Brazilian agency Universidade Federal de Ouro Preto (UFOP) FX This study was funded by Brazilian agencies CNPq (grant 476951/2013-5) FAPEMIG (grants APQ-01358-12, APQ-01008-14, and PRONEX APQ-01373-14), INCT-DT, CAPES, and Universidade Federal de Ouro Preto (UFOP). NR 60 TC 0 Z9 0 U1 2 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD MAR 7 PY 2017 VL 8 AR UNSP 217 DI 10.3389/fimmu.2017.00217 PG 14 WC Immunology SC Immunology GA EM8FU UT WOS:000395547600001 PM 28321217 ER PT J AU Bagh, MB Peng, SY Chandra, G Zhang, ZJ Singh, SP Pattabiraman, N Liu, AY Mukherjee, AB AF Bagh, Maria B. Peng, Shiyong Chandra, Goutam Zhang, Zhongjian Singh, Satya P. Pattabiraman, Nagarajan Liu, Aiyi Mukherjee, Anil B. TI Misrouting of v-ATPase subunit V0a1 dysregulates lysosomal acidification in a neurodegenerative lysosomal storage disease model SO NATURE COMMUNICATIONS LA English DT Article ID PALMITOYL-PROTEIN THIOESTERASE; NEURONAL CEROID-LIPOFUSCINOSIS; IN-VITRO; MICE; EXPRESSION; DISORDERS; AUTOPHAGY; PH; COLOCALIZATION; IDENTIFICATION AB Defective lysosomal acidification contributes to virtually all lysosomal storage disorders (LSDs) and to common neurodegenerative diseases like Alzheimer's and Parkinson's. Despite its fundamental importance, the mechanism(s) underlying this defect remains unclear. The v-ATPase, a multisubunit protein complex composed of cytosolic V1-sector and lysosomal membrane-anchored V0-sector, regulates lysosomal acidification. Mutations in the CLN1 gene, encoding PPT1, cause a devastating neurodegenerative LSD, INCL. Here we report that in Cln1(-/-) mice, which mimic INCL, reduced v-ATPase activity correlates with elevated lysosomal pH. Moreover, v-ATPase subunit a1 of the V0 sector (V0a1) requires palmitoylation for interacting with adaptor protein-2 (AP-2) and AP-3, respectively, for trafficking to the lysosomal membrane. Notably, treatment of Cln1(-/-) mice with a thioesterase (Ppt1)-mimetic, NtBuHA, ameliorated this defect. Our findings reveal an unanticipated role of Cln1 in regulating lysosomal targeting of V0a1 and suggest that varying factors adversely affecting v-ATPase function dysregulate lysosomal acidification in other LSDs and common neurodegenerative diseases. C1 [Bagh, Maria B.; Peng, Shiyong; Chandra, Goutam; Zhang, Zhongjian; Mukherjee, Anil B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Dev Genet, PEMG, NIH, Bethesda, MD 20892 USA. [Singh, Satya P.] NIAID, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Pattabiraman, Nagarajan] MolBox LLC, 8115 Fenton St 304, Silver Spring, MD 20910 USA. [Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD 20892 USA. [Peng, Shiyong] XinXiang Med Univ, Inst Psychiat & Neurosci, Xinxiang 453003, Henan, Peoples R China. RP Bagh, MB; Mukherjee, AB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Dev Genet, PEMG, NIH, Bethesda, MD 20892 USA. EM baghmb@mail.nih.gov; mukherja@exchange.nih.gov FU intramural programme of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health FX We thank J.Y. Chou, I. Owens and S.W. Levin for review of the manuscript and suggestions. We also thank S.L. Hofmann for a generous gift of the PPT1 antibody raised in the rabbit. We are grateful to V. Schram, Microscopy and Imaging Core, for assistance in confocal microscopy. We also thank the animal core facility of the NICHD for providing the care of the animals housed in the animal facilities in Building 10A and 6B. Anti-d-SA4 was deposited to the DSHB by Peden, A.A. (DSHB hybridoma product anti-d-SA4). This work was supported in full by the intramural programme of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. NR 64 TC 0 Z9 0 U1 6 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 7 PY 2017 VL 8 AR 14612 DI 10.1038/ncomms14612 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN3LE UT WOS:000395909200001 PM 28266544 ER PT J AU Zheng, HP Shao, FY Martin, S Xu, XL Deng, CX AF Zheng, Hongping Shao, Fangyuan Martin, Scots Xu, Xiaoling Deng, Chu-Xia TI WEE1 inhibition targets cell cycle checkpoints for triple negative breast cancers to overcome cisplatin resistance SO SCIENTIFIC REPORTS LA English DT Article ID TO-MESENCHYMAL TRANSITION; DRUG-RESISTANCE; STEM-CELLS; PANCREATIC-CANCER; DNA-REPLICATION; TYROSINE KINASE; MICROARRAY DATA; PHASE-II; S-PHASE; GENOME AB Cisplatin is one of the most commonly used therapeutic drugs for cancer therapy, yet prolonged cisplatin treatment frequently results in drug resistance. To enhance therapeutic effect of cisplatin, we conducted a high throughput screening using a kinase library containing 704 kinases against triple negative breast cancer (TNBC) cells. We demonstrated that cisplatin activates ATR, CHK1 and WEE1, which shut down DNA replication and attenuate cisplatin induced-lethality. WEE1 inhibition sensitizes TNBCs and cisplatin resistant cancer cells to cisplatin-induced lethality, because it not only impairs DNA replication checkpoint more profoundly than inhibition of ATR or CHK1, but also defects G2-M cell cycle checkpoint. Finally, we demonstrated that combined cisplatin treatment and WEE1 inhibition synergistically inhibits xenograft cancer growth accompanied by markedly reduced expression of TNBC signature genes. Thus targeting DNA replication and G2-M cell cycle checkpoint simultaneously by cisplatin and WEE1 inhibition is promising for TNBCs treatment, and for overcoming their cisplatin resistance. C1 [Zheng, Hongping; Deng, Chu-Xia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Shao, Fangyuan; Xu, Xiaoling; Deng, Chu-Xia] Univ Macau, Fac Hlth Sci, Zhuhai, Macau, Peoples R China. [Martin, Scots] NIH, Div Preclin Innovat, NCATS, Bldg 10, Bethesda, MD 20892 USA. RP Deng, CX (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA.; Deng, CX (reprint author), Univ Macau, Fac Hlth Sci, Zhuhai, Macau, Peoples R China. EM cxdeng@umac.mo FU Intramural Research Program of DIDDK; NIH, USA; Chair Professor Grant (CPG); Startup Research Grant (SRG); University of Macau, Macau SAR, China FX We thank members of the Deng laboratory for critical discussions. This work was supported, in part, by the Intramural Research Program of DIDDK, NIH, USA, as well as the Chair Professor Grant (CPG) and Startup Research Grant (SRG) granted to CXD by University of Macau, Macau SAR, China. NR 56 TC 0 Z9 0 U1 7 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 6 PY 2017 VL 7 AR 43517 DI 10.1038/srep43517 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EM6NJ UT WOS:000395429100001 PM 28262781 ER PT J AU Adler, S Seidel, J Choyke, P Knopp, MV Binzel, K Zhang, J Barker, C Conant, S Maass-Moreno, R AF Adler, Stephen Seidel, Jurgen Choyke, Peter Knopp, Michael V. Binzel, Katherine Zhang, Jun Barker, Craig Conant, Shielah Maass-Moreno, Roberto TI Minimum lesion detectability as a measure of PET system performance SO EJNMMI PHYSICS LA English DT Article DE PET/CT imaging; Lesion detection; Human observer study; Signal to noise AB Background: A phantom in combination with an imaging protocol was developed to measure the limit of small lesion detection on different PET systems. Seven small spheres with inner diameters ranging from 3.95 up to 15.43 mm were imaged in a Jaszczak ECT Phantom, in air, in a cold background, and with sphere to background contrast ratios of 15: 1 down to 1.88:1. The imaging times varied from 1 to 16 min. The imaging protocol was performed on the Gemini TF and Vereos by Philips, the mCT and HRRT by Siemens, and the Discovery 710 by General Electric. For each scanning condition, the images were reconstructed with image voxel sizes of 1 to 4 mm cubic voxels. The reconstruction method used for each system was the one recommended by the manufacture to achieve best small image lesion detection results. A human observer study was performed to determine the smallest observable sphere for each scanning condition. Results: All systems were able to image the smallest sphere of 3.95 mm inner diameter at the 15 to 1 signal to background ratio when imaged for 16 min. For a typical whole body per bed position scan time of 2 to 4 min, the smallest imaged sphere varied between 4.95 and 6.23 mm at the 15: 1 contrast ratio and 12.43 and 15. 43 mm at a contrast ratio of 1.88: 1. In general, all systems were consistent with the Rose criteria when determining lesion detectability. Conclusions: Besides demonstrating that the current state of the art clinical PET/CT systems have the same lesion detection ability, the study demonstrates how sensitive scan time can be to detecting small lesions which have a relatively small contrast uptake in the range of just 2: 1. This should help guide imaging protocols to use longer scan times over regions of the subject in which small lesions are suspect. C1 [Adler, Stephen; Seidel, Jurgen] Leidos Biomed Res Inc, Clin Res Directorate, Clin Monitoring Res Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Choyke, Peter] NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. [Knopp, Michael V.; Binzel, Katherine; Zhang, Jun] Ohio State Univ, Dept Radiol, Wexner Med Ctr, Columbus, OH 43210 USA. [Barker, Craig; Conant, Shielah; Maass-Moreno, Roberto] NIH, Positron Emiss Tomog Dept, Warren G Magnuson Clin Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Adler, S (reprint author), Leidos Biomed Res Inc, Clin Res Directorate, Clin Monitoring Res Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM stephen.adler@nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 25 TC 0 Z9 0 U1 9 U2 9 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 2197-7364 J9 EJNMMI PHYS JI EJNMMI Phys. PD MAR 4 PY 2017 VL 4 AR 13 DI 10.1186/s40658-017-0179 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EP1BR UT WOS:000397120900001 PM 28260215 ER PT J AU Riddick, G Kotliarova, S Rodriguez, V Kim, HS Linkous, A Storaska, AJ Ahn, S Walling, J Belova, G Fine, HA AF Riddick, Gregory Kotliarova, Svetlana Rodriguez, Virginia Kim, H. S. Linkous, Amanda Storaska, Andrew J. Ahn, Susie Walling, Jennifer Belova, Galina Fine, Howard A. TI A Core Regulatory Circuit in Glioblastoma Stem Cells Links MAPK Activation to a Transcriptional Program of Neural Stem Cell Identity SO SCIENTIFIC REPORTS LA English DT Article ID SUPPRESSOR GENE; TUMOR-CELL; GLIOMA; PROLIFERATION; GROWTH; P53; EXPRESSION; SURVIVAL; RENEWAL; PATHWAY AB Glioblastoma, the most common primary malignant brain tumor, harbors a small population of tumor initiating cells (glioblastoma stem cells) that have many properties similar to neural stem cells. To investigate common regulatory networks in both neural and glioblastoma stem cells, we subjected both cell types to in-vitro differentiation conditions and measured global gene-expression changes using gene expression microarrays. Analysis of enriched transcription factor DNA-binding sites in the promoters of differentially expressed genes was used to reconstruct regulatory networks involved in differentiation. Computational predictions, which were biochemically validated, show an extensive overlap of regulatory circuitry between cell types including a network centered on the transcription factor KLF4. We further demonstrate that EGR1, a transcription factor previously shown to be downstream of the MAPK pathway, regulates KLF4 expression and that KLF4 in turn transcriptionally activates NOTCH as well as SOX2. These results demonstrate how known genomic alterations in glioma that induce constitutive activation of MAPK are transcriptionally linked to master regulators essential for neural stem cell identify. C1 [Riddick, Gregory; Kotliarova, Svetlana; Rodriguez, Virginia; Ahn, Susie; Walling, Jennifer; Belova, Galina] NCI, Neurooncol Branch, Bethesda, MD 20892 USA. [Kim, H. S.] Macrogen, Seoul, South Korea. [Linkous, Amanda; Storaska, Andrew J.; Fine, Howard A.] Weill Cornell Med Coll, New York, NY USA. RP Fine, HA (reprint author), Weill Cornell Med Coll, New York, NY USA. EM haf9016@med.cornell.edu NR 30 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 3 PY 2017 VL 7 AR 43605 DI 10.1038/srep43605 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN8VP UT WOS:000396278200001 PM 28256619 ER PT J AU Sweeney, AM Fleming, KE McCauley, JP Rodriguez, MF Martin, ET Sousa, AA Leapman, RD Scimemi, A AF Sweeney, Amanda M. Fleming, Kelsey E. McCauley, John P. Rodriguez, Marvin F. Martin, Elliot T. Sousa, Alioscka A. Leapman, Richard D. Scimemi, Annalisa TI PAR1 activation induces rapid changes in glutamate uptake and astrocyte morphology SO SCIENTIFIC REPORTS LA English DT Article ID SYNAPTICALLY RELEASED GLUTAMATE; PAIRED-PULSE FACILITATION; LONG-TERM POTENTIATION; NMDA RECEPTORS; MULTIVESICULAR RELEASE; HIPPOCAMPAL SYNAPSES; TIME-COURSE; TRANSPORTER CURRENTS; EXCITATORY SYNAPSES; VASCULAR BIOLOGY AB The G-protein coupled, protease-activated receptor 1 (PAR1) is a membrane protein expressed in astrocytes. Fine astrocytic processes are in tight contact with neurons and blood vessels and shape excitatory synaptic transmission due to their abundant expression of glutamate transporters. PAR1 is proteolytically-activated by bloodstream serine proteases also involved in the formation of blood clots. PAR1 activation has been suggested to play a key role in pathological states like thrombosis, hemostasis and inflammation. What remains unclear is whether PAR1 activation also regulates glutamate uptake in astrocytes and how this shapes excitatory synaptic transmission among neurons. Here we show that, in the mouse hippocampus, PAR1 activation induces a rapid structural re-organization of the neuropil surrounding glutamatergic synapses, which is associated with faster clearance of synaptically-released glutamate from the extracellular space. This effect can be recapitulated using realistic 3D Monte Carlo reaction-diffusion simulations, based on axial scanning transmission electron microscopy (STEM) tomography reconstructions of excitatory synapses. The faster glutamate clearance induced by PAR1 activation leads to short-and long-term changes in excitatory synaptic transmission. Together, these findings identify PAR1 as an important regulator of glutamatergic signaling in the hippocampus and a possible target molecule to limit brain damage during hemorrhagic stroke. C1 [Sweeney, Amanda M.; Fleming, Kelsey E.; McCauley, John P.; Rodriguez, Marvin F.; Martin, Elliot T.; Scimemi, Annalisa] SUNY Albany, Dept Biol, 1400 Washington Ave, Albany, NY 12222 USA. [Rodriguez, Marvin F.] SUNY Coll Oneonta, Dept Comp Sci, 9000 Rockville Pike, Bethesda, MD 20852 USA. [Sousa, Alioscka A.; Leapman, Richard D.] Natl Inst Biomed Imaging & Bioengineering, Natl Inst Hlth, 9000 Rockville Pike, Bethesda, MD 20852 USA. [Sweeney, Amanda M.] Univ Rochester Med Ctr, 77 Ridgeland Rd, Rochester, NY 14623 USA. [Rodriguez, Marvin F.] SUNY Coll Oneonta, IT Enterprise Applicat Serv, 108 Ravine Pkwy, Oneonta, NY 13820 USA. [Sousa, Alioscka A.] Univ Fed Sao Paulo, Dept Biochem, Rua Tres Maio 100, BR-04044 Sao Paulo, Brazil. RP Scimemi, A (reprint author), SUNY Albany, Dept Biol, 1400 Washington Ave, Albany, NY 12222 USA. EM scimemia@gmail.com FU SUNY Albany; SUNY Albany Research Foundation; SUNY Brain Network of Excellence; Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health FX This work was supported by SUNY Albany, SUNY Albany Research Foundation, SUNY Brain Network of Excellence and the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health. The authors would like to thank G. Lnenicka, M. Beato and T. F. Monaghan for comments on the manuscript. NR 81 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 3 PY 2017 VL 7 AR 43606 DI 10.1038/srep43606 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN8WC UT WOS:000396279600001 PM 28256580 ER PT J AU Lee, PR Cohen, JE Iacobas, DA Iacobas, S Fields, RD AF Lee, Philip R. Cohen, Jonathan E. Iacobas, Dumitru A. Iacobas, Sanda Fields, R. Douglas TI Gene networks activated by specific patterns of action potentials in dorsal root ganglia neurons SO SCIENTIFIC REPORTS LA English DT Article ID NF-KAPPA-B; TRANSCRIPTIONAL REPRESSOR; SENSORY NEURONS; ETS FAMILY; EXPRESSION; PROTEIN; KINASE; PROFILES; PROMOTER; HIPPOCAMPUS AB Gene regulatory networks underlie the long-term changes in cell specification, growth of synaptic connections, and adaptation that occur throughout neonatal and postnatal life. Here we show that the transcriptional response in neurons is exquisitely sensitive to the temporal nature of action potential firing patterns. Neurons were electrically stimulated with the same number of action potentials, but with different inter-burst intervals. We found that these subtle alterations in the timing of action potential firing differentially regulates hundreds of genes, across many functional categories, through the activation or repression of distinct transcriptional networks. Our results demonstrate that the transcriptional response in neurons to environmental stimuli, coded in the pattern of action potential firing, can be very sensitive to the temporal nature of action potential delivery rather than the intensity of stimulation or the total number of action potentials delivered. These data identify temporal kinetics of action potential firing as critical components regulating intracellular signalling pathways and gene expression in neurons to extracellular cues during early development and throughout life. C1 [Lee, Philip R.; Cohen, Jonathan E.; Fields, R. Douglas] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Nervous Syst Dev & Plast Sect, NIH, Bethesda, MD 20892 USA. [Iacobas, Dumitru A.; Iacobas, Sanda] New York Med Coll, Dept Pathol, Valhalla, NY 10595 USA. [Iacobas, Dumitru A.] Albert Einstein Coll Med, DP Purpura Dept Neurosci, New York, NY USA. RP Fields, RD (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Nervous Syst Dev & Plast Sect, NIH, Bethesda, MD 20892 USA. EM fieldsd@mail.nih.gov FU Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) of the National Institutes of Health (NIH); [5R01HL092001] FX We would like to thank Peter Wadeson and William Huffman for DRG neurons in multicompartment chambers, Daniel Abebe for help with experimental animals and Tanya Barrett for editing the manuscript. P.R L., J.E.C. and R.D.F. are supported by the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) of the National Institutes of Health (NIH). D.A.I. and S.I. were supported by 5R01HL092001. NR 52 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 3 PY 2017 VL 7 AR 43765 DI 10.1038/srep43765 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN4JJ UT WOS:000395973500001 PM 28256583 ER PT J AU Jana, S Al-Huniti, MH Yang, BY Lu, SY Pike, VW Lepore, SD AF Jana, Susovan Al-huniti, Mohammed H. Yang, Bo Yeun Lu, Shuiyu Pike, Victor W. Lepore, Salvatore D. TI Crown Ether Nucleophilic Catalysts (CENCs): Agents for Enhanced Silicon Radiofluorination SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID CHELATING LEAVING GROUPS; ARTIFICIAL PHOSPHODIESTERASES; BUILDING-BLOCKS; LARIAT ETHERS; PET; PEPTIDES; ACCEPTOR AB New bifunctional phase transfer agents were synthesized and investigated for their abilities to promote rapid fluorination at silicon. These agents, dubbed crown ether nucleophilic catalysts (CENCs), are 18-crown-6 derivatives containing a side-arm and a potentially nucleophilic hydroxyl group. These CENCs proved efficacious in the fluorination of hindered silicon substrates, with fluorination yields dependent on the length of linker connecting the metal chelating unit to the hydroxyl group. The efficacy of these CENCs was also demonstrated for rapid radiofluorination under mild conditions for eventual application in molecular imaging with positron emission tomography (PET). The hydrolysis-resistant aryl silicon fragment is promising as a convenient synthon for labeling potential PET radiotracers. C1 [Jana, Susovan; Al-huniti, Mohammed H.; Lepore, Salvatore D.] Florida Atlantic Univ, Dept Chem & Biochem, Boca Raton, FL 33431 USA. [Yang, Bo Yeun; Lu, Shuiyu; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Lepore, SD (reprint author), Florida Atlantic Univ, Dept Chem & Biochem, Boca Raton, FL 33431 USA.; Lu, SY (reprint author), NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. EM shuiyu.lu@mail.nih.gov; slepore@fau.edu FU National Institutes Health [MH087932, GM110651]; Intramural Research Program of the National Institutes of Health (NIMH) [ZIA MH002793] FX This work was supported by grants from the National Institutes Health (MH087932 and GM110651). B.Y.Y., S.L., and V.W.P. were supported by the Intramural Research Program of the National Institutes of Health (NIMH, ZIA MH002793). The authors are grateful to the NIH Clinical PET Center for the cyclotron production of fluorine-18. NR 40 TC 0 Z9 0 U1 3 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD MAR 3 PY 2017 VL 82 IS 5 BP 2329 EP 2335 DI 10.1021/acs.joc.6b02457 PG 7 WC Chemistry, Organic SC Chemistry GA EN0UM UT WOS:000395726000003 PM 28171724 ER PT J AU Weiss, S Xu, ZZ Peddada, S Amir, A Bittinger, K Gonzalez, A Lozupone, C Zaneveld, JR Vazquez-Baeza, Y Birmingham, A Hyde, ER Knight, R AF Weiss, Sophie Xu, Zhenjiang Zech Peddada, Shyamal Amir, Amnon Bittinger, Kyle Gonzalez, Antonio Lozupone, Catherine Zaneveld, Jesse R. Vazquez-Baeza, Yoshiki Birmingham, Amanda Hyde, Embriette R. Knight, Rob TI Normalization and microbial differential abundance strategies depend upon data characteristics SO MICROBIOME LA English DT Article DE Microbiome; Normalization; Differential abundance; Statistics ID COMPOSITIONAL DATA-ANALYSIS; RNA-SEQ EXPERIMENTS; EXPRESSION ANALYSIS; SEQUENCING DATA; MULTIVARIATE-ANALYSIS; COMMUNITIES; SAMPLE; BIOCONDUCTOR; DIVERSITY; MODELS AB Background: Data from 16S ribosomal RNA (rRNA) amplicon sequencing present challenges to ecological and statistical interpretation. In particular, library sizes often vary over several ranges of magnitude, and the data contains many zeros. Although we are typically interested in comparing relative abundance of taxa in the ecosystem of two or more groups, we can only measure the taxon relative abundance in specimens obtained from the ecosystems. Because the comparison of taxon relative abundance in the specimen is not equivalent to the comparison of taxon relative abundance in the ecosystems, this presents a special challenge. Second, because the relative abundance of taxa in the specimen (as well as in the ecosystem) sum to 1, these are compositional data. Because the compositional data are constrained by the simplex (sum to 1) and are not unconstrained in the Euclidean space, many standard methods of analysis are not applicable. Here, we evaluate how these challenges impact the performance of existing normalization methods and differential abundance analyses. Results: Effects on normalization: Most normalization methods enable successful clustering of samples according to biological origin when the groups differ substantially in their overall microbial composition. Rarefying more clearly clusters samples according to biological origin than other normalization techniques do for ordination metrics based on presence or absence. Alternate normalization measures are potentially vulnerable to artifacts due to library size. Effects on differential abundance testing: We build on a previous work to evaluate seven proposed statistical methods using rarefied as well as raw data. Our simulation studies suggest that the false discovery rates of many differential abundance-testing methods are not increased by rarefying itself, although of course rarefying results in a loss of sensitivity due to elimination of a portion of available data. For groups with large (similar to 10x) differences in the average library size, rarefying lowers the false discovery rate. DESeq2, without addition of a constant, increased sensitivity on smaller datasets (< 20 samples per group) but tends towards a higher false discovery rate with more samples, very uneven (similar to 10x) library sizes, and/or compositional effects. For drawing inferences regarding taxon abundance in the ecosystem, analysis of composition of microbiomes (ANCOM) is not only very sensitive (for > 20 samples per group) but also critically the only method tested that has a good control of false discovery rate. Conclusions: These findings guide which normalization and differential abundance techniques to use based on the data characteristics of a given study. C1 [Weiss, Sophie] Univ Colorado, Dept Chem & Biol Engn, Boulder, CO 80309 USA. [Xu, Zhenjiang Zech; Amir, Amnon; Gonzalez, Antonio; Hyde, Embriette R.; Knight, Rob] Univ Calif San Diego, Dept Pediat, 9500 Gilman Dr,MC 0763, La Jolla, CA 92093 USA. [Peddada, Shyamal] NIH, NIEHS, Biostat & Computat Biol Branch, Durham, NC USA. [Bittinger, Kyle] Univ Penn, Dept Microbiol, Philadelphia, PA 18014 USA. [Lozupone, Catherine] Univ Colorado, Dept Med, Denver, CO 80204 USA. [Zaneveld, Jesse R.] Oregon State Univ, Dept Microbiol, 226 Nash Hall, Corvallis, OR 97331 USA. [Vazquez-Baeza, Yoshiki; Knight, Rob] Univ Calif San Diego, Dept Comp Sci & Engn, La Jolla, CA 92093 USA. [Birmingham, Amanda] Univ Calif San Diego, Ctr Computat Biol & Bioinformat, Dept Med, La Jolla, CA 92093 USA. [Knight, Rob] Univ Calif San Diego, Ctr Microbiome Innovat, La Jolla, CA 92093 USA. RP Knight, R (reprint author), Univ Calif San Diego, Dept Pediat, 9500 Gilman Dr,MC 0763, La Jolla, CA 92093 USA.; Knight, R (reprint author), Univ Calif San Diego, Dept Comp Sci & Engn, La Jolla, CA 92093 USA.; Knight, R (reprint author), Univ Calif San Diego, Ctr Microbiome Innovat, La Jolla, CA 92093 USA. EM robknight@ucsd.edu FU National Human Genome Research Institute [3 R01 HG004872-03S2]; National Institute of Health [5 U01 HG004866-04]; Intramural Research Program of the National Institute of Environmental Health Sciences, NIH [Z01 ES101744-04]; CTRI [UL1TR001442] FX SJW was funded by the National Human Genome Research Institute Grant No. 3 R01 HG004872-03S2 and the National Institute of Health Grant No. 5 U01 HG004866-04. Research of SDP was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH (Z01 ES101744-04). AB's participation was partially funded by CTRI grant no. UL1TR001442. NR 82 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2049-2618 J9 MICROBIOME JI Microbiome PD MAR 3 PY 2017 VL 5 AR 27 DI 10.1186/s40168-017-0237-y PG 18 WC Microbiology SC Microbiology GA EP3UU UT WOS:000397308000002 PM 28253908 ER PT J AU White, A Thom, TD White, MC Geiger, AM AF White, Arica Thom, Trevor D. White, Mary C. Geiger, Ann M. TI Cancer Screening Test Use - United States, 2015 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Editorial Material ID ALASKA NATIVE WOMEN; BREAST C1 [White, Arica; Thom, Trevor D.; White, Mary C.] CDC, Div Canc Prevent & Control, Bethesda, MD 20889 USA. [Geiger, Ann M.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. RP White, A (reprint author), CDC, Div Canc Prevent & Control, Bethesda, MD 20889 USA. EM awhite5@cdc.gov NR 7 TC 0 Z9 0 U1 0 U2 0 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD MAR 3 PY 2017 VL 66 IS 8 BP 1 EP 6 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EN4GL UT WOS:000395965900001 ER PT J AU Bussi, C Ramos, JMP Arroyo, DS Gaviglio, EA Gallea, JI Wang, JM Celej, MS Iribarren, P AF Bussi, Claudio Peralta Ramos, Javier Maria Arroyo, Daniela S. Gaviglio, Emilia A. Ignacio Gallea, Jose Wang, Ji Ming Soledad Celej, Maria Iribarren, Pablo TI Autophagy down regulates pro-inflammatory mediators in BV2 microglial cells and rescues both LPS and alpha-synuclein induced neuronal cell death SO SCIENTIFIC REPORTS LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; PARKINSONS-DISEASE; ACTIVATION; NEURODEGENERATION; EXPRESSION; INJURY; NEUROINFLAMMATION; NEUROTOXICITY; CLEARANCE; TREHALOSE AB Autophagy is a fundamental cellular homeostatic mechanism, whereby cells autodigest parts of their cytoplasm for removal or turnover. Neurodegenerative disorders are associated with autophagy dysregulation, and drugs modulating autophagy have been successful in several animal models. Microglial cells are phagocytes in the central nervous system (CNS) that become activated in pathological conditions and determine the fate of other neural cells. Here, we studied the effects of autophagy on the production of pro-inflammatory molecules in microglial cells and their effects on neuronal cells. We observed that both trehalose and rapamycin activate autophagy in BV2 microglial cells and down-regulate the production of pro-inflammatory cytokines and nitric oxide (NO), in response to LPS and alpha-synuclein. Autophagy also modulated the phosphorylation of p38 and ERK1/2 MAPKs in BV2 cells, which was required for NO production. These actions of autophagy modified the impact of microglial activation on neuronal cells, leading to suppression of neurotoxicity. Our results demonstrate a novel role for autophagy in the regulation of microglial cell activation and pro-inflammatory molecule secretion, which may be important for the control of inflammatory responses in the CNS and neurotoxicity. C1 [Bussi, Claudio; Peralta Ramos, Javier Maria; Arroyo, Daniela S.; Gaviglio, Emilia A.; Iribarren, Pablo] Univ Nacl Cordoba, Fac Ciencias Quim, Dept Bioquim Clin, Ctr Invest Bioquim Clin & Inmunol CIBIC CONICET, Cordoba, Argentina. [Ignacio Gallea, Jose; Soledad Celej, Maria] Univ Nacl Cordoba, Fac Ciencias Quim, Dept Bioquim Clin, Ctr Invest Quim Biol Cordoba CIBIC CONICET, Cordoba, Argentina. [Wang, Ji Ming] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Iribarren, P (reprint author), Univ Nacl Cordoba, Fac Ciencias Quim, Dept Bioquim Clin, Ctr Invest Bioquim Clin & Inmunol CIBIC CONICET, Cordoba, Argentina. EM piribarr@fcq.unc.edu.ar FU Fogarty International Center, National Institutes of Health, USA [1R01TW007621]; FONCyT, Argentina; CONICET, Argentina; SECyT-UNC, Argentina FX This work was supported in part by Fogarty International Center, National Institutes of Health, USA, (Grant Number 1R01TW007621), FONCyT, CONICET and SECyT-UNC, Argentina. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Fogarty International Center (FIC), National Institutes of Health, USA. NR 46 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 3 PY 2017 VL 7 AR 43153 DI 10.1038/srep43153 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EM4LP UT WOS:000395284800001 PM 28256519 ER PT J AU Porter, SS Stepp, WH Stamos, JD McBride, AA AF Porter, Samuel S. Stepp, Wesley H. Stamos, James D. McBride, Alison A. TI Host cell restriction factors that limit transcription and replication of human papillomavirus SO VIRUS RESEARCH LA English DT Review DE HPV; Sp100; IFI16; IFIT1; Restriction factor; Intrinsic immunity ID DNA-DAMAGE RESPONSE; INTERFERON-INDUCIBLE PROTEIN; SIMPLEX-VIRUS TYPE-1; MINOR CAPSID PROTEIN; NUCLEAR DOMAIN 10; PRIMARY HUMAN KERATINOCYTES; EARLY GENE-EXPRESSION; VIRAL LIFE-CYCLE; PROMYELOCYTIC LEUKEMIA; C/EBP-BETA AB The life cycle of human papillomaviruses (HPV) is tightly regulated by the differentiation state of mucosal and cutaneous keratinocytes. To counteract viral infection, constitutively expressed cellular factors, which are defined herein as restriction factors, directly mitigate viral gene expression and replication. In turn, some HPV gene products target these restriction factors and abrogate their anti-viral effects to establish efficient gene expression and replication programs. Ironically, in certain circumstances, this delicate counterbalance between viral gene products and restriction factors facilitates persistent infection by HPVs. This review serves to recapitulate the current knowledge of nuclear restriction factors that directly affect the HPV infectious cycle. Published by Elsevier B.V. C1 [Porter, Samuel S.; Stepp, Wesley H.; Stamos, James D.; McBride, Alison A.] Natl Inst Hlth, Viral Dis Lab, Natl Inst Allergy & Infect Dis, 33 North Dr,MSC3209, Bethesda, MD 20892 USA. [Porter, Samuel S.] Univ Maryland, Biol Sci Grad Program, 4066 Campus Dr, College Pk, MD 20742 USA. [Stepp, Wesley H.] Univ N Carolina, North Carolina Jaycee Burn Ctr, Dept Surg, Sch Med, 160 Dent Circle, Chapel Hill, NC 27599 USA. RP McBride, AA (reprint author), Natl Inst Hlth, Viral Dis Lab, Natl Inst Allergy & Infect Dis, 33 North Dr,MSC3209, Bethesda, MD 20892 USA. EM amcbride@nih.gov FU Intramural Research Program of the NIAID, NIH FX We thank all members of the McBride laboratory for helpful discussions. We apologize to colleagues whose primary work we could not cite, because of space limitations. A portion of this review is derived from the Introduction chapter in the thesis of WHS (Stepp, 2015). This research was supported by the Intramural Research Program of the NIAID, NIH. NR 173 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 EI 1872-7492 J9 VIRUS RES JI Virus Res. PD MAR 2 PY 2017 VL 231 SI SI BP 10 EP 20 DI 10.1016/j.virusres.2016.11.014 PG 11 WC Virology SC Virology GA EP0KT UT WOS:000397076900003 PM 27863967 ER PT J AU Cerqueira, C Schiller, JT AF Cerqueira, Carla Schiller, John T. TI Papillomavirus assembly: An overview and perspectives SO VIRUS RESEARCH LA English DT Review DE Papillomavirus; Virion assembly; Pseudovirus ID MINOR CAPSID PROTEIN; NUCLEAR IMPORT RECEPTORS; VIRUS-LIKE PARTICLES; TOBACCO-MOSAIC-VIRUS; BOVINE PAPILLOMAVIRUS; VIRAL-DNA; NEUTRALIZATION ASSAY; TYPE-11 INTERACTS; L1/L2 CAPSIDS; CELL-SURFACE AB Papillomavirus life cycle is tightly coupled to epithelial cell differentiation, which has hindered the investigation of many aspects of papillomavirus biology, including virion assembly. The development of in vitro production methods of papillomavirus pseudoviruses, and the production of "native" virus in raft cultures have facilitated the study of some aspects of the assembly process. In this paper we review the current knowledge of papillomavirus assembly, directions for future research, and the implications of these studies on new therapeutic interventions. Published by Elsevier B.V. C1 [Cerqueira, Carla; Schiller, John T.] Natl Inst Hlth, Natl Canc Inst, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Schiller, JT (reprint author), Natl Inst Hlth, Natl Canc Inst, Cellular Oncol Lab, Bethesda, MD 20892 USA. EM schillej@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX The authors were supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 73 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 EI 1872-7492 J9 VIRUS RES JI Virus Res. PD MAR 2 PY 2017 VL 231 SI SI BP 103 EP 107 DI 10.1016/j.virusres.2016.11.010 PG 5 WC Virology SC Virology GA EP0KT UT WOS:000397076900012 PM 27840111 ER PT J AU Meana-Paneda, R Xu, XF Ma, H Truhlar, DG AF Meana-Paneda, Ruben Xu, Xuefei Ma, He Truhlar, Donald G. TI Computational Kinetics by Variational Transition-State Theory with Semiclassical Multidimensional Tunneling: Direct Dynamics Rate Constants for the Abstraction of H from CH3OH by Triplet Oxygen Atoms SO JOURNAL OF PHYSICAL CHEMISTRY A LA English DT Article ID CHEMICAL-REACTION RATES; MAIN-GROUP THERMOCHEMISTRY; DENSITY FUNCTIONALS; PERTURBATION-THEORY; BASIS-SETS; AB-INITIO; METHANOL OXIDATION; MODEL CHEMISTRIES; NONCOVALENT INTERACTIONS; COMPREHENSIVE MECHANISM AB Rate constants and the product branching ratio for hydrogen abstraction from CH3OH by O(P-3) were computed with multistructural variational transition-state theory including microcanonically optimized multidimensional tunneling. Benchmark calculations of the forward and reverse classical barrier heights and the reaction energetics have been carried out by using coupled cluster theory and multireference calculations to select the most reliable density functional method for direct dynamics computations of the rate constants. The dynamics calculations included the anharmonicity of the zero-point energies and partition functions, with specific-reaction-parameter scaling factors for reactants and transition states, and multistructural torsional anharmonicity was included for the torsion around the C-O bond in methanol and in the transition states. The resulting rate constants are presented over a wider range than they are available from experiment, but in the temperature range where experiments are available, they agree well with experimental values, which is encouraging for their reliability over the wider temperature range and for future computations of oxygen atom reaction rates. In contrast to a previous computational prediction, the branching ratio predicted by the present work shows that the formation of CH2OH + OH is the dominant channel over the whole range of temperature from 250 to 2000 K. C1 [Meana-Paneda, Ruben; Xu, Xuefei; Ma, He; Truhlar, Donald G.] Univ Minnesota, Dept Chem, Chem Theory Ctr, 207 Pleasant St SE, Minneapolis, MN 55455 USA. [Meana-Paneda, Ruben; Xu, Xuefei; Ma, He; Truhlar, Donald G.] Univ Minnesota, Inst Supercomp, Minneapolis, MN 55455 USA. [Meana-Paneda, Ruben] NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. [Xu, Xuefei] Tsinghua Univ, Ctr Combust Energy, Beijing 100084, PR, Peoples R China. [Xu, Xuefei] Tsinghua Univ, Dept Thermal Engn, Beijing 100084, PR, Peoples R China. RP Truhlar, DG (reprint author), Univ Minnesota, Dept Chem, Chem Theory Ctr, 207 Pleasant St SE, Minneapolis, MN 55455 USA.; Truhlar, DG (reprint author), Univ Minnesota, Inst Supercomp, Minneapolis, MN 55455 USA. EM truhlar@umn.edu OI Truhlar, Donald/0000-0002-7742-7294 FU U.S. Department of Energy, Office of Basic Energy Sciences [DE-FG02-86ER13579, DE-SC0015997] FX The authors are grateful to Alek Marenich for helpful discussions. This work was supported in part by the U.S. Department of Energy, Office of Basic Energy Sciences, under grants no. DE-FG02-86ER13579 and DE-SC0015997. NR 107 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1089-5639 J9 J PHYS CHEM A JI J. Phys. Chem. A PD MAR 2 PY 2017 VL 121 IS 8 BP 1694 EP 1708 DI 10.1021/acs.jpca.6b10600 PG 15 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA EM9EZ UT WOS:000395615600019 ER PT J AU Sherling, ES Knuepfer, E Brzostowski, JA Miller, LH Blackman, MJ van Ooij, C AF Sherling, Emma S. Knuepfer, Eiien Brzostowski, Joseph A. Miller, Louis H. Blackman, Michael J. van Ooij, Christiaan TI The Plasmodium falciparum rhoptry protein RhopH3 plays essential roles in host cell invasion and nutrient uptake SO ELIFE LA English DT Article ID RED-BLOOD-CELLS; MEROZOITE SURFACE PROTEIN-1; MALARIA PARASITE; INFECTED ERYTHROCYTES; MONOCLONAL-ANTIBODIES; FUNCTIONAL-ANALYSIS; COMPLEX; GENE; BINDING; MEMBRANE AB Merozoites of the protozoan parasite responsible for the most virulent form of malaria, Plasmodium falciparum, invade erythrocytes. Invasion involves discharge of rhoptries, specialized secretory organelles. Once intracellular, parasites induce increased nutrient uptake by generating new permeability pathways (NPP) including a Plasmodium surface anion channel (PSAC). RhopH1/Clag3, one member of the three-protein RhopH complex, is important for PSAC/NPP activity. However, the roles of the other members of the RhopH complex in PSAC/NPP establishment are unknown and it is unclear whether any of the RhopH proteins play a role in invasion. Here we demonstrate that RhopH3, the smallest component of the complex, is essential for parasite survival. Conditional truncation of RhopH3 substantially reduces invasive capacity. Those mutant parasites that do invade are defective in nutrient import and die. Our results identify a dual role for RhopH3 that links erythrocyte invasion to formation of the PSAC/NPP essential for parasite survival within host erythrocytes. C1 [Sherling, Emma S.; Blackman, Michael J.; van Ooij, Christiaan] Francis Crick Inst, Malaria Biochem Lab, London, England. [Sherling, Emma S.; Miller, Louis H.] Natl Inst Allergy & Infect Dis, Natl Inst Hlth, Lab Malaria & Vector Res, Rockville, MD USA. [Knuepfer, Eiien] Francis Crick Inst, Malaria Parasitol Lab, London, England. [Brzostowski, Joseph A.] Natl Inst Allergy & Infect Dis, Natl Inst Hlth, Lab Immunogenet Imaging Facil, Rockville, MD USA. [Blackman, Michael J.] London Sch Hyg Trop Med, Dept Pathogen Mol Biol, London, England. RP Blackman, MJ; van Ooij, C (reprint author), Francis Crick Inst, Malaria Biochem Lab, London, England.; Blackman, MJ (reprint author), London Sch Hyg Trop Med, Dept Pathogen Mol Biol, London, England. EM Blackman@crick.ac.uk; Christiaan.vanOoij@crick.ac.uk NR 69 TC 0 Z9 0 U1 0 U2 0 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAR 2 PY 2017 VL 6 AR e23239 DI 10.7554/eLife.23239 PG 23 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EP8TI UT WOS:000397647300001 ER PT J AU Sanderson, SC Brothers, KB Mercaldo, ND Clayton, EW Antommaria, AHM Aufox, SA Brilliant, MH Campos, D Carrell, DS Connolly, J Conway, P Fullerton, SM Garrison, NA Horowitz, CR Jarvik, GP Kaufman, D Kitchner, TE Li, RL Ludman, EJ McCarty, CA McCormick, JB McManus, VD Myers, MF Scro, A Williams, JL Shrubsole, MJ Schildcrout, JS Smith, ME Hom, IA AF Sanderson, Saskia C. Brothers, Kyle B. Mercaldo, Nathaniel D. Clayton, Ellen Wright Antommaria, Armand H. Matheny Aufox, Sharon A. Brilliant, Murray H. Campos, Diego Carrell, David S. Connolly, John Conway, Pat Fullerton, Stephanie M. Garrison, Nanibaa' A. Horowitz, Carol R. Jarvik, Gail P. Kaufman, David Kitchner, Terrie E. Li, Rongling Ludman, Evette J. McCarty, Catherine A. McCormick, Jennifer B. McManus, Valerie D. Myers, Melanie F. Scro, Aaron Williams, Janet L. Shrubsole, Martha J. Schildcrout, Jonathan S. Smith, Maureen E. Hom, Ingrid A. TI Public Attitudes toward Consent and Data Sharing in Biobank Research: A Large Multi-site Experimental Survey in the US SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; RESEARCH PARTICIPANTS; BROAD CONSENT; INFORMED-CONSENT; UNITED-STATES; PERSPECTIVES; INFORMATION; MODELS; NANOTECHNOLOGY; PREFERENCES AB Individuals participating in biobanks and other large research projects are increasingly asked to provide broad consent for open-ended research use and widespread sharing of their biosamples and data. We assessed willingness to participate in a biobank using different consent and data sharing models, hypothesizing that willingness would be higher under more restrictive scenarios. Perceived benefits, concerns, and information needs were also assessed. In this experimental survey, individuals from 11 US healthcare systems in the Electronic Medical Records and Genomics (eMERGE) Network were randomly allocated to one of three hypothetical scenarios: tiered consent and controlled data sharing; broad consent and controlled data sharing; or broad consent and open data sharing. Of 82,328 eligible individuals, exactly 13,000 (15.8%) completed the survey. Overall, 66% (95% CI: 63%-69%) of population-weighted respondents stated they would be willing to participate in a biobank; willingness and attitudes did not differ between respondents in the three scenarios. Willingness to participate was associated with self-identified white race, higher educational attainment, lower religiosity, perceiving more research benefits, fewer concerns, and fewer information needs. Most (86%, CI: 84%-87%) participants would want to know what would happen if a researcher misused their health information; fewer (51%, CI: 47%-55%) would worry about their privacy. The concern that the use of broad consent and open data sharing could adversely affect participant recruitment is not supported by these findings. Addressing potential participants' concerns and information needs and building trust and relationships with communities may increase acceptance of broad consent and wide data sharing in biobank research. C1 [Sanderson, Saskia C.] UCL, Dept Behav Sci & Hlth, London WC1E 6BT, England. [Sanderson, Saskia C.] Great Ormond St Hosp Sick Children, London WC1N 3JH, England. [Sanderson, Saskia C.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Brothers, Kyle B.] Univ Louisville, Dept Pediat, Louisville, KY 40202 USA. [Mercaldo, Nathaniel D.; Schildcrout, Jonathan S.] Vanderbilt Univ, Dept Biostat, Nashville, TN 37203 USA. [Clayton, Ellen Wright] Vanderbilt Univ, Ctr Biomed Eth & Soc, Nashville, TN 37203 USA. [Antommaria, Armand H. Matheny] Cincinnati Childrens Hosp Med Ctr, Eth Ctr, Cincinnati, OH 45229 USA. [Aufox, Sharon A.; Smith, Maureen E.] Northwestern Univ, Ctr Genet Med, Chicago, IL 60611 USA. [Brilliant, Murray H.; Kitchner, Terrie E.] Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI 54449 USA. [Campos, Diego] Childrens Hosp Philadelphia, Dept Biomed & Hlth Informat, Philadelphia, PA 19104 USA. [Carrell, David S.; Ludman, Evette J.; Scro, Aaron] Grp Hlth Res Inst, Seattle, WA 98101 USA. [Connolly, John] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Conway, Pat; McCarty, Catherine A.] Essentia Inst Rural Hlth, Duluth, MN 55805 USA. [Fullerton, Stephanie M.] Univ Washington, Dept Bioeth & Humanities, Seattle, WA 98195 USA. [Garrison, Nanibaa' A.] Seattle Childrens Res Inst, Treuman Katz Ctr Pediat Bioeth, Seattle, WA 98101 USA. [Horowitz, Carol R.] Icahn Sch Med Mt Sinai, Dept Populat Hlth Sci & Policy, New York, NY 10029 USA. [Jarvik, Gail P.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Kaufman, David] NHGRI, Div Genom & Soc, Bethesda, MD 20892 USA. [Li, Rongling] NHGRI, Div Genom Med, Bethesda, MD 20892 USA. [McCormick, Jennifer B.] Mayo Clin, Biomed Eth Program, Rochester, MN 55905 USA. [McManus, Valerie D.] Marshfield Clin Res Fdn, Biomed Informat Res Ctr, Marshfield, WI 54449 USA. [Myers, Melanie F.] Cincinnati Childrens Hosp Med Ctr, Genet Counseling Grad Program, Cincinnati, OH 45229 USA. [Myers, Melanie F.] Univ Cincinnati, Cincinnati, OH 45229 USA. [Williams, Janet L.] Geisinger Hlth Syst, Genom Med Inst, Danville, PA 17822 USA. [Shrubsole, Martha J.] Vanderbilt Univ, Med Ctr, Vanderbilt Epidemiol Ctr, Nashville, TN 37203 USA. [Hom, Ingrid A.] Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA. [Hom, Ingrid A.] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. [Garrison, Nanibaa' A.] Univ Washington, Div Bioeth, Dept Pediat, Seattle, WA 98101 USA. RP Sanderson, SC (reprint author), UCL, Dept Behav Sci & Hlth, London WC1E 6BT, England.; Sanderson, SC (reprint author), Great Ormond St Hosp Sick Children, London WC1N 3JH, England.; Sanderson, SC (reprint author), Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA.; Brothers, KB (reprint author), Univ Louisville, Dept Pediat, Louisville, KY 40202 USA. EM saskia.sanderson@ucl.ac.uk; kyle.brothers@louisville.edu FU NHGRI; NIH Office of the Director [U01HG006828, U01HG006830, UOIHG006389, U01HG006382, U01HG006375, 3U01HG006379, U01HG006380, 3U01-HG006388, U01HG006378, 3U01HG0006385] FX The CERC Survey project within the eMERGE Network was initiated and funded by NHGRI with additional funding by the NIH Office of the Director through the following grants: U01HG006828 (Cincinnati Children's Hospital Medical Center/Boston Children's Hospital), U01HG006830 (Children's Hospital of Philadelphia), UOIHG006389 (Essentia Institute of Rural Health, Marshfield Clinic Research Foundation, and Pennsylvania State University), U01HG006382 (Geisinger Clinic), U01HG006375 (Group Health Cooperative/University of Washington), 3U01HG006379 (Mayo Clinic), U01HG006380 (Icahn School of Medicine at Mount Sinai), 3U01-HG006388 (Northwestern University), U01HG006378 (Vanderbilt University Medical Center), and 3U01HG0006385 (Vanderbilt University Medical Center serving as the Coordinating Center). NR 53 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAR 2 PY 2017 VL 100 IS 3 BP 414 EP 427 DI 10.1016/j.ajhg.2017.01.021 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA EN2PH UT WOS:000395851900009 PM 28190457 ER PT J AU Civelek, M Wu, Y Pan, C Raulerson, CK Ko, A He, AQ Tilford, C Saleem, NK Stantcakova, A Scott, LJ Fuchsberger, C Stringham, HM Jackson, AU Narisu, N Chines, PS Small, KS Kuusisto, J Parks, BW Pajukanta, P Kirchgessner, T Collins, FS Gargalovic, PS Boehnke, M Laakso, M Mohlke, KL Lusis, AJ AF Civelek, Mete Wu, Ying Pan, Calvin Raulerson, Chelsea K. Ko, Arthur He, Aiqing Tilford, Charles Saleem, Niyas K. Stantcakova, Alena Scott, Laura J. Fuchsberger, Christian Stringham, Heather M. Jackson, Anne U. Narisu, Narisu Chines, Peter S. Small, Kerrin S. Kuusisto, Johanna Parks, Brian W. Pajukanta, Paivi Kirchgessner, Todd Collins, Francis S. Gargalovic, Peter S. Boehnke, Michael Laakso, Markku Mohlke, Karen L. Lusis, Aldons J. TI Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; BODY-MASS INDEX; CONGENITAL SIDEROBLASTIC ANEMIA; TYPE-2 DIABETES SUSCEPTIBILITY; INSULIN SENSITIVITY; COMMON VARIANTS; ADIPOCYTE DIFFERENTIATION; CARDIOVASCULAR-DISEASE; GLUCOSE-HOMEOSTASIS AB Subcutaneous adipose tissue stores excess lipids and maintains energy balance. We performed expression quantitative trait locus (eQTL) analyses by using abdominal subcutaneous adipose tissue of 770 extensively phenotyped participants of the METSIM study. We identified cis-eQTLs for 12,400 genes at a 1% false-discovery rate. Among an approximately 680 known genome-wide association study (GWAS) loci for cardio-metabolic traits, we identified 140 coincident cis-eQTLs at 109 GWAS loci, including 93 eQTLs not previously described. At 49 of these 140 eQTLs, gene expression was nominally associated (p < 0.05) with levels of the GWAS trait. The size of our dataset enabled identification of five loci associated (p < 5 x 10(-8)) with at least five genes located >5 Mb away. These trans-eQTL signals confirmed and extended the previously reported KLF14-mediated network to 55 target genes, validated the CIITA regulation of class II MHC genes, and identified ZNF800 as a candidate master regulator. Finally, we observed similar expression-clinical trait correlations of genes associated with GWAS loci in both humans and a panel of genetically diverse mice. These results provide candidate genes for further investigation of their potential roles in adipose biology and in regulating cardio-metabolic traits. C1 [Civelek, Mete; Pan, Calvin; Parks, Brian W.; Lusis, Aldons J.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. [Civelek, Mete] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. [Civelek, Mete] Univ Virginia, Dept Biomed Engn, Charlottesville, VA 22908 USA. [Wu, Ying; Raulerson, Chelsea K.; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Ko, Arthur; Pajukanta, Paivi; Lusis, Aldons J.] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA. [Ko, Arthur; Pajukanta, Paivi; Lusis, Aldons J.] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. [He, Aiqing; Tilford, Charles; Kirchgessner, Todd; Gargalovic, Peter S.] Bristol Myers Squibb, Pennington, NJ 08534 USA. [Saleem, Niyas K.; Stantcakova, Alena; Kuusisto, Johanna; Laakso, Markku] Univ Eastern Finland, Dept Med, Kuopio 70210, Finland. [Saleem, Niyas K.; Stantcakova, Alena; Kuusisto, Johanna; Laakso, Markku] Kuopio Univ Hosp, SF-70210 Kuopio, Finland. [Scott, Laura J.; Fuchsberger, Christian; Stringham, Heather M.; Jackson, Anne U.; Boehnke, Michael] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Scott, Laura J.; Fuchsberger, Christian; Stringham, Heather M.; Jackson, Anne U.; Boehnke, Michael] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Narisu, Narisu; Chines, Peter S.; Collins, Francis S.] NHGRI, NIH, Bethesda, MD 20892 USA. [Small, Kerrin S.] Kings Coll London, Sch Med, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Lusis, Aldons J.] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA. RP Lusis, AJ (reprint author), Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA.; Mohlke, KL (reprint author), Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA.; Lusis, AJ (reprint author), Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA.; Lusis, AJ (reprint author), Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA.; Lusis, AJ (reprint author), Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA. EM mohlke@med.unc.edu; jlusis@mednet.ucla.edu FU NIH [R00HL121172, P01HL28481, R01DK093757, U01DK105561, R01DK072193, U01DK062370, 1-ZIA-HG000024, R01HL095056, F31HL127921, R00HL123021, T32GM067553]; Academy of Finland [77299, 124243]; Finnish Heart Foundation; Finnish Diabetes Foundation; Finnish Funding Agency for Technology and Innovation (TEKES) [1510/31/06]; Commission of the European Community [HEALTH-F2-2007-201681] FX This study was supported by NIH grants R00HL121172 (M.C.), P01HL28481 (A.J.L. and P.P.), R01DK093757 (K.L.M.), U01DK105561 (K.L.M.), R01DK072193 (K.L.M.), U01DK062370 (M.B.), 1-ZIA-HG000024 (F.S.C.), R01HL095056 (P.P.), F31HL127921 (A.K.), and R00HL123021 (B.W.P.); Academy of Finland grants 77299 and 124243 (M.L.); the Finnish Heart Foundation (M.L.); the Finnish Diabetes Foundation (M.L.); Finnish Funding Agency for Technology and Innovation (TEKES) contract 1510/31/06 (M.L.); and the Commission of the European Community HEALTH-F2-2007-201681 (M.L.). C.K.R. was supported by NIH T32GM067553. Bristol-Myers Squibb supported the generation of METSIM and HMDP microarray data. NR 91 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAR 2 PY 2017 VL 100 IS 3 BP 428 EP 443 DI 10.1016/j.ajhg.2017.01.027 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA EN2PH UT WOS:000395851900010 PM 28257690 ER PT J AU Wiessner, M Roos, A Munn, CJ Viswanathan, R Whyte, T Cox, D Schoser, B Sewry, C Roper, H Phadke, R Bettolo, CM Barresi, R Charlton, R Bonnemann, CG Neto, OA Reed, UC Zanoteli, E Moreno, CAM Ertl-Wagner, B Stucka, R De Goede, C da Silva, TB Hathazi, D Dell'Aica, M Zahedi, RP Thiele, S Muller, J Kingston, H Muller, S Curtis, E Walter, MC Strom, TM Straub, V Bushby, K Muntoni, F Swan, LE Lochmuller, H Senderek, J AF Wiessner, Manuela Roos, Andreas Munn, Christopher J. Viswanathan, Ranjith Whyte, Tamieka Cox, Dan Schoser, Benedikt Sewry, Caroline Roper, Helen Phadke, Rahul Bettolo, Chiara Marini Barresi, Rita Charlton, Richard Bonnemann, Carsten G. Neto, Osorio Abath Reed, Umbertina C. Zanoteli, Edmar Moreno, Cristiane Araujo Martins Ertl-Wagner, Birgit Stucka, Rolf De Goede, Christian da Silva, Tamiris Borges Hathazi, Denisa Dell'Aica, Margherita Zahedi, Rene P. Thiele, Simone Muller, Juliane Kingston, Helen Mueller, Susanna Curtis, Elizabeth Walter, Maggie C. Strom, Tim M. Straub, Volker Bushby, Kate Muntoni, Francesco Swan, Laura E. Lochmuller, Hanns Senderek, Jan TI Mutations in INPPSK, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID MARINESCO-SJOGREN-SYNDROME; POLYPHOSPHATE PHOSPHATASE SKIP; UNFOLDED PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM; MEMBRANE TRAFFICKING; SIGNAL-TRANSDUCTION; SKELETAL-MUSCLE; MYOPATHY; GENE; DISEASE AB Phosphoinositides are small phospholipids that control diverse cellular downstream signaling events. Their spatial and temporal availability is tightly regulated by a set of specific lipid kinases and phosphatases. Congenital muscular dystrophies are hereditary disorders characterized by hypotonia and weakness from birth with variable eye and central nervous system involvement. In individuals exhibiting congenital muscular dystrophy, early-onset cataracts, and mild intellectual disability but normal cranial magnetic resonance imaging, we identified bi-allelic mutations in INPP5K, encoding inositol polyphosphate-5-phosphatase K. Mutations impaired phosphatase activity toward the phosphoinositide phosphatidylinositol (4,5)-bisphosphate or altered the subcellular localization of INPP5K. Down regulation of INPP5K orthologs in zebrafish embryos disrupted muscle fiber morphology and resulted in abnormal eye development. These data link congenital muscular dystrophies to defective phosphoinositide 5-phosphatase activity that is becoming increasingly recognized for its role in mediating pivotal cellular mechanisms contributing to disease. C1 [Wiessner, Manuela; Viswanathan, Ranjith; Schoser, Benedikt; Stucka, Rolf; Thiele, Simone; Walter, Maggie C.; Senderek, Jan] Ludwig Maximilians Univ Munchen, Dept Neurol, Friedrich Baur Inst, D-80336 Munich, Germany. [Roos, Andreas; Cox, Dan; Bettolo, Chiara Marini; Barresi, Rita; Charlton, Richard; Muller, Juliane; Straub, Volker; Bushby, Kate; Lochmuller, Hanns] Newcastle Univ, Inst Med Genet, MRC Ctr Neuromuscular Dis, John Walton Muscular Dystrophy Res Ctr, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England. [Roos, Andreas; Hathazi, Denisa; Dell'Aica, Margherita; Zahedi, Rene P.] Leibniz Inst Analyt Wissensch ISAS, D-44227 Dortmund, Germany. [Munn, Christopher J.; da Silva, Tamiris Borges; Swan, Laura E.] Univ Liverpool, Inst Translat Med, Dept Cellular & Mol Physiol, Crown St, Liverpool L69 3BX, Merseyside, England. [Whyte, Tamieka; Sewry, Caroline; Phadke, Rahul; Muntoni, Francesco] UCL Great Ormond St Inst Child Hlth, London WC1N 1EH, England. [Whyte, Tamieka; Sewry, Caroline; Phadke, Rahul; Muntoni, Francesco] Great Ormond St Hosp Sick Children, London WC1N 1EH, England. [Whyte, Tamieka; Muntoni, Francesco] UCL Inst Neurol, MRC Ctr Neuromuscular Dis, London WC1N 3BG, England. [Sewry, Caroline] RJAH Orthopaed Hosp, Wolfson Ctr Inherited Neuromuscular Disorders, Oswestry SY10 7AG, Shrops, England. [Roper, Helen] Heart England NHS Fdn Trust, Birmingham Heartlands Hosp, Birmingham B9 5SS, W Midlands, England. [Barresi, Rita; Charlton, Richard] Newcastle Upon Tyne Hosp NHS Fdn Trust, Rare Dis Advisory Grp, Serv Neuromuscular Dis, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England. [Bonnemann, Carsten G.; Neto, Osorio Abath] NINDS, Neuromuscular & Neurogenet Disorders Childhood Se, Neurogenet Branch, NIH, Bethesda, MD 20814 USA. [Reed, Umbertina C.; Zanoteli, Edmar; Moreno, Cristiane Araujo Martins] Univ Sao Paulo, Fac Med, Dept Neurol, BR-01246903 Sao Paulo, Brazil. [Ertl-Wagner, Birgit] Ludwig Maximilians Univ Munchen, Inst Clin Radiol, D-81377 Munich, Germany. [De Goede, Christian] Lancashire Teaching Hosp NHS Fdn Trust, Royal Preston Hosp, Dept Paediat Neurol, Preston PR2 9HT, Lancs, England. [De Goede, Christian] Univ Lancaster, Fac Hlth & Med, Lancaster LA1 4YG, England. [Kingston, Helen] Cent Manchester Univ Hosp NHS Fdn Trust, St Marys Hosp, Manchester Ctr Genom Med, Oxford Rd, Manchester M13 9WL, Lancs, England. [Mueller, Susanna] Ludwig Maximilians Univ Munchen, Inst Pathol, D-80337 Munich, Germany. [Curtis, Elizabeth] Univ Hosp Birmingham NHS Fdn Trust, Queen Elizabeth Hosp Birmingham, Dept Cellular Pathol, Birmingham B15 2TH, W Midlands, England. [Strom, Tim M.] Helmholtz Zentrum Munchen, Inst Human Genet, D-85764 Neuherberg, Germany. [Strom, Tim M.] Tech Univ Munich, Inst Human Genet, D-81675 Munich, Germany. [Viswanathan, Ranjith] EMBL Heidelberg, Dev Biol Unit, D-69117 Heidelberg, Germany. RP Senderek, J (reprint author), Ludwig Maximilians Univ Munchen, Dept Neurol, Friedrich Baur Inst, D-80336 Munich, Germany. EM jan.senderek@med.uni-muenchen.de FU Friedrich-Baur-Stiftung; Wellcome Trust Institutional Strategic Support Fund [105616/Z/14/Z]; Medical Research Council [MRC/N010035/1]; National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London; European Union Seventh Framework Programme [305444, 305121]; Muscular Dystrophy UK [512315]; Medical Research Council; Nationally Commissioned Highly Specialised Service (HSS) for Neuromuscular Diseases (NHS England); Sanofi Genzyme; Trophos; GlaxoSmithKline; AVI BioPharma; PTC; Sarepta Therapeutics FX We wish to thank the families and study individuals for their contribution. We are grateful to Professor Heinrich Leonhardt and Dr. Joel Ryan for critical reading of the manuscript and their valuable comments. This work was supported by the Friedrich-Baur-Stiftung (to J.S.), the Wellcome Trust Institutional Strategic Support Fund (105616/Z/14/Z to L.E.S.), the Medical Research Council (MRC/N010035/1 to L.E.S.), the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London (to EM.), and the European Union Seventh Framework Programme (grant agreements 305444 [RD-Connect] and 305121 [NeurOmics] to H.L., EM., and V.S.). The support of the Muscular Dystrophy UK to the Dubowitz Neuromuscular Centre (grant 512315 and centre grant) and of the Medical Research Council to the Neuromuscular Centres in London (UCL) and Newcastle for the Biobank is also gratefully acknowledged. Diagnostic facilities in Newcastle and London are supported by the Nationally Commissioned Highly Specialised Service (HSS) for Neuromuscular Diseases (NHS England).; B.S. has served on scientific advisory boards for Sanofi Genzyme, BioMarin, Amicus Therapeutics, and Audentes Therapeutics and receives research support from Sanofi Genzyme. C.S. is a member of the scientific advisory board of Audentes Therapeutics. F.M. has served on scientific advisory boards for Acceleron Pharma, Sanofi Genzyme, AVI BioPharma, Debiopharma Group, GlaxoSmithKline, Prosensa, Servier, Summit, and Santhera Pharmaceutical, receives research support from Trophos and GlaxoSmithKline, and has received funding for clinical trials from AVI BioPharma, PTC, and Sarepta Therapeutics. NR 64 TC 0 Z9 0 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAR 2 PY 2017 VL 100 IS 3 BP 523 EP 536 DI 10.1016/j.ajhg.2017.01.024 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA EN2PH UT WOS:000395851900016 PM 28190456 ER PT J AU Jullien, J Vodnala, M Pasque, V Oikawa, M Miyamoto, K Allen, G David, SA Brochard, V Wang, S Bradshaw, C Koseki, H Sartorelli, V Beaujean, N Gurdon, J AF Jullien, Jerome Vodnala, Munender Pasque, Vincent Oikawa, Mami Miyamoto, Kei Allen, George David, Sarah Anne Brochard, Vincent Wang, Stan Bradshaw, Charles Koseki, Haruhiko Sartorelli, Vittorio Beaujean, Nathalie Gurdon, John TI Gene Resistance to Transcriptional Reprogramming following Nuclear Transfer Is Directly Mediated by Multiple Chromatin-Repressive Pathways SO MOLECULAR CELL LA English DT Article ID EMBRYONIC STEM-CELLS; DNA METHYLATION; HISTONE H2A; EXPRESSION; PLURIPOTENCY; INACTIVATION; IDENTITY; ELEMENTS; GENOME; OOCYTE AB Understanding the mechanism of resistance of genes to reactivation will help improve the success of nuclear reprogramming. Using mouse embryonic fibroblast nuclei with normal or reduced DNA methylation in combination with chromatin modifiers able to erase H3K9me3, H3K27me3, and H2AK119ub1 from transplanted nuclei, we reveal the basis for resistance of genes to transcriptional reprogramming by oocyte factors. A majority of genes is affected by more than one type of treatment, suggesting that resistance can require repression through multiple epigenetic mechanisms. We classify resistant genes according to their sensitivity to 11 chromatin modifier combinations, revealing the existence of synergistic as well as adverse effects of chromatin modifiers on removal of resistance. We further demonstrate that the chromatin modifier USP21 reduces resistance through its H2AK119 deubiquitylation activity. Finally, we provide evidence that H2A ubiquitylation also contributes to resistance to transcriptional reprogramming in mouse nuclear transfer embryos. C1 [Jullien, Jerome; Vodnala, Munender; Oikawa, Mami; Allen, George; Wang, Stan; Bradshaw, Charles; Gurdon, John] Univ Cambridge, Wellcome Trust Canc Res UK Gurdon Inst, Cambridge CB2 1QN, England. [Pasque, Vincent] Univ Leuven, KU Leuven, Dept Dev & Regenerat, Herestr 49, B-3000 Leuven, Belgium. [Miyamoto, Kei] Kinki Univ, Grad Sch Biol Oriented Sci & Technol, Lab Mol Dev Biol, Wakayama 6496493, Japan. [David, Sarah Anne; Brochard, Vincent; Beaujean, Nathalie] Univ Paris Saclay, ENVA, INRA, UMR BDR, F-78350 Jouy En Josas, France. [Wang, Stan; Sartorelli, Vittorio] NIAMS, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. [Koseki, Haruhiko] RIKEN Ctr Integrat Med Sci, Lab Dev Genet, Tsurumi Ku, North Res Bldg,1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan. RP Jullien, J (reprint author), Univ Cambridge, Wellcome Trust Canc Res UK Gurdon Inst, Cambridge CB2 1QN, England. EM j.jullien@gurdon.cam.ac.uk FU Wellcome Trust [101050/Z/13/Z, 092096/Z/10/Z, 081277]; MRC [(MR/ K011022/1]; Gurdon Institute core grant from Cancer Research UK [C6946/A14492]; Intramural Research Program of NIAMS at the NIH [1Z01AR041126-17]; Svenska Sallskapet for Medicinsk Forskning (SSMF); Gates Cambridge Trust and NIH-Cambridge MD/PhD Program [T32GM007367]; Society for the Promotion of Science (JSPS); Human Frontier Science Program [RGP0021/2016]; JSPS KAKENHI [JP16H01321, JP16H01222]; Grant for Basic Science Research Projects from The Sumitomo Foundation [150810]; Wallonia-Brussels International Excellence Grant; Research Foundation -Flanders (FWO) [G0F7716N]; KU Leuven Research Fund (BOFZAP) [StG/15/021BF, C14/16/077] FX We would like to thanks Dr. H. Cedar, Dr. E.M. Meyerhowitz, Dr. S. Urbe, Dr. D. Ron, Dr. R. Janknecht, Dr. K. Helin, and Dr. R. Meehan for providing us with reagents and the processed dataset used in this study. This work is funded by grants from the Wellcome Trust (101050/Z/13/Z) and the MRC (MR/ K011022/1) and supported by the Gurdon Institute core grant from Cancer Research UK (C6946/A14492) and the Wellcome Trust (092096/Z/10/Z). This research was supported in part by the Intramural Research Program of NIAMS at the NIH (1Z01AR041126-17). M. V. was supported by a Svenska Sallskapet for Medicinsk Forskning (SSMF) postdoctoral fellowship. S. W. was supported in part by fellowships from the Gates Cambridge Trust and NIH-Cambridge MD/PhD Program (T32GM007367). M. O. was supported by a postdoctoral fellowship from the Japan Society for the Promotion of Science (JSPS). K. M. is supported by Human Frontier Science Program (RGP0021/2016), JSPS KAKENHI grants JP16H01321 and JP16H01222, and by a Grant for Basic Science Research Projects from The Sumitomo Foundation (150810). V.P. was supported by the Wellcome Trust (081277), the Wallonia-Brussels International Excellence Grant, The Research Foundation -Flanders (FWO) (Odysseus Return Grant G0F7716N), the KU Leuven Research Fund (BOFZAP starting grant StG/15/021BF, C1 grant C14/16/077, and project financing). We also acknowledge the platform MIMA2 for microscopy equipment (Microscopie et Imagerie des Microorganismes, Animaux et Elements, INRA). NR 52 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD MAR 2 PY 2017 VL 65 IS 5 BP 873 EP + DI 10.1016/j.molcel.2017.01.030 PG 20 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EO1BD UT WOS:000396431700011 PM 28257702 ER PT J AU Folco, HD Chalamcharla, VR Sugiyama, T Thillainadesan, G Zofall, M Balachandran, V Dhakshnamoorthy, J Mizuguchi, T Grewal, SIS AF Folco, H. Diego Chalamcharla, Venkata R. Sugiyama, Tomoyasu Thillainadesan, Gobi Zofall, Martin Balachandran, Vanivilasini Dhakshnamoorthy, Jothy Mizuguchi, Takeshi Grewal, Shiv I. S. TI Untimely expression of gametogenic genes in vegetative cells causes uniparental disomy SO NATURE LA English DT Article ID FACULTATIVE HETEROCHROMATIN FORMATION; FISSION YEAST; SCHIZOSACCHAROMYCES-POMBE; CHROMOSOME SEGREGATION; RAPID METHOD; MEIOSIS-I; COHESION; CENTROMERES; ELIMINATION; ATTACHMENT AB Uniparental disomy (UPD), in which an individual contains a pair of homologous chromosomes originating from only one parent, is a frequent phenomenon that is linked to congenital disorders and various cancers(1,2). UPD is thought to result mostly from pre- or post-zygotic chromosome missegregation(2). However, the factors that drive UPD remain unknown. Here we use the fission yeast Schizosaccharomyces pombe as a model to investigate UPD, and show that defects in the RNA interference (RNAi) machinery or in the YTH domain-containing RNA elimination factor Mmi1 cause high levels of UPD in vegetative diploid cells. This phenomenon is not due to defects in heterochromatin assembly at centromeres. Notably, in cells lacking RNAi components or Mmi1, UPD is associated with the untimely expression of gametogenic genes. Deletion of the upregulated gene encoding the meiotic cohesin Rec8 or the cyclin Crs1 suppresses UPD in both RNAi and mmi1 mutants. Moreover, overexpression of Rec8 is sufficient to trigger UPD in wild-type cells. Rec8 expressed in vegetative cells localizes to chromosomal arms and to the centromere core, where it is required for localization of the cohesin subunit Psc3. The centromeric localization of Rec8 and Psc3 promotes UPD by uniquely affecting chromosome segregation, causing a reductional segregation of one homologue. Together, these findings establish the untimely vegetative expression of gametogenic genes as a causative factor of UPD, and provide a solid foundation for understanding this phenomenon, which is linked to diverse human diseases. C1 [Folco, H. Diego; Chalamcharla, Venkata R.; Sugiyama, Tomoyasu; Thillainadesan, Gobi; Zofall, Martin; Balachandran, Vanivilasini; Dhakshnamoorthy, Jothy; Mizuguchi, Takeshi; Grewal, Shiv I. S.] NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. [Mizuguchi, Takeshi] Yokohama City Univ, Grad Sch Med, Dept Human Genet, Fukuura 3-9, Yokohama, Kanagawa 2360004, Japan. RP Grewal, SIS (reprint author), NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. EM grewals@mail.nih.gov FU National Institutes of Health, National Cancer Institute FX We thank Y. Watanabe, M. Yamamoto, Y. Hiraoka, F. Ishikawa, G. Smith and the National BioResource Project (NBRP) Japan for reagents, J. Barrowman for editing the manuscript, N. Taneja and A. Fernandez-Alvarez for technical assistance and members of the Laboratory of Biochemistry and Molecular Biology, in particular the Grewal laboratory, for discussions. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 43 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAR 2 PY 2017 VL 543 IS 7643 BP 126 EP + DI 10.1038/nature21372 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN0AA UT WOS:000395671500046 PM 28199302 ER PT J AU Casey, BM Thom, EA Peaceman, AM Varner, MW Sorokin, Y Hirtz, DG Reddy, UM Wapner, RJ Thorp, JM Saade, G Tita, ATN Rouse, DJ Sibai, B Iams, JD Mercer, BM Tolosa, J Caritis, SN VanDorsten, JP AF Casey, B. M. Thom, E. A. Peaceman, A. M. Varner, M. W. Sorokin, Y. Hirtz, D. G. Reddy, U. M. Wapner, R. J. Thorp, J. M., Jr. Saade, G. Tita, A. T. N. Rouse, D. J. Sibai, B. Iams, J. D. Mercer, B. M. Tolosa, J. Caritis, S. N. VanDorsten, J. P. CA Eunice Kennedy Shriver Natl Inst C Human Dev Maternal-Fetal Med Units TI Treatment of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID AMERICAN THYROID ASSOCIATION; POPULATION-BASED COHORT; MATERNAL HYPOTHYROXINEMIA; COMPLICATING PREGNANCY; ENDOCRINE-SOCIETY; DISEASE; DYSFUNCTION; POSTPARTUM; MANAGEMENT; DEFICIENCY AB BACKGROUND Subclinical thyroid disease during pregnancy may be associated with adverse outcomes, including a lower-than-normal IQ in offspring. It is unknown whether levothyroxine treatment of women who are identified as having subclinical hypothyroidism or hypothyroxinemia during pregnancy improves cognitive function in their children. METHODS We screened women with a singleton pregnancy before 20 weeks of gestation for subclinical hypothyroidism, defined as a thyrotropin level of 4.00 mU or more per liter and a normal free thyroxine (T-4) level (0.86 to 1.90 ng per deciliter [11 to 24 pmol per liter]), and for hypothyroxinemia, defined as a normal thyrotropin level (0.08 to 3.99 mU per liter) and a low free T-4 level (<0.86 ng per deciliter). In separate trials for the two conditions, women were randomly assigned to receive levothyroxine or placebo. Thyroid function was assessed monthly, and the levothyroxine dose was adjusted to attain a normal thyrotropin or free T-4 level (depending on the trial), with sham adjustments for placebo. Children underwent annual developmental and behavioral testing for 5 years. The primary outcome was the IQ score at 5 years of age (or at 3 years of age if the 5-year examination was missing) or death at an age of less than 3 years. RESULTS A total of 677 women with subclinical hypothyroidism underwent randomization at a mean of 16.7 weeks of gestation, and 526 with hypothyroxinemia at a mean of 17.8 weeks of gestation. In the subclinical hypothyroidism trial, the median IQ score of the children was 97 (95% confidence interval [CI], 94 to 99) in the levothyroxine group and 94 (95% CI, 92 to 96) in the placebo group (P = 0.71). In the hypothyroxinemia trial, the median IQ score was 94 (95% CI, 91 to 95) in the levothyroxine group and 91 (95% CI, 89 to 93) in the placebo group (P = 0.30). In each trial, IQ scores were missing for 4% of the children. There were no significant between-group differences in either trial in any other neurocognitive or pregnancy outcomes or in the incidence of adverse events, which was low in both groups. CONCLUSIONS Treatment for subclinical hypothyroidism or hypothyroxinemia beginning between 8 and 20 weeks of gestation did not result in significantly better cognitive outcomes in children through 5 years of age than no treatment for those conditions. C1 [Casey, B. M.] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. [Saade, G.] Univ Texas Med Branch, Galveston, TX 77555 USA. [Sibai, B.] Univ Texas Hlth Sci Ctr Houston, McGovern Med Sch, Childrens Mem Hermann Hosp, Houston, TX 77030 USA. [Thom, E. A.] George Washington Univ, Biostat Ctr, Washington, DC USA. [Peaceman, A. M.] Northwestern Univ, Chicago, IL 60611 USA. [Varner, M. W.] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. [Sorokin, Y.] Wayne State Univ, Detroit, MI USA. [Hirtz, D. G.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Reddy, U. M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Wapner, R. J.] Columbia Univ, New York, NY USA. [Thorp, J. M., Jr.] Univ North Carolina Chapel Hill, Chapel Hill, NC USA. [Tita, A. T. N.] Univ Alabama Birmingham, Birmingham, AL USA. [Rouse, D. J.] Brown Univ, Providence, RI 02912 USA. [Iams, J. D.] Ohio State Univ, Columbus, OH 43210 USA. [Mercer, B. M.] Case Western Reserve Univ, MetroHlth Med Ctr, Cleveland, OH 44106 USA. [Tolosa, J.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Caritis, S. N.] Univ Pittsburgh, Pittsburgh, PA USA. [VanDorsten, J. P.] Med Univ South Carolina, Charleston, SC USA. RP Casey, BM (reprint author), Univ Texas Southwestern Med Ctr Dallas, Dept Obstet & Gynecol, 5323 Harry Hines Blvd, Dallas, TX 75235 USA. EM brian.casey@utsouthwestern.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD34116, HD40512, HD27917, HD34208, HD40485, HD40560, HD53097, HD27869, HD40500, HD40545, HD27915, HD40544, HD53118, HD21410, HD36801]; National Institute of Neurological Disorders and Stroke FX Supported by grants (HD34116, HD40512, HD27917, HD34208, HD40485, HD40560, HD53097, HD27869, HD40500, HD40545, HD27915, HD40544, HD53118, HD21410, and HD36801) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke. NR 27 TC 1 Z9 1 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 2 PY 2017 VL 376 IS 9 BP 815 EP 825 DI 10.1056/NEJMoa1606205 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EM9JK UT WOS:000395627500005 PM 28249134 ER PT J AU Grady, C Cummings, SR Rowbotham, MC McConnell, MV Ashley, EA Kang, G AF Grady, Christine Cummings, Steven R. Rowbotham, Michael C. McConnell, Michael V. Ashley, Euan A. Kang, Gagandeep TI The Changing Face of Informed Consent SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID PERSONAL HEALTH INFORMATION; BIOLOGICAL SAMPLES; CLINICAL-TRIALS; RESEARCH PARTICIPANTS; PRECISION MEDICINE; PUBLIC-ATTITUDES; RESEARCH ETHICS; BIG DATA; BIOBANK; MULTIMEDIA C1 [Grady, Christine; Cummings, Steven R.; Rowbotham, Michael C.; McConnell, Michael V.; Ashley, Euan A.; Kang, Gagandeep] NIH, Dept Bioeth, Ctr Clin, Bldg 10,1C118, Bethesda, MD 20892 USA. RP Grady, C (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,1C118, Bethesda, MD 20892 USA. EM cgrady@nih.gov NR 86 TC 0 Z9 0 U1 2 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 2 PY 2017 VL 376 IS 9 BP 856 EP 867 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA EM9JK UT WOS:000395627500009 PM 28249147 ER PT J AU Bellatorre, A Jackson, SH Choi, K AF Bellatorre, Anna Jackson, Sharon H. Choi, Kelvin TI Development of the diabetes typology model for discerning Type 2 diabetes mellitus with national survey data SO PLOS ONE LA English DT Article ID INSULIN-RESISTANCE; UNITED-STATES; METAANALYSIS; DISEASE; YOUTH; RISK; PREVALENCE; SEARCH; COHORT; WOMEN AB Objective To classify individuals with diabetes mellitus (DM) into DM subtypes using population-based studies. Design Population-based survey Setting Individuals participated in 2003-2004, 2005-2006, or 2009-2010 the National Health and Nutrition Examination Survey (NHANES), and 2010 Coronary Artery Risk Development in Young Adults (CARDIA) survey (research materials obtained from the National Heart, Lung, and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center) Participants 3084, 3040 and 3318 US adults from the 2003-2004, 2005-2006 and 2009-2010 NHANES samples respectively, and 5,115 US adults in the CARDIA cohort Primary outcome measures We proposed the Diabetes Typology Model (DTM) through the use of six composite measures based on the Homeostatic Model Assessment (HOMA-IR , HOMA-%beta, high HOMA-%S), insulin and glucose levels, and body mass index and conducted latent class analyses to empirically classify individuals into different classes. Results Three empirical latent classes consistently emerged across studies (entropy = 0.81-0.998). These three classes were likely Type 1 DM, likely Type 2 DM, and atypical DM. The classification has high sensitivity (75.5%), specificity (83.3%), and positive predictive value (97.4%) when validated against C-peptide level. Correlates of Type 2 DM were significantly associated with model-identified Type 2 DM. Compared to regression analysis on known correlates of Type 2 DM using all diabetes cases as outcomes, using DTM to remove likely Type 1 DM and atypical DM cases results in a 2.5-5.3% r-square improvement in the regression analysis, as well as model fits as indicated by significant improvement in -2 log likelihood (p<0.01). Lastly, model-defined likely Type 2 DM was significantly associated with known correlates of Type 2 DM (e.g., age, waist circumference), which provide additional validation of the DTM-defined classes. Conclusions Our Diabetes Typology Model reflects a promising first step toward discerning likely DM types from population-based data. This novel tool will improve how large population-based studies can be used to examine behavioral and environmental factors associated with different types of DM. C1 [Bellatorre, Anna; Jackson, Sharon H.; Choi, Kelvin] Natl Inst Minor Hlth & Hlth Dispar, Div Intramural Res, Bethesda, MD 20892 USA. RP Choi, K (reprint author), Natl Inst Minor Hlth & Hlth Dispar, Div Intramural Res, Bethesda, MD 20892 USA. EM kelvin.choi@nih.gov FU Division of Intramural Research, National Institute on Minority Health and Health Disparities, National Institutes of Health FX This work is supported by the Division of Intramural Research, National Institute on Minority Health and Health Disparities, National Institutes of Health. NR 23 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 2 PY 2017 VL 12 IS 3 AR e0173103 DI 10.1371/journal.pone.0173103 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EN4XX UT WOS:000396011300076 PM 28253317 ER PT J AU Johnson, TA Milan-Lobo, L Che, T Ferwerda, M Lambu, E McIntosh, NL Li, F He, L Lorig-Roach, N Crews, P Whistler, JL AF Johnson, Tyler A. Milan-Lobo, Laura Che, Tao Ferwerda, Madeline Lambu, Eptisam McIntosh, Nicole L. Li, Fei He, Li Lorig-Roach, Nicholas Crews, Phillip Whistler, Jennifer L. TI Identification of the First Marine-Derived Opioid Receptor "Balanced" Agonist with a Signaling Profile That Resembles the Endorphins SO ACS CHEMICAL NEUROSCIENCE LA English DT Article DE opioid; endorphins; signaling profile; biased agonism; balanced agonism; G protein-coupled receptor (GPCR); tolerance; dependence; aaptamine; fascaplysin ID NATURAL-PRODUCT LIBRARIES; ANTIDEPRESSANT-LIKE ACTIVITIES; DRUG DISCOVERY; BIASED LIGAND; SELECTIVE AGONIST; REDUCES TOLERANCE; INDOLE ALKALOIDS; ANXIOLYTIC-LIKE; BETA-ARRESTIN; DOUBLE-BLIND AB Opioid therapeutics are excellent analgesics, whose utility is compromised by dependence. Morphine (1) and its clinically relevant derivatives such as OxyContin (2), Vicodin (3), and Dilaudid (4) are "biased" agonists at the mu opioid receptor (OR), wherein they engage G protein signaling but poorly engage ss-arrestin and the endocytic machinery. In contrast, endorphins, the endogenous peptide agonists for ORs, are potent analgesics, show reduced liability for tolerance and dependence, and engage both G protein and ss-arrestin pathways as "balanced" agonists. We set out to determine if marine-derived alkaloids could serve as novel OR agonist chemotypes with a signaling profile distinct from morphine and more similar to the endorphins. Screening of 96 sponge-derived extracts followed by LC-MS-based purification to pinpoint the active compounds and subsequent evaluation of a mini library of related alkaloids identified two structural classes that modulate the ORs. These included the following: aaptamine (10), 9-demethyl aaptamine (11), demethyl (oxy) aaptamine (12) with activity at the delta-OR (EC50: 5.1, 4.1, 2.3 mu M, respectively) and fascaplysin (17), and 10-bromo fascaplysin (18) with activity at the mu-OR (EC50: 6.3, 4.2 mu M respectively). An in vivo evaluation of 10 using delta-KO mice indicated its previously reported antidepressant like effects are dependent on the delta-OR. Importantly, 17 functioned as a balanced agonist promoting both G protein signaling and ss-arrestin recruitment along with receptor endocytosis similar to the endorphins. Collectively these results demonstrate the burgeoning potential for marine natural products to serve as novel lead compounds for therapeutic targets in neuroscience research. C1 [Milan-Lobo, Laura; Ferwerda, Madeline; Li, Fei; He, Li; Whistler, Jennifer L.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA. [Johnson, Tyler A.; Lorig-Roach, Nicholas; Crews, Phillip] Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA. [Johnson, Tyler A.; Lambu, Eptisam; McIntosh, Nicole L.] Dominican Univ Calif, Dept Nat Sci & Math, San Rafael, CA 94901 USA. [Che, Tao] Univ N Carolina, Natl Inst Mental Hlth Psychoact Drug Screening Pr, Chapel Hill, NC 27514 USA. RP Whistler, JL (reprint author), Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA.; Johnson, TA (reprint author), Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA.; Johnson, TA (reprint author), Dominican Univ Calif, Dept Nat Sci & Math, San Rafael, CA 94901 USA. EM tyler.johnson@dominican.edu; jennifer.whistler@ucsf.edu FU NIH [R01DA019958, R01DA015232, R21DA031574, R01CA47135]; NSF MS Instrument Grant [UCSC CHE-147922]; Fletcher Jones Fund of Dominican University of California FX We thank Carsten K Nielsen and Selena Bartlett for assistance in screening compounds (10-20). T.A.J. thanks David Barnes for inspiring philosophical discussions related to the power of the endorphins. This work was supported by grants from the NIH, R01DA019958 (J.L.W.), R01DA015232 (J.L.W.), R21DA031574 (J.L.W.), R01CA47135 (P.C.), NSF MS Instrument Grant UCSC CHE-147922 (P.C.), and the Fletcher Jones Fund of Dominican University of California (T.A.J.). NR 97 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7193 J9 ACS CHEM NEUROSCI JI ACS Chem. Neurosci. PD MAR PY 2017 VL 8 IS 3 BP 473 EP 485 DI 10.1021/acschemneuro.6b00167 PG 13 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA EO6MT UT WOS:000396807900010 PM 27744679 ER PT J AU Schroeder, FA Gilbert, TM Feng, NP Taillon, BD Volkow, ND Innis, RB Hooker, JM Lipska, BK AF Schroeder, Frederick A. Gilbert, Tonya M. Feng, Ningping Taillon, Brendan D. Volkow, Nora D. Innis, Robert B. Hooker, Jacob M. Lipska, Barbara K. TI Expression of HDAC2 but Not HDAC1 Transcript Is Reduced in Dorsolateral Prefrontal Cortex of Patients with Schizophrenia SO ACS CHEMICAL NEUROSCIENCE LA English DT Article DE Epigenetics; chromatin; schizophrenia; mood disorders unipolar; mood disorders bipolar; neuropsychiatry ID AGE-RELATED-CHANGES; MESSENGER-RNA; PSYCHIATRIC-DISORDERS; HISTONE ACETYLATION; HUMAN BRAIN; ABNORMALITIES; CONNECTIVITY; INHIBITION; SYSTEM; MICE AB Postmortem brain studies support dysregulated expression of the histone deacetylase enzymes, HDAC1 and HDAC2, as a central feature in diseases including schizophrenia, bipolar disorder, and depression. Our objective was to investigate HDAC expression in a large postmortem sample set representing healthy and disease brains. We used >700 well-characterized samples from patients diagnosed with schizophrenia (n = 175), major depressive disorder (n = 135), and bipolar disorder (n = 61) to measure HDAC1 and HDAC2 transcript levels by quantitative real-time PCR in dorsolateral prefrontal cortex (DLPFC) and caudate compared to control samples. HDAC expression was calculated relative to the geometric mean of beta-2-microglobulin, beta-glucuronidase, and beta-actin. In adult-age DLPFC, HDAC2 was decreased by 34% in schizophrenia samples compared to controls (p < 10(-4)). HDAC2 was significantly upregulated in major depressive disorder samples by 17% versus controls (p = 0.002). Neither smoking history nor therapeutic drugs impacted HDAC2 levels and no HDAC1 patient-control differences were observed. In caudate, HDAC levels were unchanged between patient and control groups. In control DLPFC, age fetal week 14 to 97 years (n = 326), both HDAC1 and HDAC2 levels sharply declined around birth and stabilized thereafter. Using by far the largest postmortem sample set on this topic, our major finding (decreased HDAC2 transcript) showed notable specificity in disease (schizophrenia but not major depressive disorder), HDAC subtype (HDAC2 but not HDAC1) and brain region (DLPFC but not caudate). These differences shape understanding of regional components of neural circuitry in the diseased brain and set a benchmark to quantify HDAC density and distribution using in vivo neuroimaging tools. C1 [Schroeder, Frederick A.; Gilbert, Tonya M.; Taillon, Brendan D.; Hooker, Jacob M.] Harvard Med Sch, Athinoula Martinos Ctr, Dept Radiol, Massachusetts Gen Hosp, Bldg 149,13th St,Suite 2301, Charlestown, MA 02129 USA. [Feng, Ningping; Lipska, Barbara K.] Natl Inst Hlth, Human Brain Collect Core, Div Intramural Res Programs, Natl Inst Mental Hlth, Bethesda, MD 20892 USA. [Volkow, Nora D.] Natl Inst Hlth, Natl Inst Alcohol Abuse & Alcoholism, Bethesda, MD 20892 USA. [Innis, Robert B.] Natl Inst Hlth, Mol Imaging Branch, Natl Inst Mental Hlth, Bethesda, MD 20892 USA. RP Schroeder, FA (reprint author), Harvard Med Sch, Athinoula Martinos Ctr, Dept Radiol, Massachusetts Gen Hosp, Bldg 149,13th St,Suite 2301, Charlestown, MA 02129 USA. EM fschroeder@mgh.harvard.edu RI Lipska, Barbara/E-4569-2017 FU National Institute of Mental Health; Molecular Imaging Branch [ZIAMH002795]; Harvard/MGH Nuclear Medicine Training Program from the Department of Energy [DE-SC0008430]; National Institute of Drug Abuse of the National Institutes of Health [R0IDA030321]; Brain and Behavior Research Foundation Independent Investigator Award FX Research was supported by the National Institute of Mental Health through programmatic funding to the Human Brain Collection Core (B.K.L.) and Molecular Imaging Branch (Project ZIAMH002795 to R.B.I.), by the Harvard/MGH Nuclear Medicine Training Program from the Department of Energy under Grant DE-SC0008430 (to T.M.G.), and by the National Institute of Drug Abuse of the National Institutes of Health under Grant Number R0IDA030321 and the Brain and Behavior Research Foundation Independent Investigator Award (J.M.H.). NR 41 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7193 J9 ACS CHEM NEUROSCI JI ACS Chem. Neurosci. PD MAR PY 2017 VL 8 IS 3 BP 662 EP 668 DI 10.1021/acschemneuro.6b00372 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA EO6MT UT WOS:000396807900025 PM 27959513 ER PT J AU Hoffman, AF Lycas, MD Kaczmarzyk, JR Spivak, CE Baumann, MH Lupica, CR AF Hoffman, Alexander F. Lycas, Matthew D. Kaczmarzyk, Jakub R. Spivak, Charles E. Baumann, Michael H. Lupica, Carl R. TI Disruption of hippocampal synaptic transmission and long-term potentiation by psychoactive synthetic cannabinoid 'Spice' compounds: comparison with Delta(9)-tetrahydrocannabinol SO ADDICTION BIOLOGY LA English DT Article DE Drug abuse; electrophysiology; marijuana ID MEDICINAL CHEMISTRY PERSPECTIVE; CB1 RECEPTOR; AXON TERMINALS; DESIGNER DRUGS; HERBAL BLENDS; MEMORY; NEURONS; MECHANISMS; AGONIST; ENDOCANNABINOIDS AB There has been a marked increase in the availability of synthetic drugs designed to mimic the effects of marijuana. These cannabimimetic drugs, sold illicitly as Spice' and related products, are associated with serious medical complications in some users. In vitro studies suggest that synthetic cannabinoids in these preparations are potent agonists at central cannabinoid CB1 receptors (CB1Rs), but few investigations have delineated their cellular effects, particularly in comparison with the psychoactive component of marijuana, Delta(9)-tetrahydrocannabinol (Delta(9)-THC). We compared the ability of three widely abused synthetic cannabinoids and Delta(9)-THC to alter glutamate release and long-term potentiation in the mouse hippocampus. JWH-018 was the most potent inhibitor of hippocampal synaptic transmission (EC50 similar to 15nM), whereas its fluoropentyl derivative, AM2201, inhibited synaptic transmission with slightly lower potency (EC50 similar to 60nM). The newer synthetic cannabinoid, XLR-11, displayed much lower potency (EC50 similar to 900nM) that was similar to Delta(9)-THC (EC50 similar to 700nM). The effects of all compounds occurred via activation of CB1Rs, as demonstrated by reversal with the selective antagonist/inverse agonist AM251 or the neutral CB1R antagonist PIMSR1. Moreover, AM2201 was without effect in the hippocampus of transgenic mice lacking the CB1R. Hippocampal slices exposed to either synthetic cannabinoids or Delta(9)-THC exhibited significantly impaired long-term potentiation (LTP). We find that, compared with Delta(9)-THC, the first-generation cannabinoids found in Spice preparations display higher potency, whereas a recent synthetic cannabinoid is roughly equipotent with Delta(9)-THC. The disruption of synaptic function by these synthetic cannabinoids is likely to lead to profound impairments in cognitive and behavioral function. C1 [Hoffman, Alexander F.; Lycas, Matthew D.; Kaczmarzyk, Jakub R.; Spivak, Charles E.; Lupica, Carl R.] Natl Inst Drug Abuse Intramural Res Program, Cellular Neurobiol Branch, Electrophysiol Res Sect, Baltimore, MD USA. [Baumann, Michael H.] Natl Inst Drug Abuse Intramural Res Program, Designer Drug Res Unit, Baltimore, MD USA. RP Lupica, CR (reprint author), Natl Inst Hlth, Natl Inst Drug Abuse Intramural Res Program, Electrophysiol Res Sect, Baltimore, MD USA. EM clupica@mail.nih.gov OI Hoffman, Alex/0000-0002-2676-0628 FU National Institute on Drug Abuse Intramural Research Program FX This research was supported by the National Institute on Drug Abuse Intramural Research Program. The views expressed herein are those of the authors and do not necessarily represent the views of the Drug Enforcement Administration, the US Department of Justice or any officer or entity of the United States of America. NR 60 TC 1 Z9 1 U1 1 U2 1 PU WILEY 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 2017 VL 22 IS 2 BP 390 EP 399 DI 10.1111/adb.12334 PG 10 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA EM0DH UT WOS:000394988500010 PM 26732435 ER PT J AU Radke, AK Jury, NJ Kocharian, A Marcinkiewcz, CA Lowery-Gionta, EG Pleil, KE McElligott, ZA McKlveen, JM Kash, TL Holmes, A AF Radke, Anna K. Jury, Nicholas J. Kocharian, Adrina Marcinkiewcz, Catherine A. Lowery-Gionta, Emily G. Pleil, Kristen E. McElligott, Zoe A. McKlveen, Jessica M. Kash, Thomas L. Holmes, Andrew TI Chronic EtOH effects on putative measures of compulsive behavior in mice SO ADDICTION BIOLOGY LA English DT Article DE Addiction; alcohol; CIE; mouse; NMDAR; orbitofrontal cortex ID CHRONIC INTERMITTENT ETHANOL; NMDA RECEPTOR EXPRESSION; ADDICTION-LIKE BEHAVIOR; INBRED MOUSE STRAINS; ALCOHOL-DRINKING; NUCLEUS-ACCUMBENS; C57BL/6J MICE; RAT-BRAIN; COCAINE SEEKING; REPEATED CYCLES AB Addictions, including alcohol use disorders, are characterized by the loss of control over drug seeking and consumption, but the neural circuits and signaling mechanisms responsible for the transition from controlled use to uncontrolled abuse remain incompletely understood. Prior studies have shown that compulsive-like' behaviors in rodents, for example, persistent responding for ethanol (EtOH) despite punishment, are increased after chronic exposure to EtOH. The main goal of the current study was to assess the effects of chronic intermittent EtOH (CIE) exposure on multiple, putative measures of compulsive-like EtOH seeking in C57BL/6J mice. Mice were exposed to two or four weekly cycles of CIE and then, post-withdrawal, tested for progressive ratio responding for EtOH, sustained responding during signaled EtOH unavailability and (footshock) punished suppression of responding for EtOH. Results showed that mice exposed to CIE exhibited attenuated suppression of EtOH seeking during punishment, as compared with air-exposed controls. By contrast, CIE exposure affected neither punished food reward-seeking behavior, nor other putative measures of compulsive-like EtOH seeking. Ex vivo reverse transcription polymerase chain reaction analysis of brain tissue found reduced sensitivity to punished EtOH seeking after CIE exposure was accompanied by a significant increase in gene expression of the GluN1 and GluN2A subunits of the N-methyl-d-aspartate receptor, specifically in the medial orbitofrontal cortex. Moreover, slice electrophysiological analysis revealed increased N-methyl-d-aspartate receptor-mediated currents in the orbitofrontal cortex after CIE exposure in test-naive mice. Collectively, the current findings add to the growing body of evidence demonstrating that chronic exposure to EtOH fosters resistance to punished EtOH seeking in association with adaptations in cortical glutamatergic transmission. C1 [Radke, Anna K.; Jury, Nicholas J.; Kocharian, Adrina; Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD USA. [Marcinkiewcz, Catherine A.; Lowery-Gionta, Emily G.; Pleil, Kristen E.; McElligott, Zoe A.; McKlveen, Jessica M.; Kash, Thomas L.] UNC Chapel Hill Sch Med, Bowles Ctr Alcohol Studies, Chapel Hill, NC USA. [Marcinkiewcz, Catherine A.; Lowery-Gionta, Emily G.; Pleil, Kristen E.; McKlveen, Jessica M.; Kash, Thomas L.] UNC Chapel Hill Sch Med, Dept Pharmacol, Chapel Hill, NC USA. [McElligott, Zoe A.] UNC Chapel Hill Sch Med, Dept Psychiat, Chapel Hill, NC USA. RP Radke, AK (reprint author), NIAAA, NIH, 5625 Fishers Lane Room 2 N09, Rockville, MD 20852 USA. EM anna.radke@nih.gov FU NIAAA IRP; Bowles Center for Alcohol Studies; NIH [AA019454, AA020911, AA011605, AA022549, AA023559, AA023555, AA007573] FX We are very grateful to Mr. Miguel Mendez for technical assistance and Dr. Jonathan Brigman for cartoons of behavioral procedures. Research supported by the NIAAA IRP (AR, NJ, AH), The Bowles Center for Alcohol Studies (TK), and NIH grants AA019454, AA020911, AA011605 (TK), AA022549 (EL), AA023559 (KP), AA023555 (ZM), AA007573 (JM). NR 72 TC 1 Z9 1 U1 1 U2 1 PU WILEY 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 2017 VL 22 IS 2 BP 423 EP 434 DI 10.1111/adb.12342 PG 12 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA EM0DH UT WOS:000394988500013 PM 26687341 ER PT J AU Rose, R Lamers, SL Dollar, JJ Grabowski, MK Hodcroft, EB Ragonnet-Cronin, M Wertheim, JO Redd, AD German, D Laeyendecker, O AF Rose, Rebecca Lamers, Susanna L. Dollar, James J. Grabowski, Mary K. Hodcroft, Emma B. Ragonnet-Cronin, Manon Wertheim, Joel O. Redd, Andrew D. German, Danielle Laeyendecker, Oliver TI Identifying Transmission Clusters with Cluster Picker and HIV-TRACE SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article DE HIV; viral clustering; Uganda ID UNITED-STATES; SAN-DIEGO; UGANDA; POL; SUPERINFECTION; SURVEILLANCE; CHIMPANZEES; PREVENTION; CALIFORNIA; NETWORKS AB We compared the behavior of two approaches (Cluster Picker and HIV-TRACE) at varying genetic distances to identify transmission clusters. We used three HIV gp41 sequence datasets originating from the Rakai Community Cohort Study: (1) next-generation sequence (NGS) data from nine linked couples; (2) NGS data from longitudinal sampling of 14 individuals; and (3) Sanger consensus sequences from a cross-sectional dataset (n=1,022) containing 91 epidemiologically linked heterosexual couples. We calculated the optimal genetic distance threshold to separate linked versus unlinked NGS datasets using a receiver operating curve analysis. We evaluated the number, size, and composition of clusters detected by Cluster Picker and HIV-TRACE at six genetic distance thresholds (1%-5.3%) on all three datasets. We further tested the effect of using all NGS, versus only a single variant for each patient/time point, for datasets (1) and (2). The optimal gp41 genetic distance threshold to distinguish linked and unlinked couples and individuals was 5.3% and 4%, respectively. HIV-TRACE tended to detect larger and fewer clusters, whereas Cluster Picker detected more clusters containing only two sequences. For NGS datasets (1) and (2), HIV-TRACE and Cluster Picker detected all linked pairs at 3% and 4% genetic distances, respectively. However, at 5.3% genetic distance, 20% of couples in dataset (3) did not cluster using either program, and for >1/3 of couples cluster assignment were discordant. We suggest caution in choosing thresholds for clustering analyses in a generalized epidemic. C1 [Rose, Rebecca; Lamers, Susanna L.; Dollar, James J.] BioInfoExperts, Thibodaux, LA USA. [Grabowski, Mary K.; German, Danielle] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Hodcroft, Emma B.; Ragonnet-Cronin, Manon] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland. [Wertheim, Joel O.] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Redd, Andrew D.; Laeyendecker, Oliver] NIAID, Immunoregulat Lab, Div Intramural Res, Nihon Univ, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Redd, Andrew D.; Laeyendecker, Oliver] Johns Hopkins Univ, Sch Med, 855 North Wolfe St,Rangos Bldg,Room 538A, Baltimore, MD 21205 USA. RP Laeyendecker, O (reprint author), Johns Hopkins Univ, Sch Med, 855 North Wolfe St,Rangos Bldg,Room 538A, Baltimore, MD 21205 USA. EM olaeyen1@jhmi.edu OI Ragonnet-Cronin, Manon/0000-0002-4879-2209 FU NIH-NIAID [K01AI110181]; NIH [5 P30 AI094189-04, K01DA041259]; Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health FX The authors would like to acknowledge the support of the participants and staff of the Rakai Health Sciences Program and the Rakai Community Cohort Study, without whom, this research could not have been possible. J.O.W. was supported by an NIH-NIAID Career Development Award (K01AI110181). D.G. was supported by NIH supplement to CFAR award #5 P30 AI094189-04 and K01DA041259. This work was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health. NR 33 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD MAR PY 2017 VL 33 IS 3 BP 211 EP 218 DI 10.1089/aid.2016.0205 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA EM8HX UT WOS:000395553200002 PM 27824249 ER PT J AU Hsu, PF Cheng, HM Sung, SH Chuang, SY Lakatta, EG Yin, FCP Chou, P Chen, CH AF Hsu, Pai-Feng Cheng, Hao-Min Sung, Shih-Hsien Chuang, Shao-Yuan Lakatta, Edward G. Yin, Frank C. P. Chou, Pesus Chen, Chen-Huan TI Hemodynamic Determinants of the Short-Term Blood Pressure Variability: Differential Roles of Arterial Stiffness and Wave Reflection SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE ambulatory blood pressure; blood pressure variability; hemodynamics; hypertension ID LEFT-VENTRICULAR MASS; HYPERTENSIVE PATIENTS; PROGNOSTIC-SIGNIFICANCE; PULSE-WAVE; POPULATION; AMLODIPINE; INDEX; YOUNG AB BACKGROUND A high 24-hour ambulatory diastolic (DBP) but not systolic (SBP) blood pressure variability (BPV) is significantly predictive of long-term cardiovascular mortality in untreated hypertensive subjects, independent of office or 24-hour SBP. The present study was aimed to investigate hemodynamic factors that are independently associated with systolic and diastolic BPV from the 24-hour ambulatory blood pressure monitoring (ABPM). METHODS A cohort of 624 normotensive and 633 untreated hypertensive participants with baseline ABPM was drawn from a community-based survey. BPV was assessed by the read-to-read average real variability of the 24-hour SBP and DBP (ARVs and ARVd, respectively). Hemodynamic variables including total peripheral resistance (TPR), carotid-femoral pulse wave velocity (cf-PWV), and amplitudes of the decomposed forward (Pf) and backward (Pb) carotid pressure waves were analyzed. RESULTS In multivariable analyses, hemodynamic variables independently associated with 24-hour SBP were 24-hour heart rate (HR), TPR, cf-PWV, Pf, and Pb (model r(2) = 0.535). Hemodynamic factors independently associated with ARV were 24-hour HR, Pf, and Pb for ARVs, and 24-hour HR, cf-PWV, Pf, and Pb for ARVd (model R-2 = 0.345 and 0.220, respectively). Addition of 24-hour SBP to the ARV models only slightly improved variance explained by the models (R-2 = 0.383 and 0.224, respectively). Pb accounted for >50% of total variance of ARVs and ARVd, whereas cf-PWV was a minor determinant of ARVd (<5% of total variance). CONCLUSIONS ARVd was associated with fewer hemodynamic variables than to 24-hour SBP. Among those hemodynamic variables wave reflection but not arterial stiffness had the dominant independent association with ARV. C1 [Hsu, Pai-Feng; Cheng, Hao-Min; Sung, Shih-Hsien; Chen, Chen-Huan] Taipei Vet Gen Hosp, Dept Med, Taipei, Taiwan. [Hsu, Pai-Feng; Cheng, Hao-Min; Sung, Shih-Hsien; Chou, Pesus; Chen, Chen-Huan] Natl Yang Ming Univ, Inst Publ Hlth, Taipei, Taiwan. [Hsu, Pai-Feng; Cheng, Hao-Min; Sung, Shih-Hsien; Chen, Chen-Huan] Natl Yang Ming Univ, Fac Med, Taipei, Taiwan. [Cheng, Hao-Min; Chen, Chen-Huan] Taipei Vet Gen Hosp, Dept Med Educ, Taipei, Taiwan. [Chuang, Shao-Yuan] Natl Hlth Res Inst, Miaoli, Taiwan. [Lakatta, Edward G.] NIA, Lab Cardiovasc Sci, Intramural Res Program, Baltimore, MD 21224 USA. [Yin, Frank C. P.] Washington Univ, Dept Biomed Engn, St Louis, MO USA. RP Chen, CH (reprint author), Taipei Vet Gen Hosp, Dept Med, Taipei, Taiwan.; Chen, CH (reprint author), Natl Yang Ming Univ, Inst Publ Hlth, Taipei, Taiwan.; Chen, CH (reprint author), Natl Yang Ming Univ, Fac Med, Taipei, Taiwan.; Chen, CH (reprint author), Taipei Vet Gen Hosp, Dept Med Educ, Taipei, Taiwan. EM chench@vghtpe.gov.tw NR 37 TC 0 Z9 0 U1 0 U2 0 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 2017 VL 30 IS 3 BP 256 EP 263 DI 10.1093/ajh/hpw144 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EO9SC UT WOS:000397027400011 ER PT J AU Shen, C Landsittel, D Irazabal, MV Yu, ASL Chapman, AB Mrug, M Grantham, JJ Bae, KT Bennett, WM Flessner, MF Torres, VE AF Shen, Chengli Landsittel, Douglas Irazabal, Maria V. Yu, Alan S. L. Chapman, Arlene B. Mrug, Michal Grantham, Jared J. Bae, Kyongtae T. Bennett, William M. Flessner, Michael F. Torres, Vicente E. TI Performance of the CKD-EPI Equation to Estimate GFR in a Longitudinal Study of Autosomal Dominant Polycystic Kidney Disease SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Letter ID GLOMERULAR-FILTRATION-RATE; CONSORTIUM; CREATININE; COHORT; ADPKD C1 [Shen, Chengli; Landsittel, Douglas; Bae, Kyongtae T.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Irazabal, Maria V.; Torres, Vicente E.] Mayo Clin Coll Med, Rochester, MN USA. [Yu, Alan S. L.; Grantham, Jared J.] Kansas Univ Med Ctr, Kansas City, KS USA. [Chapman, Arlene B.] Univ Chicago, Chicago, IL USA. [Mrug, Michal] Univ Alabama Birmingham, Birmingham, AL USA. [Bennett, William M.] Legacy Good Samaritan Hosp, Portland, OR USA. [Flessner, Michael F.] NIH, NIDDK, Bethesda, MD USA. RP Torres, VE (reprint author), Mayo Clin Coll Med, Rochester, MN USA. FU NIH/NIDDK [DK056943, DK056956, DK056957, DK056961]; NIDDK [DK106912, DK090728]; National Center for Research Resources General Clinical Research Center at (Emory University) [RR000039]; National Center for Research Resources General Clinical Research Center at (Mayo College of Medicine) [RR00585]; National Center for Research Resources General Clinical Research Center at (Kansas University Medical Center) [RR23940]; National Center for Research Resources General Clinical Research Center at (University of Alabama at Birmingham) [RR000032]; National Center for Advancing Translational Sciences Clinical and Translational Science Award at (Emory) [RR025008, TR000454]; National Center for Advancing Translational Sciences Clinical and Translational Science Award at (Mayo College of Medicine) [RR024150, TR000135]; National Center for Advancing Translational Sciences Clinical and Translational Science Award at (Kansas University Medical Center) [RR033179, TR000001]; National Center for Advancing Translational Sciences Clinical and Translational Science Award at (University of Alabama at Birmingham) [RR025777, TR000165, TR001417]; National Center for Advancing Translational Sciences Clinical and Translational Science Award at (University of Pittsburgh School of Medicine) [RR024153, TR000005] FX CRISP is supported by cooperative agreements from NIH/NIDDK (DK056943, DK056956, DK056957, DK056961). This study was also supported in part by the NIDDK via P30 grants to the Kansas PKD Research and Translation Core Center (DK106912) and the Mayo Translational PKD Center (DK090728), by the National Center for Research Resources General Clinical Research Centers at each institution (RR000039, Emory University; RR00585, Mayo College of Medicine; RR23940, Kansas University Medical Center; RR000032, University of Alabama at Birmingham), and the National Center for Advancing Translational Sciences Clinical and Translational Science Awards at each institution (RR025008 and TR000454, Emory; RR024150 and TR000135, Mayo College of Medicine; RR033179 and TR000001, Kansas University Medical Center; RR025777, TR000165 and TR001417, University of Alabama at Birmingham; RR024153 and TR000005, University of Pittsburgh School of Medicine). NR 10 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD MAR PY 2017 VL 69 IS 3 BP 482 EP 484 DI 10.1053/j.ajkd.2016.10.021 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA EM0ZV UT WOS:000395047900024 PM 28027795 ER PT J AU Norton, JM Newman, EP Romancito, G Mahooty, S Kuracina, T Narva, AS AF Norton, Jenna M. Newman, Eileen P. Romancito, Gayle Mahooty, Stephanie Kuracina, Theresa Narva, Andrew S. TI Improving Outcomes for Patients with Chronic Kidney Disease: Part 2 SO AMERICAN JOURNAL OF NURSING LA English DT Review DE chronic kidney disease; collaborative care; end-stage kidney failure; end-stage renal failure; interdisciplinary care; kidney disease ID 25-HYDROXYVITAMIN D LEVELS; DIALYSIS PATIENTS; ALBUMIN SYNTHESIS; SERUM-ALBUMIN; VASCULAR CALCIFICATION; PROTEIN-INTAKE; RENAL-DISEASE; MANAGEMENT; INFLAMMATION; BENEFITS AB Coping with chronic kidney disease (CKD) is challenging for many people, since symptoms often don't appear until the disease is advanced and the patient is close to requiring dialysis. This two-part article aims to provide nurses with the basic information necessary to assess and manage patients with CKD. Part 1, which appeared last month, offered an overview of the disease, described identification and etiology, and discussed ways to slow disease progression. Part 2 addresses disease complications and treatment for kidney failure. C1 [Norton, Jenna M.] NIDDK, Natl Kidney & Urol Sci Translat Program, NIH, Bethesda, MD 20892 USA. [Newman, Eileen P.; Narva, Andrew S.] NIDDK, Natl Kidney Dis Educ Program, Div Kidney Urol & Hematol Dis, Bethesda, MD 20892 USA. [Romancito, Gayle] Indian Hlth Serv, Zuni Comprehens Community Hlth Ctr, Zuni, NM USA. [Mahooty, Stephanie] Renal Med Associates, Albuquerque, NM USA. [Mahooty, Stephanie] Desert Kidney Associates, Albuquerque, NM USA. [Kuracina, Theresa] Indian Hlth Serv, Albuquerque Indian Hlth Ctr, Albuquerque, NM USA. RP Narva, AS (reprint author), NIDDK, Natl Kidney Dis Educ Program, Div Kidney Urol & Hematol Dis, Bethesda, MD 20892 USA. EM narvaa@niddk.nih.gov NR 43 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 0002-936X EI 1538-7488 J9 AM J NURS JI Am. J. Nurs. PD MAR PY 2017 VL 117 IS 3 BP 26 EP 35 PG 10 WC Nursing SC Nursing GA EN1UK UT WOS:000395795500019 PM 28187016 ER PT J AU Jones, CM Baldwin, GT Compton, WM AF Jones, Christopher McCall Baldwin, Grant T. Compton, Wilson M. TI Recent Increases in Cocaine-Related Overdose Deaths and the Role of Opioids SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID UNITED-STATES; BRITISH-COLUMBIA; CANADA AB Objectives. To assess trends in cocaine overdose deaths and examine the role opioids play in these deaths. Methods. We used data on drug overdose deaths in the United States from 2000 to 2015 collected in the National Vital Statistics System to calculate annual rates and numbers of cocaine-related overdose deaths overall and deaths both involving and not involving opioids. We assessed statistically significant changes in trends with joinpoint regression. Results. Rates of cocaine-related overdose deaths increased significantly from 1.26 to 2.50 per 100 000 population from 2000 to 2006, declined to 1.35 in 2010, and increased to 2.13 in 2015. Cocaine-related overdose deaths involving opioids increased from 0.37 to 0.91 from 2000 to 2006, declined to 0.57 in 2010, and then increased to 1.36 in 2015. Cocaine-related overdose deaths not involving opioids increased from 0.89 to 1.59 from 2000 to 2006 and then declined to 0.78 in 2015. Conclusions. Opioids, primarily heroin and synthetic opioids, have been driving the recent increase in cocaine-related overdose deaths. This corresponds to the growing supply and use of heroin and illicitly manufactured fentanyl in the United States. C1 [Jones, Christopher McCall] US Dept HHS, Div Sci Policy, Off Assistant Secretary Planning & Evaluat, Washington, DC 20201 USA. [Baldwin, Grant T.] Natl Ctr Injury Prevent & Control, Div Unintent Injury Prevent, Atlanta, GA USA. [Compton, Wilson M.] NIDA, NIH, Rockville, MD USA. RP Jones, CM (reprint author), 200 Independence Ave SW, Washington, DC 20201 USA. EM christopher.jones@hhs.gov NR 13 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAR PY 2017 VL 107 IS 3 BP 430 EP 432 DI 10.2105/AJPH.2016.303627 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EO9YV UT WOS:000397044900028 ER PT J AU Pitolli, C Pietroni, V Marekov, L Terrinoni, A Yamanishi, K Mazzanti, C Melino, G Candi, E AF Pitolli, Consuelo Pietroni, Valentina Marekov, Lyuben Terrinoni, Alessandro Yamanishi, Kiyofumi Mazzanti, Cinzia Melino, Gerry Candi, Eleonora TI Characterization of TG2 and TG1-TG2 double knock-out mouse epidermis SO AMINO ACIDS LA English DT Article DE Keratinocyte differentiation; Cornified cell envelope; Transglutaminase ID CORNIFIED CELL-ENVELOPE; TRANSGLUTAMINASE SUBSTRATE PROPERTIES; EPITHELIAL BARRIER FUNCTION; PROLINE-RICH PROTEIN-1; CROSS-LINKING ENZYMES; TISSUE TRANSGLUTAMINASE; LAMELLAR ICHTHYOSIS; KERATINOCYTE TRANSGLUTAMINASE; 3T3 FIBROBLASTS; MICE LACKING AB Transglutaminases (TGs) are a family of enzymes that catalyse the formation of isopeptide bonds between the gamma-carboxamide groups of glutamine residues and the epsilon-amino groups of lysine residues leading to cross-linking reactions among proteins. Four members, TG1, TG2, TG3, and TG5, of the nine mammalian enzymes are expressed in the skin. TG1, TG3 and TG5 crosslinking properties are fundamental for cornified envelope assembly. In contrast, the role of TG2 in keratinization has never been studied at biochemical level in vivo. In this study, taking advantage of the TG2 knock-out (KO) and TG1 heterozygous mice, we generated and characterized the epidermis of TG1-TG2 double knock-out (DKO) mice. We performed morphological analysis of the epidermis and evaluation of the expression of differentiation markers. In addition, we performed analysis of the amino acid composition from isolated corneocytes. We found a significant change in amino acid composition in TG1KO cornified cell envelopes (CEs) while TG2KO amino acid composition was similar to wild-type CEs. Our results confirm a key role of TG1 in skin differentiation and CE assembly and demonstrate that TG2 is not essential for CE assembly and skin formation. C1 [Pitolli, Consuelo; Pietroni, Valentina; Melino, Gerry; Candi, Eleonora] Univ Roma Tor Vergata, Dept Expt Med & Surg, Rome, Italy. [Marekov, Lyuben] NIH, Bldg 10, Bethesda, MD 20892 USA. [Terrinoni, Alessandro; Mazzanti, Cinzia; Candi, Eleonora] IRCCS, Biochem Lab, IDI, Rome, Italy. [Yamanishi, Kiyofumi] Hyogo Coll Med, Dept Dermatol, Nishinomiya, Hyogo 6638501, Japan. RP Candi, E (reprint author), Univ Roma Tor Vergata, Dept Expt Med & Surg, Rome, Italy. EM candi@uniroma2.it FU Italian Ministry of Health [RC-1]; Medical Research Council (MRC), "Fondazione Roma" NCD Grant FX This work was mainly supported by "Ricerca Corrente RC-1" Italian Ministry of Health to AT, and partially supported by the Medical Research Council (MRC), "Fondazione Roma" NCD Grant to GM and EC. NR 49 TC 0 Z9 0 U1 0 U2 0 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 2017 VL 49 IS 3 BP 635 EP 642 DI 10.1007/s00726-016-2356-3 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EN2UR UT WOS:000395866200020 PM 27864691 ER PT J AU Price, DK AF Price, D. K. TI Efficacy of androgen deprivation therapy and the role of oxidative stress SO ANNALS OF ONCOLOGY LA English DT Editorial Material ID RESISTANT PROSTATE-CANCER; INCREASED SURVIVAL; MITOXANTRONE; PREDNISONE C1 [Price, D. K.] Natl Canc Inst, Natl Inst Hlth, Genitourinary Malignancies Branch, Bethesda, MD USA. RP Price, DK (reprint author), Natl Canc Inst, Natl Inst Hlth, Genitourinary Malignancies Branch, Bethesda, MD USA. EM dkprice@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. No grant numbers apply. NR 16 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD MAR PY 2017 VL 28 IS 3 BP 451 EP 453 DI 10.1093/annonc/mdx001 PG 4 WC Oncology SC Oncology GA EP3RT UT WOS:000397300100005 ER PT J AU Ward, MM Guthrie, LC Dasgupta, A AF Ward, Michael M. Guthrie, Lori C. Dasgupta, Abhijit TI Direct and Indirect Determinants of the Patient Global Assessment in Rheumatoid Arthritis: Differences by Level of Disease Activity SO ARTHRITIS CARE & RESEARCH LA English DT Article ID SELF-MANAGEMENT PROGRAM; QUALITY-OF-LIFE; RANDOMIZED-TRIAL; GENERAL HEALTH; DEPRESSION; REMISSION; FIBROMYALGIA; DEFINITION; DISABILITY; PHYSICIANS AB Objective: In rheumatoid arthritis (RA), the patient global assessment (PGA) has been strongly associated with pain severity, but less often with other measures, including disease activity measures. We tested whether RA activity and psychological measures had direct associations with the PGA or indirect associations that were mediated by pain. We also tested whether the correlates of the PGA differed with the degree of RA activity. Methods: We studied 260 patients with active RA on 2 visits in a prospective longitudinal study. We used path analysis to test direct and indirect associations of Disease Activity Score in 28 joints (DAS28), morning stiffness, Health Assessment Questionnaire (HAQ), fatigue, physical role limitations, social functioning, depressive symptoms, and health distress with the PGA. Results: Among the 509 visits, the median PGA score was 50 (25th-75th percentile: 24-66). Pain severity had the strongest association with the PGA, but direct associations were also found for morning stiffness severity, health distress, fatigue, and DAS28. Morning stiffness severity, DAS28, health distress, and HAQ were also indirectly associated with the PGA through pain. Among visits with DAS28 >= 5.4, pain, morning stiffness severity, and HAQ were the only determinants of the PGA. Among visits with DAS28 <4.2, health distress and age were additional determinants, and fatigue was marginally associated with the PGA. Conclusion: Although pain was the strongest determinant of the PGA in RA, morning stiffness severity, health distress, fatigue, and DAS28 were also important. Determinants of the PGA differed with RA activity, with health distress, age, and to a lesser degree, fatigue, contributing only in patients with less active RA. C1 [Ward, Michael M.; Guthrie, Lori C.; Dasgupta, Abhijit] NIH, Natl Inst Arthrit & Musculoskeletal & Skin Diseas, Bldg 10 CRC,Room 4-1339,10 Ctr Dr, Washington, DC USA. RP Ward, MM (reprint author), NIH, Natl Inst Arthrit & Musculoskeletal & Skin Diseas, Bldg 10 CRC,Room 4-1339,10 Ctr Dr, Washington, DC USA. EM wardm1@mail.nih.gov FU Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH FX Supported by the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH. NR 34 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD MAR PY 2017 VL 69 IS 3 BP 323 EP 329 DI 10.1002/acr.22953 PG 7 WC Rheumatology SC Rheumatology GA EM0DK UT WOS:000394988800002 PM 27273981 ER PT J AU Bayefsky, MJ AF Bayefsky, Michelle J. TI The human genome as public: Justifications and implications SO BIOETHICS LA English DT Article DE genomics; public health; common heritage; common resource; genetic privacy ID GENETICS RESEARCH; COMMON HERITAGE; CONSENT MODELS; HEALTH; ATTITUDES; BIOBANKS; MEDICINE; CONFIDENTIALITY; PERSPECTIVES; INFORMATION AB Since the human genome was decoded, great emphasis has been placed on the unique, personal nature of the genome, along with the benefits that personalized medicine can bring to individuals and the importance of safeguarding genetic privacy. As a result, an equally important aspect of the human genome - its common nature - has been underappreciated and underrepresented in the ethics literature and policy dialogue surrounding genetics and genomics. This article will argue that, just as the personal nature of the genome has been used to reinforce individual rights and justify important privacy protections, so too the common nature of the genome can be employed to support protections of the genome at a population level and policies designed to promote the public's wellbeing. In order for public health officials to have the authority to develop genetics policies for the sake of the public good, the genome must have not only a common, but also a public, dimension. This article contends that DNA carries a public dimension through the use of two conceptual frameworks: the common heritage (CH) framework and the common resource (CR) framework. Both frameworks establish a public interest in the human genome, but the CH framework can be used to justify policies aimed at preserving and protecting the genome, while the CR framework can be employed to justify policies for utilizing the genome for the public benefit. A variety of possible policy implications are discussed, with special attention paid to the use of large-scale genomics databases for public health research. C1 [Bayefsky, Michelle J.] Harvard Med Sch, Boston, MA USA. [Bayefsky, Michelle J.] NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. RP Bayefsky, MJ (reprint author), 1575 Tremont St 1104, Boston, MA 02120 USA. EM michelle_bayefsky@hms.harvard.edu NR 57 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-9702 EI 1467-8519 J9 BIOETHICS JI Bioethics PD MAR PY 2017 VL 31 IS 3 BP 209 EP 219 DI 10.1111/bioe.12329 PG 11 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA EM9OY UT WOS:000395642200008 PM 28032365 ER PT J AU Fox, AR Chew, EY Meyerle, C Vitale, S Ferris, FL Nussenblatt, RB Sen, HN AF Fox, Austin R. Chew, Emily Y. Meyerle, Catherine Vitale, Susan Ferris, Frederick L. Nussenblatt, Robert B. Sen, H. Nida TI y Age-related macular degeneration in patients with uveitis SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Article DE Inflammation; Immunology; Macula; Degeneration ID ANTI-RETINAL ANTIBODIES; FACTOR-H POLYMORPHISM; ASPIRIN USE; DRUSEN; CLASSIFICATION; MACULOPATHY; MICROGLIA; EYE AB Purpose To evaluate the prevalence of large drusen in a uveitis clinic population. Design Retrospective, cohort study. Methods Patients with primary, non-infectious uveitis 55years or older who were seen at the National Eye Institute of the National Institutes of Health from 2004 through August 2013 were reviewed using electronic medical records and photographic databases. Patients were classified as having age-related macular degeneration (AMD) if either eye had large drusen, geographic atrophy or neovascular AMD according to definitions used by the Eye Diseases Prevalence Research Group (EDPRG). The expected number of cases and standardised mortality ratio (SMR) for large drusen were estimated based on EDPRG estimates. Results We identified 177 patients aged 55years as having primary non-infectious uveitis; 170 (96.0%) had gradable fundus photos. Average age was 65.07.5years (range 55-87), and 87 were non-Hispanic white, 66 non-Hispanic black, 6 Hispanic white and 11 of other race/ethnicity. Large drusen were identified in four patients (2.4%; 95% CI 0.6 to 6.0). No patients were identified to have late AMD. In the uveitis cohort, the SMR for cases of large drusen, which was adjusted for age, was calculated to be 0.32 (95% CI 0.12 to 0.70) for the whole cohort, 0.28 (95% CI 0.09 to 0.79) for non-Hispanic whites and 0.46 (95% CI 0.14 to 1.29) for non-Hispanic blacks. Conclusions Large drusen prevalence among patients with uveitis 55years of age appears less than the prevalence in the general US population after accounting for differences in age distribution, especially for non-Hispanic whites. Although the racial and gender distribution in this study population is not directly representative of the general US population, results of this study suggest possible sparing of patients with uveitis from AMD. A larger systematic study with greater power would be needed to confirm these findings. C1 [Fox, Austin R.; Chew, Emily Y.; Vitale, Susan; Ferris, Frederick L.; Nussenblatt, Robert B.; Sen, H. Nida] NEI, NIH, 10 Ctr Dr 10D45, Bethesda, MD 20892 USA. [Meyerle, Catherine] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. RP Sen, HN (reprint author), NEI, NIH, 10 Ctr Dr 10D45, Bethesda, MD 20892 USA. EM senh@nei.nih.gov FU NEI Intramural Research Program; NIH Medical Research Scholars Program; NIH; Pfizer; Doris Duke Charitable Foundation; Newport Foundation; American Association for Dental Research; Howard Hughes Medical Institute; Colgate-Palmolive Company FX This work is supported by the NEI Intramural Research Program and the NIH Medical Research Scholars Program. The NIH Medical Research Scholars Program is a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer, the Doris Duke Charitable Foundation, the Newport Foundation, the American Association for Dental Research, the Howard Hughes Medical Institute and the Colgate-Palmolive Company, as well as other private donors. For a complete list, please visit the Foundation website at http://fnih.org/work/education-training-0/medical-research-scholars-prog ram. NR 28 TC 1 Z9 1 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 EI 1468-2079 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD MAR PY 2017 VL 101 IS 3 BP 342 EP 347 DI 10.1136/bjophthalmol-2016-308587 PG 6 WC Ophthalmology SC Ophthalmology GA EM8BQ UT WOS:000395536600019 ER PT J AU Ahmet, I Tae, HJ Lakatta, EG Talan, M AF Ahmet, Ismayil Tae, Hyun-Jin Lakatta, Edward G. Talan, Mark TI Long-term low dose dietary resveratrol supplement reduces cardiovascular structural and functional deterioration in chronic heart failure in rats SO CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY LA English DT Article DE heart failure; resveratrol; echocardiography; remodeling; pulse wave velocity ID DILATED ISCHEMIC CARDIOMYOPATHY; INDUCED CARDIAC-HYPERTROPHY; QUALITY-OF-LIFE; MYOCARDIAL-ISCHEMIA; FAILING HEART; IMPROVES; HEALTH; DISEASE; ANTIOXIDANT; CARDIOPROTECTION AB A short-term exposure to resveratrol at high dosages exerts a remarkable cardioprotective effect. Whether a long-term exposure to resveratrol at low dosages that can be obtained through consumption of a resveratrol-rich diet is beneficial to heart diseases is unknown. We tested the effects of a resveratrol-enriched diet on cardiovascular remodeling of chronic heart failure (CHF) in rats resulting from permanent ligation of left coronary artery. Two weeks after surgery, rats were started on either a resveratrol-enriched (R; 5 mg/kg per day; n = 23) or normal (Control; n = 23) diet for next 10 months. Serial echocardiography in Control showed a significant decline in LV ejection fraction, increases in LV end-systolic and end-diastolic volumes, and expansion in myocardial infarct from pre-treatment values. In R, compared with Control, there were substantial improvements in those parameters. End-point LV pressure-volume loop analysis showed a significantly improved LV systolic function and AV-coupling, an index of energy transfer efficacy between the heart and aortic tree, in R compared with Control (p < 0.05). Aortic pulse wave velocity, a measure of arterial stiffness, was significantly lower in R (389 +/- 15 cm/s; p < 0.05) compared with Control (489 +/- 38 cm/s). These results demonstrated that long-term dietary resveratrol supplement reduces cardiovascular structural and functional deterioration in CHF. C1 [Ahmet, Ismayil; Tae, Hyun-Jin; Lakatta, Edward G.; Talan, Mark] NIH, NIA, Lab Cardiovascular Sci, Intramural Res Program, Baltimore, MD 21224 USA. RP Ahmet, I (reprint author), NIH, NIA, Lab Cardiovascular Sci, Intramural Res Program, Baltimore, MD 21224 USA. EM ismayilah@grc.nia.nih.gov FU NIA intramural research FX This study was fully supported by NIA intramural research program. NR 38 TC 1 Z9 1 U1 2 U2 2 PU CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS PI OTTAWA PA 65 AURIGA DR, SUITE 203, OTTAWA, ON K2E 7W6, CANADA SN 0008-4212 EI 1205-7541 J9 CAN J PHYSIOL PHARM JI Can. J. Physiol. Pharmacol. PD MAR PY 2017 VL 95 IS 3 BP 268 EP 274 DI 10.1139/cjpp-2016-0512 PG 7 WC Pharmacology & Pharmacy; Physiology SC Pharmacology & Pharmacy; Physiology GA EO6ZC UT WOS:000396840000007 PM 28134561 ER PT J AU Gao, L Mutlu, E Collins, LB Walker, NJ Hartwell, HJ Olson, JR Sun, W Gold, A Ball, LM Swenberg, JA AF Gao, Lina Mutlu, Esra Collins, Leonard B. Walker, Nigel J. Hartwell, Hadley J. Olson, James R. Sun, Wei Gold, Avram Ball, Louise M. Swenberg, James A. TI DNA Product Formation in Female Sprague-Dawley Rats Following Polyhalogenated Aromatic Hydrocarbon (PHAH) Exposure SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID TANDEM MASS-SPECTROMETRY; TOXIC EQUIVALENCY FACTORS; DIOXIN-LIKE COMPOUNDS; LC-MS/MS METHOD; LIPID-PEROXIDATION; OXIDATIVE STRESS; POLYCHLORINATED-BIPHENYLS; SUBCHRONIC EXPOSURE; RISK-ASSESSMENT; CHEMICAL CARCINOGENESIS AB DNA oxidation damage has been regarded as one of the possible mechanisms for the hepatic carcinogenesis of dioxin-like compounds (DLCs). In this study, we evaluated the toxic equivalency factor (TEF) from the standpoint of induced DNA oxidation products and their relationship to toxicity and carcinogenicity. Nine DNA oxidation products were analyzed in the liver of female Sprague-Dawley rats exposed to 2,3,7,8tetrachlorodibenzo-pdioxin (TCDD) alone or the tertiary mixture of TCDD, 3,3',4,4',5-pentachlorobiphenyl (PCB 126), and 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) by gavage for 14, 31, and 53 weeks (5 days/week) by LC-MS/MS: 8-oxo-7,8dihydro-2'-deoxyguanosine (8-oxo-dGuo); 1,N6-etheno-2'-deoxyadenosine (1,N6-edAdo); N2,3-ethenoguanine (N2,3-8G); 7-(2oxoethly)guanine (7-OEG); 1,N2-etheno-2'-deoxyguanosine (1,N2-edGuo); malondialdehyde (M1dGuo); acrolein (AcrdGuo); crotonaldehyde (CrdGuo); and 4-hydroxynonenal (HNEdGuo) derived 2'-deoxyguanosine adducts. Exposure to TCDD (100 ng/kg/day) significantly induced 1,N6-edAdo at 31 and 53 weeks, while no increase of 8-oxo-dGuo was observed. Significant increases were observed for 8-oxo-dGuo and 1,N6-edAdo at all time points following exposure to the tertiary mixture (TEQ100 ng/kg/day). Exposure to TCDD for 53 weeks only significantly increased 1,N6-edAdo, while increases of N2,3-eG and 7-OEG were only found in the highest dose group (100 ng/kg/day). Exposure to the tertiary mixture for 53 weeks had no effect on N2,3eG in any exposure group (TEQO, 22, 46, or 100 ng/kg/day), while significant increases were observed for 1,N6-edAdo (all dose groups), 8-oxo-dGuo (46 and 100 ng/kg/day), and 7-OEG (100 ng/kg/day). While no significant increase was observed at 53 weeks for 1,N2-epsilon dGuo, M1dGuo, AcrdGuo, or CrdGuo following exposure to TCDD (100 ng/kg/day), all of them were significantly induced in animals exposed to the tertiary mixture (TEQ100 ng/kg/day). This oxidation DNA product data suggest that the simple TEF methodology cannot be applied to evaluate the diverse patterns of toxic effects induced by DLCs. C1 [Gao, Lina; Collins, Leonard B.; Hartwell, Hadley J.; Gold, Avram; Ball, Louise M.; Swenberg, James A.] Univ N Carolina, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. [Sun, Wei] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Mutlu, Esra; Walker, Nigel J.] NIH, Natl Inst Environm Hlth Sci, Natl Toxicol Program, RTP, Durham, NC 27709 USA. [Olson, James R.] SUNY Buffalo, Dept Pharmacol & Toxicol, Buffalo, NY 14214 USA. RP Swenberg, JA (reprint author), Univ N Carolina, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. EM jswenber@email.unc.edu FU NIEHS Superfund Basic Research Program [P42-ES05948]; NIEHS Center for Environmental Health and Susceptibility [P30 ES 10126]; intramural research program of the NIEHS FX This work was supported by the NIEHS Superfund Basic Research Program P42-ES05948 and the NIEHS Center for Environmental Health and Susceptibility P30 ES 10126 and in part by the intramural research program of the NIEHS. NR 66 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X EI 1520-5010 J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD MAR PY 2017 VL 30 IS 3 BP 794 EP 803 DI 10.1021/acs.chemrestox.6b00368 PG 10 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA EP1VB UT WOS:000397171300006 PM 28207250 ER PT J AU Papadakis, GZ Millo, C Jassel, IS Bagci, U Sadowski, SM Karantanas, AH Patronas, NJ AF Papadakis, Georgios Z. Millo, Corina Jassel, Inderbir S. Bagci, Ulas Sadowski, Samira M. Karantanas, Apostolos H. Patronas, Nicholas J. TI F-18-FDG and Ga-68-DOTATATE PET/CT in von Hippel-Lindau Disease-Associated Retinal Hemangioblastoma SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material DE F-18-FDG PET/CT; Ga-68-DOTATATE PET/CT; retinal hemangioblastomas; von Hippel-Lindau disease; MRI ID GA-68 DOTATATE PET/CT; TUMORS; FDG AB Retinal hemangioblastomas are highly vascular benign tumors that can be encountered either sporadically or within the von Hippel-Lindau (VHL) syndrome. We report a case of a VHL patient with retinal hemangioblastoma who underwent PET/CT scans using F-18-FDG and Ga-68-DOTATATE. The tumor showed low-level F-18-FDG and increased Ga-68-DOTATATE activity, suggesting cell-surface overexpression of somatostatin receptors. The presented case indicates the clinical applications of somatostatin receptor imaging with Ga-68-DOTA-conjugated peptides in detection and follow-up of VHL manifestations, screening of asymptomatic gene carriers, and in diagnosis of sporadic retinal hemangioblastomas, which may have similar features on MRI with other retinal tumors. C1 [Papadakis, Georgios Z.; Patronas, Nicholas J.] NIH, Radiol & Imaging Sci, Warren Grant Magnuson Clin Ctr, Bldg 10, Bethesda, MD 20892 USA. [Millo, Corina] NIH, Ctr Clin, PET Dept, Bethesda, MD 20892 USA. [Jassel, Inderbir S.] Leeds Med Sch, Leeds, W Yorkshire, England. [Bagci, Ulas] Univ Cent Florida, Dept Elect & Comp Sci, Ctr Comp Vis Res, Orlando, FL 32816 USA. [Sadowski, Samira M.] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Sadowski, Samira M.] Univ Hosp Geneva, Endocrine & Thorac Surg, Geneva, Switzerland. [Karantanas, Apostolos H.] Univ Crete, Sch Med, Dept Radiol, Iraklion, Greece. RP Patronas, NJ (reprint author), NIH, Neuroradiol Branch, Warren Grant Magnuson Clin Ctr, Bldg 10,Room 1C361X,10 Ctr Dr,Mail Stop 1182, Bethesda, MD 20814 USA. EM NPatronas@cc.nih.gov NR 13 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 0363-9762 EI 1536-0229 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD MAR PY 2017 VL 42 IS 3 BP 189 EP 190 DI 10.1097/RLU.0000000000001511 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EL2KJ UT WOS:000394448300017 PM 28033220 ER PT J AU Papadakis, GZ Millo, C Sadowski, SM Karantanas, AH Bagci, U Patronas, NJ AF Papadakis, Georgios Z. Millo, Corina Sadowski, Samira M. Karantanas, Apostolos H. Bagci, Ulas Patronas, Nicholas J. TI Fibrous Dysplasia Mimicking Malignancy on Ga-68-DOTATATE PET/CT SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material DE Ga-68-DOTATATE PET/CT; CT; MRI; fibrous dysplasia of bone; somatostatin receptors (SSTRs) ID GA-68 DOTATATE PET/CT; TUMOR AB Fibrous dysplasia of the bone is a developmental benign skeletal disorder characterized by replacement of normal bone and normal bone marrow with abnormal fibro-osseous tissue. We report on a case of a biopsy-proven fibrous dysplasia lesion in the left temporal bone, with intensely increased activity (SUVmax, 56.7) on Ga-68-DOTATATE PET/CT. The presented data indicate cell surface overexpression of somatostatin receptors by fibrous dysplastic cells and highlight the need of cautious management of Ga-68-DOTATATE-avid bone lesions, which could mimic malignancy especially in patients with history of neuroendocrine tumors. C1 [Papadakis, Georgios Z.; Patronas, Nicholas J.] NCI, Radiol & Imaging Sci, Warren Grant Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. [Millo, Corina] NCI, PET Dept, NIH, Bethesda, MD 20892 USA. [Millo, Corina] NCI, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Sadowski, Samira M.] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. [Sadowski, Samira M.] Univ Hosp Geneva, Endocrine & Thorac Surg, Geneva, Switzerland. [Karantanas, Apostolos H.] Univ Crete, Dept Radiol, Sch Med, Rethimnon, Greece. [Bagci, Ulas] Univ Cent Florida, Dept Elect & Comp Sci, Ctr Comp Vis Res, Orlando, FL 32816 USA. RP Papadakis, GZ (reprint author), NIH, Dept Radiol & Imaging Sci, Warren Grant Magnuson Clin Ctr, Bldg 10,Room 1C370,10 Ctr Dr, Bethesda, MD 20814 USA. EM papadakisg@cc.nih.gov FU Intramural NIH HHS [Z99 CL999999, Z99 DE999999] NR 11 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 0363-9762 EI 1536-0229 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD MAR PY 2017 VL 42 IS 3 BP 209 EP 210 DI 10.1097/RLU.0000000000001527 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EL2KJ UT WOS:000394448300025 PM 28072620 ER PT J AU Janssen, I Wolf, KI Chui, CH Millo, CM Pacak, K AF Janssen, Ingo Wolf, Katherine I. Chui, Chan H. Millo, Corina M. Pacak, Karel TI Relevant Discordance Between Ga-68-DOTATATE and Ga-68-DOTANOC in SDHB-Related Metastatic Paraganglioma Is Affinity to Somatostatin Receptor 2 the Key? SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material DE Ga-68-DOTANOC; Ga-68-DOTATATE; metastatic; paraganglioma; pheochromocytoma; positron emission tomography ID PET/CT; RADIOMETALS; EXPRESSION; ANALOGS AB Pheochromocytomas/paragangliomas are somatostatin receptor 2-overexpressing tumors. Ga-68-DOTA-peptide imaging has recently shown excellent results in the detection of metastatic lesions in these tumors. However, currently used Ga-68-DOTA peptides show different somatostatin receptor affinities. Here, we report the remarkable differences in a patient who was imaged with Ga-68-DOTANOC and Ga-68-DOTATATE PET/CT within a 7-month period. The patient presented with a nearly negative Ga-68-DOTANOC PET/CT scan, whereas on Ga-68-DOTATATE PET/CT, multiple highly positive lesions were identified. C1 [Janssen, Ingo; Wolf, Katherine I.; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Endocrinol, NIH, Bethesda, MD USA. [Chui, Chan H.] Mt Elizabeth Med Ctr, Surg Ctr Children, Singapore, Singapore. [Millo, Corina M.] NIH, Positron Emiss Tomog Dept, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), Eunice Kennedy Shriver NICHD, Sect Med Neuroendocrinol, NIH, Bldg 10,CRC,Room 1E-3140,10 Ctr Dr,MSC-1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 8 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 0363-9762 EI 1536-0229 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD MAR PY 2017 VL 42 IS 3 BP 211 EP 213 DI 10.1097/RLU.0000000000001504 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EL2KJ UT WOS:000394448300026 PM 28033222 ER PT J AU Papadakis, GZ Millo, C Karantanas, AH Bagci, U Patronas, NJ AF Papadakis, Georgios Z. Millo, Corina Karantanas, Apostolos H. Bagci, Ulas Patronas, Nicholas J. TI Avascular Necrosis of the Hips With Increased Activity on Ga-68-DOTATATE PET/CT SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material DE avascular bone necrosis; Ga-68-DOTATATE PET/CT; inflammation; macrophages; MRI; somatostatin receptors (SSTRs) ID FEMORAL-HEAD; OSTEONECROSIS AB Prolonged exposure to cortisol is one of the major causes of avascular bone necrosis (AVN). We report on a case of awoman with Cushing syndrome attributed to ectopic adrenocorticotropic hormone-secreting tumor who was evaluated with whole-body PET/CT study using Ga-68-DOTATATE. The scan showed increased activity by both femoral heads, corresponding to the margins of bilateral AVN seen on MRI. The presented data suggests AVN-induced reactive inflammatory alterations adjacent to the necrotic segment of the bone, which can be effectively targeted using radiolabeled somatostatin (SST) analogs. C1 [Papadakis, Georgios Z.; Patronas, Nicholas J.] Warren Grant Magnuson Clin Ctr CC, Radiol & Imaging Sci, Bethesda, MD USA. [Millo, Corina] NIH, PET Dept, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Karantanas, Apostolos H.] Univ Crete, Sch Med, Dept Radiol, Iraklion, NE, Greece. [Bagci, Ulas] Univ Cent Florida, CRCV, Dept Elect & Comp Sci, Orlando, FL 32816 USA. RP Papadakis, GZ (reprint author), NIH, Dept Radiol & Imaging Sci, Warren Grant Magnuson Clin Ctr, Bldg 10,Room 1C370,10 Ctr Dr,Mail Stop 1182, Bethesda, MD 20814 USA. EM papadakisg@cc.nih.gov FU Intramural NIH HHS [Z99 CL999999, Z99 DE999999] NR 10 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 0363-9762 EI 1536-0229 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD MAR PY 2017 VL 42 IS 3 BP 214 EP 215 DI 10.1097/RLU.0000000000001513 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EL2KJ UT WOS:000394448300027 PM 28033218 ER PT J AU Silva, AC AF Silva, Afonso C. TI Anatomical and functional neuroimaging in awake, behaving marmosets SO DEVELOPMENTAL NEUROBIOLOGY LA English DT Review DE marmoset; neuroimaging; functional magnetic resonance imaging; two-photon laser scanning microscopy; transgenic marmosets ID MANGANESE-ENHANCED MRI; FLUORESCENT CA2+ INDICATOR; RESONANCE-IMAGING MEMRI; COMMON MARMOSET; CALLITHRIX-JACCHUS; VISUAL-CORTEX; IN-VIVO; TRANSGENIC MICE; NEURAL ACTIVITY; SOMATOSENSORY CORTEX AB The common marmoset (Callithrix jacchus) is a small New World monkey that has gained significant recent interest in neuroscience research, not only because of its compatibility with gene editing techniques, but also due to its tremendous versatility as an experimental animal model. Neuroimaging modalities, including anatomical (MRI) and functional magnetic resonance imaging (fMRI), complemented by two-photon laser scanning microscopy and electrophysiology, have been at the forefront of unraveling the anatomical and functional organization of the marmoset brain. High-resolution anatomical MRI of the marmoset brain can be obtained with remarkable cytoarchitectonic detail. Functional MRI of the marmoset brain has been used to study various sensory systems, including somatosensory, auditory, and visual pathways, while resting-state fMRI studies have unraveled functional brain networks that bear great correspondence to those previously described in humans. Two-photon laser scanning microscopy of the marmoset brain has enabled the simultaneous recording of neuronal activity from thousands of neurons with single cell spatial resolution. In this article, we aim to review the main results obtained by our group and by our colleagues in applying neuroimaging techniques to study the marmoset brain. (c) 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 373-389, 2017 C1 [Silva, Afonso C.] NINDS, Cerebral Microcirculat Sect, Lab Funct & Mol Imaging, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Silva, AC (reprint author), NINDS, Cerebral Microcirculat Sect, Lab Funct & Mol Imaging, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM SilvaA@ninds.nih.gov FU NIH, NINDS FX Contract grant sponsor: NIH, NINDS. NR 119 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1932-8451 EI 1932-846X J9 DEV NEUROBIOL JI Dev. Neurobiol. PD MAR PY 2017 VL 77 IS 3 BP 373 EP 389 DI 10.1002/dneu.22456 PG 17 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA EM9PJ UT WOS:000395643300010 PM 27706916 ER PT J AU Yun, K Perantoni, AO AF Yun, Kangsun Perantoni, Alan O. TI Hydronephrosis in the Wnt5a-ablated kidney is caused by an abnormal ureter-bladder connection SO DIFFERENTIATION LA English DT Article DE Wnt5a; Kidney development; Hydronephrosis; Nephric duct; Metanephric mesenchyme; Renal medulla ID DOMINANT ROBINOW SYNDROME; NEPHRIC DUCT INSERTION; CELL-DIVISION; WNT5A; MORPHOGENESIS; TRACT; DISEASE; MICE; MESENCHYME; MOUSE AB The Wnt5a null mouse is a complex developmental model which, among its several posterior-localized axis defects, exhibits multiple kidney phenotypes, including duplex kidney and loss of the medullary zone. We previously reported that ablation of Wnt5a in nascent mesoderm causes duplex kidney formation as a result of aberrant development of the nephric duct and abnormal extension of intermediate mesoderm. However, these mice also display a loss of the medullary region late in gestation. We have now genetically isolated duplex kidney formation from the medullary defect by specifically targeting the progenitors for both the ureteric bud and metanephric mesenchyme. The conditional mutants fail to form a normal renal medulla but no longer exhibit duplex kidney formation. Approximately 1/3 of the mutants develop hydronephrosis in the kidneys either unior bilaterally when using DILICre. The abnormal kidney phenotype becomes prominent at E16.5, which approximates the time when urine production begins in the mouse embryonic kidney, and is associated with a dramatic increase in apoptosis only in mutant kidneys with hydronephrosis. Methylene blue dye injection and histologic examination reveal that aberrant cell death likely results from urine toxicity due to an abnormal ureter-bladder connection. This study shows that Wnt5a is not required for development of the renal medulla and that loss of the renal medullary region in the Wnt5a-deleted kidney is caused by an abnormal ureter bladder connection. C1 [Yun, Kangsun; Perantoni, Alan O.] Natl Canc Inst, Natl Inst Hlth, Canc & Dev Biol Lab, Frederick, MD 21702 USA. RP Perantoni, AO (reprint author), Natl Canc Inst, Natl Inst Hlth, Canc & Dev Biol Lab, Frederick, MD 21702 USA. EM perantoa@mail.nih.gov FU National Institutes of Health; National Cancer Institute and Center for Cancer Research FX We thank members of Cancer and Developmental Biology Laboratory for their critical review of the data, Nirmala Sharma for her excellent technical assistance, and Dr. Michael Hall for a review of the manuscript. We thank Dr. Mark Lewandoski for help with the Dll1Cre line, Dr. Terry Yamaguchi for the Wnt5a flox/flox line, and Trevor Williams for the AP2Cre line. We are also grateful to Drs. Jing Yun and Frank Costantini for the Hoxb7/myr-Venus line. This study referenced data from the GUDMAP database http://www.gudmap.org (08/2016), i.e., in situ hybridization data from the McMahon lab. This work was supported by the National Institutes of Health, National Cancer Institute and Center for Cancer Research. NR 29 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0301-4681 EI 1432-0436 J9 DIFFERENTIATION JI Differentiation PD MAR-APR PY 2017 VL 94 BP 1 EP 7 DI 10.1016/j.diff.2016.11.006 PG 7 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA EP0LH UT WOS:000397078300001 PM 27923152 ER PT J AU Babalonis, S Haney, M Malcolm, RJ Lofwall, MR Votaw, VR Sparenborg, S Walsh, SL AF Babalonis, Shanna Haney, Margaret Malcolm, Robert J. Lofwall, Michelle R. Votaw, Victoria R. Sparenborg, Steven Walsh, Sharon L. TI Oral cannabidiol does not produce a signal for abuse liability in frequent marijuana smokers SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Cannabidiol; CBD; Abuse liability; Smoked marijuana; Human ID DELTA(9)-TETRAHYDROCANNABINOL; CANNABINOIDS; RECEPTORS; EPILEPSY; DELTA-9-TETRAHYDROCANNABINOL; POTENCY; ANXIETY; HUMANS; TRIAL AB Background: Cannabidiol (CBD) is a naturally occurring constituent of the marijuana plant. In the past few years, there has been great interest in the therapeutic effects of isolated CBD and it is currently being explored for numerous disease conditions (e.g., pain, epilepsy, cancer, various drug dependencies). However, CBD remains a Schedule I drug on the U.S. Controlled Substances Act (CSA). Despite its status, there are no well-controlled data available regarding its abuse liability. Methods: Healthy, frequent marijuana users (n = 31) were enrolled in this within subject, randomized, placebo-controlled, double-blind, multisite study that administered oral cannabidiol (0, 200, 400, 800 mg) alone and in combination with smoked marijuana (0.01%, 5.3-5.8% THC). Participants received one dose combination across 8 once-weekly outpatient sessions (7.5 h). The primary findings on the drug interaction effects were previously reported (Haney et al., 2016). The present study is a secondary analysis of the data to examine the abuse liability profile of oral cannabidiol (200, 400, 800 mg) in comparison to oral placebo and active smoked marijuana (5.3-5.8% THC). Results: Active marijuana reliably produced abuse-related subjective effects (e.g., high) (p < 0.05). However, CBD was placebo-like on all measures collected (p > 0.05). Conclusions: Overall, CBD did not display any signals of abuse liability at the doses tested and these data may help inform U.S. regulatory decisions regarding CBD schedule on the CSA. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Babalonis, Shanna; Lofwall, Michelle R.; Walsh, Sharon L.] Univ Kentucky, Ctr Drug & Alcohol Res, Dept Behav Sci, Lexington, KY USA. [Haney, Margaret] Columbia Univ, Med Ctr, New York State Psychiat Inst, Div Subst Abuse, New York, NY USA. [Haney, Margaret] Dept Psychiat, New York, NY USA. [Malcolm, Robert J.] Med Univ South Carolina, Charleston, SC 29425 USA. [Votaw, Victoria R.] McLean Hosp, Div Alcohol & Drug Abuse, Belmont, MA 02178 USA. [Sparenborg, Steven] Natl Inst Drug Abuse, Bethesda, MD USA. RP Babalonis, S (reprint author), Univ Kentucky, Coll Med, Ctr Drug & Alcohol Res, Dept Behav Sci, 845 Angliana Ave, Lexington, KY 40508 USA. EM babalonis@uky.edu FU National Institute on Drug Abuse [DA009236, U10DA013727, U10DA13732]; National Center for Research Resources and National Center for Advancing of Translational Sciences [UL1TR000117-04, KL2TR000116-04] FX Grants from the National Institute on Drug Abuse (DA009236, U10DA013727, U10DA13732) and the National Center for Research Resources and National Center for Advancing of Translational Sciences (UL1TR000117-04 [UK CTSA]; KL2TR000116-04) provided support for this research. NR 30 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD MAR 1 PY 2017 VL 172 BP 9 EP 13 DI 10.1016/j.drugalcdep.2016.11.030 PG 5 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA EM3LV UT WOS:000395217500002 PM 28088032 ER PT J AU Grillon, C Robinson, OJ Krimsky, M O'Connell, K Alvarez, G Ernst, M AF Grillon, Christian Robinson, Oliver J. Krimsky, Marissa O'Connell, Katherine Alvarez, Gabriella Ernst, Monique TI Anxiety-Mediated Facilitation of Behavioral Inhibition: Threat Processing and Defensive Reactivity During a Go/No-Go Task SO EMOTION LA English DT Article DE anxiety; go/no-go task; response inhibition; fear-potentiated startle; distraction ID WORKING-MEMORY CAPACITY; MIND; INDIVIDUALS; PERFORMANCE; MODULATION; DEPLETION; CONTEXTS; THOUGHT; CORTEX; REWARD AB Anxiety can be broken down into multiple facets including behavioral components, such as defensive reactivity, and cognitive components, such as distracting anxious thoughts. In a previous study, we showed that anticipation of unpredictable shocks facilitated response inhibition to infrequent no-go trials during a go/no-go task. The present study extends this work to examine the distinct contribution of defensive reactivity, measures with fear-potentiated startle, and anxious thought, assessed with thought probes, on go and no-go performance. Consistent with our prior findings, shock anticipation facilitated response inhibition (i.e., reduced errors of commission) on the no-go trials. Regression analyses showed that (a) no-go accuracy was positively associated with fear-potentiated startle and negatively associated with threat-related/task-unrelated thoughts and (b) go accuracy correlated negatively with fear-potentiated startle. Thus, while the present findings confirm the influence of anxiety on response inhibition, they also show that such influence reflects the balance C1 [Grillon, Christian; Alvarez, Gabriella; Ernst, Monique] NIMH, Sect Neurobiol Fear & Anxiety, 15K North Dr,Bldg 15k, Bethesda, MD 20892 USA. [Robinson, Oliver J.] UCL, Inst Cognit Neurosci, London, England. [Krimsky, Marissa] Univ Miami, Dept Psychol, Coral Gables, FL 33124 USA. [O'Connell, Katherine] Georgetown Univ, Interdisciplinary Program Neurosci, Washington, DC 20057 USA. RP Grillon, C (reprint author), NIMH, Sect Neurobiol Fear & Anxiety, 15K North Dr,Bldg 15k, Bethesda, MD 20892 USA. EM Christian.grillon@nih.gov FU Intramural Research Program of the National Institute of Mental Health [ZI-AMH002798] FX Financial support of this study was provided by the Intramural Research Program of the National Institute of Mental Health, ZI-AMH002798 (ClinicalTrial.gov Identifier: NCT00026559: Protocol ID 01-M-0185). NR 39 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1528-3542 EI 1931-1516 J9 EMOTION JI Emotion PD MAR PY 2017 VL 17 IS 2 BP 259 EP 266 DI 10.1037/emo0000214 PG 8 WC Psychology, Experimental SC Psychology GA EN4TS UT WOS:000396000400009 PM 27642657 ER PT J AU Xu, JY Wu, L Shi, Z Zhang, XJ Englert, NA Zhang, SY AF Xu, Jia-Yi Wu, Liang Shi, Zhe Zhang, Xiao-Jie Englert, Neal A. Zhang, Shu-Yun TI Upregulation of human CYP2C9 expression by Bisphenol A via estrogen receptor alpha (ER alpha) and Med25 SO ENVIRONMENTAL TOXICOLOGY LA English DT Article DE bisphenol A; CYP2C9; ER alpha; Med25; transcriptional regulation ID CONSTITUTIVE ANDROSTANE RECEPTOR; GLUCOCORTICOID-RECEPTOR; ENVIRONMENTAL LEVELS; HUMAN HEALTH; MEN; BPA; SUBFAMILY; CHEMICALS; QUALITY; DAMAGE AB Bisphenol A (BPA) is an important industrial chemical, mainly used in the manufacture of polycarbonate plastic and epoxy resins. Due to its widespread use, humans have a high risk of exposure to BPA. BPA has been found to have adverse health effects such as interfering with hormone-related pathways and is well-known to act as an endocrine disruptor. The present study is the first to show the induction effect of BPA on gene expression and enzyme activity of CYP2C9, an important hepatic drug metabolizing enzyme in human. We further identify the mechanism of BPA upregulation of CYP2C9 expression. We show that BPA is able to transcriptionally activate CYP2C9 promoter through ER and ERE site within the CYP2C9 promoter region in HepG2 cells, and can induce CYP2C9 gene expression and enzyme activity in human primary hepatocytes. Moreover, we demonstrate that Med25, a variable member of the Mediator complex, is a coactivator of ligand-activated ER that interacts with ER through its C-terminal LXXLL motif after BPA exposure, and is functionally involved in BPA-induced transcriptional regulation of CYP2C9 expression and enzyme activity. Our findings suggest that BPA exposure has a potential risk for adverse health effects in human liver metabolism by upregulation of CYP2C9 expression. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 970-978, 2017. C1 [Xu, Jia-Yi; Shi, Zhe; Zhang, Xiao-Jie; Zhang, Shu-Yun] Wenzhou Med Univ, Sch Environm Sci & Publ Hlth, Dept Prevent Med, Wenzhou 325035, Zhejiang, Peoples R China. [Wu, Liang] Wenzhou Med Univ, Dept Pathol, Affiliated Hosp 1, Wenzhou 325035, Zhejiang, Peoples R China. [Englert, Neal A.] NIEHS, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Zhang, SY (reprint author), Wenzhou Med Univ, Sch Environm Sci & Publ Hlth, Dept Prevent Med, Wenzhou 325035, Zhejiang, Peoples R China. EM shuyunzh@yahoo.com FU National Natural Science Foundation of China [31500946]; Department of Medical Technology and Education of Zhejiang Province [2016KYA134]; Science and Technology Bureau of Wenzhou [Y20150089]; Department of Education of Zhejiang Province [Y201534186]; Wenzhou Medical University [QTJ13011] FX Contract grant sponsor: National Natural Science Foundation of China. Contract grant number: 31500946.; Contract grant sponsor: Department of Medical Technology and Education of Zhejiang Province.; Contract grant number: 2016KYA134.; Contract grant sponsor: Science and Technology Bureau of Wenzhou.; Contract grant number: Y20150089.; Contract grant sponsor: Department of Education of Zhejiang Province.; Contract grant number: Y201534186.; Contract grant sponsor: Wenzhou Medical University.; Contract grant number: QTJ13011. NR 34 TC 0 Z9 0 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1520-4081 EI 1522-7278 J9 ENVIRON TOXICOL JI Environ. Toxicol. PD MAR PY 2017 VL 32 IS 3 BP 970 EP 978 DI 10.1002/tox.22297 PG 9 WC Environmental Sciences; Toxicology; Water Resources SC Environmental Sciences & Ecology; Toxicology; Water Resources GA EL4GX UT WOS:000394580800021 PM 27273787 ER PT J AU Hall, KD AF Hall, K. D. TI A review of the carbohydrate-insulin model of obesity SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Review ID HIGH-FAT DIET; ENERGY-EXPENDITURE; WEIGHT-LOSS; BODY-COMPOSITION; KETOGENIC DIETS; BALANCE; OXIDATION; HUMANS; MEN; THERMODYNAMICS AB The carbohydrate-insulin model of obesity theorizes that diets high in carbohydrate are particularly fattening due to their propensity to elevate insulin secretion. Insulin directs the partitioning of energy toward storage as fat in adipose tissue and away from oxidation by metabolically active tissues and purportedly results in a perceived state of cellular internal starvation. In response, hunger and appetite increases and metabolism is suppressed, thereby promoting the positive energy balance associated with the development of obesity. Several logical consequences of this carbohydrate-insulin model of obesity were recently investigated in a pair of carefully controlled inpatient feeding studies whose results failed to support key model predictions. Therefore, important aspects of carbohydrate-insulin model have been experimentally falsified suggesting that the model is too simplistic. This review describes the current state of the carbohydrate-insulin model and the implications of its recent experimental tests. C1 [Hall, K. D.] Natl Inst Diabet & Digest & Kidney Dis, 12A South Dr,Room 4007, Bethesda, MD 20892 USA. RP Hall, KD (reprint author), Natl Inst Diabet & Digest & Kidney Dis, 12A South Dr,Room 4007, Bethesda, MD 20892 USA. EM kevinh@niddk.nih.gov FU Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. NR 50 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0954-3007 EI 1476-5640 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD MAR PY 2017 VL 71 IS 3 SI SI BP 323 EP 326 DI 10.1038/ejcn.2016.260 PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EN0KE UT WOS:000395697900006 PM 28074888 ER PT J AU Brychta, RJ Chen, KY AF Brychta, R. J. Chen, K. Y. TI Cold-induced thermogenesis in humans SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Review ID BROWN ADIPOSE-TISSUE; INDUCED ADAPTIVE THERMOGENESIS; LOW ENVIRONMENTAL-TEMPERATURE; ENERGY-EXPENDITURE; MILD COLD; PARTITIONAL CALORIMETRY; AMBIENT-TEMPERATURE; BODY-TEMPERATURE; ADULT HUMANS; NONSHIVERING THERMOGENESIS AB A basic property of endothermic thermoregulation is the ability to generate heat by increasing metabolism in response to cold ambient temperatures to maintain a stable core body temperature. This process, known as cold-induced thermogenesis (CIT), has been measured in humans as early as 1780 by Antoine Lavoisier, but has found renewed interest because of the recent 'rediscovery' of thermogenic, cold-activated brown adipose tissue (BAT) in adult humans. In this review, we summarize some of the key findings of the work involving CIT over the past two centuries and highlight some of the seminal studies focused on this topic. There has been a substantial range of variability in the reported CIT in these studies, from 0 to 280% above basal metabolism. We identify and discuss several potential sources of this variability, including both methodological (measurement device, cold exposure temperature and duration) and biological (age and body composition of subject population) discrepancies. These factors should be considered when measuring CIT going forward to better assess whether BAT or other thermogenic organs are viable targets to combat chronic positive energy balance based on their relative capacities to elevate human metabolism. C1 [Brychta, R. J.; Chen, K. Y.] NIH, Natl Inst Diabet & Digest & Kidney Dis, Diabet Endocrinol, Bldg 10-CRC,Room 5-5752,10 Ctr Dr MSC 1613, Bethesda, MD 20892 USA. [Brychta, R. J.; Chen, K. Y.] NIH, Obes Branch, Bldg 10-CRC,Room 5-5752,10 Ctr Dr MSC 1613, Bethesda, MD 20892 USA. RP Chen, KY (reprint author), NIH, Natl Inst Diabet & Digest & Kidney Dis, Diabet Endocrinol, Bldg 10-CRC,Room 5-5752,10 Ctr Dr MSC 1613, Bethesda, MD 20892 USA.; Chen, KY (reprint author), NIH, Obes Branch, Bldg 10-CRC,Room 5-5752,10 Ctr Dr MSC 1613, Bethesda, MD 20892 USA. EM chenkong@niddk.nih.gov FU NIH (NIDDK); NIH (Clinical Center) FX This work was funded by NIH Intramural research funding resources (NIDDK and Clinical Center). NR 73 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0954-3007 EI 1476-5640 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD MAR PY 2017 VL 71 IS 3 SI SI BP 345 EP 352 DI 10.1038/ejcn.2016.223 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EN0KE UT WOS:000395697900010 PM 27876809 ER PT J AU Vege, SS Ziring, B Jain, R Scheiman, JM Hwang, JH Moayyedi, P AF Vege, Santhi Swaroop Ziring, Barry Jain, Rajeev Scheiman, James M. Hwang, Joo Ha Moayyedi, Paul TI Optimal strategies for pancreatic cyst surveillance: we need better comparative data, not more case series SO GASTROINTESTINAL ENDOSCOPY LA English DT Letter ID MANAGEMENT; DIAGNOSIS C1 [Vege, Santhi Swaroop] NCI, Pancreas Interest Grp, Bethesda, MD 20892 USA. [Vege, Santhi Swaroop] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN 55905 USA. [Ziring, Barry] Thomas Jefferson Univ, Sidney Kimmel Med Coll, Div Internal Med, Philadelphia, PA 19107 USA. [Jain, Rajeev] Texas Digest Dis Consultants, Dallas, TX USA. [Scheiman, James M.] Univ Michigan, Sch Med, Dept Internal Med & Gastroenterol, Ann Arbor, MI USA. [Hwang, Joo Ha] Univ Washington, Dept Med, Div Gastroenterol, Seattle, WA USA. [Moayyedi, Paul] McMaster Univ, Div Gastroenterol, Hamilton, ON, Canada. RP Vege, SS (reprint author), NCI, Pancreas Interest Grp, Bethesda, MD 20892 USA.; Vege, SS (reprint author), Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN 55905 USA. NR 3 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 EI 1097-6779 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD MAR PY 2017 VL 85 IS 3 BP 685 EP 686 DI 10.1016/j.gie.2016.09.007 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EP1UK UT WOS:000397169600039 PM 28215775 ER PT J AU Reiss, KA Herman, JM Armstrong, D Zahurak, M Fyles, A Brade, A Milosevic, M Dawson, LA Scardina, A Fischer, P Hacker-Prietz, A Kinders, RJ Wang, LH Chen, A Temkin, S Horiba, N Stayner, LA Siu, LL Azad, NS AF Reiss, Kim A. Herman, Joseph M. Armstrong, Deborah Zahurak, Marianna Fyles, Anthony Brade, Anthony Milosevic, Michael Dawson, Laura A. Scardina, Angela Fischer, Patricia Hacker-Prietz, Amy Kinders, Robert J. Wang, Lihua Chen, Alice Temkin, Sarah Horiba, Naomi Stayner, Lee-Anne Siu, Lillian L. Azad, Nilofer S. TI A final report of a phase I study of veliparib (ABT-888) in combination with low-dose fractionated whole abdominal radiation therapy (LDFWAR) in patients with advanced solid malignancies and peritoneal carcinomatosis with a dose escalation in ovarian and fallopian tube cancers SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Peritoneal carcinomatosis; PARP inhibition; Veliparib; Radiation; Ovarian cancer; BRCA ID POLY(ADP-RIBOSE) POLYMERASE INHIBITOR; MAINTENANCE THERAPY; TUMORS; RADIOSENSITIZATION; RADIOTHERAPY; IRINOTECAN; OLAPARIB; MODELS AB Background. The combination of low-dose radiation therapy with PARP inhibition enhances anti-tumor efficacy through potentiating DNA damage. We combined low-dose fractionated whole abdominal radiation (LDFWAR) with ABT-888 in patients with peritoneal carcinomatosis with a dose escalation in ovarian and fallopian cancer patients (OV). Methods. Patients were treated with veliparib, 40-400 mg orally BID on days 1-21 of 3 28-day cycles on 6 dose levels. Dose levels 5 and 6 included only OV patients. LDFWAR consisted of 21.6Gy in 36 fractions, 0.6 Gy twice daily on days 1 and 5 for weeks 1-3 of each cycle. Circulating tumor material and quality of life were serially assessed. Results. 32 pts were treated. Median follow-up was 45 months (10-50). The most common treatment-related grade 3 and 4 toxicities were lymphopenia (59%), anemia (9%), thrombocytopenia (12%), neutropenia (6%), leukopenia (6%), nausea (6%), diarrhea (6%), anorexia (6%), vomiting (6%) and fatigue (6%). The maximum tolerated dose was determined to be 250 mg PO BID. Median PFS was 3.6 months and median OS was 9.1 months. In OV patients, OS was longer for platinum -sensitive patients (10.9 mo) compared to platinum-resistant patients (5.8 mo). QoL decreased for all groups during treatment. Germline BRCA status was known for 14/18 patients with OV cancers, 5 of whom were BRCA mutation carriers. One objective response (3%) was observed. Conclusion. ABT-888 plus LDFWAR is tolerable with gastrointestinal symptoms, fatigue and myelosuppression as the most common toxicities. The single observed objective response was in a germline BRCA mutated, platinum-sensitive patient. (C) 2017 Elsevier Inc. All rights reserved. C1 [Reiss, Kim A.; Armstrong, Deborah; Scardina, Angela; Fischer, Patricia; Azad, Nilofer S.] Johns Hopkins Univ Hosp, Sidney Kimmel Comprehens Canc Ctr, Dept Med Oncol, Baltimore, MD USA. [Herman, Joseph M.; Hacker-Prietz, Amy] Johns Hopkins Univ Hosp, Sidney Kimmel Comprehens Canc Ctr, Dept Radiat Oncol, Sidney, BC, Canada. [Zahurak, Marianna] Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Dept Stat, Baltimore, MD USA. [Stayner, Lee-Anne; Siu, Lillian L.] Univ Toronto, Univ Hlth Network, Princess Margaret Canc Ctr, Dept Med Oncol & Hematol, Toronto, ON M5S 1A1, Canada. [Fyles, Anthony; Brade, Anthony; Milosevic, Michael; Dawson, Laura A.] Univ Toronto, Univ Hlth Network, Princess Margaret Canc Ctr, Dept Radiat Oncol, Toronto, ON M5S 1A1, Canada. [Kinders, Robert J.; Wang, Lihua] Natl Canc Inst, Rockville, MD USA. [Chen, Alice] Natl Canc Inst, Canc Therapy Evaluat Program, Rockville, MD USA. [Temkin, Sarah; Horiba, Naomi] Univ Maryland, Sch Med, Dept Obstet Gynecol & Reproduct Sci, College Pk, MD USA. RP Azad, NS (reprint author), 1650 Orleans St,Suite 4M10, Baltimore, MD 21287 USA. EM nazad2@jhmi.edu FU P30 UMGCC Cancer Center Support Grant; [U01-CA-070095]; [U01-CA-132123] FX This study was supported by the following grants: U01-CA-070095 (Johns Hopkins Phase I Consortium), U01-CA-132123 (Princess Margaret Phase I Consortium) and by the P30 UMGCC Cancer Center Support Grant. NR 24 TC 0 Z9 0 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 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2017 VL 144 IS 3 BP 486 EP 490 DI 10.1016/j.ygyno.2017.01.016 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA EN2PJ UT WOS:000395852100007 PM 28109627 ER PT J AU Leonard, T Ayers, C Das, SR Neeland, IJ Powell-Wiley, TM AF Leonard, Tammy Ayers, Colby Das, Sandeep R. Neeland, Ian J. Powell-Wiley, Tiffany M. TI Do neighborhoods matter differently for movers and non-movers? Analysis of weight gain in the longitudinal Dallas Heart Study SO HEALTH & PLACE LA English DT Article DE Neighborhood environment; Obesity; Cardiovascular risk; Property appraisal ID BODY-MASS INDEX; PROPENSITY SCORE METHODS; PHYSICAL-ACTIVITY; BUILT ENVIRONMENT; CARDIORESPIRATORY FITNESS; MULTIETHNIC POPULATION; SOCIOECONOMIC-STATUS; COLLECTIVE EFFICACY; PROPERTY-VALUES; OBESITY AB The few available population-based longitudinal studies examining the link between change in neighborhood condition and weight change to date have only examined neighborhood changes generated by residential mobility. Applying a difference-in-difference analytic framework to data from the Dallas Heart Study (DHS), a multi-ethnic, population-based cohort in Dallas County, TX, we evaluated the relationship between changes in neighborhood condition and weight change for both movers and non-movers over an approximate seven-year follow-up period. We employed a novel measure of neighborhood condition based on property appraisal data to capture temporally consistent measures of change in neighborhood condition regardless of residential mobility. We observed an inverse relationship between weight change and change in neighborhood condition which was more pronounced for non-movers (1.9 fewer kilograms gained per 1-standard deviation improvement in neighborhood condition) than for movers (1.5 fewer kilograms gained per 1-standard deviation improvement in neighborhood condition). C1 [Leonard, Tammy] Univ Dallas, 1845 E Northgate Dr, Irving, TX 75062 USA. [Ayers, Colby; Das, Sandeep R.; Neeland, Ian J.] Univ Texas Southwestern Med Ctr Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. [Powell-Wiley, Tiffany M.] NHLBI, Div Intramural Res, NIH, Bldg 10 CRC,5E-3340, Bethesda, MD 20892 USA. RP Leonard, T (reprint author), Univ Dallas, 1845 E Northgate Dr, Irving, TX 75062 USA. EM tleonard@udallas.edu; powelltm2@nhlbi.nih.gov OI Leonard, Tammy/0000-0002-8621-9358 FU National Science Foundation [NSF/SES-0827350]; Division of Intramural Research of the National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health (NIH); Division of Intramural Research of NHLBI at NIH [HHSN268201300173P]; National Institute of Diabetes and Digestive and Kidney Diseases of the National Institute of Health [K23DK106520]; Dedman Family Scholarship in Clinical Care from UT Southwestern FX This work was supported in part by a grant from the National Science Foundation (NSF/SES-0827350). Funding support for Dr. Powell-Wiley is provided by the Division of Intramural Research of the National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health (NIH). Funding support for Mr. Ayers is provided through a professional services contract (contract #HHSN268201300173P) through the Division of Intramural Research of NHLBI at NIH. Funding support for Dr. Neeland is provided by grant K23DK106520 from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institute of Health and by a Dedman Family Scholarship in Clinical Care from UT Southwestern. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. NR 67 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8292 EI 1873-2054 J9 HEALTH PLACE JI Health Place PD MAR PY 2017 VL 44 BP 52 EP 60 DI 10.1016/j.healthplace.2017.01.002 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EO8QV UT WOS:000396955900006 PM 28167268 ER PT J AU Xiao, Q Berrigan, D Matthews, CE AF Xiao, Qian Berrigan, David Matthews, Charles E. TI A prospective investigation of neighborhood socioeconomic deprivation and self-rated health in a large US cohort SO HEALTH & PLACE LA English DT Article DE Neighborhood; Socioeconomic deprivation; Self-rated health ID NATIONAL INSTITUTES; PHYSICAL-ACTIVITY; MENTAL-HEALTH; UNITED-STATES; WEIGHT-GAIN; MORTALITY; OBESITY; ADULTS; ASSOCIATIONS; DISPARITIES AB Background: Neighborhood characteristics play a critical role in health. Self-rated health (SRH) is an important indicator of quality of life and a strong predictor of premature death. Prospective study on neighborhood deprivation and SRH is limited. Methods: We examined neighborhood socioeconomic deprivation with reporting fair/poor SRH at follow-up (2004-2006) in 249,265 men and women (age 50-71) who reported SRH as good or better at baseline (1995-1996) in the NIH-AARP Health and Diet Study. Baseline addresses were geocoded and linked to 2000 Census. Census tract level variables were used to generate a socioeconomic deprivation index by principle component analysis. Results: Residents of more deprived neighborhoods had a higher risk of developing poor/fair SRH at follow-up, even after adjusting for individual-level factors (Odds ratio (95% confidence interval) Q5 1.26 (1.20, 1.32), p-trend: <0.0001). The results were largely consistent across subgroups with different demographics, health behaviors, and disease conditions and after excluding participants who moved away from their baseline address. Conclusion: Neighborhood disadvantage predicts SRH over 10 years. C1 [Xiao, Qian] Univ Iowa, Dept Hlth & Human Physiol, Iowa City, IA 52242 USA. [Berrigan, David] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Matthews, Charles E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Xiao, Q (reprint author), Univ Iowa, Dept Hlth & Human Physiol, Iowa City, IA 52242 USA. EM qian-xiao@uiowa.edu FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, National Institutes of Health, Department of Health and Human Services FX The work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 38 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8292 EI 1873-2054 J9 HEALTH PLACE JI Health Place PD MAR PY 2017 VL 44 BP 70 EP 76 DI 10.1016/j.healthplace.2017.01.003 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EO8QV UT WOS:000396955900008 PM 28183012 ER PT J AU Bellucci, G Chernyak, SV Goodyear, K Eickhoff, SB Krueger, F AF Bellucci, Gabriele Chernyak, Sergey V. Goodyear, Kimberly Eickhoff, Simon B. Krueger, Frank TI Neural Signatures of Trust in Reciprocity: A Coordinate-Based Meta-Analysis SO HUMAN BRAIN MAPPING LA English DT Article DE trust; reciprocity; investment game; trust game; fMRI; activation likelihood estimation; social cognition; meta-analysis ID SOCIAL DECISION-MAKING; HUMAN VENTRAL STRIATUM; DORSAL STRIATUM; HUMAN BRAIN; PHYSIOLOGICAL CONDITION; INSULA ACTIVATION; PREDICTION ERRORS; NUCLEUS-ACCUMBENS; BETRAYAL AVERSION; ECONOMIC EXCHANGE AB Trust in reciprocity (TR) is defined as the risky decision to invest valued resources in another party with the hope of mutual benefit. Several fMRI studies have investigated the neural correlates of TR in one-shot and multiround versions of the investment game (IG). However, an overall characterization of the underlying neural networks remains elusive. Here, a coordinate-based meta- analysis was employed (activation likelihood estimation method, 30 articles) to investigate consistent brain activations in each of the IG stages (i.e., the trust, reciprocity and feedback stage). Results showed consistent activations in the anterior insula (AI) during trust decisions in the one-shot IG and decisions to reciprocate in the multiround IG, likely related to representations of aversive feelings. Moreover, decisions to reciprocate also consistently engaged the intraparietal sulcus, probably involved in evaluations of the reciprocity options. On the contrary, trust decisions in the multiround IG consistently activated the ventral striatum, likely associated with reward prediction error signals. Finally, the dorsal striatum was found consistently recruited during the feedback stage of the multiround IG, likely related to reinforcement learning. In conclusion, our results indicate different neural networks underlying trust, reciprocity, and feedback learning. These findings suggest that although decisions to trust and reciprocate may elicit aversive feelings likely evoked by the uncertainty about the decision outcomes and the pressing requirements of social standards, multiple interactions allow people to build interpersonal trust for cooperation via a learning mechanism by which they arguably learn to distinguish trustworthy from untrustworthy partners. (C) 2016 Wiley Periodicals, Inc. C1 [Bellucci, Gabriele] Univ Lubeck, Dept Psychol, Lubeck, Germany. [Chernyak, Sergey V.] George Mason Univ, Mol Neurosci Dept, Fairfax, VA 22030 USA. [Goodyear, Kimberly] Brown Univ, Dept Behav & Social Sci, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. [Goodyear, Kimberly] NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, Bethesda, MD USA. [Goodyear, Kimberly] NIDA, Bethesda, MD 20892 USA. [Eickhoff, Simon B.] Res Ctr Julich, Inst Neurosci & Med INM 1, Julich, Germany. [Eickhoff, Simon B.] Heinrich Heine Univ Dusseldorf, Inst Clin Neurosci & Med Psychol, Dusseldorf, Germany. [Krueger, Frank] George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. RP Krueger, F (reprint author), George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. EM fkrueger@gmu.edu FU German Federal Ministry of Education and Research [P-57191936]; Deutsche Forschungsgemeinschaft [EI 816/4-1]; National Institute of Mental Health [R01MH074457]; Helmholtz Portfolio Theme; European Union Seventh Framework Program [604102] FX Contract grant sponsor: German Federal Ministry of Education and Research; Contract grant number: P-57191936 to F.K.; Contract grant sponsor: the Deutsche Forschungsgemeinschaft; Contract grant number: DFG, EI 816/4-1; Contract grant sponsor: the National Institute of Mental Health; Contract grant number: R01-MH074457; Contract grant sponsor: the Helmholtz Portfolio Theme "Supercomputing and Modelling for the Human Brain"; Contract grant sponsor: the European Union Seventh Framework Program; Contract grant number: FP7/2007-2013) under grant agreement no. 604102 (to S.B.E.). NR 129 TC 0 Z9 0 U1 5 U2 5 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD MAR PY 2017 VL 38 IS 3 BP 1233 EP 1248 DI 10.1002/hbm.23451 PG 16 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EN5FW UT WOS:000396032000010 PM 27859899 ER PT J AU Gheysen, F Lasne, G Pelegrini-Issac, M Albouy, G Meunier, S Benali, H Doyon, J Popa, T AF Gheysen, Freja Lasne, Gabriel Pelegrini-Issac, Melanie Albouy, Genevieve Meunier, Sabine Benali, Habib Doyon, Julien Popa, Traian TI Taking the Brakes off the Learning Curve SO HUMAN BRAIN MAPPING LA English DT Article DE basal ganglia; cerebellum; explicit sequence learning; functional MRI; theta-burst stimulation ID MOTOR SKILL ACQUISITION; BASAL GANGLIA; FUNCTIONAL CONNECTIVITY; CEREBELLAR CONTROL; BROCAS AREA; HUMAN BRAIN; CORTEX; PERFORMANCE; NETWORKS; STIMULATION AB Motor learning is characterized by patterns of cerebello-striato-cortical activations shifting in time, yet the early dynamic and function of these activations remains unclear. Five groups of subjects underwent either continuous or intermittent theta-burst stimulation of one cerebellar hemisphere, or no stimulation just before learning a new motor sequence during fMRI scanning. We identified three phases during initial learning: one rapid, one slow, and one quasi-asymptotic performance phase. These phases were not changed by left cerebellar stimulation. Right cerebellar inhibition, however, accelerated learning and enhanced brain activation in critical motor learning-related areas during the first phase, continuing with reduced brain activation but high-performance in late phase. Right cerebellar excitation did not affect the early learning process, but slowed learning significantly in late phase, along with increased brain activation. We conclude that the right cerebellum is a key factor coordinating other neuronal loops in the early acquisition of an explicit motor sequential skill. (C) 2016 Wiley Periodicals, Inc. C1 [Gheysen, Freja] Univ Ghent, Dept Movement & Sport Sci, Ghent, Belgium. [Gheysen, Freja] Univ Ghent, Dept Expt Psychol, Ghent, Belgium. [Lasne, Gabriel; Pelegrini-Issac, Melanie; Benali, Habib] UPMC Univ Paris 06, Sorbonne Univ, CNRS UMR7371, Inserm U1146,Lab Imagerie Biomed, Paris, France. [Albouy, Genevieve; Doyon, Julien] Univ Montreal, Funct Neuroimaging Unit, Geriatr Inst, Montreal, PQ, Canada. [Albouy, Genevieve; Doyon, Julien] Univ Montreal, Dept Psychol, Montreal, PQ, Canada. [Albouy, Genevieve] Katholieke Univ Leuven, Movement Control & Neuroplast Res Grp, Dept Kinesiol, Leuven, Belgium. [Meunier, Sabine; Popa, Traian] UPMC Univ Paris 06 UMR S975, CNRS UMR 7225, Inserm U1127, Inst Cerveau & Moelle Epiniere ICM, Paris, France. RP Popa, T (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10,Room 7D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM traian.popa@nih.gov FU Canadian Institutes of Health Research [MOP 97830]; Research Council of Ghent University; Institut National de la Sante et de la Recherche Medicale; "Investissements d'avenir" [ANR-10-IAIHU-06]; Paris Institute of Translational Neuroscience FX Contract grant sponsor: Canadian Institutes of Health Research; Contract grant number: MOP 97830; Contract grant sponsor: Research Council of Ghent University (to F.G.); Contract grant sponsor: Institut National de la Sante et de la Recherche Medicale (Inserm; to T.P. and S.M.); Contract grant sponsor: "Investissements d'avenir" ANR-10-IAIHU-06; Contract grant sponsor: Paris Institute of Translational Neuroscience (to T. P.) NR 75 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD MAR PY 2017 VL 38 IS 3 BP 1676 EP 1691 DI 10.1002/hbm.23489 PG 16 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EN5FW UT WOS:000396032000037 PM 28009072 ER PT J AU Baltussen, R Mitton, C Danis, M Williams, I Gold, M AF Baltussen, Rob Mitton, Craig Danis, Marion Williams, Iestyn Gold, Marthe TI Global Developments in Priority Setting in Health SO INTERNATIONAL JOURNAL OF HEALTH POLICY AND MANAGEMENT LA English DT Editorial Material DE Priority Setting; Legitimacy; Stakeholder Participation ID COST-EFFECTIVENESS; COVERAGE AB Countries around the world are experiencing an ever-increasing need to make choices in investments in health and healthcare. This makes it incumbent upon them to have formal processes in place to optimize the legitimacy of eventual decisions. There is now growing experience among countries of the implementation of stakeholder participation, and a developing convergence of methods to support decision-makers within health authorities in making tough decisions when faced with the stark reality of limited resources. We call for further interaction among health authorities, and the research community to develop best practices in order to confront the difficult choices that need to be made. C1 [Baltussen, Rob] Radboud Univ Nijmegen, Med Ctr, Nijmegen, Netherlands. [Mitton, Craig] Univ British Columbia, Vancouver, BC, Canada. [Danis, Marion] NIH, Bldg 10, Bethesda, MD 20892 USA. [Williams, Iestyn] Univ Birmingham, Birmingham, W Midlands, England. [Gold, Marthe] New York Acad Med, New York, NY USA. [Gold, Marthe] CUNY City Coll, New York, NY 10031 USA. RP Baltussen, R (reprint author), Radboud Univ Nijmegen, Med Ctr, Nijmegen, Netherlands. EM Rob.baltussen@radboudumc.nl NR 11 TC 0 Z9 0 U1 0 U2 0 PU KERMAN UNIV MEDICAL SCIENCES PI KERMAN PA JAHAD BLVD, KERMAN, 7619813159, IRAN SN 2322-5939 J9 INT J HEALTH POLICY JI Int. J. Health Policy Manag. PD MAR PY 2017 VL 6 IS 3 BP 127 EP 128 DI 10.15171/ijhpm.2017.10 PG 2 WC Health Policy & Services SC Health Care Sciences & Services GA EO9XE UT WOS:000397040600001 ER PT J AU Moss, B AF Moss, Bernard TI Investigating Viruses during the Transformation of Molecular Biology SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INFECTIOUS VACCINIA VIRUS; DEPENDENT RNA-POLYMERASE; HERPES-SIMPLEX-VIRUS; GENETICALLY-ENGINEERED POXVIRUSES; INVERTED TERMINAL REPETITION; METHYLATED MESSENGER-RNA; DOUBLE-STRANDED-RNA; AMPHIBIAN METAMORPHOSIS; NUCLEOTIDE-SEQUENCES; HEMOGLOBIN-SYNTHESIS AB This Reflections article describes my early work on viral enzymes and the discovery of mRNA capping, how my training in medicine and biochemistry merged as I evolved into a virologist, the development of viruses as vaccine vectors, and how scientific and technological developments during the 1970s and beyond set the stage for the interrogation of nearly every step in the reproductive cycle of vaccinia virus (VACV), a large DNA virus with about 200 genes. The reader may view this article as a work in progress, because I remain actively engaged in research at the National Institutes of Health (NIH) notwithstanding 50 memorable years there. C1 [Moss, Bernard] NIH, NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIH, NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM bmoss@niaid.nih.gov OI Moss, Bernard/0000-0002-2154-8564 FU Division of Intramural Research, NIAID, National Institutes of Health FX Two individuals stand out in my scientific development: Vernon Ingram and Norman Salzman. Both encouraged and supported me to become an independent investigator. Norman nominated me for tenure at NIH and promoted me to a Section Head. The NIH now honors Norman's memory by holding an annual virology symposium in his name. I thank Stuart Isaacs for comments on an early draft of the manuscript. Most importantly, I am grateful to my wife Toby and children Rob, Jennifer, and David for their patience and love when I neglected them for work. Preparation of this article was supported by the Division of Intramural Research, NIAID, National Institutes of Health. NR 97 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAR PY 2017 VL 292 IS 10 BP 3958 EP 3969 DI 10.1074/jbc.X117.778712 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EN2JZ UT WOS:000395837100001 PM 28154190 ER PT J AU DeBalsi, KL Longley, MJ Hoff, KE Copeland, WC AF DeBalsi, Karen L. Longley, Matthew J. Hoff, Kirsten E. Copeland, William C. TI Synergistic Effects of the in cis T251I and P587L Mitochondrial DNA Polymerase gamma Disease Mutations SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA; POLG MUTATIONS; PATHOGENIC MUTATIONS; EXONUCLEASE ACTIVITY; BIOCHEMICAL-ANALYSIS; AUTOSOMAL-DOMINANT; ACCESSORY SUBUNIT; REPLICATION; DISORDERS; TOXICITY AB Human mitochondrial DNA (mtDNA) polymerase gamma (Pol gamma) is the only polymerase known to replicate the mitochondrial genome. The Pol gamma holoenzyme consists of the p140 catalytic subunit (POLG) and the p55 homodimeric accessory subunit (POLG2), which enhances binding of Pol gamma to DNA and promotes processivity of the holoenzyme. Mutations within POLG impede maintenance of mtDNA and cause mitochondrial diseases. Two common POLG mutations usually found in cis in patients primarily with progressive external ophthalmoplegia generate T251I and P587L amino acid substitutions. To determine whether T251I or P587L is the primary pathogenic allele or whether both substitutions are required to cause disease, we overproduced and purified WT, T251I, P587L, and T251I + P587L double variant forms of recombinant Pol gamma. Biochemical characterization of these variants revealed impaired DNA binding affinity, reduced thermostability, diminished exonuclease activity, defective catalytic activity, and compromisedDNAprocessivity, even in the presence of the p55 accessory subunit. However, physical association with p55 was unperturbed, suggesting intersubunit affinities similar to WT. Notably, although the single mutants were similarly impaired, a dramatic synergistic effect was found for the double mutant across all parameters. In conclusion, our analyses suggest that individually both T251I and P587L substitutions functionally impair Pol gamma, with greater pathogenicity predicted for the single P587L variant. Combining T251I and P587L induces extreme thermal lability and leads to synergistic nucleotide and DNA binding defects, which severely impair catalytic activity and correlate with presentation of disease in patients. C1 [DeBalsi, Karen L.; Longley, Matthew J.; Hoff, Kirsten E.; Copeland, William C.] NIH, NIEHS, Genome Integr & Struct Biol Lab, 111 TW Alexander Dr,Bldg 101,Rm E316, Res Triangle Pk, NC 27709 USA. RP Copeland, WC (reprint author), NIH, NIEHS, Genome Integr & Struct Biol Lab, 111 TW Alexander Dr,Bldg 101,Rm E316, Res Triangle Pk, NC 27709 USA. EM copelan1@niehs.nih.gov FU Intramural Research Program of the NIEHS, National Institutes of Health [ES 065078] FX This study was supported by the Intramural Research Program of the NIEHS, National Institutes of Health, Grant ES 065078. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 67 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAR PY 2017 VL 292 IS 10 BP 4198 EP 4209 DI 10.1074/jbc.M116.773341 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EN2JZ UT WOS:000395837100018 PM 28154168 ER PT J AU Tang, LY Heller, M Meng, Z Yu, LR Tang, Y Zhou, M Zhang, YE AF Tang, Liu-Ya Heller, Mary Meng, Zhaojing Yu, Li-Rong Tang, Yi Zhou, Ming Zhang, Ying E. TI Transforming Growth Factor-beta (TGF-beta) Directly Activates the JAK1-STAT3 Axis to Induce Hepatic Fibrosis in Coordination with the SMAD Pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STAT3 SIGNALING ACTIVATION; STELLATE CELLS; JUNB PROMOTER; LIVER; EXPRESSION; APOPTOSIS; IL-6; PHOSPHORYLATION; TRANSCRIPTION-3; TRANSDUCTION AB Transforming growth factor-beta (TGF-beta) signals through both SMAD and non-SMAD pathways to elicit a wide array of biological effects. Existing data have shown the association and coordination between STATs and SMAD sin mediating TGF-beta functions in hepatic cells, but it is not clear how STATs are activated under these circumstances. Here, we report that JAK1 is a constitutive TGF beta RI binding protein and is absolutely required for phosphorylation of STATs in a SMAD-independent manner within minutes of TGF-beta stimulation. Following the activation of SMADs, TGF-beta also induces a second phase of STAT phosphorylation that requires SMADs, de novo protein synthesis, and contribution from JAK1. Our global gene expression profiling indicates that the non-SMAD JAK1/STAT pathway is essential for the expression of a subset of TGF-beta target genes in hepatic stellate cells, and the cooperation between the JAK1STAT3 and SMAD pathways is critical to the roles of TGF-beta in liver fibrosis. C1 [Tang, Liu-Ya; Heller, Mary; Tang, Yi; Zhang, Ying E.] Natl Inst Hlth, NCI, Ctr Canc Res, Lab Cellular & Mol Biol, Bethesda, MD 20892 USA. [Meng, Zhaojing; Yu, Li-Rong; Zhou, Ming] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Prot Characterizat Lab, Frederick, MD 21702 USA. [Yu, Li-Rong] Div System Biol, Biomarkers & Alternat Models Branch, Food & Drug Adm, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Zhang, Ying E.] Natl Inst Hlth, NCI, Ctr Canc Res, Lab Cellular & Mol Biol, Bldg 37, Bethesda, MD 20892 USA. RP Zhang, YE (reprint author), Natl Inst Hlth, NCI, Ctr Canc Res, Lab Cellular & Mol Biol, Bethesda, MD 20892 USA. EM zhangyin@mail.nih.gov FU National Institutes of Health; NCI, Center for Cancer Research FX This work was supported by the intramural research program of the National Institutes of Health, NCI, Center for Cancer Research (to Y.E.Z.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 36 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAR PY 2017 VL 292 IS 10 BP 4302 EP 4312 DI 10.1074/jbc.M116.773085 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EN2JZ UT WOS:000395837100027 PM 28154170 ER PT J AU Waxse, BJ Sengupta, P Hesketh, GG Lippincott-Schwartz, J Buss, F AF Waxse, Bennett J. Sengupta, Prabuddha Hesketh, Geoffrey G. Lippincott-Schwartz, Jennifer Buss, Folma TI Myosin VI facilitates connexin 43 gap junction accretion SO JOURNAL OF CELL SCIENCE LA English DT Article DE Connexin; Endocytosis; Gap junction; Myosin ID PLASMA-MEMBRANE; INTERCELLULAR COMMUNICATION; HYPERTROPHIC CARDIOMYOPATHY; CARDIAC MYOCYTES; ALTERED PATTERNS; BINDING PARTNER; GOLGI-COMPLEX; CELL-ADHESION; BRUSH-BORDER; HAIR-CELLS AB In this study, we demonstrate myosin VI enrichment at Cx43 (also known as GJA1)-containing gap junctions (GJs) in heart tissue, primary cardiomyocytes and cell culture models. In primary cardiac tissue and in fibroblasts from the myosin VI-null mouse as well as in tissue culture cells transfected with siRNA against myosin VI, we observe reduced GJ plaque size with a concomitant reduction in intercellular communication, as shown by fluorescence recovery after photobleaching (FRAP) and a new method of selective calcein administration. Analysis of the molecular role of myosin VI in Cx43 trafficking indicates that myosin VI is dispensable for the delivery of Cx43 to the cell surface and connexon movement in the plasma membrane. Furthermore, we cannot corroborate clathrin or Dab2 localization at gap junctions and we do not observe a function for the myosin-VI-Dab2 complex in clathrin-dependent endocytosis of annular gap junctions. Instead, we found that myosin VI was localized at the edge of Cx43 plaques by using total internal reflection fluorescence (TIRF) microscopy and use FRAP to identify a plaque accretion defect as the primary manifestation of myosin VI loss in Cx43 homeostasis. A fuller understanding of this derangement may explain the cardiomyopathy or gliosis associated with the loss of myosin VI. C1 [Waxse, Bennett J.; Sengupta, Prabuddha; Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD 20892 USA. [Waxse, Bennett J.; Buss, Folma] Univ Cambridge, Cambridge Inst Med Res, Cambridge CB2 2XY, England. [Hesketh, Geoffrey G.] Mount Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G IX5, Canada. RP Lippincott-Schwartz, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD 20892 USA.; Buss, F (reprint author), Univ Cambridge, Cambridge Inst Med Res, Cambridge CB2 2XY, England. EM lippincottschwartzj@janelia.hhmi.org FU National Institutes of Health Oxford-Cambridge; Eunice Shriver National Institute of Child Health and Human Development; Wellcome Trust [100140]; Medical Research Council [MR/K000888/1, MR/N000048/1]; British Heart Foundation [PG/15/12/31280]; [093026] FX B. W. is a National Institutes of Health Oxford-Cambridge scholar supported by funding obtained by J. L.-S. from the Eunice Shriver National Institute of Child Health and Human Development. F. B. thanks the Wellcome Trust for funding of the Cambridge Institute for Medical Research (CIMR) Strategic Award (100140), an equipment grant (093026), the Medical Research Council (MR/K000888/1 and MR/N000048/1) and the British Heart Foundation for funding of the project grant (PG/15/12/31280). Deposited in PMC for immediate release. NR 72 TC 0 Z9 0 U1 0 U2 0 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 2017 VL 130 IS 5 BP 827 EP 840 DI 10.1242/jcs.199083 PG 14 WC Cell Biology SC Cell Biology GA EN0RX UT WOS:000395718400003 PM 28096472 ER PT J AU Panzer, K Ekhaguere, OA Darbro, B Cook, J Shchelochkov, OA AF Panzer, Karin Ekhaguere, Osayame A. Darbro, Benjamin Cook, Jennifer Shchelochkov, Oleg A. TI Uniparental Isodisomy of Chromosome 1 Unmasking an Autosomal Recessive 3-Beta Hydroxysteroid Dehydrogenase Type II-Related Congenital Adrenal Hyperplasia SO JOURNAL OF CLINICAL RESEARCH IN PEDIATRIC ENDOCRINOLOGY LA English DT Article DE Steroid 3 beta-HSD2 deficiency; HSD3B2 gene; uniparental isodisomy ID DISOMY; DEFICIENCY; MECHANISMS; MUTATION; DISEASE; FAMILY AB Steroid 3-beta hydroxysteroid dehydrogenase type II (3 beta-HSD2) deficiency is a rare autosomal recessive form of congenital adrenal hyperplasia (CAH). We report the genetic basis of 3 beta-HSD2 deficiency arising from uniparental isodisomy (UPD) of chromosome 1. We describe a term undervirilized male whose newborn screen indicated borderline CAH. The patient presented on the 7(th) day of life in salt-wasting adrenal crisis. Steroid hormone testing revealed a complex pattern suggestive of 3 beta-HSD deficiency. Chromosomal microarray and single nucleotide polymorphism analysis revealed complete UPD of chromosome 1. Sanger sequencing of HSD3B2 revealed a previously described missense mutation, c.424G>A (p.E142K) in homozygous state, thus confirming the diagnosis of 3 beta-HSD2 deficiency. We provide evidence of the existence of an uncommon mechanism for HSD3B2 gene-related CAH arising from UPD of chromosome 1. C1 [Panzer, Karin; Darbro, Benjamin; Shchelochkov, Oleg A.] Univ Iowa Hosp & Clin, Stead Dept Pediat, Iowa City, IA 52242 USA. [Ekhaguere, Osayame A.] Childrens Hosp Philadelphia, Div Neonatal & Perinatal Med, Philadelphia, PA 19104 USA. [Cook, Jennifer] Blank Childrens Hosp, Dept Pediat Endocrinol, Des Moines, IA USA. [Shchelochkov, Oleg A.] NHGRI, Bethesda, MD 20892 USA. RP Ekhaguere, OA (reprint author), Childrens Hosp Philadelphia, Div Neonatal & Perinatal Med, Philadelphia, PA 19104 USA. EM ekhaguereo@email.chop.edu NR 19 TC 0 Z9 0 U1 1 U2 1 PU GALENOS YAYINCILIK PI FINDIKZADE PA ERKAN MOR, MOLLA GURANI CAD 21-1, FINDIKZADE, ISTANBUL 34093, TURKEY SN 1308-5727 EI 1308-5735 J9 J CLIN RES PEDIATR E JI J. Clin Res. Pediatr. Endocrinol. PD MAR PY 2017 VL 9 IS 1 BP 70 EP 73 DI 10.4274/jcrpe.3680 PG 4 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA EP1AM UT WOS:000397117800011 PM 27796263 ER PT J AU Tanofsky-Kraff, M Shomaker, LB Wilfley, DE Young, JF Sbrocco, T Stephens, M Brady, SM Galescu, O Demidowich, A Olsen, CH Kozlosky, M Reynolds, JC Yanovski, JA AF Tanofsky-Kraff, Marian Shomaker, Lauren B. Wilfley, Denise E. Young, Jami F. Sbrocco, Tracy Stephens, Mark Brady, Sheila M. Galescu, Ovidiu Demidowich, Andrew Olsen, Cara H. Kozlosky, Merel Reynolds, James C. Yanovski, Jack A. TI Excess Weight Gain Prevention in Adolescents: Three-Year Outcome Following a Randomized Controlled Trial SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE preventive adolescent IPT; social-adjustment problems; anxiety; BMIz; adiposity ID BINGE-EATING DISORDER; INTERPERSONAL PSYCHOTHERAPY; HIGH-RISK; DEPRESSED ADOLESCENTS; CHILDHOOD OVERWEIGHT; ADULT OBESITY; CHILDREN; ANXIETY; MAINTENANCE; EFFICACY AB Objective: Interpersonal psychotherapy (IPT) prevents weight gain in adults with obesity and binge-eating-disorder, and is especially effective among those with increased psychosocial problems. However, IPT was not superior to health education (HE) to prevent excess weight gain at 1-year follow-up in 113 adolescent girls at high-risk for excess weight gain because of loss-of-control eating and high body mass index (BMI; kg/m(2); Tanofsky-Kraff et al., 2014). Method: Participants from the original trial were recontacted 3 years later for assessment. At baseline, adolescent-and parent-reported social-adjustment problems and trait anxiety were evaluated. At baseline and follow-ups, BMIz and adiposity by dual-energy x-ray absorptiometry were obtained. Results: Nearly 60% were reassessed at 3 years, with no group differences in participation (ps >= .70). Consistent with 1 year, there was no main effect of group on change in BMIz/adiposity (ps >= .18). In exploratory analyses, baseline social-adjustment problems and trait-anxiety moderated outcome (ps < .01). Among girls with high self-reported baseline social-adjustment problems or anxiety, IPT, compared to HE, was associated with the steepest declines in BMIz (p < .001). For adiposity, girls with high or low anxiety in HE and girls with low anxiety in IPT experienced gains (ps <= .03), while girls in IPT with high anxiety stabilized. Parent-reports yielded complementary findings. Conclusion: In obesity-prone adolescent girls, IPT was not superior to HE in preventing excess weight gain at 3 years. Consistent with theory, exploratory analyses suggested that IPT was associated with improvements in BMIz over 3 years among youth with high social-adjustment problems or trait anxiety. Future studies should test the efficacy of IPT for obesity prevention among at-risk girls with social-adjustment problems and/or anxiety. C1 [Tanofsky-Kraff, Marian; Sbrocco, Tracy] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. [Tanofsky-Kraff, Marian; Shomaker, Lauren B.; Brady, Sheila M.; Galescu, Ovidiu; Demidowich, Andrew; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, NIH, Bethesda, MD USA. [Shomaker, Lauren B.] Colorado State Univ, Dept Human Dev & Family Studies, Ft Collins, CO 80523 USA. [Shomaker, Lauren B.] Colorado State Univ, Dept Publ Hlth, Ft Collins, CO 80523 USA. [Wilfley, Denise E.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63130 USA. [Young, Jami F.] Rutgers State Univ, Dept Appl & Profess Psychol, Piscataway, NJ USA. [Stephens, Mark] Uniformed Serv Univ Hlth Sci, Dept Family Med, Bethesda, MD 20814 USA. [Olsen, Cara H.] Uniformed Serv Univ Hlth Sci, Dept Preventat Med & Biometr, Bethesda, MD 20814 USA. [Kozlosky, Merel] NIH, Dept Nutr, Hatfield Clin Res Ctr, Bldg 10, Bethesda, MD 20892 USA. [Reynolds, James C.] NIH, Dept Nucl Med, Hatfield Clin Res Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Tanofsky-Kraff, M (reprint author), Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM marian.tanofsky-kraff@usuhs.edu FU Uniformed Services University of the Health Sciences Grant [R072IC]; National Institute of Child Health and Human Development, Intramural Research Program [ZIA-HD-00641] FX Jack A. Yanovski and Merel Kozlosky are commissioned officers in the U.S. Public Health Service. The opinions and assertions expressed herein are those of the authors and are not to be construed as reflecting the views of the Public Health Service, the Department of the Navy, Uniformed Services University, or the U.S. Department of Defense. Denise E. Wilfley is a consultant to Shire and Sunovian Pharmaceuticals. National Institute of Diabetes and Digestive and Kidney Diseases 1R01DK080906 (Marian Tanofsky-Kraff), Uniformed Services University of the Health Sciences Grant R072IC (Marian Tanofsky-Kraff), National Institute of Child Health and Human Development, Intramural Research Program ZIA-HD-00641 (Jack A. Yanovski), and National Institute of Mental Health 1K24MH070446 (Denise E. Wilfley). NR 50 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X EI 1939-2117 J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD MAR PY 2017 VL 85 IS 3 BP 218 EP 227 DI 10.1037/ccp0000153 PG 10 WC Psychology, Clinical SC Psychology GA EN0SO UT WOS:000395720100003 PM 27808536 ER PT J AU Hamilton, JG Abdiwahab, E Edwards, HM Fang, ML Jdayani, A Breslau, ES AF Hamilton, Jada G. Abdiwahab, Ekland Edwards, Heather M. Fang, Min-Lin Jdayani, Andrew Breslau, Erica S. TI Primary care providers' cancer genetic testing-related knowledge, attitudes, and communication behaviors: A systematic review and research agenda SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Review DE primary care; knowledge; health beliefs; communication; cancer; genetic testing ID SERVICES TASK-FORCE; BRCA-RELATED CANCER; BREAST-CANCER; HEREDITARY BREAST; RISK-ASSESSMENT; PROSTATE-CANCER; OVARIAN-CANCER; COLORECTAL-CANCER; FAMILY-HISTORY; LYNCH SYNDROME AB Primary care providers (PCPs) can play a critical role in helping patients receive the preventive health benefits of cancer genetic risk information. Thus, the objective of this systematic review was to identify studies of US PCPs' knowledge, attitudes, and communication-related behaviors regarding genetic tests that could inform risk-stratification approaches for breast, colorectal, and prostate cancer screening in order to describe current findings and research gaps. We conducted a systematic search of six electronic databases to identify peer-reviewed empirical articles relating to US PCPs and genetic testing for breast, colorectal, or prostate cancer published in English from 2008 to 2016. We reviewed these data and used narrative synthesis methods to integrate findings into a descriptive summary and identify research needs. We identified 27 relevant articles. Most focused on genetic testing for breast cancer (23/27) and colorectal cancer risk (12/27); only one study examined testing for prostate cancer risk. Most articles addressed descriptive research questions (24/27). Many studies (24/27) documented PCPs' knowledge, often concluding that providers' knowledge was incomplete. Studies commonly (11/27) examined PCPs' attitudes. Across studies, PCPs expressed some concerns about ethical, legal, and social implications of testing. Attitudes about the utility of clinical genetic testing, including for targeted cancer screening, were generally favorable; PCPs were more skeptical of direct-to-consumer testing. Relatively fewer studies (9/27) examined PCPs' communication practices regarding cancer genetic testing. This review indicates a need for investigators to move beyond descriptive research questions related to PCPs' knowledge and attitudes about cancer genetic testing. Research is needed to address important gaps regarding the development, testing, and implementation of innovative interventions and educational programs that can improve PCPs' genetic testing knowledge, assuage concerns about the appropriateness of cancer genetic testing, and promote open and effective patient-provider communication about genetic risk and genetic testing. C1 [Hamilton, Jada G.] Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, 1275 York Ave, New York, NY 10021 USA. [Abdiwahab, Ekland] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Edwards, Heather M.] Patient Ctr Outcomes Res Inst, Washington, DC USA. [Fang, Min-Lin] Univ Calif San Francisco, UCSF Lib, San Francisco, CA 94143 USA. [Jdayani, Andrew] Torrance Mem Hlth Syst, Torrance Hlth IPA, Torrance, CA USA. [Breslau, Erica S.] NCI, Div Canc Control & Populat Sci, Healthcare Delivery Res Program, Rockville, MD USA. RP Hamilton, JG (reprint author), Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, 1275 York Ave, New York, NY 10021 USA. EM hamiltoj@mskcc.org FU [HHSN261201400046M]; [HHSN261201600149M]; [NCI P30 CA008748] FX Dr. Hamilton was supported by HHSN261201400046M, HHSN261201600149M and NCI P30 CA008748. Dr. Edwards was employed by Leidos Biomedical Research Inc. as a contractor supporting the National Cancer Institute. Dr. Edwards is currently employed by Patient-Centered Outcomes Research Institute. Ms. Abdiwahab was a Cancer Research Training Award Fellow at the National Cancer Institute and is currently a doctoral student at the University of California San Francisco. Mr. Jdayani was an Introduction to Cancer Research Careers Fellow at the National Cancer Institute and is currently employed by Torrance Memorial Health System. The funders had no direct role in study design; collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 80 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD MAR PY 2017 VL 32 IS 3 BP 315 EP 324 DI 10.1007/s11606-016-3943-4 PG 10 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EM2YI UT WOS:000395181300020 PM 27995427 ER PT J AU Lih, CJ Harrington, RD Sims, DJ Harper, KN Bouk, CH Datta, V Yau, J Singh, RR Routbort, MJ Luthra, R Patel, KP Mantha, GS Krishnamurthy, S Ronski, K Walther, Z Finberg, KE Canosa, S Robinson, H Raymond, A Le, LP Mcshane, LM Polley, EC Conley, BA Doroshow, JH Iafrate, AJ Sklar, JL Hamilton, SR Williams, PM AF Lih, Chih-Jian Harrington, Robin D. Sims, David J. Harper, Kneshay N. Bouk, Courtney H. Datta, Vivekananda Yau, Jonathan Singh, Rajesh R. Routbort, Mark J. Luthra, Rajyalakshmi Patel, Keyur P. Mantha, Geeta S. Krishnamurthy, Savitri Ronski, Karyn Walther, Zenta Finberg, Karin E. Canosa, Sandra Robinson, Hayley Raymond, Amelia Le, Long P. Mcshane, Lisa M. Polley, Eric C. Conley, Barbara A. Doroshow, James H. Iafrate, A. John Sklar, Jeffrey L. Hamilton, Stanley R. Williams, P. Mickey TI Analytical Validation of the Next-Generation Sequencing Assay for a Nationwide Signal-Finding Clinical Trial Molecular Analysis for Therapy Choice Clinical Trial SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID CHALLENGES; IMPACT AB The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial is a national signal-finding precision medicine study that relies on genomic assays to screen and enroll patients with relapsed or refractory cancer after standard treatments. We report the analytical validation processes for the next-generation sequencing (NGS) assay that was tailored for regulatory compliant use in the trial. The Oncomine Cancer Panel assay and the Personal Genome Machine were used in four networked laboratories accredited for the Clinical Laboratory Improvement Amendments. Using formaLin-fixed paraffin-embedded clinical specimens and cell lines, we found that the assay achieved overall sensitivity of 96.98% for 265 known mutations and 99.99% specificity. High reproducibility in detecting all reportable variants was observed, with a 99.99% mean interoperator pairwise concordance across the four laboratories. The limit of detection for each variant type was 2.8% for single-nucleotide variants, 10.5% for insertion/deletions, 6.8% for large insertion/deletions (gap >= 4 bp), and four copies for gene amplification. The assay system from biopsy collection through reporting was tested and found to be fully fit for purpose. Our results indicate that the NCI-MATCH NGS assay met the criteria for the intended clinical use and that high reproducibility of a complex NGS assay is achievable across multiple clinical laboratories. Our validation approaches can serve as a template for development and validation of other NGS assays for precision medicine. C1 [Lih, Chih-Jian; Harrington, Robin D.; Sims, David J.; Harper, Kneshay N.; Bouk, Courtney H.; Datta, Vivekananda; Williams, P. Mickey] Frederick Natl Lab Canc Res, Mol Characterizat & Clin Assay Dev Lab, Frederick, MD USA. [Yau, Jonathan; Singh, Rajesh R.; Routbort, Mark J.; Luthra, Rajyalakshmi; Patel, Keyur P.; Mantha, Geeta S.; Krishnamurthy, Savitri; Finberg, Karin E.; Canosa, Sandra; Hamilton, Stanley R.] Univ Texas MD Anderson Canc Ctr, Div Pathol & Lab Med, Houston, TX USA. [Ronski, Karyn; Walther, Zenta; Sklar, Jeffrey L.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT USA. [Robinson, Hayley; Raymond, Amelia; Le, Long P.; Iafrate, A. John] Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. [Mcshane, Lisa M.; Polley, Eric C.; Conley, Barbara A.; Doroshow, James H.] Natl Canc Inst, Div Canc Treatment & Diagnosis, Bethesda, MD USA. RP Williams, PM (reprint author), Frederick Natl Lab Canc Res, Bldg 320,Room 2,1050 Boyles St, Frederick, MD 21702 USA. EM mickey.williams@nih.gov FU NIH grants [HHSN261200800001E, NO1-CO-2008-00001]; Eastern Cooperative Oncology Group-American College of Radiology [1U24CA196172]; ECOG-ACRIN Medical Research Foundation; Frederick F. Becker Distinguished University Chair in Cancer Research from The University of Texas FX Supported by NIH grants HHSN261200800001E and NO1-CO-2008-00001, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) Cancer Research Group Central Biorepository and Pathology Facility in the Division of Pathology and Laboratory Medicine at The University of Texas MD Anderson Cancer Center grant 1U24CA196172, and the ECOG-ACRIN Medical Research Foundation. S.R.H. is supported by the Frederick F. Becker Distinguished University Chair in Cancer Research from The University of Texas. NR 18 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD MAR PY 2017 VL 19 IS 2 BP 313 EP 327 DI 10.1016/j.jmoldx.2016.10.007 PG 15 WC Pathology SC Pathology GA EL9DS UT WOS:000394920200013 PM 28188106 ER PT J AU Nahin, RL AF Nahin, Richard L. TI Severe Pain in Veterans: The Effect of Age and Sex, and Comparisons With the General Population SO JOURNAL OF PAIN LA English DT Article DE Veteran; pain severity; back pain; joint pain; migraine ID LIGHT MULTIDISCIPLINARY TREATMENT; GULF-WAR VETERANS; QUALITY-OF-LIFE; LOW-BACK-PAIN; UNITED-STATES; HEALTH-STATUS; NATIONAL-HEALTH; US MILITARY; PREVALENCE; AFFAIRS AB This study provides national prevalence estimates of US military veterans with severe pain, and compares veterans with nonveterans of similar age and sex. Data used are from the 2010 to 2014 National Health Interview Survey on 67,696 adults who completed the Adult Functioning and Disability Supplement. Participants with severe pain were identified using a validated pain severity coding system imbedded in the National Health Interview Survey Adult Functioning and Disability Supplement. It was estimated that 65.5% of US military veterans reported pain in the previous 3 months, with 9.1% classified as having severe pain. Compared with veterans, fewer nonveterans reported any pain (56.4%) or severe pain (6.4%). Whereas veterans aged 18 to 39 years had significantly higher prevalence rates for severe pain (7.8%) than did similar-aged nonveterans (3.2%), veterans age 70 years or older were less likely to report severe pain (7.1%) than nonveterans (9.6%). Male veterans (9.0%) were more likely to report severe pain than male nonveterans (4.7%); however, no statistically significant difference was seen between the 2 female groups. The prevalence of severe pain was significantly higher in veterans with back pain (21.6%), jaw pain (37.5%), severe headaches or migraine (26.4%), and neck pain (27.7%) than in nonveterans with these conditions (respectively; 16.7%, 22.9%, 15.9%, and 21.4%). Although veterans (43.6%) were more likely than nonveterans (31.5%) to have joint pain, no difference was seen in the prevalence of severe pain associated with this condition. Perspective: Prevalence of severe pain, defined as that which occurs "most days" or "every day" and bothers the individual "a lot," is strikingly more common in veterans than in members of the general population, particularly in veterans who served during recent conflicts. Additional assistance may be necessary to help veterans cope with their pain. Published by Elsevier Inc. on behalf of the American Pain Society C1 [Nahin, Richard L.] NIH, Natl Ctr Complementary & Integrat Hlth, 6707 Democracy Blvd,Suite 401, Bethesda, MD 20892 USA. RP Nahin, RL (reprint author), NIH, Natl Ctr Complementary & Integrat Hlth, 6707 Democracy Blvd,Suite 401, Bethesda, MD 20892 USA. EM nahinr@mail.nih.gov FU Intramural NIH HHS [Z99 AT999999] NR 48 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD MAR PY 2017 VL 18 IS 3 BP 247 EP 254 DI 10.1016/j.jpain.2016.10.021 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EO6LG UT WOS:000396803400002 PM 27884688 ER PT J AU Robichaux, WG Branham-O'Connor, M Hwang, IY Vural, A Kehrl, JH Blumer, JB AF Robichaux, William G., III Branham-O'Connor, Melissa Hwang, Il-Young Vural, Ali Kehrl, Johne H. Blumer, Joe B. TI Regulation of Chemokine Signal Integration by Activator of G-Protein Signaling 4 (AGS4) SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID HEROIN-SEEKING BEHAVIOR; BETA-GAMMA-SUBUNIT; GENE-EXPRESSION; NEUTROPHIL CHEMOTAXIS; CELL-MIGRATION; LYMPH-NODES; G-ALPHA; T-LYMPHOCYTES; B-LYMPHOCYTES; RECEPTOR AB Activator of G-protein signaling 4 (AGS4)/G-protein signaling modulator 3 (Gpsm3) contains three G-protein regulatory (GPR) motifs, each of which can bind G alpha i-GDP free of G beta gamma. We previously demonstrated that the AGS4-G alpha i interaction is regulated by seven transmembrane-spanning receptors (7-TMR), which may reflect direct coupling of the GPR-G alpha i module to the receptor analogous to canonical G alpha beta gamma heterotrimer. We have demonstrated that the AGS4-G alpha i complex is regulated by chemokine receptors in an agonist-dependent manner that is receptor-proximal. As an initial approach to investigate the functional role(s) of this regulated interaction in vivo, we analyzed leukocytes, in which AGS4/Gpsm3 is predominantly expressed, from AGS4/Gpsm3-null mice. Loss of AGS4/Gpsm3 resulted in mild but significant neutropenia and leukocytosis. Dendritic cells, T lymphocytes, and neutrophils from AGS4/Gpsm3-null mice also exhibited significant defects in chemoattractant-directed chemotaxis and extracellular signal-regulated kinase activation. An in vivo peritonitis model revealed a dramatic reduction in the ability of AGS4/Gpsm3-null neutrophils to migrate to primary sites of inflammation. Taken together, these data suggest that AGS4/Gpsm3 is required for proper chemokine signal processing in leukocytes and provide further evidence for the importance of the GPR-G alpha i module in the regulation of leukocyte function. C1 [Robichaux, William G., III; Branham-O'Connor, Melissa; Blumer, Joe B.] Med Univ South Carolina, Dept Cell & Mol Pharmacol & Expt Therapeut, Dept Neurosci, 173 Ashley Ave,BSB358,MSC509, Charleston, SC 29425 USA. [Hwang, Il-Young; Vural, Ali; Kehrl, Johne H.] NIAID, B Cell Mol Immunol Sect, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Robichaux, William G., III] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Branham-O'Connor, Melissa] Charleston Southern Univ, Dept Biol, N Charleston, SC USA. [Hwang, Il-Young] Wayne State Univ, Dept Pharmacol, Detroit, MI 48201 USA. RP Blumer, JB (reprint author), Med Univ South Carolina, Dept Cell & Mol Pharmacol & Expt Therapeut, Dept Neurosci, 173 Ashley Ave,BSB358,MSC509, Charleston, SC 29425 USA. EM blumerjb@musc.edu FU National Institutes of Health (NIH) National Institute of General Medical Sciences [R01-GM086510]; National Institute of General Medical Sciences South Carolina Institutional Development Awards Networks of Biomedical Research Excellence [P20-GM103499]; National Cancer Institute [T32-CA119945, P30 CA138313]; MUSC institutional funds; National Institute of Allergy and Infectious Diseases; National Institutes of Health National Institute on Neurologic Diseases and Stroke [R01-NS24821]; National Institute on Drug Abuse [R01-DA025896]; Flow Cytometry and Cell Sorting Shared Resource; Cancer Center; National Center for Research Resources and the Office of the Director of the National Institutes of Health [C06 RR015455] FX This work was supported by the National Institutes of Health (NIH) National Institute of General Medical Sciences [Grant R01-GM086510 to J.B.B.], National Institute of General Medical Sciences South Carolina Institutional Development Awards Networks of Biomedical Research Excellence [Grant P20-GM103499 to M.B.O.], National Cancer Institute [Grant T32-CA119945 to M.B.O.), MUSC institutional funds (to J.B.B.), and the intramural research program of the National Institute of Allergy and Infectious Diseases (to J.H.K.). This work was also enabled by support from the National Institutes of Health National Institute on Neurologic Diseases and Stroke [Grant R01-NS24821] and National Institute on Drug Abuse [Grant R01-DA025896], both to Dr. Stephen M. Lanier (Wayne State University). The research presented in this article was supported in part by the Flow Cytometry and Cell Sorting Shared Resource, funded by a Cancer Center Support grant from the National Cancer Institute [Grant P30 CA138313 to the Hollings Cancer Center at the Medical University of South Carolina] and in part by the National Center for Research Resources and the Office of the Director of the National Institutes of Health [Grant C06 RR015455 to the Hollings Cancer Center at the Medical University of South Carolina]. NR 80 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD MAR 1 PY 2017 VL 360 IS 3 BP 424 EP 433 DI 10.1124/jpet.116.238436 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EL3SQ UT WOS:000394539900005 PM 28062526 ER PT J AU Angelo, MA Grifoni, A O'Rourke, PH Sidney, J Paul, S Peters, B de Silva, AD Phillips, E Mallal, S Diehl, SA Kirkpatrick, BD Whitehead, SS Durbin, AP Sette, A Weiskopf, D AF Angelo, Michael A. Grifoni, Alba O'Rourke, Patrick H. Sidney, John Paul, Sinu Peters, Bjoern de Silva, Aruna D. Phillips, Elizabeth Mallal, Simon Diehl, Sean A. Kirkpatrick, Beth D. Whitehead, Stephen S. Durbin, Anna P. Sette, Alessandro Weiskopf, Daniela TI Human CD4(+) T Cell Responses to an Attenuated Tetravalent Dengue Vaccine Parallel Those Induced by Natural Infection in Magnitude, HLA Restriction, and Antigen Specificity SO JOURNAL OF VIROLOGY LA English DT Article DE dengue virus; live attenuated vaccine; TV005; CD4(+) T cell; CD4; HLA; MHC; T cells; live attenuated; tetravalent; vaccines ID VIRUS-INFECTION; PROTECTIVE ROLE; SECONDARY INFECTION; LIVE; CHILDREN; SEROTYPE; COHORT AB Dengue virus (DENV) is responsible for growing numbers of infections worldwide and has proven to be a significant challenge for vaccine development. We previously demonstrated that CD8(+) T cell responses elicited by a dengue live attenuated virus (DLAV) vaccine resemble those observed after natural infection. In this study, we screened peripheral blood mononuclear cells (PBMCs) from donors vaccinated with a tetravalent DLAV vaccine (TV005) with pools of dengue virus-derived predicted major histocompatibility complex (MHC) class II binding peptides. The definition of CD4(+) T cell responses after live vaccination is important because CD4(+) T cells are known contributors to host immunity, including cytokine production, help for CD8(+) T and B cells, and direct cytotoxicity against infected cells. While responses to all antigens were observed, DENV-specific CD4(+) T cells were focused predominantly on the capsid and nonstructural NS3 and NS5 antigens. Importantly, CD4(+) T cell responses in vaccinees were similar in magnitude and breadth to those after natural infection, recognized the same antigen hierarchy, and had similar profiles of HLA restriction. We conclude that TV005 vaccination has the capacity to elicit CD4(+) cell responses closely mirroring those observed in a population associated with natural immunity. IMPORTANCE The development of effective vaccination strategies against dengue virus infection is of high global public health interest. Here we study the CD4 T cell responses elicited by a tetravalent live attenuated dengue vaccine and show that they resemble responses seen in humans naturally exposed to dengue virus. This is an important issue, since it is likely that optimal immunity induced by a vaccine requires induction of CD4(+) responses against the same antigens as those recognized as dominant in natural infection. Detailed knowledge of the T cell response may further contribute to the identification of robust correlates of protection against dengue virus. C1 [Angelo, Michael A.; Grifoni, Alba; O'Rourke, Patrick H.; Sidney, John; Paul, Sinu; Peters, Bjoern; de Silva, Aruna D.; Sette, Alessandro; Weiskopf, Daniela] La Jolla Inst Allergy & Immunol, Div Vaccine Discovery, La Jolla, CA 92037 USA. [Phillips, Elizabeth; Mallal, Simon] Murdoch Univ, Inst Immunol & Infect Dis, Perth, WA, Australia. [Phillips, Elizabeth; Mallal, Simon] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. [Diehl, Sean A.; Kirkpatrick, Beth D.] Univ Vermont, Coll Med, Burlington, VT USA. [Diehl, Sean A.; Kirkpatrick, Beth D.] Vaccine Testing Ctr, Burlington, VT USA. [Whitehead, Stephen S.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Durbin, Anna P.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [de Silva, Aruna D.] Genetech Res Inst, Colombo, Sri Lanka. RP Weiskopf, D (reprint author), La Jolla Inst Allergy & Immunol, Div Vaccine Discovery, La Jolla, CA 92037 USA. EM Daniela@lji.org FU National Institutes of Health [HHSN272200900042C, HHSN27220140045C]; BMGF grant [OPP1104710]; Intramural Research Program of the NIH National Institute of Allergy and Infectious Diseases FX This work was supported by National Institutes of Health contracts HHSN272200900042C and HHSN27220140045C (to A.S.), by BMGF grant OPP1104710 (to A.P.D.), and by the Intramural Research Program of the NIH National Institute of Allergy and Infectious Diseases. NR 33 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD MAR PY 2017 VL 91 IS 5 AR UNSP e02147-16 DI 10.1128/JVI.02147-16 PG 12 WC Virology SC Virology GA EL1BV UT WOS:000394356400024 ER PT J AU Balinsky, CA Schmeisser, H Wells, AI Ganesan, S Jin, TC Singh, K Zoon, KC AF Balinsky, Corey A. Schmeisser, Hana Wells, Alexandra I. Ganesan, Sundar Jin, Tengchuan Singh, Kavita Zoon, Kathryn C. TI IRAV (FLJ11286), an Interferon-Stimulated Gene with Antiviral Activity against Dengue Virus, Interacts with MOV10 SO JOURNAL OF VIROLOGY LA English DT Article DE IRAV; FLJ11286; C19orf66; UPF0515; dengue; flavivirus; interferon; MOV10; P body ID INFLUENZA-A VIRUS; WEST NILE VIRUS; BLOOD MONONUCLEAR-CELLS; MESSENGER-RNA STABILITY; HEPATITIS-C; PROCESSING BODIES; ENDOTHELIAL-CELLS; STRESS GRANULES; IN-VITRO; INFECTION AB Dengue virus (DENV) is a member of the genus Flavivirus and can cause severe febrile illness. Here, we show that FLJ11286, which we refer to as IRAV, is induced by DENV in an interferon-dependent manner, displays antiviral activity against DENV, and localizes to the DENV replication complex. IRAV is an RNA binding protein and localizes to cytoplasmic processing bodies (P bodies) in uninfected cells, where it interacts with the MOV10 RISC complex RNA helicase, suggesting a role for IRAV in the processing of viral RNA. After DENV infection, IRAV, along with MOV10 and Xrn1, localizes to the DENV replication complex and associates with DENV proteins. Depletion of IRAV or MOV10 results in an increase in viral RNA. These data serve to characterize an interferon-stimulated gene with antiviral activity against DENV, as well as to propose a mechanism of activity involving the processing of viral RNA. IMPORTANCE Dengue virus, a member of the family Flaviviridae, can result in a lifethreatening illness and has a significant impact on global health. Dengue virus has been shown to be particularly sensitive to the effects of type I interferon; however, little is known about the mechanisms by which interferon-stimulated genes function to inhibit viral replication. A better understanding of the interferon-mediated antiviral response to dengue virus may aid in the development of novel therapeutics. Here, we examine the influence of the interferon-stimulated gene IRAV (FLJ11286) on dengue virus replication. We show that IRAV associates with P bodies in uninfected cells and with the dengue virus replication complex after infection. IRAV also interacts with MOV10, depletion of which is associated with increased viral replication. Our results provide insight into a newly identified antiviral gene, as well as broadening our understanding of the innate immune response to dengue virus infection. C1 [Balinsky, Corey A.; Schmeisser, Hana; Wells, Alexandra I.; Zoon, Kathryn C.] NIAID, Cytokine Biol Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Ganesan, Sundar] NIAID, Biol Imaging Sect, Res Technol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Jin, Tengchuan] NIAID, Struct Immunobiol Unit, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Singh, Kavita] NIAID, Struct Biol Sect, Res Technol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Zoon, KC (reprint author), NIAID, Cytokine Biol Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kzoon@niaid.nih.gov FU Intramural Research Program of the NIAID, NIH FX This work was supported by the Intramural Research Program of the NIAID, NIH. NR 73 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD MAR PY 2017 VL 91 IS 5 AR UNSP e01606 DI 10.1128/JVI.01606-16 PG 17 WC Virology SC Virology GA EL1BV UT WOS:000394356400003 ER PT J AU Nivarthi, UK Kose, N Sapparapu, G Widman, D Gallichotte, E Pfaff, JM Doranz, BJ Weiskopf, D Sette, A Durbin, AP Whitehead, SS Baric, R Crowe, JE de Silva, AM AF Nivarthi, Usha K. Kose, Nurgun Sapparapu, Gopal Widman, Douglas Gallichotte, Emily Pfaff, Jennifer M. Doranz, Benjamin J. Weiskopf, Daniela Sette, Alessandro Durbin, Anna P. Whitehead, Steve S. Baric, Ralph Crowe, James E., Jr. de Silva, Aravinda M. TI Mapping the Human Memory B Cell and Serum Neutralizing Antibody Responses to Dengue Virus Serotype 4 Infection and Vaccination SO JOURNAL OF VIROLOGY LA English DT Article DE Dengue virus serotype 4; human; neutralization; antibody responses; epitope; infection; memory B cells; vaccination ID ENVELOPE PROTEIN; HIGHLY POTENT; DETERMINANTS; EPITOPES; BINDING; FUSION; GLYCOPROTEIN; ENHANCEMENT; RECOGNITION; PROTECTION AB The four dengue virus (DENV) serotypes are mosquito-borne flaviviruses responsible for dengue fever and dengue hemorrhagic fever. People exposed to DENV develop antibodies (Abs) that strongly neutralize the serotype responsible for infection. Historically, infection with DENV serotype 4 (DENV4) has been less common and less studied than infections with the other three serotypes. However, DENV4 has been responsible for recent large and sustained epidemics in Asia and Latin America. The neutralizing antibody responses and the epitopes targeted against DENV4 have not been characterized in human infection. In this study, we mapped and characterized epitopes on DENV4 recognized by neutralizing antibodies in people previously exposed to DENV4 infections or to a live attenuated DENV4 vaccine. To study the fine specificity of DENV4 neutralizing human antibodies, B cells from two people exposed to DENV4 were immortalized and screened to identify DENV-specific clones. Two human monoclonal antibodies (MAbs) that neutralized DENV4 were isolated, and their epitopes were finely mapped using recombinant viruses and alanine scan mutation array techniques. Both antibodies bound to quaternary structure epitopes near the hinge region between envelope protein domain I (EDI) and EDII. In parallel, to characterize the serum neutralizing antibody responses, convalescence-phase serum samples from people previously exposed to primary DENV4 natural infections or a monovalent DENV4 vaccine were analyzed. Natural infection and vaccination also induced serum-neutralizing antibodies that targeted similar epitope domains at the EDI/II hinge region. These studies defined a target of neutralizing antigenic site on DENV4 targeted by human antibodies following natural infection or vaccination. IMPORTANCE The four serotypes of dengue virus are the causative agents of dengue fever and dengue hemorrhagic fever. People exposed to primary DENV infections develop long-term neutralizing antibody responses, but these principally recognize only the infecting serotype. An effective vaccine against dengue should elicit long-lasting protective antibody responses to all four serotypes simultaneously. We and others have defined antigenic sites on the envelope (E) protein of viruses of dengue virus serotypes 1, 2, and 3 targeted by human neutralizing antibodies. The epitopes on DENV4 E protein targeted by the human neutralizing antibodies and the mechanisms of serotype 4 neutralization are poorly understood. Here, we report the properties of human antibodies that neutralize dengue virus serotype 4. People exposed to serotype 4 infections or a live attenuated serotype 4 vaccine developed neutralizing antibodies that bound to similar sites on the viral E protein. These studies have provided a foundation for developing and evaluating DENV4 vaccines. C1 [Nivarthi, Usha K.; Widman, Douglas; Gallichotte, Emily; Baric, Ralph; de Silva, Aravinda M.] Univ N Carolina, Sch Med, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. [Kose, Nurgun; Sapparapu, Gopal; Crowe, James E., Jr.] Vanderbilt Univ, Med Ctr, Vanderbilt Vaccine Ctr, Nashville, TN 37232 USA. [Sapparapu, Gopal; Crowe, James E., Jr.] Vanderbilt Univ, Med Ctr, Dept Pediat, Nashville, TN 37232 USA. [Crowe, James E., Jr.] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 USA. [Pfaff, Jennifer M.; Doranz, Benjamin J.] Integral Mol Inc, Philadelphia, PA USA. [Weiskopf, Daniela; Sette, Alessandro] La Jolla Inst Allergy & Immunol, La Jolla, CA USA. [Durbin, Anna P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Durbin, Anna P.] Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Immunizat Res, Baltimore, MD USA. [Whitehead, Steve S.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP de Silva, AM (reprint author), Univ N Carolina, Sch Med, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA.; Crowe, JE (reprint author), Vanderbilt Univ, Med Ctr, Vanderbilt Vaccine Ctr, Nashville, TN 37232 USA.; Crowe, JE (reprint author), Vanderbilt Univ, Med Ctr, Dept Pediat, Nashville, TN 37232 USA.; Crowe, JE (reprint author), Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 USA. EM james.crowe@vanderbilt.edu; aravinda_desilva@med.unc.edu FU U.S. National Institutes of Health [R01 AI107731, R01 AI125198, U19 AI109761, P01 AI106695]; Bill and Melinda Gates Foundation FX This research was supported by funding from U.S. National Institutes of Health grants R01 AI107731, (principal investigator [PI], Aravinda M. de Silva), R01 AI125198 (PI, Aravinda M. de Silva), U19 AI109761 (PI, Ralph S. Baric), and P01 AI106695 (PI, Eva Harris) and the Bill and Melinda Gates Foundation (PI, Anna P. Durbin). NR 54 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD MAR PY 2017 VL 91 IS 5 AR UNSP e02041 DI 10.1128/JVI.02041-16 PG 14 WC Virology SC Virology GA EL1BV UT WOS:000394356400017 ER PT J AU Ooms, M Letko, M Simon, V AF Ooms, Marcel Letko, Michael Simon, Viviana TI The Structural Interface between HIV-1 Vif and Human APOBEC3H SO JOURNAL OF VIROLOGY LA English DT Article DE HIV-1; APOBEC3H; Vif; restriction factor; APOBEC3; A3H; HIV ID VIRUS TYPE-1 VIF; ENZYME APOBEC3G; IDENTIFICATION; RESTRICTION; DEGRADATION; DOCKING; COMPLEX; DNA AB Human APOBEC3H (A3H) is a cytidine deaminase that inhibits HIV-1 replication. To evade this restriction, the HIV-1 Vif protein binds A3H and mediates its proteasomal degradation. To date, little information on the Vif-A3H interface has been available. To decipher how both proteins interact, we first mapped the Vifbinding site on A3H by functionally testing a large set of A3H mutants in singlecycle infectivity and replication assays. Our data show that the two A3H alpha-helixes alpha 3 and alpha 4 represent the Vif-binding site of A3H. We next used viral adaptation and a set of Vif mutants to identify novel, reciprocal Vif variants that rescued viral infectivity in the presence of two Vif-resistant A3H mutants. These A3H-Vif interaction points were used to generate the first A3H-Vif structure model, which revealed that the A3H helixes alpha 3 and alpha 4 interact with the Vif beta-sheet (beta 2-beta 5). This model is in good agreement with previously reported Vif and A3H amino acids important for interaction. Based on the predicted A3H-Vif interface, we tested additional points of contact, which validated our model. Moreover, these experiments showed that the A3H and A3G binding sites on HIV-1 Vif are largely distinct, with both host proteins interacting with Vif beta-strand 2. Taken together, this virus-host interface model explains previously reported data and will help to identify novel drug targets to combat HIV-1 infection. IMPORTANCE HIV-1 needs to overcome several intracellular restriction factors in order to replicate efficiently. The human APOBEC3 locus encodes seven proteins, of which A3D, A3F, A3G, and A3H restrict HIV-1. HIV encodes the Vif protein, which binds to the APOBEC3 proteins and leads to their proteasomal degradation. No HIV-1 Vif-APOBEC3 costructure exists to date despite extensive research. We and others previously generated HIV-1 Vif costructure models with A3G and A3F by mapping specific contact points between both proteins. Here, we applied a similar approach to HIV-1 Vif and A3H and successfully generated a Vif-A3H interaction model. Importantly, we find that the HIV-1 Vif-A3H interface is distinct from the Vif-A3G and Vif-A3F interfaces, with a small Vif region being important for recognition of both A3G and A3H. Our Vif-A3H structure model informs on how both proteins interact and could guide toward approaches to block the Vif-A3H interface to target HIV replication. C1 [Ooms, Marcel; Letko, Michael; Simon, Viviana] Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA. [Letko, Michael] Icahn Sch Med Mt Sinai, Grad Sch Biomed Sci, New York, NY 10029 USA. [Simon, Viviana] Icahn Sch Med Mt Sinai, Global Hlth & Emerging Pathogens Inst, New York, NY 10029 USA. [Simon, Viviana] Icahn Sch Med Mt Sinai, Dept Med, Div Infect Dis, New York, NY 10029 USA. [Letko, Michael] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. RP Ooms, M; Simon, V (reprint author), Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA.; Simon, V (reprint author), Icahn Sch Med Mt Sinai, Global Hlth & Emerging Pathogens Inst, New York, NY 10029 USA.; Simon, V (reprint author), Icahn Sch Med Mt Sinai, Dept Med, Div Infect Dis, New York, NY 10029 USA. EM marcel.ooms@mssm.edu; viviana.simon@mssm.edu FU NIH/NIAID [AI064001, AI120998]; Public Health Service Institutional Research Training Award [T32A107647] FX This work was funded by NIH/NIAID grants AI064001 (V.S.) and AI120998 (V.S.) and Public Health Service Institutional Research Training Award T32A107647 (M.L.). NR 33 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD MAR PY 2017 VL 91 IS 5 AR UNSP e02289-16 DI 10.1128/JVI.02289-16 PG 11 WC Virology SC Virology GA EL1BV UT WOS:000394356400034 ER PT J AU Burg, MB AF Burg, Maurice B. TI Jared Grantham (1936-2017) obituary SO KIDNEY INTERNATIONAL LA English DT Biographical-Item C1 [Burg, Maurice B.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Burg, MB (reprint author), NHLBI, NIH, Bethesda, MD 20892 USA. EM burgm@nhlbi.nih.gov NR 1 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 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD MAR PY 2017 VL 91 IS 3 BP 518 EP 518 DI 10.1016/j.kint.2017.01.023 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA EL9ED UT WOS:000394921400001 ER PT J AU Garg, AX Suri, RS Eggers, P Finkelstein, FO Greene, T Kimmel, PL Kliger, AS Larive, B Lindsay, RM Pierratos, A Unruh, M Chertow, GM AF Garg, Amit X. Suri, Rita S. Eggers, Paul Finkelstein, Fredric O. Greene, Tom Kimmel, Paul L. Kliger, Alan S. Larive, Brett Lindsay, Robert M. Pierratos, Andreas Unruh, Mark Chertow, Glenn M. CA Frequent Hemodialysis Network Tria TI Patients receiving frequent hemodialysis have better health-related quality of life compared to patients receiving conventional hemodialysis SO KIDNEY INTERNATIONAL LA English DT Article DE clinical trial; daily hemodialysis; health-related quality of life; nocturnal hemodialysis ID IN-CENTER HEMODIALYSIS; REPORTED OUTCOMES; TRIALS; RECOVERY; DIALYSIS; DESIGN AB Most patients with end-stage kidney disease value their health-related quality of life (HRQoL) and want to know how it will be affected by their dialysis modality. We extended the findings of two prior clinical trial reports to estimate the effects of frequent compared to conventional hemodialysis on additional measures of HRQoL. The Daily Trial randomly assigned 245 patients to receive frequent (six times per week) or conventional (three times per week) in-center hemodialysis. The Nocturnal Trial randomly assigned 87 patients to receive frequent nocturnal (six times per week) or conventional (three times per week) home hemodialysis. All patients were on conventional hemodialysis prior to randomization, with an average feeling thermometer score of 70 to 75 (a visual analog scale from 0 to 100 where 100 is perfect health), an average general health scale score of 40 to 47 (a score from 0 to 100 where 100 is perfect health), and an average dialysis session recovery time of 2 to 3 hours. Outcomes are reported as the between-treatment group differences in one-year change in HRQoL measures and analyzed using linear mixed effects models. After one year in the Daily Trial, patients assigned to frequent in-center hemodialysis reported a higher feeling thermometer score, better general health, and a shorter recovery time after a dialysis session compared to standard thrice-weekly dialysis. After one year in the Nocturnal Trial, patients assigned to frequent home hemodialysis also reported a shorter recovery time after a dialysis session, but no statistical difference in their feeling thermometer or general health scores compared to standard home dialysis schedules. Thus, patients receiving day or nocturnal hemodialysis on average recovered approximately one hour earlier from a frequent compared to conventional hemodialysis session. Patients treated in an in-center dialysis facility reported better HRQoL with frequent compared to conventional hemodialysis. C1 [Garg, Amit X.; Lindsay, Robert M.] Univ Western Ontario, Dept Med, Div Nephrol, London, ON, Canada. [Suri, Rita S.] CHUM, Ctr Rech, Nephrol Sect, Dept Med, Montreal, PQ, Canada. [Eggers, Paul] NIDDK, NIH, Bethesda, MD 20892 USA. [Finkelstein, Fredric O.; Kliger, Alan S.] Yale Sch Med, New Haven, CT USA. [Finkelstein, Fredric O.; Kliger, Alan S.] New Haven Hlth Syst, New Haven, CT USA. [Greene, Tom] Univ Utah, Med Ctr, Salt Lake City, UT USA. [Kimmel, Paul L.] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. [Larive, Brett] Cleveland Clin Fdn, Dept Quantitat Hlth Sci, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Pierratos, Andreas] Univ Toronto, Humber River Hosp, Toronto, ON, Canada. [Unruh, Mark] Univ New Mexico, Div Nephrol, Dept Internal Med, Albuquerque, NM 87131 USA. [Chertow, Glenn M.] Stanford Univ, Sch Med, Dept Med, Palo Alto, CA 94304 USA. RP Garg, AX (reprint author), London Hlth Sci Ctr, ICES Western, Room ELL-708,800 Commissioners Rd East, London, ON N6A 5W9, Canada. EM amit.garg@lhsc.on.ca FU Dr. Adam Linton Chair in Kidney Health Analytics; Fresenius; Baxter Inc Extramural Grant Program; research scholarship from le Fonds de recherch du Quebec-Sante; Baxter; Satellite Healthcare; DCI Inc. FX AG was a co-investigator on investigator-initiated research project sponsored by Fresenius, and is supported by the Dr. Adam Linton Chair in Kidney Health Analytics. His work was conducted in the Lilibeth Caberto London Kidney Clinical Research Unit. RS received an investigator-initiated research grant from the Baxter Inc Extramural Grant Program, and is supported by a research scholarship from le Fonds de recherch du Quebec-Sante. MU has received research support from Baxter, Satellite Healthcare, and DCI Inc. GC served on the Board of Directors for Satellite Healthcare. All other authors declared no competing interests. NR 20 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 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD MAR PY 2017 VL 91 IS 3 BP 746 EP 754 DI 10.1016/j.kint.2016.10.033 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA EL9ED UT WOS:000394921400029 PM 28094031 ER PT J AU Karliner, LS Perez-Stable, EJ Gregorich, SE AF Karliner, Leah S. Perez-Stable, Eliseo J. Gregorich, Steven E. TI Convenient Access to Professional Interpreters in the Hospital Decreases Readmission Rates and Estimated Hospital Expenditures for Patients With Limited English Proficiency SO MEDICAL CARE LA English DT Article DE language access; quality of care aging; disparities; health care costs; health care delivery; interventions; quasiexper-imental design; readmissions; underserved populations ID LENGTH-OF-STAY; HEALTH-CARE; LANGUAGE PROFICIENCY; ADVERSE EVENTS; SERVICES; SATISFACTION; DISPARITIES; MORTALITY; BARRIERS; IMPROVE AB Background: Twenty-five million people in the United States have limited English proficiency (LEP); this growing and aging population experiences worse outcomes when hospitalized. Federal requirements that hospitals provide language access services are very challenging to implement in the fast-paced, 24-hour hospital environment. Objective: To determine if increasing access to professional interpreters improves hospital outcomes for older patients with LEP. Design: Natural experiment on a medicine floor of an academic hospital. Participants: Patients age 50 years or above discharged between January 15, 2007 and January 15, 2010. Exposure: Dual-handset interpreter telephone at every bedside July 15, 2008 to Mar 14, 2009. Outcome Measures: Thirty-day readmission, length of stay, estimated hospital expenditures. Results: Of 8077 discharges, 1963 were for LEP, and 6114 for English proficient patients. There was a significant decrease in observed 30-day readmission rates for the LEP group during the 8-month intervention period compared with 18 months preintervention (17.8% vs. 13.4%); at the same time English proficient readmission rates increased (16.7% vs. 19.7%); results remained significant in adjusted analyses. This improved readmission outcome for the LEP group was not maintained during the subsequent postintervention period when the telephones became less accessible. There was no significant intervention impact on length of stay in either unadjusted or adjusted analyses. After accounting for interpreter services costs, the estimated 119 readmissions averted during the intervention period were associated with estimated monthly hospital expenditure savings of $ 161,404. Conclusions: Comprehensive language access represents an important, high value service that all medical centers should provide to achieve equitable, quality healthcare for vulnerable LEP populations. C1 [Karliner, Leah S.; Perez-Stable, Eliseo J.; Gregorich, Steven E.] Univ Calif San Francisco, Dept Med, Div Gen Internal Med, Multiethn Hlth Equ Res Ctr, San Francisco, CA USA. [Perez-Stable, Eliseo J.] Natl Inst Minor Hlth & Hlth Dispar, NIH, 6707 Democracy Blvd,Suite 800, Bethesda, MD 20892 USA. RP Karliner, LS (reprint author), 1545 Divisadero St,3rd Floor, San Francisco, CA 94143 USA. EM leah.karliner@ucsf.edu FU National Institute on Aging, National Institutes of Health [R01 AG038684]; Resource Centers for Minority Aging Research program of the National Institute on Aging, National Institutes of Health [P30 AG15272] FX Supported by the National Institute on Aging, National Institutes of Health (R01 AG038684). P.S. was supported in part by the Resource Centers for Minority Aging Research program of the National Institute on Aging, National Institutes of Health (P30 AG15272). NR 35 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 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD MAR PY 2017 VL 55 IS 3 BP 199 EP 206 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA EL3GD UT WOS:000394506700001 PM 27579909 ER PT J AU Prosser, G Brandenburg, J Reiling, N Barry, CE Wilkinson, RJ Wilkinson, KA AF Prosser, Gareth Brandenburg, Julius Reiling, Norbert Barry, Clifton Earl, III Wilkinson, Robert J. Wilkinson, Katalin A. TI The bacillary and macrophage response to hypoxia in tuberculosis and the consequences for T cell antigen recognition SO MICROBES AND INFECTION LA English DT Article DE Tuberculosis; Hypoxia; T cells; Antigens; Macrophage; Lipid droplets ID HOST-PATHOGEN INTERACTIONS; ENDOTHELIAL GROWTH-FACTOR; TUMOR-NECROSIS-FACTOR; MYCOBACTERIUM-TUBERCULOSIS; LATENT TUBERCULOSIS; GENE-EXPRESSION; PULMONARY TUBERCULOSIS; IN-VITRO; LIPID-METABOLISM; DOSR REGULON AB Mycobacterium tuberculosis is a facultative anaerobe and its characteristic pathological hallmark, the granuloma, exhibits hypoxia in humans and in most experimental models. Thus the host and bacillary adaptation to hypoxia is of central importance in understanding pathogenesis and thereby to derive new drug treatments and vaccines. (C) 2016 The Author(s). Published by Elsevier Masson SAS on behalf of Institut Pasteur. C1 [Prosser, Gareth; Barry, Clifton Earl, III] Natl Inst Allergy & Infect Dis, TB Res Sect, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Brandenburg, Julius; Reiling, Norbert] Forschungszentrum Borstel, Leibniz Ctr Med & Biosciences, Microbial Interface Biol, Prior Res Area Infect, Parkallee 1-40, D-23845 Borstel, Germany. [Barry, Clifton Earl, III; Wilkinson, Robert J.; Wilkinson, Katalin A.] Univ Cape Town, Inst Infect Dis & Mol Med, Clin Infect Dis Res Initiat, Observ, ZA-7925 Cape Town, South Africa. [Wilkinson, Robert J.; Wilkinson, Katalin A.] Francis Crick Inst, London NW1 2AT, England. [Wilkinson, Robert J.] Imperial Coll, Dept Med, London W2 IPG, England. [Reiling, Norbert] German Ctr Infect Res DZIF, Partner Site Hamburg Borstel Labeck, Borstel, Germany. RP Wilkinson, RJ (reprint author), Univ Cape Town, Inst Infect Dis & Mol Med, Clin Infect Dis Res Initiat, Observ, ZA-7925 Cape Town, South Africa.; Wilkinson, RJ (reprint author), Francis Crick Inst, London NW1 2AT, England.; Wilkinson, RJ (reprint author), Imperial Coll, Dept Med, London W2 IPG, England. EM r.j.wilkinson@imperial.ac.uk FU Francis Crick Institute from Cancer Research UK [FC00110218]; UK Medical Research Council [FC00110218]; Wellcome Trust [FC00110218, 104803]; National Institutes of Health [1U01AI115940, U19 AI 111276]; Medical Research Council of South Africa via its strategic health innovations partnerships; National Research Foundation of South Africa [96841]; Intramural Research Program of the MAID; NIH; Deutsche Forschungsgemeinschaft [Re1228/5-1, Re1228/5-2, SPP1580]; Deutsches Zentrum fur Infektionsforschung (DZIF) within the "Thematic translational unit tuberculosis (TTU TB)" FX RJW is supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC00110218), the UK Medical Research Council (FC00110218), and the Wellcome Trust (FC00110218); by the Wellcome Trust (104803), National Institutes of Health (1U01AI115940, U19 AI 111276), Medical Research Council of South Africa via its strategic health innovations partnerships, and National Research Foundation of South Africa (96841). This research was supported (in part) by the Intramural Research Program of the MAID, NIH. JB and NR are supported in part by the Deutsche Forschungsgemeinschaft (grants Re1228/5-1 and Re1228/5-2 within the priority programme SPP1580; Cluster of excellence 306 "Inflammation at interfaces") and a grant of the Deutsches Zentrum fur Infektionsforschung (DZIF) within the "Thematic translational unit tuberculosis (TTU TB)". NR 156 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 EI 1769-714X J9 MICROBES INFECT JI Microbes Infect. PD MAR PY 2017 VL 19 IS 3 SI SI BP 177 EP 192 DI 10.1016/j.micinf.2016.10.001 PG 16 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP0KU UT WOS:000397077000005 PM 27780773 ER PT J AU Henson, JH Ditzler, CE Germain, A Irwin, PM Vogt, ET Yang, SC Wu, XF Shuster, CB AF Henson, John H. Ditzler, Casey E. Germain, Aphnie Irwin, Patrick M. Vogt, Eric T. Yang, Shucheng Wu, Xufeng Shuster, Charles B. TI The ultrastructural organization of actin and myosin II filaments in the contractile ring: new support for an old model of cytokinesis SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID SEA-URCHIN EGGS; FISSION YEAST; CLEAVAGE FURROW; CULTURED-CELLS; STRESS FIBERS; FLUORESCENCE MICROSCOPY; STRUCTURED ILLUMINATION; HELA-CELLS; LOCALIZATION; FIBROBLASTS AB Despite recent advances in our understanding of the components and spatial regulation of the contractile ring (CR), the precise ultrastructure of actin and myosin II within the animal cell CR remains an unanswered question. We used superresolution light microscopy and platinum replica transmission electron microscopy (TEM) to determine the structural organization of actin and myosin II in isolated cortical cytoskeletons prepared from dividing sea urchin embryos. Three-dimensional structured illumination microscopy indicated that within the CR, actin and myosin II filaments were organized into tightly packed linear arrays oriented along the axis of constriction and restricted to a narrow zone within the furrow. In contrast, myosin II filaments in earlier stages of cytokinesis were organized into small, discrete, and regularly spaced clusters. TEM showed that actin within the CR formed a dense and anisotropic array of elongate, antiparallel filaments, whereas myosin II was organized into laterally associated, head-to-head filament chains highly reminiscent of mammalian cell stress fibers. Together these results not only support the canonical "purse-string" model for contractile ring constriction, but also suggest that the CR may be derived from foci of myosin II filaments in a manner similar to what has been demonstrated in fission yeast. C1 [Henson, John H.; Ditzler, Casey E.; Germain, Aphnie; Irwin, Patrick M.; Vogt, Eric T.; Yang, Shucheng] Dickinson Coll, Dept Biol, Carlisle, PA 17013 USA. [Henson, John H.; Shuster, Charles B.] Univ Washington, Friday Harbor Labs, Friday Harbor, WA 98250 USA. [Wu, Xufeng] NHLBI, NIH, Bethesda, MD 20824 USA. [Shuster, Charles B.] New Mexico State Univ, Dept Biol, Las Cruces, NM 88003 USA. RP Henson, JH (reprint author), Dickinson Coll, Dept Biol, Carlisle, PA 17013 USA.; Henson, JH (reprint author), Univ Washington, Friday Harbor Labs, Friday Harbor, WA 98250 USA. EM henson@dickinson.edu FU National Science Foundation [0856704, MCB-1412688, MCB-1412734] FX We thank Tanya Svitkina and Jonathan Chia (University of Pennsylvania, Philadelphia, PA) for expert assistance with the generation of platinum replicas and TEM imaging; Billie Swalla (University of Washington, Seattle, WA) for access to instrumentation and reagents at Friday Harbor Laboratories; Rodney Jones, Jesse Bissell, Courtney Gamache, Zoe Irons, and Erik Williams (Dickinson College, Carlisle, PA) for help with experimentation and image analysis; and the late Ray Rappaport, memory of whom continues to inspire our work on cytokinesis. This research was supported by National Science Foundation STEP Grant 0856704 to Dickinson College and collaborative research grants to J.H.H. (MCB-1412688) and C.B.S. (MCB-1412734). NR 68 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD MAR 1 PY 2017 VL 28 IS 5 BP 613 EP 623 DI 10.1091/mbc.E16-06-0466 PG 11 WC Cell Biology SC Cell Biology GA EN8GY UT WOS:000396240100005 PM 28057763 ER PT J AU Kim, GY Lee, YM Kwon, JH Cho, JH Pan, CJ Starost, MF Mansfield, BC Chou, JY AF Kim, Goo-Young Lee, Young Mok Kwon, Joon Hyun Cho, Jun -Ho Pan, Chi-Jiunn Starost, Matthew F. Mansfield, Brian C. Chou, Janice Y. TI Glycogen storage disease type Ia mice with less than 2% of normal hepatic glucose-6-phosphatase-alpha activity restored are at risk of developing hepatic tumors SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Gene therapy; Recombinant adeno-associated virus vector; Hepatocellular adenoma; Hepatocellular carcinoma ID HEPATOCELLULAR ADENOMAS; INSULIN-RESISTANCE; GENE-THERAPY; EXPRESSION; CODON; OPTIMIZATION; DEFICIENCY; MANAGEMENT; TRANSPORT; GLUCOSE AB Glycogen storage disease type la (GSD-Ia), characterized by impaired glucose homeostasis and chronic risk of hepatocellular adenoma (HCA) and carcinoma (HCC), is caused by a deficiency in glucose-6-phosphatase-alpha (G6Pase-alpha or G6PC). We have previously shown that G6pc-/- mice receiving gene transfer mediated by rAAV-G6PC, a recombinant adeno-associated virus (rAAV) vector expressing G6Pase-alpha, and expressing 3-63% of normal hepatic G6Pase-alpha activity maintain glucose homeostasis and do not develop HCA/HCC. However, the threshold of hepatic G6Pase-alpha activity required to prevent tumor formation remained unknown. In this study, we constructed rAAV-co-G6PC, a rAAV vector expressing a codon-optimized (co) G6Pase-alpha and showed that rAAV-co-G6PC was more efficacious than rAAV-G6PC in directing hepatic G6Pase-alpha expression. Over an 88-week study, we showed that both rAAV-G6PC- and rAAV-co-G6PC-treated G6pc-/- mice expressing 3-33% of normal hepatic G6Pase-alpha activity (AAV mice) maintained glucose homeostasis, lacked HCA/HCC, and were protected against age-related obesity and insulin resistance. Of the eleven rAAV-G6PC/rAAV-co-G6PC-treated G6pc-/- mice harboring 0.9-2.4% of normal hepatic G6Pase-alpha activity (AAV-low mice), 3 expressing 0.9-1.3% of normal hepatic G6Pase-alpha activity developed HCA/HCC, while 8 did not (AAV-low-NT). Finally, we showed that the MV-low-NT mice exhibited a phenotype indistinguishable from that of AAV mice expressing >= 3% of normal hepatic G6Pase-alpha activity. The results establish the threshold of hepatic G6Pase-alpha activity required to prevent HCA/HCC and show that GSD-Ia mice harboring <2% of normal hepatic G6Pase-alpha activity are at risk of tumor development. Published by Elsevier Inc. C1 [Kim, Goo-Young; Lee, Young Mok; Kwon, Joon Hyun; Cho, Jun -Ho; Pan, Chi-Jiunn; Mansfield, Brian C.; Chou, Janice Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Differentiat, Rockville, MD USA. [Starost, Matthew F.] NIH, Div Vet Resources, Bldg 10, Bethesda, MD 20892 USA. [Mansfield, Brian C.] Fdn Fighting Blindness, Columbia, MD 21046 USA. RP Chou, JY (reprint author), NIH, Bldg 10,Room 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM chouja@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Children's Fund for Glycogen Storage Disease Research FX We thank Dr. Thomas J. Conlon for helpful discussions of codon optimization methods. 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, and The Children's Fund for Glycogen Storage Disease Research. NR 25 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2017 VL 120 IS 3 BP 229 EP 234 DI 10.1016/j.ymgme.2017.01.003 PG 6 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA EP0ME UT WOS:000397080600009 PM 28096054 ER PT J AU Ferreira, CR Chen, D Abraham, SM Adams, DR Simon, KL Malicdan, MC Markello, TC Gunay-Aygun, M Gahl, WA AF Ferreira, Carlos R. Chen, Dong Abraham, Shirley M. Adams, David R. Simon, Karen L. Malicdan, May C. Markello, Thomas C. Gunay-Aygun, Meral Gahl, William A. TI Combined alpha-delta platelet storage pool deficiency is associated with mutations in GFI1B SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Combined alpha-delta platelet storage pool deficiency; alpha delta-SPD; GFI1B ID BLEEDING DISORDER; LINKED GATA-1; VARIANTS; GFI-1B; PROTEIN; HEMATOPOIESIS; EXPRESSION; GRANULES; DISTINCT; NBEAL2 AB Combined alpha-delta platelet storage pool deficiency is characterized by the absence or reduction in the number of both alpha granules and dense bodies. This disorder can have variable severity as well as a variable inheritance pattern. We describe two patients from unrelated families with combined alpha-delta storage pool deficiency due to mutations in GFI1B, a zinc finger protein known to act as a transcriptional repressor of various genes. We demonstrate that this disease is associated with either a heterozygous mutation (de novo or familial) abrogating the binding of the zinc fingers with the promoter of its target genes, or by hypomorphic biallelic mutations in GFT1B leading to autosomal recessive inheritance. Published by Elsevier Inc. C1 [Ferreira, Carlos R.; Adams, David R.; Simon, Karen L.; Malicdan, May C.; Gunay-Aygun, Meral; Gahl, William A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Ferreira, Carlos R.] Childrens Natl Hlth Syst, Div Genet & Metab, Washington, DC USA. [Chen, Dong] Mayo Clin, Coll Med, Dept Lab Med & Pathol, Special Coagulat Lab,Div Hematopathol, Rochester, MN USA. [Abraham, Shirley M.] Univ New Mexico, Dept Pediat, Div Hematol & Oncol, Albuquerque, NM 87131 USA. [Adams, David R.; Malicdan, May C.; Markello, Thomas C.; Gahl, William A.] NIH, Undiagnosed Dis Program, Common Fund, Bldg 10, Bethesda, MD 20892 USA. [Adams, David R.; Gahl, William A.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Gunay-Aygun, Meral] Johns Hopkins Univ, Sch Med, Dept Pediat, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. RP Ferreira, CR (reprint author), 10 Ctr Dr,MSC 1851,Bldg 10,Room 10C-103, Bethesda, MD 20892 USA. EM ferreiracr@mail.nih.gov FU National Human Genome Research Institute, National Institutes of Health FX This study was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. The authors thank the patients and their families for their kind support and assistance. We dedicate this work to the late Dr. James G. White, who contributed to the evaluation of patient 1. NR 43 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2017 VL 120 IS 3 BP 288 EP 294 DI 10.1016/j.ymgme.2016.12.006 PG 7 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA EP0ME UT WOS:000397080600016 PM 28041820 ER PT J AU Isgrig, K Shteamer, JW Belyantseva, IA Drummond, MC Fitzgerald, TS Vijayakumar, S Jones, SM Griffith, AJ Friedman, TB Cunningham, LL Chien, WW AF Isgrig, Kevin Shteamer, Jack W. Belyantseva, Inna A. Drummond, Meghan C. Fitzgerald, Tracy S. Vijayakumar, Sarath Jones, Sherri M. Griffith, Andrew J. Friedman, Thomas B. Cunningham, Lisa L. Chien, Wade W. TI Gene Therapy Restores Balance and Auditory Functions in a Mouse Model of Usher Syndrome SO MOLECULAR THERAPY LA English DT Article ID SENSORINEURAL HEARING-LOSS; ADENOASSOCIATED VIRUS VECTORS; HAIR-CELL STEREOCILIA; PDZ-DOMAIN PROTEIN; VESTIBULAR SYSTEM; WHIRLIN ISOFORMS; SCALA MEDIA; INNER-EAR; DEAFNESS; DFNB31 AB Dizziness and hearing loss are among the most common disabilities. Many forms of hereditary balance and hearing disorders are caused by abnormal development of stereocilia, mechanosensory organelles on the apical surface of hair cells in.the inner ear. The deaf whirler mouse, a model of human Usher syndrome (manifested by hearing loss, dizziness, and blindness), has a recessive mutation in the whirlin gene, which renders hair cell stereocilia short and dysfunctional. In this study, wild-type whirlin cDNA was delivered to the inner ears of neonatal whirler mice using adeno-associated virus serotype 2/8 (AAV8-whirlin) by injection into the posterior semicircular canal. Unilateral whirlin gene therapy injection was able to restore balance function as well as improve hearing in whirler mice for at least 4 months. Our data indicate that gene therapy is likely to become a treatment option for hereditary disorders of balance and hearing. C1 [Isgrig, Kevin; Shteamer, Jack W.; Chien, Wade W.] NIDCD, Neurotol Program, NIH, 35A Convent Dr,Room 1F220, Bethesda, MD 20892 USA. [Belyantseva, Inna A.; Drummond, Meghan C.; Friedman, Thomas B.] NIDCD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. [Fitzgerald, Tracy S.] NIDCD, Mouse Auditory Testing Core Facil, NIH, Bethesda, MD 20892 USA. [Vijayakumar, Sarath; Jones, Sherri M.] Univ Nebraska, Dept Special Educ & Commun Disorders, Lincoln, NE 68583 USA. [Griffith, Andrew J.] NIDCD, Mol Biol & Genet Sect, NIH, Bethesda, MD 20892 USA. [Cunningham, Lisa L.] NIDCD, Sect Sensory Cell Biol, NIH, Bethesda, MD 20892 USA. [Chien, Wade W.] Johns Hopkins Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21287 USA. [Isgrig, Kevin; Shteamer, Jack W.] Regeneron Pharmaceut Inc, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 USA. RP Chien, WW (reprint author), NIDCD, Neurotol Program, NIH, 35A Convent Dr,Room 1F220, Bethesda, MD 20892 USA. EM wade.chien@nih.gov FU NIH NIDCD Division of Intramural Research [DC000082-02, DC000079-03, DC000048-19, DC000080, DC000060-13]; Nebraska Tobacco Settlement Biomedical Research Development Fund FX We are grateful to the NIDCD animal facility staff for caring for our animals. This work was supported by funds from the NIH NIDCD Division of Intramural Research (DC000082-02 to W.W.C., DC000079-03 to L.L.C., DC000048-19 to T.B.F., DC000080 to T.S.F., and DC000060-13 to A.J.G.) and from the Nebraska Tobacco Settlement Biomedical Research Development Fund (to S.M.J.). NR 45 TC 0 Z9 0 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD MAR 1 PY 2017 VL 25 IS 3 BP 780 EP 791 DI 10.1016/j.ymthe.2017.01.007 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA EO4AF UT WOS:000396635500020 PM 28254438 ER PT J AU McCance, D Gilman, SL Hutcheon, L Hutcheon, M Tiffin, H AF McCance, Dawne Gilman, Sander L. Hutcheon, Linda Hutcheon, Michael Tiffin, Helen TI Roundtable on Interdisciplinarity SO MOSAIC-A JOURNAL FOR THE INTERDISCIPLINARY STUDY OF LITERATURE LA English DT Editorial Material C1 [Gilman, Sander L.] Emory Univ, Liberal Arts & Sci, Atlanta, GA 30322 USA. [Gilman, Sander L.] Emory Univ, Psychiat, Atlanta, GA 30322 USA. [Gilman, Sander L.] Cornell Univ, Fac Humanities, Ithaca, NY 14853 USA. [Gilman, Sander L.] Cornell Univ, Fac Med, Ithaca, NY 14853 USA. [Gilman, Sander L.] Cornell Univ, Humane Studies, Ithaca, NY 14853 USA. [Gilman, Sander L.] Univ Chicago, Liberal Arts Human Biol, Chicago, IL 60637 USA. [Gilman, Sander L.] Univ Illinois, Liberal Arts & Med, Humanities Lab, Chicago, IL USA. [Gilman, Sander L.] Natl Lib Med, Bethesda, MD USA. [Gilman, Sander L.] Ctr Adv Study Behav Sci, Stanford, CA 94305 USA. [Gilman, Sander L.] Amer Acad, Berlin, Germany. [Gilman, Sander L.] Univ Oxford, European Comparat Literature, Oxford, England. [Gilman, Sander L.] Birkbeck Coll, Inst Humanities, London, England. [Gilman, Sander L.] Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. [Gilman, Sander L.] Amer Psychoanalyt Assoc, Hong Kong, Hong Kong, Peoples R China. [Gilman, Sander L.] Amer Acad Arts & Sci, Cambridge, MA USA. [Hutcheon, Michael] Univ Toronto, Toronto, ON, Canada. [Hutcheon, Michael] Toronto Gen Hosp, Pulm Funct Lab, Toronto, ON, Canada. [Tiffin, Helen] Univ Queensland, English, Brisbane, Qld, Australia. RP Gilman, SL (reprint author), Emory Univ, Liberal Arts & Sci, Atlanta, GA 30322 USA.; Gilman, SL (reprint author), Emory Univ, Psychiat, Atlanta, GA 30322 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU UNIV MANITOBA PI WINNIPEG PA MOSAIC 208 TIER BLDG, WINNIPEG, MANITOBA R3T 2N2, CANADA SN 0027-1276 EI 1925-5683 J9 MOSAIC JI Mosaic-J. Interdiscip. Study Lit. PD MAR PY 2017 VL 50 IS 1 BP 95 EP 113 PG 19 WC Literature SC Literature GA EN7KG UT WOS:000396181100007 ER PT J AU Watanabe, T Kudo, M Strober, W AF Watanabe, T. Kudo, M. Strober, W. TI Immunopathogenesis of pancreatitis SO MUCOSAL IMMUNOLOGY LA English DT Review ID NF-KAPPA-B; MONOCYTE CHEMOATTRACTANT PROTEIN-1; GROUP BOX CHROMOSOMAL-PROTEIN-1; ACUTE NECROTIZING PANCREATITIS; CERULEIN-INDUCED PANCREATITIS; BLOOD MONONUCLEAR-CELLS; NECROSIS-FACTOR-ALPHA; ACINAR-CELLS; INFLAMMATORY-RESPONSE; IN-VIVO AB The conventional view of the pathogenesis of acute and chronic pancreatitis is that it is due to a genetic-or environment-based abnormality of intracellular acinar trypsinogen activation and thus to the induction of acinar cell injury that, in turn, sets in motion an intra-pancreatic inflammatory process. More recent studies, reviewed here, present strong evidence that while such trypsinogen activation is likely a necessary first step in the inflammatory cascade underlying pancreatitis, sustained pancreatic inflammation is dependent on damage-associated molecular patterns-mediated cytokine activation causing the translocation of commensal (gut) organisms into the circulation and their induction of innate immune responses in acinar cells. Quite unexpectedly, these recent studies reveal that the innate responses involve activation of responses by an innate factor, nucleotide-binding oligomerization domain 1 (NOD1), and that such NOD1 responses have a critical role in the activation/production of nuclear factor-kappa B and type I interferon. In addition, they reveal that chronic inflammation and its accompanying fibrosis are dependent on the generation of IL-33 by injured acinar cells and its downstreaminduction of Tcells producing IL-13. These recent studies thus establish that pancreatitis is quite a unique form of inflammation and one susceptible to newer, more innovative therapy. C1 [Watanabe, T.; Kudo, M.] Kindai Univ, Fac Med, Dept Gastroenterol & Hepatol, Osaka, Japan. [Watanabe, T.; Strober, W.] NIAID, Mucosal Immun Sect, Lab Host Defenses, NIH, Bethesda, MD 20892 USA. RP Watanabe, T (reprint author), Kindai Univ, Fac Med, Dept Gastroenterol & Hepatol, Osaka, Japan.; Watanabe, T; Strober, W (reprint author), NIAID, Mucosal Immun Sect, Lab Host Defenses, NIH, Bethesda, MD 20892 USA. EM tomohiro@med.kindai.ac.jp; wstrober@niaid.nih.gov FU Japan Society for the Promotion of Science [15K15370]; Kato Memorial Trust for Nambyo Research; Health and Labor Sciences Research Grants for Research on Intractable Diseases from the Ministry of Health, Labor and Welfare, Japan. FX This work was supported by Grant-in-Aid for Scientific Research (15K15370) from the Japan Society for the Promotion of Science, the Kato Memorial Trust for Nambyo Research, and the Health and Labor Sciences Research Grants for Research on Intractable Diseases from the Ministry of Health, Labor and Welfare, Japan. NR 128 TC 0 Z9 0 U1 0 U2 0 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 2017 VL 10 IS 2 BP 283 EP 298 DI 10.1038/mi.2016.101 PG 16 WC Immunology SC Immunology GA EN1ZV UT WOS:000395810000001 PM 27848953 ER PT J AU Barber, DL AF Barber, D. L. TI Vaccination for Mycobacterium tuberculosis infection: reprogramming CD4 T-cell homing into the lung SO MUCOSAL IMMUNOLOGY LA English DT Article ID TERMINAL DIFFERENTIATION; PHENOTYPE AB Development of effective tuberculosis vaccines is hampered by insufficient understanding of protective immunity. Here, Woodworth et al.(1) show secondary effector CD4 T cells generated after Mtb challenge of H56/CAF01 vaccinated mice display superior lung homing compared with primary effectors. Vaccination generates large populations of parenchymal lungeffector cellsby inducing CXCR3(+)KLRG1(-) cells that continuously migrate from lymph nodes to lung, and limiting the generation of non-protective CX3CR1(+)KLRG1(+) intravascular effectors, providing insight vaccine-mediated protection against tuberculosis. C1 [Barber, D. L.] NIAID, Tlymphocyte Biol Unit, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Barber, DL (reprint author), NIAID, Tlymphocyte Biol Unit, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM barberd@niaid.nih.gov FU Intramural Research Program of NIAID/NIH FX D.L.B.is supported by the Intramural Research Program of the NIAID/NIH. NR 10 TC 0 Z9 0 U1 0 U2 0 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 2017 VL 10 IS 2 BP 318 EP 321 DI 10.1038/mi.2016.110 PG 4 WC Immunology SC Immunology GA EN1ZV UT WOS:000395810000004 PM 27966550 ER PT J AU Caucheteux, SM Hu-Li, J Mohammed, RN Ager, A Paul, WE AF Caucheteux, S. M. Hu-Li, J. Mohammed, R. N. Ager, A. Paul, W. E. TI Cytokine regulation of lung Th17 response to airway immunization using LPS adjuvant SO MUCOSAL IMMUNOLOGY LA English DT Article ID INFLUENZA-VIRUS INFECTION; TOLL-LIKE RECEPTOR; CD4 T-CELLS; DENDRITIC CELLS; DIFFERENTIAL REGULATION; DEPENDENT PATHWAY; IL-1 ACTS; MACROPHAGES; TRIF; LIPOPOLYSACCHARIDE AB Infections caused by bacteria in the airway preferentially induce a Th17 response. However, the mechanisms involved in the regulation of CD4T-cell responses in the lungs are incompletely understood. Here, we have investigated the mechanisms involved in the regulation of Th17 differentia tion in the lungs in response to immunization with lipopolysaccharide (LPS) as an adjuvant. Our data show that both Myd88 and TRIF are necessary for Th17 induction. This distinctive fate determination can be accounted for by the pattern of inflammatory cytokines induced by airway administration of LPS. We identified the production of interleukin (IL)-1 beta and IL-6 by small macrophages and IL-23 by alveolar dendritic cells (DCs), favoring Th17 responses, and IL-10 repressing interferon (IFN)-gamma production. Furthermore, we show that exogenous IL-1 beta can drastically alter Th1 responses driven by influenza and lymphocytic choriomeningitis virus infection models and induce IL-17 production. Thus, the precision of the lung immune responses to potential threats is orchestrated by the cytokine microenvironment, can be repolarized and targeted therapeutically by altering the cytokine milieu. These results indicate that how the development of Th17 responses in the lung is regulated by the cytokines produced by lung DCs and macrophages in response to intranasal immunization with LPS adjuvant. C1 [Caucheteux, S. M.; Hu-Li, J.; Paul, W. E.] NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Caucheteux, S. M.; Mohammed, R. N.; Ager, A.] Cardiff Univ, Inst Infect & Immun, Cardiff, Wales. RP Caucheteux, SM (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA.; Caucheteux, SM (reprint author), Cardiff Univ, Inst Infect & Immun, Cardiff, Wales. EM caucheteuxs@cardiff.ac.uk FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases FX This work is dedicated to the memory of Dr Paul. We thank G. A. Punkosdy for Lymphocytic Choriomeningitis Virus Clone 13; M Brandes- Kuchen for influenza Tx91; A Gallimore ( I& I, Cardiff) for antibodies and for critically reading themanuscript; members of the Laboratory ofImmunology at NIAID for discussions. This research was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases. NR 50 TC 0 Z9 0 U1 1 U2 1 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 2017 VL 10 IS 2 BP 361 EP 372 DI 10.1038/mi.2016.54 PG 12 WC Immunology SC Immunology GA EN1ZV UT WOS:000395810000009 PM 27328989 ER PT J AU Morabito, KM Ruckwardt, T Redwood, A Moin, SM Price, DA Graham, BS AF Morabito, K. M. Ruckwardt, T. R. Redwood, A. J. Moin, S. M. Price, D. A. Graham, B. S. TI Intranasal administration of RSV antigen-expressing MCMV elicits robust tissue-resident effector and effector memory CD8+T cells in the lung SO MUCOSAL IMMUNOLOGY LA English DT Article ID CD8(+) T-CELLS; MURINE CYTOMEGALOVIRUS-INFECTION; HIGHLY PATHOGENIC SIV; VIRUS CHALLENGE; NONLYMPHOID TISSUE; VIRAL-INFECTION; VACCINE VECTOR; EBOLA-VIRUS; RESPONSES; MICE AB Cytomegalovirus vectors are promising delivery vehicles for vaccine strategies that aim to elicit effector CD8+ T cells. To determinehowthe route of immunization affects CD8+ T-cell responses in the lungs of mice vaccinated with a murine cytomegalovirus vector expressing the respiratory syncytial virus matrix (M) protein, we infected CB6F1 mice via the intranasal or intraperitoneal route and evaluated the M-specific CD8+ T-cell response at early and late time points. We found that intranasal vaccination generated robust and durable tissue-resident effector and effector memory CD8+ T-cell populations that were undetectable after intraperitoneal vaccination. The generation of these antigen-experienced cells by intranasal vaccination resulted in earlier T-cell responses, interferon gamma secretion, and viral clearance after respiratory syncytial virus challenge. Collectively, these findings validate a novel approach to vaccination that emphasizes the route of delivery as a key determinant of immune priming at the site of vulnerability. C1 [Morabito, K. M.; Ruckwardt, T. R.; Moin, S. M.; Graham, B. S.] NIH, Natl Inst Allergy & Infect Dis, Vaccine Res Ctr, Viral Pathogenesis Lab, Bldg 10, Bethesda, MD 20892 USA. [Morabito, K. M.] Georgetown Univ, Med Ctr, Dept Microbiol & Immunol, Washington, DE USA. [Redwood, A. J.] Murdoch Univ, Inst Immunol & Infect Dis, Perth, WA, Australia. [Price, D. A.] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF10 3AX, S Glam, Wales. [Price, D. A.] NIH, Natl Inst Allergy & Infect Dis, Vaccine Res Ctr, Human Immunol, Bldg 10, Bethesda, MD 20892 USA. RP Graham, BS (reprint author), NIH, Natl Inst Allergy & Infect Dis, Vaccine Res Ctr, Viral Pathogenesis Lab, Bldg 10, Bethesda, MD 20892 USA. EM bgraham@mail.nih.gov FU Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank Brenda Hartman for help with figure preparation. This work was supported by intramural funding from the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health. DAP is a Wellcome Trust Senior Investigator. NR 50 TC 0 Z9 0 U1 0 U2 0 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 2017 VL 10 IS 2 BP 545 EP 554 DI 10.1038/mi.2016.48 PG 10 WC Immunology SC Immunology GA EN1ZV UT WOS:000395810000024 PM 27220815 ER PT J AU Sethi, V Nair, G Absinta, M Sati, P Venkataraman, A Ohayon, J Wu, TX Yang, K Shea, C Dewey, BE Cortese, ICM Reich, DS AF Sethi, Varun Nair, Govind Absinta, Martina Sati, Pascal Venkataraman, Arun Ohayon, Joan Wu, Tianxia Yang, Kelly Shea, Colin Dewey, Blake E. Cortese, Irene C. M. Reich, Daniel S. TI Slowly eroding lesions in multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Article DE Slowly expanding lesion; multiple sclerosis; magnetic resonance imaging; proton density ID ABNORMAL WHITE-MATTER; INTRAVENOUS METHYLPREDNISOLONE; BRAIN ATROPHY; DISABILITY; LOAD; IMMUNOPATHOLOGY; PROGRESSION; EVOLUTION; RECOVERY; DETECT AB Background: At autopsy, 20%-40% of chronic multiple sclerosis (MS) lesions are labeled slowly expanding and feature myelin phagocytosis at the lesion edge. As pathological lesion classification relies on a single, terminal time point, the rate of lesion expansion cannot be directly measured. Objective: To study long-term volume changes in individual MS lesions. Methods: Volumes of individual lesions on proton density magnetic resonance imaging (MRI) acquired between 1992 and 2015 were measured in 22 individuals (one lesion per person). After correction for acquisition protocol, a mixed model evaluated lesion volume changes. Results: The mean (standard deviation) lesion volume at baseline was 142 (82)mL, falling to 74 (51)mL after 16 (3)years. All lesions shrank over time. Change in lesion volume did not correlate with change in supratentorial brain volume (p=0.33). In simulations, the results could be explained by a process of slow radial expansion superimposed on substantially more rapid resorption of damaged tissue. Conclusion: We noted sustained radiological contraction of MS lesions, a surprising result given that fresh myelin breakdown products within chronic active lesions are observed relatively frequently at autopsy. Therefore, the primary pathological process in chronic lesions, even those described as slowly expanding, is likely to be tissue loss. C1 [Sethi, Varun; Nair, Govind; Absinta, Martina; Sati, Pascal; Venkataraman, Arun; Ohayon, Joan; Wu, Tianxia; Yang, Kelly; Shea, Colin; Dewey, Blake E.; Cortese, Irene C. M.; Reich, Daniel S.] NINDS, NIH, 10 Ctr Dr MSC 1400,Bldg 10 Room 5C103, Bethesda, MD 20852 USA. RP Reich, DS (reprint author), NINDS, Translat Neuroradiol Sect, NIH, 10 Ctr Dr MSC 1400,Bldg 10 Room 5C103, Bethesda, MD 20852 USA. EM reichds@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke. NR 35 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD MAR PY 2017 VL 23 IS 3 BP 464 EP 472 DI 10.1177/1352458516655403 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EM8JL UT WOS:000395557300017 PM 27339071 ER PT J AU Lehky, TJ Groden, C Lear, B Toro, C Introne, WJ AF Lehky, Tanya J. Groden, Catherine Lear, Barbara Toro, Camilo Introne, Wendy J. TI Peripheral nervous system manifestations of Chediak-Higashi disease SO MUSCLE & NERVE LA English DT Article DE Chediak-Higashi disease; genetic disorders; neurodegeneration; peripheral nervous system; peripheral neuropathy ID LYST; NEUROPATHY; PHENOTYPE; DEGENERATION; GENOTYPE; DOMAIN AB IntroductionChediak-Higashi disease (CHD) is a rare autosomal recessive disorder with hematologic, infectious, pigmentary, and neurologic manifestations. Classic CHD (C-CHD) presents in early childhood with severe infectious or hematologic complications unless treated with bone marrow transplantation. Atypical CHD (A-CHD) has less severe hematologic and infectious manifestations. Both C-CHD and A-CHD develop neurological problems. MethodsEighteen patients with CHD (9 A-CHD and 9 C-CHD) underwent electrodiagnostic studies as part of a natural history study (NCT 00005917). Longitudinal studies were available for 10 patients. ResultsAll A-CHD patients had either sensory neuropathy, sensorimotor neuropathy, and/or diffuse neurogenic findings. In C-CHD, 3 adults had sensorimotor neuropathies with diffuse neurogenic findings, and 1 adult had a sensory neuropathy. The 5 children with C-CHD had normal electrodiagnostic findings. ConclusionsCHD can result in sensory or sensorimotor neuropathies and/or a diffuse motor neuronopathy. It may take 2-3 decades for the neuropathic findings to develop, because children appear to be spared. Muscle Nerve55: 359-365, 2017 C1 [Lehky, Tanya J.; Lear, Barbara] NINDS, EMG Sect, 10 Ctr Dr MSC 1404,Bldg 10 CRC Room 7SW-5680NIH, Bethesda, MD 20892 USA. [Groden, Catherine; Toro, Camilo; Introne, Wendy J.] NIH, Off Clin Director, Human Genome Res Inst, Bldg 10, Bethesda, MD 20892 USA. RP Lehky, TJ (reprint author), NINDS, EMG Sect, 10 Ctr Dr MSC 1404,Bldg 10 CRC Room 7SW-5680NIH, Bethesda, MD 20892 USA. EM lehkyt@ninds.nih.gov FU Intramural Research Programs of NINDS; NIHGRI FX Chediak This research was supported by the Intramural Research Programs of NINDS and NIHGRI. NR 22 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0148-639X EI 1097-4598 J9 MUSCLE NERVE JI Muscle Nerve PD MAR PY 2017 VL 55 IS 3 BP 359 EP 365 DI 10.1002/mus.25259 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EM9RE UT WOS:000395648000013 PM 27429304 ER PT J AU Stoeckel, LE Birch, LL Heatherton, T Mann, T Hunter, C Czajkowski, S Onken, L Berger, PK Savage, CR AF Stoeckel, Luke E. Birch, Leann L. Heatherton, Todd Mann, Traci Hunter, Christine Czajkowski, Susan Onken, Lisa Berger, Paige K. Savage, Cary R. TI Psychological and Neural Contributions to Appetite Self-Regulation SO OBESITY LA English DT Article ID RESTING METABOLIC-RATE; Y GASTRIC BYPASS; LAPAROSCOPIC SLEEVE GASTRECTOMY; CHILDRENS FOOD PREFERENCES; DAILY ENERGY-INTAKE; OBESITY-PRONE RATS; FAT-FREE MASS; WEIGHT-LOSS; BODY-COMPOSITION; BARIATRIC SURGERY AB Objective: This paper reviews the state of the science on psychological and neural contributions to appetite self-regulation in the context of obesity. Methods: Three content areas (neural systems and cognitive functions; parenting and early childhood development; and goal setting and goal striving) served to illustrate different perspectives on the psychological and neural factors that contribute to appetite dysregulation in the context of obesity. Talks were initially delivered at an NIH workshop consisting of experts in these three content areas, and then content areas were further developed through a review of the literature. Results: Self-regulation of appetite involves a complex interaction between multiple domains, including cognitive, neural, social, and goal-directed behaviors and decision-making. Self-regulation failures can arise from any of these factors, and the resulting implications for obesity should be considered in light of each domain. In some cases, self-regulation is amenable to intervention; however, this does not appear to be universally true, which has implications for both prevention and intervention efforts. Conclusions: Appetite regulation is a complex, multifactorial construct. When considering its role in the obesity epidemic, it is advisable to consider its various dimensions together to best inform prevention and treatment efforts. C1 [Stoeckel, Luke E.; Hunter, Christine] Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD USA. [Birch, Leann L.; Berger, Paige K.] Univ Georgia, Dept Foods & Nutr, Athens, GA USA. [Heatherton, Todd] Dept Psychol & Brain Sci, Dartmouth Coll, Hanover, NH USA. [Mann, Traci] Univ Minnesota, Dept Psychol, Minneapolis, MN USA. [Czajkowski, Susan] Natl Canc Inst, Bethesda, MD USA. [Onken, Lisa] Natl Inst Aging, Bethesda, MD USA. [Savage, Cary R.] Banner Alzheimers Inst, Phoenix, AZ USA. RP Stoeckel, LE (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD USA.; Savage, CR (reprint author), Banner Alzheimers Inst, Phoenix, AZ USA. EM luke.stoeckel@nih.gov; cary.savage@bannerhealth.com FU NIH [R01DK080090, R01DK085605, R01DK088244, R01DA022582, R01HL114092, R01AA021347, R01HL088887]; NASA [NNX12AE56G]; USDA [276-59-5000-0-0069] FX NIH R01DK080090, R01DK085605 (CS); R01DK088244 (LB); R01DA022582, R01HL114092, R01AA021347, (TH); R01HL088887, NASA Grant NNX12AE56G (TM), USDA Grant 276-59-5000-0-0069 (TM). NR 97 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD MAR PY 2017 VL 25 SU 1 SI SI BP S17 EP S25 DI 10.1002/oby.21789 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA EL9YC UT WOS:000394975000003 PM 28229541 ER PT J AU Young-Hyman, D AF Young-Hyman, Deborah TI Introduction to Special Issue: Self-Regulation of Appetite-It's Complicated SO OBESITY LA English DT Editorial Material ID WEIGHT-LOSS MAINTENANCE; CHILDHOOD OBESITY; TRIAL AB Objective: A meeting of multidisciplinary biobehavioral scientists and National Institutes of Health (NIH) program staff was convened by the Office of Behavioral and Social Sciences Research, Division of Program Coordination, Planning, and Strategic Initiatives, Office of the Director, NIH to examine mechanisms associated with humans' ability to self-regulate appetite and appetitive behavior. Methods: Based upon prior discussions of the NIH Obesity Research Task Force Behavioral Phenotyping Work Group, the premise was adopted that, in modern society, multiple factors on multiple levels interact to create circumstances wherein self-control of appetite is difficult, leading to overconsumption of unhealthy foods versus healthy eating patterns, contributing to our current levels of obesity. Through presentations and group discussions, the panel examined how foundational processes/ mechanisms directly and indirectly affect appetitive behavior and how these processes can be manipulated to affect food intake and thereby weight. The meeting identified evidence-based mechanisms with the potential to impact self-regulation of appetite and appetitive states (hunger, satiety, food wanting, restraint, reward) and associated behaviors such as overconsumption, eating in the absence of hunger, food seeking, and decision-making that could inform novel weight intervention strategies in free-living, nonlaboratory settings. Conclusion: The three summary papers contained in this issue represent the synthesis of the material presented at the meeting and the panel's recommendations on how existing evidence regarding mechanisms and pathways to appetitive behavior can be used to inform future research and novel prevention and intervention strategies to impact prevalence of obesity. C1 [Young-Hyman, Deborah] Natl Inst Hlth, Div Program Coordinat Planning & Strateg Initiat, Off Behav & Social Sci Res, Bethesda, MD USA. RP Young-Hyman, D (reprint author), Natl Inst Hlth, Div Program Coordinat Planning & Strateg Initiat, Off Behav & Social Sci Res, Bethesda, MD USA. EM deborah.young-hyman@od.nih.gov FU Office of Behavioral and Social Sciences Research, Division of Program Coordination, Planning, and Strategic Initiatives, Office of the Director, NIH; Office of Disease Prevention, Division of Program Coordination, Planning, and Strategic Initiatives, Office of the Director, NIH FX This meeting was supported by the Office of Behavioral and Social Sciences Research and Office of Disease Prevention, Division of Program Coordination, Planning, and Strategic Initiatives, Office of the Director, NIH. The following individuals participated in the NIH planning committee: Tanya Agurs-Collins, National Cancer Institute; Rachel Ballard, Office of Disease Prevention; Susan Czajkowski, National Cancer Institute (formerly at National Heart, Lung, and Blood Institute); Joseph Frascella, National Institute on Drug Abuse; Christine Hunter, National Institute of Diabetes and Digestive and Kidney Diseases; Leah Lipsky, National Institute of Child Health and Human Development; Padma Maruvada, National Institute of Diabetes and Digestive and Kidney Diseases; Lisa Onken, National Institute on Drug Abuse; William T. Riley, Office of Behavioral and Social Sciences Research; Luke Stoeckel, National Institute of Diabetes and Digestive and Kidney Diseases; and Deborah YoungHyman, Office of Behavioral and Social Sciences Research. The meeting was cochaired by Todd Heatherton and Rachel Batterham. The content of this article reflects the consensus of the scientific panel and planning group members. NR 13 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD MAR PY 2017 VL 25 SU 1 SI SI BP S5 EP S7 DI 10.1002/oby.21781 PG 3 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA EL9YC UT WOS:000394975000001 PM 28229540 ER PT J AU Rowe, LS Krauze, AV Ning, H Camphausen, KA Kaushal, A AF Rowe, Lindsay S. Krauze, Andra V. Ning, Holly Camphausen, Kevin A. Kaushal, Aradhana TI Optimizing the Benefit of CNS Radiation Therapy in the Pediatric Population PART 1: Understanding and Managing Acute and Late Toxicities SO ONCOLOGY-NEW YORK LA English DT Article ID CHILDHOOD-CANCER-SURVIVOR; CENTRAL-NERVOUS-SYSTEM; LONG-TERM SURVIVORS; AVERAGE-RISK MEDULLOBLASTOMA; DOSE NEURAXIS IRRADIATION; LOW-STAGE MEDULLOBLASTOMA; PHASE-II TRIAL; ADULT SURVIVORS; BRAIN-TUMORS; ONCOLOGY-GROUP AB Radiation therapy continues to be a key component in the management of pediatric malignancies. Increasing the likelihood of cure while minimizing late treatment toxicity in these young patients remains the primary goal. Within the realm of central nervous system neoplasms, efforts to further improve the efficacy of radiation therapy continue, while balancing risks of damage to uninvolved tissue. Radiation therapy can result in second malignancies, as well as cerebrovascular, neurotoxic, neurocognitive, endocrine, psychosocial, and quality-of-life effects. In this article we describe these acute and late effects and their implications, and we highlight strategies that have emerged to reduce both the volume of tissue that is irradiated and the radiation dose delivered. The feasibility, efficacy, and risks of these newer approaches to radiation therapy continue to be evaluated and monitored; robust outcome data are needed. C1 [Rowe, Lindsay S.; Krauze, Andra V.; Ning, Holly; Camphausen, Kevin A.; Kaushal, Aradhana] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Rowe, LS (reprint author), NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. FU intramural research program at the National Institutes of Health, National Cancer Institute, Radiation Oncology Branch [ZID BC 010990] FX This research was supported in part by the intramural research program at the National Institutes of Health, National Cancer Institute, Radiation Oncology Branch, funded by grant ZID BC 010990. NR 47 TC 0 Z9 0 U1 0 U2 0 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD MAR PY 2017 VL 31 IS 3 BP 182 EP 188 PG 7 WC Oncology SC Oncology GA EN8BU UT WOS:000396226700004 ER PT J AU Rowe, LS Krauze, AV Ning, H Camphausen, KA Kaushal, A AF Rowe, Lindsay S. Krauze, Andra V. Ning, Holly Camphausen, Kevin A. Kaushal, Aradhana TI Optimizing the Benefit of CNS Radiation Therapy in the Pediatric Population PART 2: Novel Methods of Radiation Delivery SO ONCOLOGY-NEW YORK LA English DT Article ID CHILDHOOD-CANCER SURVIVOR; NERVOUS-SYSTEM TUMORS; LONG-TERM SURVIVORS; PROTON RADIOTHERAPY; BRAIN-TUMORS; OUTCOMES; CHILDREN AB Newer approaches in the field of radiation therapy have raised the bar in the treatment of central nervous system (CNS) malignancies, with recognized advances that have aimed to increase the therapeutic index by improving conformality of the radiation dose to the planned target volume. Beyond these advances, the continued evolution of more effective systems for delivery of radiation to the CNS may offer further benefit not only to adults but also to pediatric patients, a cohort of the population that may be more sensitive to the long-term effects of radiation. This article describes several novel irradiation techniques under investigation that hold promise in the pediatric population. These include newer approaches to intensity-modulated radiation therapy; stereotactic radiosurgery and radiation therapy; particle therapy, most notably proton therapy, which may be of particular benefit in enabling young patients to avoid radiation-related adverse effects; and radioimmunotherapy strategies that spare healthy tissue from radiotoxicity by delivering therapy directly to tumor tissue. Although emerging strategies for the delivery of radiation therapy hold promise for improved outcomes in pediatric patients, there must be rigorous long-term evaluation of consequences associated with the various techniques employed, to weigh risks, benefits, and impact on quality of life. C1 [Rowe, Lindsay S.; Krauze, Andra V.; Ning, Holly; Camphausen, Kevin A.; Kaushal, Aradhana] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Rowe, LS (reprint author), NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. FU intramural research program at the National Institutes of Health, National Cancer Institute, Radiation Oncology Branch [ZID BC 010990] FX This research was supported in part by the intramural research program at the National Institutes of Health, National Cancer Institute, Radiation Oncology Branch, funded by grant ZID BC 010990. NR 22 TC 0 Z9 0 U1 0 U2 0 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD MAR PY 2017 VL 31 IS 3 BP 224 EP 228 PG 4 WC Oncology SC Oncology GA EN8BU UT WOS:000396226700009 ER PT J AU Lee, L Ito, T Nakamura, T Jensen, RT Igarashi, H Takayanagi, R AF Lee, Lingaku Ito, Tetsuhide Nakamura, Taichi Jensen, Robert T. Igarashi, Hisato Takayanagi, Ryoichi TI Antifibrotic Effect of Saturated Fatty Acids via Endoplasmic Reticulum Stress Response in Rat Pancreatic Stellate Cells SO PANCREAS LA English DT Article DE chronic pancreatitis; pancreatic stellate cells; endoplasmic reticulum stress; protein kinase-like ER kinase pathway; saturated fatty acids ID FACTOR-KAPPA-B; COLLAGEN-SPECIFIC CHAPERONE; UNFOLDED PROTEIN RESPONSE; A-COUPLED LIPOSOMES; MEDIATED APOPTOSIS; LIPID-PEROXIDATION; INDUCED-FIBROSIS; LIVER-CELLS; DEATH; DIET AB Objectives: We investigated the effect of saturated fatty acids on chronic pancreatitis pathogenesis by elucidating the endoplasmic reticulum (ER) stress response in pancreatic stellate cells (PSCs), which are major effector cells in pancreatic fibrosis. Methods: Wistar Bonn/Kobori rats were fed either control diet or high-fat diet (HFD) for 4 weeks. Meanwhile, cultured rat PSCs were stimulated with thapsigargin, an ER stress inducer, or palmitic acid (PA). Pancreatic fibrosis, expressions of fibrosis-related and ER stress-related proteins and mRNA, cell viability, and apoptosis were examined. Results: The HFD reduced fibrosis and a-smooth muscle actin expression (ie, activated PSCs) but upregulated ER stress-related mRNA expression in the pancreas of young HFD-fed Wistar Bonn/Kobori rats. Induction of ER stress response in PSCs with thapsigargin or PA induced apoptosis, activated the protein kinase-like ER kinase (PERK) pathway, inhibited cell viability, and downregulated fibrosis-related protein and mRNA expression. The PERK inhibitor negated PA-induced ER stress response. Conclusions: Saturated fatty acids can inhibit but may not promote the fibrogenesis of chronic pancreatitis, at least in the early stage, via an ER stress response (ie, the PERK pathway) in PSCs. Moreover, induction of an apoptotic ER stress response in PSCs might be a novel therapeutic strategy for pancreatic fibrosis. C1 [Lee, Lingaku; Ito, Tetsuhide; Nakamura, Taichi; Igarashi, Hisato; Takayanagi, Ryoichi] Kyushu Univ, Grad Sch Med Sci, Dept Med & Bioregulatory Sci, Fukuoka, Japan. [Nakamura, Taichi; Jensen, Robert T.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Ito, T (reprint author), Kyushu Univ, Grad Sch Med Sci, Dept Med & Bioregulatory Sci, Higashi Ku, 3-1-1 Maidashi, Fukuoka 8128582, Japan. EM itopapa@intmed3.med.kyushu-u.ac.jp FU JSPS KAKENHI [26461035] FX This study was supported by JSPS KAKENHI (grant number: 26461035). NR 54 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 2017 VL 46 IS 3 BP 385 EP 394 DI 10.1097/MPA.0000000000000757 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EL2KM UT WOS:000394448600022 PM 28099257 ER PT J AU Burns, KM Bienemann, L Camperlengo, L Cottengim, C Covington, TM Dykstra, H Faulkner, M Kobau, R Lambert, ABE MacLeod, H Parks, SE Rosenberg, E Russell, MW Shapiro-Mendoza, CK Shaw, E Tian, N Whittemore, V Kaltman, JR AF Burns, Kristin M. Bienemann, Lauren Camperlengo, Lena Cottengim, Carri Covington, Theresa M. Dykstra, Heather Faulkner, Meghan Kobau, Rosemarie Lambert, Alexa B. Erck MacLeod, Heather Parks, Sharyn E. Rosenberg, Ellen Russell, Mark W. Shapiro-Mendoza, Carrie K. Shaw, Esther Tian, Niu Whittemore, Vicky Kaltman, Jonathan R. TI The Sudden Death in the Young Case Registry: Collaborating to Understand and Reduce Mortality SO PEDIATRICS LA English DT Article ID CARDIAC DEATH; UNEXPECTED DEATH; ADOLESCENTS; CHILDREN; HEART; AGE AB Knowledge gaps persist about the incidence of and risk factors for sudden death in the young (SDY). The SDY Case Registry is a collaborative effort between the National Institutes of Health, the Centers for Disease Control and Prevention, and the Michigan Public Health Institute. Its goals are to: (1) describe the incidence of SDY in the United States by using populationbased surveillance; (2) compile data from SDY cases to create a resource of information and DNA samples for research; (3) encourage standardized approaches to investigation, autopsy, and categorization of SDY cases; (4) develop partnerships between local, state, and federal stakeholders toward a common goal of understanding and preventing SDY; and (5) support families who have lost loved ones to SDY by providing resources on bereavement and medical evaluation of surviving family members. Built on existing Child Death Review programs and as an expansion of the Sudden Unexpected Infant Death Case Registry, the SDY Case Registry achieves its goals by identifying SDY cases, providing guidance to medical examiners/coroners in conducting comprehensive autopsies, evaluating cases through child death review and an advanced review by clinical specialists, and classifying cases according to a standardized algorithm. The SDY Case Registry also includes a process to obtain informed consent from next-of-kin to save DNA for research, banking, and, in some cases, diagnostic genetic testing. The SDY Case Registry will provide valuable incidence data and will enhance understanding of the characteristics of SDY cases to inform the development of targeted prevention efforts. C1 [Burns, Kristin M.; Rosenberg, Ellen; Kaltman, Jonathan R.] NHLBI, Div Cardiovasc Sci, Bethesda, MD USA. [Bienemann, Lauren; Russell, Mark W.] Univ Michigan, Sch Med, Div Pediat Cardiol, Ann Arbor, MI USA. [Camperlengo, Lena; Cottengim, Carri; Kobau, Rosemarie; Parks, Sharyn E.; Shapiro-Mendoza, Carrie K.; Tian, Niu] Ctr Dis Control & Prevent, Atlanta, GA USA. [Covington, Theresa M.; Dykstra, Heather; Faulkner, Meghan; MacLeod, Heather; Shaw, Esther] Michigan Publ Hlth Inst, Natl Ctr Fatal Review & Prevent, Okemos, MI USA. [Lambert, Alexa B. Erck] DB Consulting Grp Inc, Silver Spring, MD USA. [Whittemore, Vicky] Natl Inst Neurol Disorders & Stroke, Natl Inst Hlth, Bethesda, MD USA. RP Burns, KM (reprint author), NHLBI, Div Cardiovasc Sci, Natl Inst Hlth, 6701 Rockledge Dr,Room 8220, Bethesda, MD 20892 USA. EM kristin.burns@nih.gov FU National Institutes of Health (National Heart, Lung, and Blood Institute and the National Institute of Neurologic Disorders and Stroke); Centers for Disease Control and Prevention; National Institutes of Health (NIH) FX The Sudden Death in the Young Case Registry is supported by funds from the National Institutes of Health (National Heart, Lung, and Blood Institute and the National Institute of Neurologic Disorders and Stroke) as well as the Centers for Disease Control and Prevention. Funded by the National Institutes of Health (NIH). NR 25 TC 0 Z9 0 U1 0 U2 0 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 2017 VL 139 IS 3 AR e20162757 DI 10.1542/peds.2016-2757 PG 9 WC Pediatrics SC Pediatrics GA EM0IY UT WOS:000395003200036 ER PT J AU Raju, TNK AF Raju, Tonse N. K. TI The "Late Preterm" Birth-Ten Years Later SO PEDIATRICS LA English DT Article ID TERM INFANTS C1 [Raju, Tonse N. K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Raju, TNK (reprint author), 6710-B Rockledge Blvd,Room 2330,Mail Stop 7002, Bethesda, MD 20892 USA. EM rajut@mail.nih.gov NR 17 TC 0 Z9 0 U1 0 U2 0 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 2017 VL 139 IS 3 AR e20163331 DI 10.1542/peds.2016-3331 PG 4 WC Pediatrics SC Pediatrics GA EM0IY UT WOS:000395003200051 ER PT J AU Aziz, N Rahman, A AF Aziz, Noreen Rahman, A. TI Physician preferences and strategies regarding different models of cancer survivorship care: a comparison of primary care providers and oncologists SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 [Aziz, Noreen] NIH, Intramural Program, Bethesda, MA USA. [Rahman, A.] Univ Maryland, College Pk, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD MAR PY 2017 VL 26 SU 2 BP 8 EP 9 PG 2 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA EN0JW UT WOS:000395697100015 ER PT J AU Aziz, N Rahman, A AF Aziz, Noreen Rahman, A. TI Lifestyle health behaviour interventions among long-term cancer survivors SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 [Aziz, Noreen] NIH, Intramural Program, Bldg 10, Bethesda, MD 20892 USA. [Rahman, A.] Univ Maryland, College Pk, MD 20742 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD MAR PY 2017 VL 26 SU 2 BP 26 EP 27 PG 2 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA EN0JW UT WOS:000395697100057 ER PT J AU Aziz, N AF Aziz, Noreen TI Follow-up care experiences, medical profiles and perceived quality of care among long-term survivors of breast, prostate, colorectal and gynecologic cancers SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 [Aziz, Noreen] NIH, Intramural Program, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD MAR PY 2017 VL 26 SU 2 BP 27 EP 27 PG 1 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA EN0JW UT WOS:000395697100058 ER PT J AU Plank, MW Kaiko, GE Maltby, S Weaver, J Tay, H Shen, W Wilson, M Durum, S Foster, PS AF Plank, M. W. Kaiko, G. E. Maltby, S. Weaver, J. Tay, H. Shen, W. Wilson, M. Durum, S. Foster, P. S. TI TH22 CELLS FORM A DISTINCT TH LINEAGE FROM TH17 CELLS IN VITRO WITH UNIQUE TRANSCRIPTIONAL PROPERTIES AND TBET-DEPENDENT TH1 PLASTICITY DURING INFLUENZA INFECTION IN VIVO SO RESPIROLOGY LA English DT Meeting Abstract C1 [Plank, M. W.; Kaiko, G. E.; Maltby, S.; Weaver, J.; Tay, H.; Foster, P. S.] Hunter Med Res Inst, Newcastle, NSW, Australia. [Shen, W.; Durum, S.] NCI, NIH, Frederick, MD 21701 USA. [Wilson, M.] Francis Crick Inst, London, England. FU National Health and Medical Research Council of Australia [APP1061413]; Australian Respiratory Council Harry Windsor Research Grant; European Respiratory Society Fellowship (STRTF) FX This work was supported by National Health and Medical Research Council of Australia Project Grant APP1061413 and an Australian Respiratory Council Harry Windsor Research Grant. MP is the recipient of a European Respiratory Society Fellowship (STRTF 2015). NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1323-7799 EI 1440-1843 J9 RESPIROLOGY JI Respirology PD MAR PY 2017 VL 22 SU 2 SI SI MA TPL-008 BP 127 EP 127 PG 1 WC Respiratory System SC Respiratory System GA EO6GU UT WOS:000396791000232 ER PT J AU Hong, KM Kim, HK Park, SY Poojan, S Kim, MK Sung, J Tsao, BP Grossman, JM Rullo, OJ Woo, JMP McCurdy, DK Rider, LG Miller, FW Song, YW AF Hong, Kyeong-Man Kim, Hyun-Kyoung Park, Seong-Yeol Poojan, Shiv Kim, Mi-Kyung Sung, Joohon Tsao, Betty P. Grossman, Jennifer M. Rullo, Ornella J. Woo, Jennifer M. P. McCurdy, Deborah K. Rider, Lisa G. Miller, Frederick W. Song, Yeong-Wook TI CD3Z hypermethylation is associated with severe clinical manifestations in systemic lupus erythematosus and reduces CD3 zeta-chain expression in T cells SO RHEUMATOLOGY LA English DT Article DE CD3Z hypermethylation; systemic lupus erythematosus; environmental factor ID RECEPTOR ZETA-CHAIN; SPLICED 3'-UNTRANSLATED REGION; MONOZYGOTIC TWINS DISCORDANT; TCR-ZETA; DNA METHYLATION; DOWN-REGULATION; TCR/CD3 COMPLEX; MESSENGER-RNA; DISEASE; DEMETHYLATION AB Objective. The importance of hypomethylation in SLE is well recognized; however, the significance of hypermethylation has not been well characterized. We screened hypermethylated marks in SLE and investigated their possible implications. Methods. DNA methylation marks were screened in SLE whole-blood DNA by microarray, and two marks (CD3Z and VHL hypermethylations) were confirmed by a methylation single-base extension method in two independent ethnic cohorts consisting of 207 SLE patients and 151 controls. The correlation with clinical manifestations and the genetic influence on those epigenetic marks were analysed. Results. Two epigenetic marks, CD3Z and VHL hypermethylation, were significantly correlated with SLE: CD3Z hypermethylation (odds ratio = 7.76; P = 1.71 x 10(-13)) and VHL hypermethylation (odds ratio = 3.77; P = 3.20 x 10(-8)), and the increased CD3Z methylation was correlated with downregulation of the CD3zchain in SLE T cells. In addition, less genetic influence on CD3Z methylation relative to VHL methylation was found in analyses of longitudinal and twin samples. Furthermore, a higher CD3Z methylation level was significantly correlated with a higher SLE disease activity index and more severe clinical manifestations, such as proteinuria, haemolytic anaemia and thrombocytopenia, whereas VHL hypermethylation was not. Conclusion. CD3Z hypermethylation is an SLE risk factor that can be modified by environmental factors and is associated with more severe SLE clinical manifestations, which are related to deranged T cell function by downregulating the CD3z-chain. C1 [Hong, Kyeong-Man; Kim, Hyun-Kyoung; Park, Seong-Yeol; Poojan, Shiv; Kim, Mi-Kyung] Natl Canc Ctr, Res Inst, Goyang, South Korea. [Sung, Joohon] Seoul Natl Univ, Sch Publ Hlth, Dept Epidemiol, Seoul, South Korea. [Tsao, Betty P.; Grossman, Jennifer M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med Rheumatol, Los Angeles, CA 90095 USA. [Rullo, Ornella J.; Woo, Jennifer M. P.; McCurdy, Deborah K.] Univ Calif Los Angeles, David Geffen Sch Med, Div Pediat Rheumatol, Los Angeles, CA 90095 USA. [Rider, Lisa G.; Miller, Frederick W.] NIEHS, Dept Hlth & Human Serv, Environm Autoimmun Grp, NIH, Bethesda, MD USA. [Song, Yeong-Wook] Seoul Natl Univ, Coll Med, Med Res Ctr, Dept Internal Med, Seoul, South Korea. [Song, Yeong-Wook] Seoul Natl Univ, Coll Med, Med Res Ctr, Dept Mol Med & Biopharmaceut Sci, Seoul, South Korea. RP Song, YW (reprint author), Seoul Natl Univ, Dept Internal Med, Coll Med, Daehak Ro 101, Seoul 110744, South Korea. EM ysong@snu.ac.kr FU Korea Health Technology R&D project through the Korea Health Industry Development Institute; Ministry of Health & Welfare, Republic of Korea [HI13C1754] FX This study is supported by the Korea Health Technology R&D project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (grant no: HI13C1754). NR 36 TC 0 Z9 0 U1 0 U2 0 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 2017 VL 56 IS 3 BP 467 EP 476 DI 10.1093/rheumatology/kew405 PG 10 WC Rheumatology SC Rheumatology GA EP0BQ UT WOS:000397052200019 ER PT J AU Agarwal, SM Bose, A Nawani, H Shivakumar, V Chhabra, H Kalmady, S Bhalerao, G Amaresha, AC Narayanaswamy, J Venkatasubramanian, G AF Agarwal, Sri Mahavir Bose, Anushree Nawani, Hema Shivakumar, Venkataram Chhabra, Harleen Kalmady, Sunil Bhalerao, Gaurav Amaresha, Anekal C. Narayanaswamy, Janardhanan Venkatasubramanian, Ganesan TI ASSOCIATION BETWEEN GLUTAMATE plus GLUTAMINE IN THE LEFT TEMPOROPARIETAL JUNCTION AND MISMATCH NEGATIVITY (MMN) IN ANTIPSYCHOTIC-NAIVE/FREE SCHIZOPHRENIA PATIENTS WITH AUDITORY HALLUCINATIONS SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Agarwal, Sri Mahavir] Natl Inst Mental Hlth, Bethesda, MD USA. [Bose, Anushree; Nawani, Hema; Shivakumar, Venkataram; Chhabra, Harleen; Kalmady, Sunil; Bhalerao, Gaurav; Amaresha, Anekal C.; Narayanaswamy, Janardhanan; Venkatasubramanian, Ganesan] Natl Inst Mental Hlth & Neurosci, Bangalore, Karnataka, India. FU Wellcome-DBT India Alliance [500236/Z/11/Z]; ICMR [DHR/HRD/Young Scientist/Type-VI(2)/2015]; DBT, Govt of India [DBT/2015/NIMHANS/345]; DST [SB/YS/LS-37/2014]; DST-SJF Grant [DST/SJF/LSA-02/2014-15]; DBT-CEIB Grant [BT/PR5322/COE/34/8/2012] FX SMA, AB, ACA, and SVK are supported by the Wellcome-DBT India Alliance (500236/Z/11/Z). VS is supported by ICMR (DHR/HRD/Young Scientist/Type-VI(2)/2015). HC is supported by DBT, Govt of India (DBT/2015/NIMHANS/345). This research work is supported by DST Grant (SB/YS/LS-37/2014) to SMA, and DST-SJF Grant (DST/SJF/LSA-02/2014-15) and DBT-CEIB Grant (BT/PR5322/COE/34/8/2012) to GV. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 164 BP S83 EP S84 PG 2 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200225 ER PT J AU Apud, J Tong, YX Rasetti, R Vargas, T Callicott, J Dickinson, D Kolachana, B Weinberger, D Mattay, V Berman, K AF Apud, Jose Tong, Yunxia Rasetti, Roberta Vargas, Teresa Callicott, Joseph Dickinson, Dwight Kolachana, Bhaskar Weinberger, Daniel Mattay, Venkata Berman, Karen TI CORTICAL INFORMATION PROCESSING IN PATIENTS WITH SCHIZOPHRENIA IS MODULATED BY TOLCAPONE: ROLE OF COMT VAL158MET GENOTYPE SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Apud, Jose; Tong, Yunxia; Rasetti, Roberta; Vargas, Teresa; Callicott, Joseph; Dickinson, Dwight; Berman, Karen] NIH, Clin & Translat Neurosci Branch, Bldg 10, Bethesda, MD 20892 USA. [Kolachana, Bhaskar] NIMH, HBCC, NIH, Bethesda, MD 20892 USA. [Weinberger, Daniel; Mattay, Venkata] Johns Hopkins Univ, Sch Med, Lieber Inst Brain Dev, Baltimore, MD 21218 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 25 BP S17 EP S17 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200046 ER PT J AU Azrin, S AF Azrin, Susan TI PRACTICAL STRATEGIES TO REDUCE THE DURATION OF UNTREATED PSYCHOSIS IN THE UNITED STATES: EARLY FINDINGS SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Azrin, Susan] NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 178 BP S94 EP S94 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200255 ER PT J AU Buonanno, A Skirzewski, M Yan, LQ Shamir, A Karavanova, I Vullhorst, D AF Buonanno, Andres Skirzewski, Miguel Yan, Leqin Shamir, Alon Karavanova, Irina Vullhorst, Detlef TI MUTATIONS IN THE NEUREGULIN-ERBB4 PATHWAY ALTER DOPAMINERGIC BALANCE AND REGULATE BEHAVIORS RELEVANT TO SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Buonanno, Andres; Skirzewski, Miguel; Yan, Leqin; Shamir, Alon; Karavanova, Irina; Vullhorst, Detlef] NIH, Bldg 10, Bethesda, MD 20892 USA. FU Eunice Kennedy Shriver NICHD IRP FX We thank the Eunice Kennedy Shriver NICHD IRP for their generous support. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 177.2 BP S92 EP S93 PG 2 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200252 ER PT J AU Dickinson, D Zaidman, S Giangrande, E Weinberger, D Berman, K AF Dickinson, Dwight Zaidman, Sofia Giangrande, Evan Weinberger, Daniel Berman, Karen TI POLYGENIC RISK PROFILE SCORES PREDICT COGNITIVE PERFORMANCE IN MANY SCHIZOPHRENIA CASES BUT FOR INDIVIDUALS WITH A LARGE PREMORBID/CURRENT IQ DIFFERENCE, THEY DON'T SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Dickinson, Dwight] NIMH, Bethesda, MD 20892 USA. [Zaidman, Sofia; Giangrande, Evan] NIMH, NIH, Bethesda, MD 20892 USA. [Weinberger, Daniel] Lieber Inst Brain Dev, Baltimore, MD USA. [Berman, Karen] NIH, Clin & Translat Neurosci Branch, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 131 BP S71 EP S71 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200192 ER PT J AU Gordon, J AF Gordon, Joshua TI FROM GENES TO BEHAVIOR: CAPITALIZING ON GENE DISCOVERY IN SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Gordon, Joshua] NIMH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 1 BP S1 EP S1 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200002 ER PT J AU Michalopoulou, P Wigton, R Averbeck, B Shergill, S AF Michalopoulou, Panayiota Wigton, Rebekah Averbeck, Bruno Shergill, Sukhwinder TI THE NEURAL EFFECTS OF OXYTOCIN ON SOCIAL DECISION-MAKING IN SCHIZOPHRENIA: AN FMRI STUDY SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Michalopoulou, Panayiota; Wigton, Rebekah; Shergill, Sukhwinder] Kings Coll London, London, England. [Averbeck, Bruno] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA M67 BP S234 EP S234 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200630 ER PT J AU Owrutsky, Z Ahmed, A Berman, K Dickinson, D AF Owrutsky, Zoe Ahmed, Alya Berman, Karen Dickinson, Dwight TI ASSOCIATIONS OF SUBCLINICAL PSYCHOSIS SPECTRUM CHARACTERISTICS, CHILDHOOD DEPRESSIVE SYMPTOMS, AND SCHIZOPHRENIA POLYGENIC RISK SCORE: ANALYSES FROM THE PHILADELPHIA NEURODEVELOPMENTAL COHORT SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Owrutsky, Zoe; Ahmed, Alya; Berman, Karen; Dickinson, Dwight] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA SA.9 BP S116 EP S116 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200313 ER PT J AU Paksarian, D Trabjerg, BB Merikangas, KR Agerbo, E AF Paksarian, Diana Trabjerg, Betina B. Merikangas, Kathleen R. Agerbo, Esben TI THE ROLE OF GENETIC LIABILITY IN THE ASSOCIATION BETWEEN URBANICITY AND SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Paksarian, Diana; Merikangas, Kathleen R.] NIMH, Bethesda, MD 20892 USA. [Trabjerg, Betina B.; Agerbo, Esben] Aarhus Univ, Aarhus, Denmark. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 35 BP S20 EP S21 PG 2 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200056 ER PT J AU Ursini, G Punzi, G Chen, Q Marenco, S Jaffe, A Straub, R Berman, K Hashimoto, R Colantuoni, C Blasi, G Annamaria, P Giancarlo, M Joshua, R Emily, H Allessandro, B Weinberger, D AF Ursini, Gianluca Punzi, Giovanna Chen, Qiang Marenco, Stefano Jaffe, Andrew Straub, Richard Berman, Karen Hashimoto, Ryota Colantuoni, Carlo Blasi, Giuseppi Annamaria, Porcelli Giancarlo, Maddalena Joshua, Robinson Emily, Hamilton Allessandro, Bertolino Weinberger, Daniel TI PLACENTAL GENE EXPRESSION MEDIATES THE INTERACTION BETWEEN OBSTETRICAL HISTORY AND GENETIC RISK FOR SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Ursini, Gianluca; Punzi, Giovanna; Chen, Qiang; Jaffe, Andrew; Straub, Richard; Colantuoni, Carlo] Lieber Inst Brain Dev, Baltimore, MD USA. [Marenco, Stefano; Berman, Karen] NIMH, Bethesda, MD USA. [Hashimoto, Ryota] Osaka Univ, Osaka, Japan. [Blasi, Giuseppi; Annamaria, Porcelli; Giancarlo, Maddalena; Allessandro, Bertolino] Univ Bari, Bari, Italy. [Joshua, Robinson; Emily, Hamilton] UCSF, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 115.1 BP S60 EP S60 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200161 ER PT J AU Wehring, H Kitchen, C Heishman, S McMahon, R Rowland, L Liu, F Feldman, S Kearns, AM Kelly, D AF Wehring, Heidi Kitchen, Christopher Heishman, Stephen McMahon, Robert Rowland, Laura Liu, Fang Feldman, Stephanie Kearns, Ann Marie Kelly, Deanna TI TOBACCO CRAVING AND TRIGGERS IN SMOKERS WITH SCHIZOPHRENIA SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Wehring, Heidi] Univ Maryland, College Pk, MD 20742 USA. [Kitchen, Christopher; McMahon, Robert; Rowland, Laura; Liu, Fang; Feldman, Stephanie; Kearns, Ann Marie; Kelly, Deanna] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, College Pk, MD 20742 USA. [Heishman, Stephen] NIDA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA SA48 BP S130 EP S130 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200352 ER PT J AU Zaidman, S Giangrande, E Weinberger, D Berman, K Dickinson, D AF Zaidman, Sofia Giangrande, Evan Weinberger, Daniel Berman, Karen Dickinson, Dwight TI EXPLORING POLYGENIC RISK IN COGNITIVE SUBGROUPS OF SCHIZOPHRENIA: ASSOCIATIONS BETWEEN RISK PROFILE SCORES AND MEASURES OF COGNITION SO SCHIZOPHRENIA BULLETIN LA English DT Meeting Abstract CT 16th International Congress on Schizophrenia Research (ICOSR) CY MAR 24-28, 2017 CL San Diego, CA SP Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Oxford Univ Press C1 [Zaidman, Sofia] NIH, Bldg 10, Bethesda, MD 20892 USA. [Giangrande, Evan] NIMH, NIH, Bethesda, MD 20892 USA. [Weinberger, Daniel] Lieber Inst Brain Dev, Baltimore, MD USA. [Berman, Karen] NIMH, Bethesda, MD 20892 USA. [Dickinson, Dwight] NIH, Clin & Translat Neurosci Branch, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2017 VL 43 SU 1 MA 69 BP S41 EP S41 PG 1 WC Psychiatry SC Psychiatry GA EP1DS UT WOS:000397126200110 ER PT J AU Fu, LZ Shi, YB AF Fu, Liezhen Shi, Yun-Bo TI The Sox transcriptional factors: Functions during intestinal development in vertebrates SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Review DE Sox genes; Thyroid hormone; Metamorphosis; Xenopus; Thyroid hormone receptor; Stem cells; Intestine; Postembryonic development ID THYROID-HORMONE RECEPTOR; STEM-CELL DEVELOPMENT; COLORECTAL-CANCER CELLS; AUTOSOMAL SEX REVERSAL; COLON-CARCINOMA CELLS; SRY-RELATED GENE; XENOPUS-LAEVIS; AMPHIBIAN METAMORPHOSIS; POSTEMBRYONIC DEVELOPMENT; CAMPOMELIC DYSPLASIA AB The intestine has long been studied as a model for adult stem cells due to the life-long self-renewal of the intestinal epithelium through the proliferation of the adult intestinal stem cells. Recent evidence suggests that the formation of adult intestinal stem cells in mammals takes place during the thyroid hormone-dependent neonatal period, also known as postembryonic development, which resembles intestinal remodeling during frog metamorphosis. Studies on the metamorphosis in Xenopus laevis have revealed that many members of the Sox family, a large family of DNA binding transcription factors, are upregulated in the intestinal epithelium during the formation and/or proliferation of the intestinal stem cells. Similarly, a number of Sox genes have been implicated in intestinal development and pathogenesis in mammals. Futures studies are needed to determine the expression and potential involvement of this important gene family in the development of the adult intestinal stem cells. These include the analyses of the expression and regulation of these and other Sox genes during postembryonic development in mammals as well as functional investigations in both mammals and amphibians by using the recently developed gene knockout technologies. Published by Elsevier Ltd. C1 [Fu, Liezhen; Shi, Yun-Bo] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, NIH, 18 Lib Dr, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, NIH, 18 Lib Dr, Bethesda, MD 20892 USA. EM Shi@helix.nih.gov FU intramural Research Program of NICHD, NIH FX This work was supported by the intramural Research Program of NICHD, NIH. NR 148 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD MAR PY 2017 VL 63 BP 58 EP 67 DI 10.1016/j.semcdb.2016.08.022 PG 10 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA EM7PL UT WOS:000395504500008 PM 27567710 ER PT J AU Earley, CJ Uhl, GR Clemens, S Ferre, S AF Earley, Christopher J. Uhl, George R. Clemens, Stefan Ferre, Sergi TI Connectome and molecular pharmacological differences in the dopaminergic system in restless legs syndrome (RLS): plastic changes and neuroadaptations that may contribute to augmentation SO SLEEP MEDICINE LA English DT Review DE Restless legs syndrome; Dopamine; Receptors; PTPRD; Heteromers; Spinal ID TYROSINE-PHOSPHATASE-DELTA; EXCITATORY SYNAPSE FORMATION; RECEPTOR HETEROMERS; SPINAL-CORD; CIRCADIAN VARIATION; PARKINSONS-DISEASE; TRANSSYNAPTIC INTERACTION; COCAINE-SEEKING; IRON-DEFICIENCY; MESSENGER-RNA AB Restless legs syndrome (RLS) is primarily treated with levodopa and dopaminergics that target the inhibitory dopamine receptor subtypes D3 and D2. The initial success of this therapy led to the idea of a hypodopaminergic state as the mechanism underlying RLS. However, multiple lines of evidence suggest that this simplified concept of a reduced dopamine function as the basis of RLS is incomplete. Moreover, long-term medication with the D2/D3 agonists leads to a reversal of the initial benefits of dopamine agonists and augmentation, which is a worsening of symptoms under therapy. The recent findings on the state of the dopamine system in RLS that support the notion that a dysfunction in the dopamine system may in fact induce a hyperdopaminergic state are summarized. On the basis of these data, the concept of a dynamic nature of the dopamine effects in a circadian context is presented. The possible interactions of cell adhesion molecules expressed by the dopaminergic systems and their possible effects on RLS and augmentation are discussed. Genome-wide association studies (GWAS) indicate a significantly increased risk for RLS in populations with genomic variants of the cell adhesion molecule receptor type protein tyrosine phosphatase D (PTPRD), and PTPRD is abundantly expressed by dopamine neurons. PTPRD may play a role in the reconfiguration of neural circuits, including shaping the interplay of G protein-coupled receptor (GPCR) homomers and heteromers that mediate dopaminergic modulation. Recent animal model data support the concept that interactions between functionally distinct dopamine receptor subtypes can reshape behavioral outcomes and change with normal aging. Additionally, long-term activation of one dopamine receptor subtype can increase the receptor expression of a different receptor subtype with opposite modulatory actions. Such dopamine receptor interactions at both spinal and supraspinal levels appear to play important roles in RLS. In addition, these interactions can extend to the adenosine A(1) and A(2A) receptors, which are also prominently expressed in the striatum. Interactions between adenosine and dopamine receptors and dopaminergic cell adhesion molecules, including PTPRD, may provide new pharmacological targets for treating RLS. In summary, new treatment options for RLS that include recovery from augmentation will have to consider dynamic changes in the dopamine system that occur during the circadian cycle, plastic changes that can develop as a function of treatment or with aging, changes in the connectome based on alterations in cell adhesion molecules, and receptor interactions that may extend beyond the dopamine system itself. (C) 2016 Elsevier B.V. All rights reserved. C1 [Earley, Christopher J.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. [Uhl, George R.] Univ New Mexico, Sch Med, Biomed Res Inst New Mexico, Res Serv,New Mexico VA Hlth Care Syst,Dept Neurol, Albuquerque, NM 87131 USA. [Uhl, George R.] Univ New Mexico, Sch Med, Biomed Res Inst New Mexico, Res Serv,New Mexico VA Hlth Care Syst,Dept Neuros, Albuquerque, NM 87131 USA. [Uhl, George R.] Univ New Mexico, Sch Med, Biomed Res Inst New Mexico, Res Serv,New Mexico VA Hlth Care Syst,Dept Mol Ge, Albuquerque, NM 87131 USA. [Uhl, George R.] Johns Hopkins Med Inst, Dept Neurol, Baltimore, MD 21205 USA. [Uhl, George R.] Johns Hopkins Med Inst, Dept Neurosci, Baltimore, MD 21205 USA. [Uhl, George R.] Johns Hopkins Med Inst, Dept Mental Hlth, Baltimore, MD 21205 USA. [Clemens, Stefan] East Carolina Univ, Dept Physiol, Brody Sch Med, Greenville, NC USA. [Ferre, Sergi] NIDA, Integrat Neurobiol Sect, Intramural Res Program, NIH, Baltimore, MD USA. RP Earley, CJ (reprint author), Johns Hopkins Bayview Med Ctr, Dept Neurol, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 USA. EM cearley@jhmi.edu OI Ferre, Sergi/0000-0002-1747-1779 FU National Institute on Drug Abuse FX S.F. is supported by the intramural funds from the National Institute on Drug Abuse. NR 96 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1389-9457 EI 1878-5506 J9 SLEEP MED JI Sleep Med. PD MAR PY 2017 VL 31 BP 71 EP 77 DI 10.1016/j.sleep.2016.06.003 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA EO8WJ UT WOS:000396970900010 PM 27539027 ER PT J AU Ferre, S Earley, C Gulyani, S Garcia-Borreguero, D AF Ferre, Sergi Earley, Christopher Gulyani, Seema Garcia-Borreguero, Diego TI In search of alternatives to dopaminergic ligands for the treatment of restless legs syndrome: iron, glutamate, and adenosine SO SLEEP MEDICINE LA English DT Review DE Restless legs syndrome; Iron deficiency; Glutamate; alpha(2)delta ligands; Adenosine ID ASPARTATE NMDA ANTAGONISTS; LONG-TERM USE; EKBOM DISEASE; RAT-BRAIN; NEUROMODULATORY ACTIONS; RECEPTOR HETEROMERS; PARKINSONS-DISEASE; NUCLEUS-ACCUMBENS; DOUBLE-BLIND; TASK-FORCE AB Dopaminergic drugs have been used as the first-line treatment for restless legs syndrome (RLS) for many years and are considered to be, at least over the short-term, effective and safe. However, the main long-term complication of dopaminergic treatment is augmentation, which is an overall increase in symptom severity and intensity, with symptoms starting earlier in the afternoon and expanding to previously unaffected parts of the body. Augmentation is a common complication, with prevalence rates of nearly 50%, and is a common cause of treatment failure. Furthermore, augmentation occurs almost exclusively during treatment with dopaminergic drugs. Due to its frequency, there is a strong clinical need for treatment alternatives to dopaminergic drugs. Moreover, recent treatment guidelines recommend that treatment be initiated, whenever possible, with non-dopaminergic drugs (ie, alpha(2)delta ligands). Alternative treatments such as intravenous iron preparations directly address iron deficiency, as well as the consequences of iron deficiency in regard to glutamate and adenosine. This article also reviews current knowledge supporting an involvement of glutamatergic and adenosinergic neurotransmission in the pathophysiology of RLS, and explores the potential development of drugs acting on both systems. (C) 2016 Published by Elsevier B.V. C1 [Ferre, Sergi] NIDA, Integrat Neurobiol Sect, Intramural Res Program, NIH, Baltimore, MD USA. [Earley, Christopher] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. [Gulyani, Seema] NIA, Human Neurosci Unit, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Garcia-Borreguero, Diego] Sleep Res Inst, Paseo Habana 151, Madrid 28036, Spain. RP Garcia-Borreguero, D (reprint author), Sleep Res Inst, Paseo Habana 151, Madrid 28036, Spain. EM dgb@iis.es OI Ferre, Sergi/0000-0002-1747-1779 FU intramural funds of National Institute on Drug Abuse and National Institute on Aging FX This work was supported by the intramural funds of National Institute on Drug Abuse and National Institute on Aging. The authors thank Anne-Marie Williams for her editorial assistance. NR 79 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1389-9457 EI 1878-5506 J9 SLEEP MED JI Sleep Med. PD MAR PY 2017 VL 31 BP 86 EP 92 DI 10.1016/j.sleep.2016.08.019 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA EO8WJ UT WOS:000396970900012 PM 27899234 ER PT J AU Lu, TS Longnecker, MP Zhou, HB AF Lu, Tsui-Shan Longnecker, Matthew P. Zhou, Haibo TI Statistical inferences for data from studies conducted with an aggregated multivariate outcome-dependent sample design SO STATISTICS IN MEDICINE LA English DT Article DE continuous multivariate responses; correlated responses; empirical likelihood; outcome-dependent sampling; semiparametric ID EMPIRICAL LIKELIHOOD METHOD; IN-UTERO EXPOSURE; POLYCHLORINATED-BIPHENYLS; REGRESSION; MODELS; EQUATIONS; CHILDREN; 2-STAGE; SCHEME AB Outcome-dependent sampling (ODS) scheme is a cost-effective sampling scheme where one observes the exposure with a probability that depends on the outcome. The well-known such design is the case-control design for binary response, the case-cohort design for the failure time data, and the general ODS design for a continuous response. While substantial work has been carried out for the univariate response case, statistical inference and design for the ODS with multivariate cases remain under-developed. Motivated by the need in biological studies for taking the advantage of the available responses for subjects in a cluster, we propose a multivariate outcome-dependent sampling (multivariate-ODS) design that is based on a general selection of the continuous responses within a cluster. The proposed inference procedure for the multivariate-ODS design is semiparametric where all the underlying distributions of covariates are modeled nonparametrically using the empirical likelihood methods. We show that the proposed estimator is consistent and developed the asymptotically normality properties. Simulation studies show that the proposed estimator is more efficient than the estimator obtained using only the simple-random-sample portion of the multivariate-ODS or the estimator from a simple random sample with the same sample size. The multivariate-ODS design together with the proposed estimator provides an approach to further improve study efficiency for a given fixed study budget. We illustrate the proposed design and estimator with an analysis of association of polychlorinated biphenyl exposure to hearing loss in children born to the Collaborative Perinatal Study. Copyright (C) 2016 John Wiley & Sons, Ltd. C1 [Lu, Tsui-Shan] Natl Taiwan Normal Univ, Dept Math, Taipei, Taiwan. [Longnecker, Matthew P.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Zhou, Haibo] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. RP Zhou, HB (reprint author), Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. EM zhou@bios.unc.edu FU U.S. National Institute of Health grant [R01 ES021900] FX This research was supported in part by grants from the U.S. National Institute of Health grants (R01 ES021900). NR 21 TC 1 Z9 1 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD MAR PY 2017 VL 36 IS 6 BP 985 EP 997 DI 10.1002/sim.7195 PG 13 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA EL7DP UT WOS:000394781600008 PM 27966260 ER PT J AU Andridge, R Noone, AM Howlader, N AF Andridge, Rebecca Noone, Anne-Michelle Howlader, Nadia TI Imputing estrogen receptor (ER) status in a population-based cancer registry: a sensitivity analysis SO STATISTICS IN MEDICINE LA English DT Article DE multiple imputation; predictive mean matching; nonignorable missingness; cancer surveillance data ID MODEL MULTIPLE IMPUTATION; NONIGNORABLE MISSING DATA; PATTERN-MIXTURE ANALYSIS; BREAST-CANCER; UNITED-STATES; CLINICAL-TRIALS; INCOMPLETE DATA; BINARY; NONRESPONSE; INFORMATION AB Breast cancers are clinically heterogeneous based on tumor markers. The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program provides baseline data on these tumor markers for reporting cancer burden and trends over time in the US general population. These tumor markers, however, are often prone to missing observations. In particular, estrogen receptor (ER) status, a key biomarker in the study of breast cancer, has been collected since 1992 but historically was not well-reported, with missingness rates as high as 25% in early years. Previous methods used to correct estimates of breast cancer incidence or ER-related odds or prevalence ratios for unknown ER status have relied on a missing-at-random (MAR) assumption. In this paper, we explore the sensitivity of these key estimates to departures from MAR. We develop a predictive mean matching procedure that can be used to multiply impute missing ER status under either an MAR or a missing not at random assumption and apply it to the SEER breast cancer data (1992-2012). The imputation procedure uses the predictive power of the rich set of covariates available in the SEER registry while also allowing us to investigate the impact of departures from MAR. We find some differences in inference under the two assumptions, although the magnitude of differences tends to be small. For the types of analyses typically of primary interest, we recommend imputing SEER breast cancer biomarkers under an MAR assumption, given the small apparent differences under MAR and missing not at random assumptions. Copyright (C) 2016 John Wiley & Sons, Ltd. C1 [Andridge, Rebecca] Ohio State Univ, Coll Publ Hlth, Columbus, OH 43210 USA. [Noone, Anne-Michelle; Howlader, Nadia] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Andridge, R (reprint author), 242 Cunz Hall,1841 Neil Ave, Columbus, OH 43210 USA. EM andridge.1@osu.edu OI Andridge, Rebecca/0000-0001-9991-9647 NR 60 TC 1 Z9 1 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD MAR PY 2017 VL 36 IS 6 BP 1014 EP 1028 DI 10.1002/sim.7193 PG 15 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA EL7DP UT WOS:000394781600010 PM 27921315 ER PT J AU Guo, L Hamre, J Eldridge, S Behrsing, HP Cutuli, FM Mussio, J Davis, M AF Guo, Liang Hamre, John, III Eldridge, Sandy Behrsing, Holger P. Cutuli, Facundo M. Mussio, Jodie Davis, Myrtle TI Multiparametric Image Analysis of Rat Dorsal Root Ganglion Cultures to Evaluate Peripheral Neuropathy-Inducing Chemotherapeutics SO TOXICOLOGICAL SCIENCES LA English DT Article DE chemotherapy-induced peripheral neuropathy (CIPN); rat dorsal root ganglion cells (DRGs); high content analysis (HCA); automated image analysis; early safety evaluation ID SOLID TUMORS; CELL-LINES; NEUROTOXICITY; ADULT; NEURONS; CISPLATIN; PHARMACOKINETICS; VINCRISTINE; THALIDOMIDE; BORTEZOMIB AB Chemotherapy-induced peripheral neuropathy (CIPN) is a major, dose-limiting adverse effect experienced by cancer patients. Advancements in mechanism-based risk mitigation and effective treatments for CIPN can be aided by suitable in vitro assays. To this end, we developed a multiparametric morphology-centered rat dorsal root ganglion (DRG) assay. Morphologic alterations in subcellular structures of neurons and non-neurons were analyzed with an automated microscopy system. Stains for NeuN (a neuron-specific nuclear protein) and Tuj-1 (beta-III tubulin) were used to identify neuronal cell nuclei and neuronal cell bodies/neurites, respectively. Vimentin staining (a component of Schwann cell intermediate filaments) was used to label non-neuronal supporting cells. Nuclei that stained with DAPI, but lacked NeuN represented non-neuronal cells. Images were analyzed following 24h of continuous exposure to CIPN-inducing agents and 72h after drug removal to provide a dynamic measure of recovery from initial drug effects. Treatment with bortezomib, cisplatin, eribulin, paclitaxel or vincristine induced a dose-dependent loss of neurite/process areas, mimicking the ` dying back' degeneration of axons, a histopathological hallmark of clinical CIPN in vivo. The IC50 for neurite loss was within 3-fold of the maximal clinical exposure (Cmax) for all five CIPN-inducing drugs, but was > 4-or >= 28-fold of the Cmax for 2 nonCIPN- inducing agents. Compound-specific effects, eg, neurite fragmentation by cisplatin or bortezomib and enlarged neuronal cell bodies by paclitaxel, were also observed. Collectively, these results support the use of a quantitative, morphologic evaluation and a DRG cell culture model to inform risk and examine mechanisms of CIPN. C1 [Guo, Liang; Hamre, John, III; Behrsing, Holger P.; Cutuli, Facundo M.; Mussio, Jodie] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Lab Investigat Toxicol, Frederick, MD 21702 USA. [Eldridge, Sandy; Davis, Myrtle] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Behrsing, Holger P.] Inst In Vitro Sci Inc, Gaithersburg, MD 20878 USA. RP Davis, M (reprint author), NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM davismillinm@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported [in part] by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NR 53 TC 0 Z9 0 U1 0 U2 0 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 2017 VL 156 IS 1 BP 275 EP 288 DI 10.1093/toxsci/kfw254 PG 14 WC Toxicology SC Toxicology GA EO9ZR UT WOS:000397047100025 PM 28115644 ER PT J AU Cservenak, M Kis, V Keller, D Dimen, D Menyhart, L Olah, S Szabo, ER Barna, J Renner, E Usdin, T Dobolyi, A AF Cservenak, Melinda Kis, Viktor Keller, David Dimen, Diana Menyhart, Lilla Olah, Szilvia Szabo, Eva R. Barna, Janos Renner, Eva Usdin, Ted B. Dobolyi, Arpad TI Maternally involved galanin neurons in the preoptic area of the rat SO BRAIN STRUCTURE & FUNCTION LA English DT Article DE Maternal behavior; Rat dams; Suckling; Prolactin; Oxytocin; Innervation; Preoptic area of hypothalamus ID HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; INDUCED PROLACTIN-RELEASE; GNRH-CONTAINING NEURONS; CENTRAL-NERVOUS-SYSTEM; NITRIC-OXIDE SYNTHASE; TUBEROINFUNDIBULAR PEPTIDE; LACTATING RATS; MESSENGER-RNA; 39 RESIDUES; MAGNOCELLULAR NEURONS AB Recent selective stimulation and ablation of galanin neurons in the preoptic area of the hypothalamus established their critical role in control of maternal behaviors. Here, we identified a group of galanin neurons in the anterior commissural nucleus (ACN), and a distinct group in the medial preoptic area (MPA). Galanin neurons in ACN but not the MPA co-expressed oxytocin. We used immunodetection of phosphorylated STAT5 (pSTAT5), involved in prolactin receptor signal transduction, to evaluate the effects of suckling-induced prolactin release and found that 76 % of galanin cells in ACN, but only 12 % in MPA were prolactin responsive. Nerve terminals containing tuberoinfundibular peptide 39 (TIP39), a neuropeptide that mediates effects of suckling on maternal motivation, were abundant around galanin neurons in both preoptic regions. In the ACN and MPA, 89 and 82 % of galanin neurons received close somatic appositions, with an average of 2.9 and 2.6 per cell, respectively. We observed perisomatic innervation of galanin neurons using correlated light and electron microscopy. The connection was excitatory based on the glutamate content of TIP39 terminals demonstrated by post-embedding immunogold electron microscopy. Injection of the anterograde tracer biotinylated dextran amine into the TIP39-expressing posterior intralaminar complex of the thalamus (PIL) demonstrated that preoptic TIP39 fibers originate in the PIL, which is activated by suckling. Thus, galanin neurons in the preoptic area of mother rats are innervated by an excitatory neuronal pathway that conveys suckling-related information. In turn, they can be topographically and neurochemically divided into two distinct cell groups, of which only one is affected by prolactin. C1 [Cservenak, Melinda; Kis, Viktor; Keller, David; Dimen, Diana; Olah, Szilvia; Szabo, Eva R.; Dobolyi, Arpad] Hungarian Acad Sci, Dept Physiol & Neurobiol, MTA ELTE NAP B Lab Mol & Syst Neurobiol, Budapest, Hungary. [Cservenak, Melinda; Kis, Viktor; Keller, David; Dimen, Diana; Olah, Szilvia; Szabo, Eva R.; Dobolyi, Arpad] Eotvos Lorand Univ, Budapest, Hungary. [Cservenak, Melinda; Keller, David; Szabo, Eva R.; Barna, Janos; Dobolyi, Arpad] Semmelweis Univ, Neuromorphol Lab, Dept Anat Histol & Embryol, H-1094 Budapest, Hungary. [Kis, Viktor; Dimen, Diana; Menyhart, Lilla] Eotvos Lorand Univ, Inst Biol, Dept Anat Cell & Dev Biol, Budapest, Hungary. [Renner, Eva] Semmelweis Univ, Human Brain Tissue Bank, Budapest, Hungary. [Renner, Eva] Semmelweis Univ, MTA SE NAP Human Brain Tissue Bank Microdissect L, Budapest, Hungary. [Usdin, Ted B.] NIMH, Sect Fundamental Neurosci, Bethesda, MD 20892 USA. RP Dobolyi, A (reprint author), Hungarian Acad Sci, Dept Physiol & Neurobiol, MTA ELTE NAP B Lab Mol & Syst Neurobiol, Budapest, Hungary.; Dobolyi, A (reprint author), Eotvos Lorand Univ, Budapest, Hungary.; Dobolyi, A (reprint author), Semmelweis Univ, Neuromorphol Lab, Dept Anat Histol & Embryol, H-1094 Budapest, Hungary. EM dobolyia@caesar.elte.hu FU HAS Postdoctoral Research Fellowship Program; OTKA [K100319, K116538, KTIA_NAP_B_13-2-2014-0004]; NIMH IRP FX Grant support was provided by HAS Postdoctoral Research Fellowship Program for MCs, OTKA K100319, OTKA K116538 and KTIA_NAP_B_13-2-2014-0004 Program for AD, and NIMH IRP for TBU. The technical assistance of Nikolett Hanak and Szilvia Deak is also acknowledged. The authors also thank Cintia K Finszter for technical contribution to pSTAT5 immunohistochemistry. NR 93 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2653 EI 1863-2661 J9 BRAIN STRUCT FUNCT JI Brain Struct. Funct. PD MAR PY 2017 VL 222 IS 2 BP 781 EP 798 DI 10.1007/s00429-016-1246-5 PG 18 WC Anatomy & Morphology; Neurosciences SC Anatomy & Morphology; Neurosciences & Neurology GA EN5GT UT WOS:000396034300007 PM 27300187 ER PT J AU Gu, ZL Yakel, JL AF Gu, Zhenglin Yakel, Jerrel L. TI Inducing theta oscillations in the entorhinal hippocampal network in vitro SO BRAIN STRUCTURE & FUNCTION LA English DT Article DE Entorhinal cortex; Hippocampus; Theta oscillation; Septum; Cholinergic transmission ID CHOLINERGIC INDUCTION; SYNAPTIC PLASTICITY; PYRAMIDAL CELLS; MEDIAL SEPTUM; RHYTHM; MEMORY; RAT; CORTEX; ACTIVATION; NEURONS AB The hippocampal theta rhythm emerges as rhythmic and synchronized activities among the hippocampus and hippocampus-associated brain regions during active exploration, providing a potential means for inter-regional communication. However, after decades of research, the origins of the theta rhythm remain elusive, at least partly due to the difficulty in recording from all three essential regions for theta generation, namely the hippocampus itself, the septum, and the entorhinal cortex. For this reason, we established an in vitro theta model in a septo-entorhinal-hippocampal brain slice tri-culture system by pairing septal cholinergic inputs with hippocampal local activities. Our study shows that the local entorhinal cortical circuit may play an active and critical role in hippocampal theta rhythm generation. Our study also reveals a potential mechanism for theta rhythms to emerge as the functional results of dynamic interactions among the septum, hippocampus, and the entorhinal cortex, in the absence of clear pace makers. C1 [Gu, Zhenglin; Yakel, Jerrel L.] NIEHS, Natl Inst Hlth, NIH, Dept Hlth & Human Serv, POB 12233,Mail Drop F2-08, Res Triangle Pk, NC 27709 USA. RP Yakel, JL (reprint author), NIEHS, Natl Inst Hlth, NIH, Dept Hlth & Human Serv, POB 12233,Mail Drop F2-08, Res Triangle Pk, NC 27709 USA. EM guz@niehs.nih.gov; yakel@niehs.nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences/NIH/DHHS FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences/NIH/DHHS. We thank Dr. Georgia Alexander and Dr. Guohong Cui for help on data analyzing and critical reading of the manuscript, Dr. Serena Dudek for critical reading of the manuscript, Patricia Lamb for animal genotyping and plasmid preparation, Dr. Bernd Gloss for virus packaging, Charles J. Tucker for assistance with fluorescent microscopy, and Dr. James M. Wilson at the University of Pennsylvania for providing the AAV serotype 9 helper plasmid. NR 43 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2653 EI 1863-2661 J9 BRAIN STRUCT FUNCT JI Brain Struct. Funct. PD MAR PY 2017 VL 222 IS 2 BP 943 EP 955 DI 10.1007/s00429-016-1256-3 PG 13 WC Anatomy & Morphology; Neurosciences SC Anatomy & Morphology; Neurosciences & Neurology GA EN5GT UT WOS:000396034300016 PM 27369465 ER PT J AU Rosenberg, AZ Kopp, JB AF Rosenberg, Avi Z. Kopp, Jeffrey B. TI Focal Segmental Glomerulosclerosis SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID RESISTANT NEPHROTIC SYNDROME; HIV-ASSOCIATED NEPHROPATHY; CHRONIC KIDNEY-DISEASE; STEROID-RESISTANT; COLLAPSING GLOMERULOPATHY; UROKINASE RECEPTOR; CLINICAL-TRIAL; PRIMARY FSGS; HISTOLOGICAL VARIANTS; MORPHOLOGIC LESIONS AB Focal segmental glomerulosclerosis (FSGS) is a leading cause of kidney disease worldwide. The presumed etiology of primary FSGS is a plasma factor with responsiveness to immunosuppressive therapy and a risk of recurrence after kidney transplant-important disease characteristics. In contrast, adaptive FSGS is associated with excessive nephron workload due to increased body size, reduced nephron capacity, or single glomerular hyperfiltration associated with certain diseases. Additional etiologies are now recognized as drivers of FSGS: high-penetrance genetic FSGS due to mutations in one of nearly 40 genes, virus-associated FSGS, and medication-associated FSGS. Emerging data support the identification of a sixth category: APOL1 risk allele-associated FSGS in individuals with sub-Saharan ancestry. The classification of a particular patient with FSGS relies on integration of findings from clinical history, laboratory testing, kidney biopsy, and in somepatients, genetic testing. The kidney biopsy can be helpful, with clues provided by features on light microscopy (e. g., glomerular size, histologic variant of FSGS, microcystic tubular changes, and tubular hypertrophy), immunofluorescence( e. g., to ruleout other primary glomerulopathies), and electron microscopy(e. g., extent of podocyte foot process effacement, podocyte microvillous transformation, and tubuloreticular inclusions). A complete assessment of renal histology is important for establishing the parenchymal setting of segmental glomerulosclerosis, distinguishing FSGS associated with one of many other glomerular diseases from the clinical-pathologic syndrome of FSGS. Genetic testing is beneficial in particular clinical settings. Identifying the etiology of FSGS guides selection of therapy and provides prognostic insight. Much progress has beenmade in our understanding of FSGS, but important outstanding issues remain, including the identity of the plasma factor believed to be responsible for primary FSGS, the value of routine implementation of genetic testing, and the identification of more effective and less toxic therapeutic interventions for FSGS. C1 [Rosenberg, Avi Z.; Kopp, Jeffrey B.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Rosenberg, Avi Z.; Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, Kidney Dis Branch, NIH, Bethesda, MD 20892 USA. RP Kopp, JB (reprint author), NIDDK, Kidney Dis Sect, 10 Ctr Dr, Bethesda, MD 20892 USA. EM jbkopp@nih.gov FU Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Departments of Pathology of the Children's National Medical Center; Johns Hopkins Medical Institutions FX This work was supported by the Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health and the Departments of Pathology of the Children's National Medical Center and Johns Hopkins Medical Institutions. NR 139 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD MAR PY 2017 VL 12 IS 3 BP 502 EP 517 DI 10.2215/CJN.05960616 PG 16 WC Urology & Nephrology SC Urology & Nephrology GA EO6SE UT WOS:000396822000018 PM 28242845 ER PT J AU Baik, M Lee, MS Kang, HJ Park, SJ Piao, MY Nguyen, TH Hennighausen, L AF Baik, Myunggi Lee, Mi Sun Kang, Hyeok Joong Park, Seung Ju Piao, Min Yu Trang Hoa Nguyen Hennighausen, Lothar TI Muscle-specific deletion of signal transducer and activator of transcription 5 augments lipid accumulation in skeletal muscle and liver of mice in response to high-fat diet SO EUROPEAN JOURNAL OF NUTRITION LA English DT Article DE STAT5 muscle deletion; Lipid and glucose metabolism; Intramyocellular lipid accumulation; Hepatic lipid accumulation ID GROWTH-HORMONE DEFICIENCY; IMPROVES GLUCOSE-HOMEOSTASIS; NONALCOHOLIC STEATOHEPATITIS; BODY-COMPOSITION; GENE-EXPRESSION; INDUCED OBESITY; ADIPOSE-TISSUE; OLDER MEN; FACTOR-I; METABOLISM AB Growth hormone (GH) controls liver metabolism through the transcription factor signal transducer and activator of transcription 5 (STAT5). However, it remains to be fully understood to what extent other GH/STAT5 target tissues contribute to lipid and glucose metabolism. This question was now addressed in muscle-specific STAT5 knockout (STAT5 MKO) mice model. Changes in lipid and glucose metabolism were investigated at physiological and molecular levels in muscle and liver tissues of STAT5 MKO mice under normal diet or high-fat diet (HFD) conditions. STAT5 MKO mice exhibited an increased intramyocellular lipid (IMCL) accumulation in the quadriceps in HFD group. Decreased lipolytic hormone-sensitive lipase transcript levels may contribute to the increased IMCL accumulation in STAT5 MKO mice. STAT5 MKO induced hepatic lipid accumulation without deregulated STAT5 signaling. The upregulation of lipoprotein lipase and Cd36 mRNA levels, an increased trend of very low-density lipoprotein receptor mRNA levels, and elevated circulating concentrations of free fatty acid, triglyceride, and total cholesterol support the increase in hepatic lipid accumulation. STAT5 MKO in conjunction with a HFD deregulated both lipid and glucose metabolism in skeletal muscle, and this deregulation induced hepatic fat accumulation via increased circulating glucose, FFA, and TG concentrations. Our study emphasizes that muscle-specific STAT5 signaling is important for balancing lipid and glucose metabolism in peripheral tissues, including muscle and liver and that the deregulation of local STAT5 signaling augments HFD-induced lipid accumulation in both muscle and liver. C1 [Baik, Myunggi; Kang, Hyeok Joong; Park, Seung Ju; Piao, Min Yu] Seoul Natl Univ, Dept Agr Biotechnol, Coll Agr & Life Sci, 1 Gwanak Ro, Seoul 151921, South Korea. [Baik, Myunggi; Kang, Hyeok Joong; Park, Seung Ju; Piao, Min Yu] Seoul Natl Univ, Res Inst Agr & Life Sci, Coll Agr & Life Sci, 1 Gwanak Ro, Seoul 151921, South Korea. [Baik, Myunggi] Inst Green Bio Sci Technol, Gangwon Do 232916, Pyeungchang Gun, South Korea. [Lee, Mi Sun] Bioneer Corp, 8-11 Munpyengseoro, Daejeon 306220, South Korea. [Trang Hoa Nguyen] Chonnam Natl Univ, Dept Mol Biotechnol, Gwangju 500757, South Korea. [Hennighausen, Lothar] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RP Baik, M (reprint author), Seoul Natl Univ, Dept Agr Biotechnol, Coll Agr & Life Sci, 1 Gwanak Ro, Seoul 151921, South Korea.; Baik, M (reprint author), Seoul Natl Univ, Res Inst Agr & Life Sci, Coll Agr & Life Sci, 1 Gwanak Ro, Seoul 151921, South Korea.; Baik, M (reprint author), Inst Green Bio Sci Technol, Gangwon Do 232916, Pyeungchang Gun, South Korea. EM mgbaik@snu.ac.kr FU National Research Laboratory Program through the NRF - Ministry of Education, Science, and Technology [ROA-2007-0056702]; Rural Development Administration, Republic of Korea [PJ01114001] FX The present study was supported by grants from the National Research Laboratory Program (ROA-2007-0056702) through the NRF funded by the Ministry of Education, Science, and Technology and the Next-Generation BioGreen 21 Program (No. PJ01114001), Rural Development Administration, Republic of Korea. NR 36 TC 0 Z9 0 U1 0 U2 0 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 2017 VL 56 IS 2 BP 569 EP 579 DI 10.1007/s00394-015-1101-0 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EN5IR UT WOS:000396039300011 PM 26582580 ER PT J AU Kreisl, WC Lyoo, CH Liow, JS Snow, J Page, E Jenko, KJ Morse, CL Zoghbi, SS Pike, VW Turner, RS Innis, RB AF Kreisl, William C. Lyoo, Chul Hyoung Liow, Jeih-San Snow, Joseph Page, Emily Jenko, Kimberly J. Morse, Cheryl L. Zoghbi, Sami S. Pike, Victor W. Turner, R. Scott Innis, Robert B. TI Distinct patterns of increased translocator protein in posterior cortical atrophy and amnestic Alzheimer ' s disease SO NEUROBIOLOGY OF AGING LA English DT Article DE Alzheimer ' s disease; Neuroinflammation; PET imaging ID PITTSBURGH COMPOUND-B; POSITRON-EMISSION-TOMOGRAPHY; VIVO RADIOLIGAND BINDING; ASSOCIATION WORKGROUPS; DIAGNOSTIC GUIDELINES; COGNITIVE IMPAIRMENT; METABOLIC DEFICITS; AMYLOID DEPOSITION; NATIONAL INSTITUTE; HUMAN BRAIN AB We sought to determine whether patients with posterior cortical atrophy (PCA) demonstrate a pattern of binding to translocator protein 18 kDa, a marker of microglial activation, that is distinct from that in patients with amnestic presentation of Alzheimer's disease (AD). Eleven PCA patients, 11 amnestic AD patients, and 15 age-matched controls underwent positron emission tomography with C-11-PBR28 to measure translocator protein 18 kDa. PCA patients showed greater C-11-PBR28 binding than controls in occipital, posterior parietal, and temporal regions. In contrast, amnestic AD patients showed greater C-11-PBR28 binding in inferior and medial temporal cortex. Increased C-11-PBR28 binding overlapped with reduced cortical volume for both PCA and amnestic AD patients, and with areas of reduced glucose metabolism in PCA patients. While both patient groups showed diffuse amyloid binding, PCA patients showed greater binding than amnestic AD patients in bilateral occipital cortex. These results suggest that microglial activation is closely associated with neurodegeneration across different subtypes of AD. (C) Published by Elsevier Inc. C1 [Kreisl, William C.; Lyoo, Chul Hyoung; Liow, Jeih-San; Page, Emily; Jenko, Kimberly J.; Morse, Cheryl L.; Zoghbi, Sami S.; Pike, Victor W.; Innis, Robert B.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Snow, Joseph] NIMH, Off Clin Director, Bethesda, MD 20892 USA. [Turner, R. Scott] Georgetown Univ, Memory Disorders Program, Washington, DC USA. RP Kreisl, WC (reprint author), Columbia Univ, Taub Inst, Med Ctr, 622 W 168th St,PH 19th Floor, New York, NY 10032 USA. EM wck2107@cumc.columbia.edu RI Turner, Raymond/G-2263-2011 OI Turner, Raymond/0000-0001-7534-2935 FU Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP- NIMH- NIH) [ZIAMH002852, ZIAMH0022793, NCT00955422, NCT00613119] FX The authors thank Yi Zhang, PhD for assistance in radioligand production, Francis McMahon and Winston Corona for TSPO genotyping, Ioline Henter for editorial assistance, Angela Summers for performing neuropsychological testing, and Maria Ferraris-Araneta, Denise Rallis-Frutos, Yulin Chu, Gerald Hodges, and the NIH PET Department for assistance with PET studies. This work was funded by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIAMH002852 and ZIAMH0022793 under clinicaltrials. gov identifiers NCT00955422 and NCT00613119). The NIMH had no further role in study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. NR 35 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 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAR PY 2017 VL 51 BP 132 EP 140 DI 10.1016/j.neurobiolaging.2016.12.006 PG 9 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA EP1UA UT WOS:000397168600014 PM 28068564 ER PT J AU Casaletto, KB Ward, ME Baker, NS Bettcher, BM Gelfand, JM Li, YQ Chen, R Dutt, S Miller, B Kramer, JH Green, AJ AF Casaletto, Kaitlin B. Ward, Michael E. Baker, Nicholas S. Bettcher, Brianne M. Gelfand, Jeffrey M. Li, Yaqiao Chen, Robert Dutt, Shubir Miller, Bruce Kramer, Joel H. Green, Ari J. TI Retinal thinning is uniquely associated with medial temporal lobe atrophy in neurologically normal older adults SO NEUROBIOLOGY OF AGING LA English DT Article DE Aging; Alzheimer ' s disease; Optical coherence tomography; Neurodegenerative disease; Dementia; Retinal imaging ID MILD COGNITIVE IMPAIRMENT; SURFACE-BASED ANALYSIS; OPEN-ANGLE GLAUCOMA; ALZHEIMERS-DISEASE; PATTERN SEPARATION; DIAGNOSTIC GUIDELINES; NATIONAL INSTITUTE; MOUSE MODEL; MEMORY; NEURODEGENERATION AB Given the converging pathologic and epidemiologic data indicating a relationship between retinal integrity and neurodegeneration, including Alzheimer's disease (AD), we aimed to determine if retinal structure correlates with medial temporal lobe (MTL) structure and function in neurologically normal older adults. Spectral-domain optical coherence tomography, verbal and visual memory testing, and 3T-magnetic resonance imaging of the brain were performed in 79 neurologically normal adults enrolled in a healthy aging cohort study. Retinal nerve fiber thinning and reduced total macular and macular ganglion cell volumes were each associated with smaller MTL volumes (ps < 0.04). Notably, these markers of retinal structure were not associated with primary motor cortex or basal ganglia volumes (regions relatively unaffected in AD) (ps > 0.70), or frontal, precuneus, or temporoparietal volumes (regions affected in later AD Braak staging ps > 0.20). Retinal structure was not significantly associated with verbal or visual memory consolidation performances (ps > 0.14). Retinal structure was associated with MTL volumes, but not memory performances, in otherwise neurologically normal older adults. Given that MTL atrophy is a neuropathological hallmark of AD, retinal integrity may be an early marker of ongoing AD-related brain health. (C) 2016 Elsevier Inc. All rights reserved. C1 [Casaletto, Kaitlin B.; Ward, Michael E.; Baker, Nicholas S.; Gelfand, Jeffrey M.; Chen, Robert; Dutt, Shubir; Miller, Bruce; Kramer, Joel H.; Green, Ari J.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Ward, Michael E.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Bettcher, Brianne M.] Univ Colorado, Dept Neurosurg, Rocky Mt Alzheimers Dis Ctr, Denver Anschutz Med Ctr, Aurora, CO USA. [Bettcher, Brianne M.] Univ Colorado, Dept Neurol, Rocky Mt Alzheimers Dis Ctr, Denver Anschutz Med Ctr, Denver, CO USA. [Li, Yaqiao] Univ Calif San Francisco, Dept Neurol, Gladstone Inst Neurol Dis, San Francisco, CA USA. RP Casaletto, KB (reprint author), Univ Calif San Francisco, Memory & Aging Ctr, 675 Nelson Rising Lane, San Francisco, CA 94158 USA. EM kaitlin.casaletto@ucsf.edu FU NIH-NIA [NIA 1R01AG032289, R01AG048234]; UCSF ADRC [P50 AG023501]; Larry L.Hillblom Network Grant for the Prevention of Age-Associated Cognitive Decline [2014-A-004-NE]; National Center for Advancing Translational Sciences of the NIH [KL2TR000143] FX This study was supported by NIH-NIA grants NIA 1R01AG032289 (principal investigator (PI): Kramer), R01AG048234 ( PI: Kramer) and UCSF ADRC P50 AG023501. Our work was also supported by Larry L.Hillblom Network Grant for the Prevention of Age-Associated Cognitive Decline 2014-A-004-NET (PI: Kramer) and National Center for Advancing Translational Sciences of the NIH under Award Number KL2TR000143 (JMG; PI: Gelfand). NR 41 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 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAR PY 2017 VL 51 BP 141 EP 147 DI 10.1016/j.neurobiolaging.2016.12.011 PG 7 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA EP1UA UT WOS:000397168600015 PM 28068565 ER PT J AU Mapstone, M Lin, F Nalls, MA Cheema, AK Singleton, AB Fiandaca, MS Federoff, HJ AF Mapstone, Mark Lin, Feng Nalls, Mike A. Cheema, Amrita K. Singleton, Andrew B. Fiandaca, Massimo S. Federoff, Howard J. TI What success can teach us about failure: the plasma metabolome of older adults with superior memory and lessons for Alzheimer ' s disease SO NEUROBIOLOGY OF AGING LA English DT Article DE Memory; Metabolomics; Alzheimer's disease; Oxidative stress; Nitric oxide; Arginine metabolism ID NITRIC-OXIDE; COGNITIVE NEUROSCIENCE; REGIONAL-DISTRIBUTION; SYNAPTIC PLASTICITY; HEALTHY HUMANS; AGING BRAIN; METABOANALYST; PERFORMANCE; EXPRESSION; PATHOLOGY AB As the world population ages, primary prevention of age-related cognitive decline and disability will become increasingly important. Prevention strategies are often developed from an understanding of disease pathobiology, but models of biological success may provide additional useful insights. Here, we studied 224 older adults, some with superior memory performance (n = 41), some with normal memory performance (n = 109), and some with mild cognitive impairment or Alzheimer's disease (AD; n = 74) to understand metabolomic differences which might inform future interventions to promote cognitive health. Plasma metabolomics revealed significant differential abundance of 12 metabolites in those with superior memory relative to controls (receiver operating characteristic area under the curve [AUC] = 0.89) and the inverse abundance pattern in the mild cognitive impairment, AD (AUC = 1.0) and even preclinical AD groups relative to controls (AUC = 0.97). The 12 metabolites are components of key metabolic pathways regulating oxidative stress, inflammation, and nitric oxide bioavailability. These findings from opposite ends of the cognitive continuum highlight the role of these pathways in superior memory abilities and whose failure may contribute to age-related memory impairment. These pathways may be targeted to promote successful cognitive aging. (C) 2016 Elsevier Inc. All rights reserved. C1 [Mapstone, Mark; Fiandaca, Massimo S.; Federoff, Howard J.] Univ Calif Irvine, Dept Neurol, Irvine, CA 92717 USA. [Lin, Feng] Univ Rochester, Sch Nursing, Rochester, NY USA. [Lin, Feng] Univ Rochester, Dept Psychiat, Rochester, NY USA. [Nalls, Mike A.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Cheema, Amrita K.] Georgetown Univ, Dept Biochem, Washington, DC USA. [Cheema, Amrita K.] Georgetown Univ, Dept Oncol, Washington, DC USA. [Fiandaca, Massimo S.] Univ Calif Irvine, Dept Neurol Surg, Irvine, CA USA. RP Federoff, HJ (reprint author), Univ Calif Irvine, Off Vice Chancellor Hlth Affairs, 1001 Hlth Sci Rd, Irvine, CA 92697 USA. EM Federoff@uci.edu FU NIH [R01AG030753]; DOD [W81XWH-09-1-0107]; Intramural Research Program of the National Institute on Aging,; National Institutes of Health, Department of Health and Human Services [Z01 AG000950-06] FX The authors thank Eileen Johnson, RN for collecting and Robert Padilla, MS for processing the blood samples. This work was funded by NIH R01AG030753 and DOD W81XWH-09-1-0107 to HJF Mike Nalls and Andrew Singleton's participation was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services, project Z01 AG000950-06. All metabolomic data from this study are freely available in the European Bioinformatics Institute MetaboLights database with accession code: MTBLS72. NR 46 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 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAR PY 2017 VL 51 BP 148 EP 155 DI 10.1016/j.neurobiolaging.2016.11.007 PG 8 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA EP1UA UT WOS:000397168600016 PM 27939698 ER PT J AU Romero, R Conde-Agudelo, A El-Refaie, W Rode, L Brizot, ML Cetingoz, E Serra, V Da Fonseca, E Abdelhafez, MS Tabor, A Perales, A Hassan, SS Nicolaides, KH AF Romero, R. Conde-Agudelo, A. El-Refaie, W. Rode, L. Brizot, M. L. Cetingoz, E. Serra, V. Da Fonseca, E. Abdelhafez, M. S. Tabor, A. Perales, A. Hassan, S. S. Nicolaides, K. H. TI Vaginal progesterone decreases preterm birth and neonatal morbidity and mortality in women with a twin gestation and a short cervix: an updated meta-analysis of individual patient data SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Review DE cervical length; prematurity; preterm delivery; progestins; progestogens; transvaginal ultrasound ID MULTIPLE PREGNANCIES; RANDOMIZED-TRIALS; TRANSVAGINAL SONOGRAPHY; CEREBRAL-PALSY; DOUBLE-BLIND; LENGTH; DELIVERY; RISK; PREDICTION; PREVENTION AB ObjectiveTo assess the efficacy of vaginal progesterone for the prevention of preterm birth and neonatal morbidity and mortality in asymptomatic women with a twin gestation and a sonographic short cervix (cervical length 25 mm) in the mid-trimester. MethodsThis was an updated systematic review and meta-analysis of individual patient data (IPD) from randomized controlled trials comparing vaginal progesterone with placebo/no treatment in women with a twin gestation and a mid-trimester sonographic cervical length 25 mm. MEDLINE, EMBASE, POPLINE, CINAHL and LILACS (all from inception to 31 December 2016), the Cochrane Central Register of Controlled Trials, Research Registers of ongoing trials, Google Scholar, conference proceedings and reference lists of identified studies were searched. The primary outcome measure was preterm birth < 33 weeks' gestation. Two reviewers independently selected studies, assessed the risk of bias and extracted the data. Pooled relative risks (RRs) with 95% confidence intervals (CI) were calculated. ResultsIPD were available for 303 women (159 assigned to vaginal progesterone and 144 assigned to placebo/no treatment) and their 606 fetuses/infants from six randomized controlled trials. One study, which included women with a cervical length between 20 and 25 mm, provided 74% of the total sample size of the IPD meta-analysis. Vaginal progesterone, compared with placebo/no treatment, was associated with a statistically significant reduction in the risk of preterm birth < 33 weeks' gestation (31.4% vs 43.1%; RR, 0.69 (95% CI, 0.51-0.93); moderate-quality evidence). Moreover, vaginal progesterone administration was associated with a significant decrease in the risk of preterm birth < 35, < 34, < 32 and < 30 weeks' gestation (RRs ranging from 0.47 to 0.83), neonatal death (RR, 0.53 (95% CI, 0.35-0.81)), respiratory distress syndrome (RR, 0.70 (95% CI, 0.56-0.89)), composite neonatal morbidity and mortality (RR, 0.61 (95% CI, 0.34-0.98)), use of mechanical ventilation (RR, 0.54 (95% CI, 0.36-0.81)) and birth weight < 1500 g (RR, 0.53 (95% CI, 0.35-0.80)) (all moderate-quality evidence). There were no significant differences in neurodevelopmental outcomes at 4-5 years of age between the vaginal progesterone and placebo groups. ConclusionAdministration of vaginal progesterone to asymptomatic women with a twin gestation and a sonographic short cervix in the mid-trimester reduces the risk of preterm birth occurring at < 30 to < 35 gestational weeks, neonatal mortality and some measures of neonatal morbidity, without any demonstrable deleterious effects on childhood neurodevelopment. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. C1 [Romero, R.; Conde-Agudelo, A.; Hassan, S. S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH,Dept Hlth & Human Serv, Bethesda, MD USA. [Romero, R.; Conde-Agudelo, A.; Hassan, S. S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH,Dept Hlth & Human Serv, Detroit, MI USA. [Romero, R.] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, R.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, R.] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Conde-Agudelo, A.; Hassan, S. S.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [El-Refaie, W.; Abdelhafez, M. S.] Mansoura Univ, Mansoura Univ Hosp, Dept Obstet & Gynecol, Mansoura, Egypt. [Rode, L.; Tabor, A.] Copenhagen Univ Hosp, Dept Obstet, Ctr Fetal Med & Pregnancy, Rigshosp, Copenhagen, Denmark. [Rode, L.] Herlev & Gentofte Hosp, Dept Clin Biochem, Herlev, Denmark. [Brizot, M. L.] Univ Sao Paulo, Dept Obstet & Gynecol, Sch Med, Sao Paulo, Brazil. [Cetingoz, E.] Zeynep Kamil Women & Children Dis Educ & Res Hosp, Dept Obstet & Gynecol, Istanbul, Turkey. [Serra, V.] Univ Valencia, Inst Valenciano Infertilidad, Maternal Fetal Med Unit, Valencia, Spain. [Serra, V.; Perales, A.] Univ Valencia, Dept Pediat Obstet & Gynecol, Valencia, Spain. [Da Fonseca, E.] Univ Sao Paulo, Hosp Servidor Publ Estadual Francisco Morato de O, Dept Obstet & Ginecol, Sao Paulo, Brazil. [Da Fonseca, E.] Univ Sao Paulo, Sch Med, Sao Paulo, Brazil. [Tabor, A.] Univ Copenhagen, Fac Hlth Sci, Copenhagen, Denmark. [Perales, A.] Univ Hosp La Fe, Dept Obstet, Valencia, Spain. [Nicolaides, K. H.] Kings Coll Hosp London, Harris Birthright Res Ctr Fetal Med, London, England. RP Romero, R (reprint author), NICHD, Perinatol Res Branch, Intramural Div, NIH,DHHS,Hutzel Womens Hosp, Box 4,3990 John R, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu FU Perinatology Research Branch; Federal funds from NICHD/NIH/DHHS [HHSN275201300006C] FX This research was supported, in part, by the Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH/DHHS); and, in part, with Federal funds from NICHD/NIH/DHHS under Contract No. HHSN275201300006C. NR 71 TC 1 Z9 1 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0960-7692 EI 1469-0705 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD MAR PY 2017 VL 49 IS 3 BP 303 EP 314 DI 10.1002/uog.17397 PG 12 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA EM8KD UT WOS:000395559200004 PM 28067007 ER PT J AU Pham, MN Apolo, AB De Santis, M Galsky, MD Leibovich, BC Pisters, LL Siefker-Radtke, AO Sonpavde, G Steinberg, GD Sternberg, CN Tagawa, ST Weizer, AZ Woods, ME Milowsky, MI AF Pham, M. N. Apolo, A. B. De Santis, M. Galsky, M. D. Leibovich, B. C. Pisters, L. L. Siefker-Radtke, A. O. Sonpavde, G. Steinberg, G. D. Sternberg, C. N. Tagawa, S. T. Weizer, A. Z. Woods, M. E. Milowsky, M. I. TI Upper tract urothelial carcinoma topical issue 2016: treatment of metastatic cancer SO WORLD JOURNAL OF UROLOGY LA English DT Article DE Upper tract urothelial carcinoma (UTUC); Chemotherapy; Targeted therapy; Immunotherapy; Anti-PD-1; Anti-PD-L1; Immune checkpoint inhibitors ID TRANSITIONAL-CELL-CARCINOMA; PHASE-III TRIAL; COOPERATIVE-ONCOLOGY-GROUP; CISPLATIN-BASED CHEMOTHERAPY; COLONY-STIMULATING FACTOR; BLADDER-CANCER; OPEN-LABEL; PULMONARY METASTASECTOMY; 2ND-LINE TREATMENT; RENAL-FUNCTION AB To review the management of metastatic upper tract urothelial carcinoma (UTUC) including recent advances in targeted and immune therapies as an update to the 2014 joint international consultation on UTUC, co-sponsored by the Soci,t, Internationale d'Urologie and International Consultation on Urological Diseases. A PubMed database search was performed between January 2013 and May 2016 related to the treatment of metastatic UTUC, and 54 studies were selected for inclusion. The management of patients with metastatic UTUC is primarily an extrapolation from evidence guiding the management of metastatic urothelial carcinoma of the bladder. The first-line therapy for metastatic UTUC is platinum-based combination chemotherapy. Standard second-line therapies are limited and ineffective. Patients with UTUC who progress following platinum-based chemotherapy are encouraged to participate in clinical trials. Recent advances in genomic profiling present exciting opportunities to guide the use of targeted therapy. Immunotherapy with checkpoint inhibitors has demonstrated extremely promising results. Retrospective studies provide support for post-chemotherapy surgery in appropriately selected patients. The management of metastatic UTUC requires a multi-disciplinary approach. New insights from genomic profiling using targeted therapies, novel immunotherapies, and surgery represent promising avenues for further therapeutic exploration. C1 [Pham, M. N.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Apolo, A. B.] NCI, NIH, Bethesda, MD 20892 USA. [De Santis, M.] Univ Warwick, Canc Res Unit, Coventry, W Midlands, England. [Galsky, M. D.] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA. [Leibovich, B. C.] Mayo Clin, Dept Urol, Rochester, MN USA. [Pisters, L. L.; Siefker-Radtke, A. O.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Sonpavde, G.] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL USA. [Steinberg, G. D.] Univ Chicago, Med Ctr, Dept Surg, Urol Sect, Chicago, IL 60637 USA. [Sternberg, C. N.] San Camillo Hosp, Rome, Italy. [Sternberg, C. N.] Forlanini Hosp, Rome, Italy. [Tagawa, S. T.] Weill Cornell Med, New York, NY USA. [Weizer, A. Z.] Univ Michigan, Dept Urol, Div Urol Oncol, Ann Arbor, MI 48109 USA. [Woods, M. E.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Urol, Chapel Hill, NC USA. [Milowsky, M. I.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Med, Div Hematol Oncol, 3rd Floor Phys Off Bldg,170 Manning Dr, Chapel Hill, NC 27599 USA. RP Milowsky, MI (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Med, Div Hematol Oncol, 3rd Floor Phys Off Bldg,170 Manning Dr, Chapel Hill, NC 27599 USA. EM matt_milowsky@med.unc.edu NR 55 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-4983 EI 1433-8726 J9 WORLD J UROL JI World J. Urol. PD MAR PY 2017 VL 35 IS 3 BP 367 EP 378 DI 10.1007/s00345-016-1885-4 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA EN2XG UT WOS:000395873000005 PM 27342991 ER PT J AU Onel, M Sumbul, F Liu, J Nussinov, R Haliloglu, T AF Onel, Melis Sumbul, Fidan Liu, Jin Nussinov, Ruth Haliloglu, Turkan TI Cullin neddylation may allosterically tune polyubiquitin chain length and topology SO BIOCHEMICAL JOURNAL LA English DT Article ID E3 UBIQUITIN LIGASES; RING LIGASES; STRUCTURAL INSIGHTS; PROTEIN-DEGRADATION; MOLECULAR-DYNAMICS; 26S PROTEASOME; COMPLEX; REVEALS; LYSINE; UBIQUITYLATION AB Conjugation of Nedd8 (neddylation) to Cullins (Cul) in Cul-RING E3 ligases (CRLs) stimulates ubiquitination and polyubiquitination of protein substrates. CRL is made up of two Cul-flanked arms: one consists of the substrate-binding and adaptor proteins and the other consists of E2 and Ring-box protein (Rbx). Polyubiquitin chain length and topology determine the substrate fate. Here, we ask how polyubiquitin chains are accommodated in the limited space available between the two arms and what determines the polyubiquitin linkage topology. We focus on Cul5 and Rbx1 in three states: before Cul5 neddylation (closed state), after neddylation (open state), and after deneddylation, exploiting molecular dynamics simulations and the Gaussian Network Model. We observe that regulation of substrate ubiquitination and polyubiquitination takes place through Rbx1 rotations, which are controlled by Nedd8-Rbx1 allosteric communication. Allosteric propagation proceeds from Nedd8 via Cul5 dynamic hinges and hydrogen bonds between the C-terminal domain of Cul5 (Cul5(CTD)) and Rbx1 (Cul5CTD residues R538/R569 and Rbx1 residue E67, or Cul5CTD E474/E478/N491 and Rbx1 K105). Importantly, at each ubiquitination step (homogeneous or heterogeneous, linear or branched), the polyubiquitin linkages fit into the distances between the two arms, and these match the inherent CRL conformational tendencies. Hinge sites may constitute drug targets. C1 [Onel, Melis; Sumbul, Fidan; Haliloglu, Turkan] Bogazici Univ, Polymer Res Ctr, Istanbul, Turkey. [Onel, Melis; Sumbul, Fidan; Haliloglu, Turkan] Bogazici Univ, Dept Chem Engn, Istanbul, Turkey. [Liu, Jin] Univ North Texas, Hlth Sci Ctr, Coll Pharm, Dept Pharmaceut Sci, Ft Worth, TX USA. [Nussinov, Ruth] Natl Canc Inst, Canc & Inflammat Program, Leidos Biomed Res Inc, Basic Sci Program, Frederick, MD USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, Tel Aviv, Israel. RP Haliloglu, T (reprint author), Bogazici Univ, Polymer Res Ctr, Istanbul, Turkey.; Haliloglu, T (reprint author), Bogazici Univ, Dept Chem Engn, Istanbul, Turkey.; Nussinov, R (reprint author), Natl Canc Inst, Canc & Inflammat Program, Leidos Biomed Res Inc, Basic Sci Program, Frederick, MD USA.; Nussinov, R (reprint author), Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, Tel Aviv, Israel. EM nussinor@helix.nih.gov; halilogt@boun.edu.tr FU Bogazici University [BAP 6512]; Turkish State Planning Organization [2009K120520]; Betil Fund; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Hungarian National Science Foundation [OTKA K83314]; EU [TAMOP-4.2.2/B-10/1-2010-0013]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was funded by Bogazici University (BAP 6512). T.H. acknowledges Turkish State Planning Organization grant 2009K120520 and Betil Fund. This project has also been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. It was also supported by research grants from the Hungarian National Science Foundation (OTKA K83314) and by the EU (TAMOP-4.2.2/B-10/1-2010-0013). This research was also supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 64 TC 0 Z9 0 U1 1 U2 1 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0264-6021 EI 1470-8728 J9 BIOCHEM J JI Biochem. J. PD MAR 1 PY 2017 VL 474 BP 781 EP 795 DI 10.1042/BCJ20160748 PN 5 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EN2BT UT WOS:000395815100011 PM 28082425 ER PT J AU Pratt, D Mehta, GU Wang, HW Chittiboina, P Quezado, M AF Pratt, Drew Mehta, Gautam U. Wang, Hao-Wei Chittiboina, Prashant Quezado, Martha TI A 47-YEAR OLD FEMALE WITH A DESTRUCTIVE SELLAR MASS SO BRAIN PATHOLOGY LA English DT Article ID ATYPICAL TERATOID/RHABDOID TUMORS C1 [Pratt, Drew; Wang, Hao-Wei; Quezado, Martha] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Mehta, Gautam U.; Chittiboina, Prashant] NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Pratt, D (reprint author), NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. FU Intramural Research Programs of the National Cancer Institute; National Institute of Neurological Disorders and Stroke FX This research was supported by the Intramural Research Programs of the National Cancer Institute, and the National Institute of Neurological Disorders and Stroke NR 4 TC 0 Z9 0 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1015-6305 EI 1750-3639 J9 BRAIN PATHOL JI Brain Pathol. PD MAR PY 2017 VL 27 IS 2 BP 241 EP 242 DI 10.1111/bpa.12491 PG 2 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA EM2ZQ UT WOS:000395184700016 PM 28217954 ER PT J AU Wagner, FF Flegel, WA Bittner, R Doscher, A AF Wagner, Franz F. Flegel, Willy A. Bittner, Rita Doescher, Andrea TI Molecular typing for blood group antigens within 40 min by direct polymerase chain reaction from plasma or serum SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE immunohematology; blood groups; red cell genotyping; direct PCR; transfusion medicine ID FREE FETAL DNA; MATERNAL PLASMA; TIME; DONORS; PCR; IMMUNOHEMATOLOGY; EXPRESSION; PHENOTYPES; ALLELES; SAMPLES AB Determining blood group antigens by serological methods may be unreliable in certainsituations, such as in patients after chronic or massive transfusion. Red cell genotyping offers a complementary approach, but current methods may take much longer than conventional serological typing, limiting their utility in urgent situations. To narrow this gap, we devised a rapid method using direct polymerase chain reaction (PCR) amplification while avoiding the DNA extraction step. DNA was amplified by PCR directly from plasma or serum of blood donors followed by a melting curve analysis in a capillary rapid-cycle PCR assay. We evaluated the single nucleotide polymorphisms underlying the clinically relevant Fy(a), Fy(b), Jk(a) and Jk(b) antigens, with our analysis being completed within 40min of receiving a plasma or serum sample. The positive predictive value was 100% and the negative predictive value at least 84%. Direct PCR with melting point analysis allowed faster red cell genotyping to predict blood group antigens than any previous molecular method. Our assay may be used as a screening tool with subsequent confirmatory testing, within the limitations of the false-negative rate. With fast turnaround times, the rapid-cycle PCR assay may eventually be developed and applied to red cell genotyping in the hospital setting. C1 [Wagner, Franz F.; Bittner, Rita] Inst Springe, DRK Blutspendedienst NSTOB, Springe, Germany. [Flegel, Willy A.] NIH, Dept Transfus Med, NIH Clin Ctr, 10 Ctr Dr, Bethesda, MD 20892 USA. [Doescher, Andrea] Inst Bremen Oldenburg, DRK Blutspendedienst NSTOB, Oldenburg, Germany. RP Flegel, WA (reprint author), NIH, Dept Transfus Med, NIH Clin Ctr, 10 Ctr Dr, Bethesda, MD 20892 USA. EM waf@nih.gov FU Intramural Research Program of the NIH Clinical Center [Z99 CL999999]; DRK Blutspendedienst NSTOB FX The authors thank Thomas H. Muller, director of the DRK Blutspendedienst NSTOB, for continuous support and research funding; Harvey Gordon Klein for critical review of the manuscript; and Elizabeth Jane Furlong for English edits. We acknowledge the expert technical assistance of Kathrin von Sohnen. This work was supported by the Intramural Research Program (project ID Z99 CL999999) of the NIH Clinical Center. NR 42 TC 0 Z9 0 U1 0 U2 0 PU WILEY 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 2017 VL 176 IS 5 BP 814 EP 821 DI 10.1111/bjh.14469 PG 8 WC Hematology SC Hematology GA EM3CG UT WOS:000395191500015 PM 27991657 ER PT J AU Mazor, R Kaplan, G Park, D Jang, YJ Lee, F Kreitman, R Pastan, I AF Mazor, Ronit Kaplan, Gilad Park, Dong Jang, Youjin Lee, Fred Kreitman, Robert Pastan, Ira TI Rational design of low immunogenic anti CD25 recombinant immunotoxin for T cell malignancies by elimination of T cell epitopes in PE38 SO CELLULAR IMMUNOLOGY LA English DT Article DE Immunogenicity; T cell epitopes; Pseudomonas exotoxin A; Domain II; Deimmunization; TAC; IL2 receptor; RIT ID DISULFIDE-STABILIZED FV; PSEUDOMONAS EXOTOXIN; FRAMEWORK REGIONS; ANIMAL TOXICITY; IDENTIFICATION; LEUKEMIA; RECEPTOR; DEIMMUNIZATION; CHEMOTHERAPY; ACTIVATION AB LMB-2, is a potent recombinant immunotoxin (RIT) that is composed of scFv antibody that targets CD25 (Tac) and a toxin fragment (PE38). It is used to treat T cell leukemias and lymphomas. To make LMB-2 less immunogenic, we introduced a large deletion in domain II and six point mutations in domain III that were previously shown to reduce T cell activation in other RITs. We found that unlike other RITs, deletion of domain II from LMB-2 severely compromised its activity. Rather than deletion, we identified T cell epitopes in domain II and used alanine substitutions to identify point mutations that diminished those epitopes. The novel RIT, LMB-142 contains a 38 kDa toxin and nine point mutations that diminished T cell response to the corresponding peptides by an average of 75%. LMB-142 has good cytotoxic activity and has lower nonspecific toxicity in mice. LMB-142 should be more efficient in cancer therapy because more treatment cycles can be given. Published by Elsevier Inc. C1 [Mazor, Ronit; Kaplan, Gilad; Park, Dong; Jang, Youjin; Lee, Fred; Kreitman, Robert; Pastan, Ira] NIH, Ctr Canc Res, Mol Biol Lab, Bethesda, MD 20892 USA. [Kaplan, Gilad] Medlmmune, Dept Antibody Discovery & Prot Engn, 1 Medlmmune Way, Gaithersburg, MD 20878 USA. [Park, Dong] Medytox Inc, 3F,21 Daewangpangyo Ro 644 Beon Gil 21, Seongnam Si, Gyeonggi Do, South Korea. RP Pastan, I (reprint author), NCI, Mol Biol Lab, 37 Convent Dr,Room 5106, Bethesda, MD 20892 USA. EM mazorr@mail.nih.gov; kaplang@medimmune.com; Parkkoon77@gmail.com; yjj8817@gmail.com; fred.lee@nih.gov; kreitmar@mail.nih.gov; pastani@mail.nih.gov FU Intramural Research Program of the NIH National Cancer Institute, Center for Cancer Research [ZO1 BC008753] FX This research was supported by the Intramural Research Program of the NIH (Project ZO1 BC008753) National Cancer Institute, Center for Cancer Research. NR 35 TC 0 Z9 0 U1 2 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0008-8749 EI 1090-2163 J9 CELL IMMUNOL JI Cell. Immunol. PD MAR PY 2017 VL 313 BP 59 EP 66 DI 10.1016/j.cellimm.2017.01.003 PG 8 WC Cell Biology; Immunology SC Cell Biology; Immunology GA EN7LY UT WOS:000396185500007 PM 28087047 ER PT J AU Jensen, K Bikas, A Patel, A Kushchayeva, Y Costello, J McDaniel, D Burman, K Vasko, V AF Jensen, Kirk Bikas, Athanasios Patel, Aneeta Kushchayeva, Yevgeniya Costello, John McDaniel, Dennis Burman, Kenneth Vasko, Vasyl TI Nelfinavir inhibits proliferation and induces DNA damage in thyroid cancer cells SO ENDOCRINE-RELATED CANCER LA English DT Article DE thyroid; carcinoma ID HIV PROTEASE INHIBITOR; PHASE-I TRIAL; MESENCHYMAL TRANSITION; PANCREATIC-CANCER; CARCINOMA; THERAPY; PAPILLARY; RECURRENCE; EXPRESSION; METASTASES AB The HIV protease inhibitor Nelfinavir (NFV) inhibits PI3K/AKT and MAPK/ERK signaling pathways, emerging targets in thyroid cancers. We examined the effects of NFV on cancer cells that derived from follicular (FTC), papillary (PTC) and anaplastic (ATC) thyroid cancers. NFV (1-20 mu M) was tested in FTC133, BCPAP and SW1736 cell lines. The effects of NFV on cell proliferation were determined in vitro using real-time microscopy and by flow cytometry. DNA damage, apoptotic cell death and expression of molecular markers of epithelial-mesenchymal transition (EMT) were determined by Western blot and real-time PCR. Real-time imaging demonstrated that NFV (10 mu M) increased the time required for the cell passage through the phases of cell cycle and induced DNA fragmentation. Growth inhibitory effects of NFV were associated with the accumulation of cells in G0/G1 phase, downregulation of cyclin D1 and cyclin-dependent kinase 4 (CDK4). NFV also induced the expression of gamma H2AX and p53BP1 indicating DNA damage. Treatment with NFV (20 mu M) resulted in caspase-3 cleavage in all examined cells. NFV (20 mu M) decreased the levels of total and p-AKT in PTEN-deficient FTC133 cells. NFV had no significant effects on total ERK and p-ERK in BRAF-positive BCPAP and SW1736 cells. NFV had no effects on the expression of EMT markers (Twist, Vimentin, E- and N-Cadherin), but inhibited the migration and decreased the abilities of thyroid cancer cells to survive in non-adherent conditions. We conclude that NFV inhibits proliferation and induces DNA damage in thyroid cancer cell lines. Our in vitro data suggest that NFV has a potential to become a new thyroid cancer therapeutic agent. C1 [Jensen, Kirk; Patel, Aneeta; Costello, John; Vasko, Vasyl] Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA. [Bikas, Athanasios] Georgetown Univ Hosp MedStar, Washington Hosp Ctr Internal Med Residency Progra, Dept Internal Med, Washington, DC USA. [Kushchayeva, Yevgeniya] NIDDK, NIH, Bethesda, MD 20892 USA. [McDaniel, Dennis] Uniformed Serv Univ Hlth Sci, Biomed Instrumentat Ctr, Bethesda, MD 20814 USA. [Burman, Kenneth] MedStar Washington Hosp Ctr, Endocrinol, Washington, DC USA. RP Jensen, K (reprint author), Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA. EM kirk.jensen@usuhs.edu NR 38 TC 0 Z9 0 U1 0 U2 0 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 EI 1479-6821 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD MAR PY 2017 VL 24 IS 3 BP 147 EP 156 DI 10.1530/ERC-16-0568 PG 10 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA EN3JK UT WOS:000395904600009 PM 28137980 ER PT J AU Ticinesi, A Lauretani, F Ceda, GP Ruggiero, C Ferrucci, L Aloe, R Larsson, A Cederholm, T Lind, L Meschi, T Maggio, M AF Ticinesi, Andrea Lauretani, Fulvio Ceda, Gian Paolo Ruggiero, Carmelinda Ferrucci, Luigi Aloe, Rosalia Larsson, Anders Cederholm, Tommy Lind, Lars Meschi, Tiziana Maggio, Marcello TI Uric acid and endothelial function in elderly community-dwelling subjects SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE Endothelium; Vasodilation; Metabolism; Nitric oxide; Aging ID UPPSALA-SENIORS PIVUS; FLOW-MEDIATED VASODILATION; C-REACTIVE PROTEIN; CARDIOVASCULAR-DISEASE; DEPENDENT VASODILATION; HEALTHY-ADULTS; RISK-FACTORS; BODY-FAT; HYPERURICEMIA; VASCULATURE AB The role of serum uric acid (SUA), an inflammatory agent and potential mediator of cardiovascular diseases, in endothelial function (EF) has been tested only in middle-aged subjects affected by specific diseases. Our aim was to assess the relationship between SUA and measures of EF in a cohort of elderly community-dwellers. This study involved 424 males and 426 females aged 70 years from the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS), having complete data on SUA and EF assessed by flow-mediated vasodilation (FMD) and by intra-arterial infusion of acetylcholine (endothelium-dependent vasodilation, EDV) and sodium nitroprusside (endothelium-independent vasodilation, EIDV). Univariate and multivariate regression models obtained by backward selection from initial fully-adjusted models were built to assess the relationship between SUA and measures of EF in both genders. Cardiovascular risk factors, serum hormonal and metabolic mediators, and body composition were considered as potential confounders. In the univariate model, SUA was inversely associated in both genders with log(EDV) ((3 SE males -039 +/- 0.17, p = 0.03; females -0.57 +/- 0.19, p = 0.003) and log(EIDV) (males -0.23 +/- 0.12, p = 0.05; females -0.49 +/- 0.15, p = 0.002), but not with log(FMD). After adjustment for BMI, only the association between SUA and log(EIDV) in females persisted, though attenuated (-0.32 +/- 0.16, p = 0.049), and was no longer significant in the fully-adjusted multivariate model including waist/hip ratio. In conclusion, in older subjects, especially women, SUA is associated with EF not independently of a list of confounders including BMI and trunk fat mass, suggesting a role as surrogate metabolic marker rather than an active player in EF. (C) 2017 Elsevier Inc. All rights reserved. C1 [Ticinesi, Andrea; Lauretani, Fulvio; Ceda, Gian Paolo; Meschi, Tiziana; Maggio, Marcello] Univ Parma, Dept Clin & Expt Med, Via Antonio Gramsci 14, I-43126 Parma, Italy. [Ruggiero, Carmelinda] Univ Perugia, Dept Med, Perugia, Italy. [Ferrucci, Luigi] NIA, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Aloe, Rosalia] Univ Hosp Parma, Lab Clin Chem & Hematol, Parma, Italy. [Larsson, Anders; Lind, Lars] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Cederholm, Tommy] Uppsala Univ, Dept Publ Hlth & Caring Sci, Uppsala, Sweden. RP Maggio, M (reprint author), Univ Parma, Dept Clin & Expt Med, Via Antonio Gramsci 14, I-43126 Parma, Italy. EM marcellomaggio2001@yahoo.it FU Swedish Research Council FX This work was supported by the Swedish Research Council. NR 36 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 EI 1873-6815 J9 EXP GERONTOL JI Exp. Gerontol. PD MAR PY 2017 VL 89 BP 57 EP 63 DI 10.1016/j.exger.2016.12.012 PG 7 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA EN2ML UT WOS:000395844500008 PM 28057563 ER PT J AU Bonilha, VL Bell, BA Rayborn, ME Samuels, IS King, A Hollyfield, JG Xie, CS Cai, HB AF Bonilha, Vera L. Bell, Brent A. Rayborn, Mary E. Samuels, Ivy S. King, Anna Hollyfield, Joe G. Xie, Chengsong Cai, Huaibin TI Absence of DJ-1 causes age-related retinal abnormalities in association with increased oxidative stress SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE DJ-1 knockout; Retina; Retinal degeneration; Photoreceptors; Retinal pigment epithelium; Vacuoles; Oxidative stress; Aging; Physiology; Histology; Immunohistology ID NITRIC-OXIDE SYNTHASE; MACULAR DEGENERATION AMD; LIGHT-EVOKED RESPONSES; PARKINSONS-DISEASE; PIGMENT-EPITHELIUM; DIABETIC-RETINOPATHY; MITOCHONDRIAL LOCALIZATION; CARBONYLATED PROTEINS; ALZHEIMERS-DISEASE; MOUSE RETINA AB Oxidative stress alters physiological function in most biological tissues and can lead to cell death. In the retina, oxidative stress initiates a cascade of events leading to focal loss of RPE and photoreceptors, which is thought to be a major contributing factor to geographic atrophy. Despite these implications, the molecular regulation of RPE oxidative stress under normal and pathological conditions remains largely unknown. A better understanding of the mechanisms involved in regulating RPE and photoreceptors oxidative stress response is greatly needed. To this end we evaluated photoreceptor and RPE changes in mice deficient in DJ-1, a protein that is thought to be important in protecting cells from oxidative stress. Young (3 months) and aged (18 months) DJ-1 knockout (DJ-1 KO) and age-matched wild-type mice were examined. In both group of aged mice, scanning laser ophthalmoscopy (SLO) showed the presence of a few autofluorescent foci. The 18 month-old DJ-1 KO retinas were also characterized by a noticeable increase in RPE fluorescence to wild-type. Optical coherence tomography (OCT) imaging demonstrated that all retinal layers were present in the eyes of both DJ-1 KO groups. ERG comparisons showed that older DJ-1 KO mice had reduced sensitivity under dark- and light-adapted conditions compared to age-matched control. Histologically, the RPE contained prominent vacuoles in young DJ-1 KO group with the appearance of enlarged irregularly shaped RPE cells in the older group. These were also evident in OCT and in whole mount RPE/choroid preparations labeled with phalloidin. Photoreceptors in the older DJ-1 KO mice displayed decreased immunoreactivity to rhodopsin and localized reduction in cone markers compared to the wild-type control group. Lower levels of activated Nrf2 were evident in retina/RPE lysates in both young and old DJ-1 KO mouse groups compared to wild-type control levels. Conversely, higher levels of protein carbonyl derivatives and iNOS immunoreactivity were detected in retina/RPE lysates from both young and old DJ-1 KO mice. These results demonstrate that DJ-1 KO mice display progressive signs of retinal/RPE degeneration in association with higher levels of oxidative stress markers. Collectively this analysis indicates that DJ-1 plays an important role in protecting photoreceptors and RPE from oxidative damage during aging. C1 [Bonilha, Vera L.; Hollyfield, Joe G.] Case Western Reserve Univ, Dept Ophthalmol, Cleveland Clin, Lerner Coll Med, Cleveland, OH 44195 USA. [Bonilha, Vera L.; Bell, Brent A.; Rayborn, Mary E.; Samuels, Ivy S.; King, Anna; Hollyfield, Joe G.] Cleveland Clin, Cole Eye Inst, Dept Ophthalm Res, Cleveland, OH 44195 USA. [Samuels, Ivy S.] Cleveland Vet Affairs Med Ctr, Res Serv, Cleveland, OH 44106 USA. [Xie, Chengsong; Cai, Huaibin] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. RP Bonilha, VL (reprint author), Case Western Reserve Univ, Dept Ophthalmol, Cleveland Clin, Lerner Coll Med, Cleveland, OH 44195 USA. EM bonilhav@ccf.org FU Research to Prevent Blindness; Wolf Family Foundation; Foundation Fighting Blindness; Biomedical Laboratory Research and Development [i01-BX002754]; National Eye Institute P30 Core Grant [IP30EY025585-01A1] FX This work was supported by an unrestricted grant from the Research to Prevent Blindness, Wolf Family Foundation, Foundation Fighting Blindness, a VA Merit Award i01-BX002754 from Biomedical Laboratory Research and Development (ISS) and a National Eye Institute P30 Core Grant (IP30EY025585-01A1). The author thanks David Schumick, BS, CMI for the preparation of the graphic abstract. NR 81 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD MAR PY 2017 VL 104 BP 226 EP 237 DI 10.1016/j.freeradbiomed.2017.01.018 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA EN4HJ UT WOS:000395968300018 PM 28088625 ER PT J AU Zhou, H Ding, L Wu, ZY Cao, X Zhang, QC Lin, L Bian, JS AF Zhou, Hong Ding, Lei Wu, Zhiyuan Cao, Xu Zhang, Qichun Lin, Li Bian, Jin-Song TI Hydrogen sulfide reduces RAGE toxicity through inhibition of its dimer formation SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Hydrogen sulfide; Free radicals; Aging; Neurodegeneration; Pharmacology ID GLYCATION END-PRODUCTS; ALZHEIMERS-DISEASE; THERAPEUTIC TARGET; OXIDATIVE STRESS; S-SULFHYDRATION; NEURONAL CELLS; RECEPTOR; ACTIVATION; PROTECTS; SYSTEM AB RAGE is important in the development of neurodegenerative diseases. The present study was designed to investigate the effect of hydrogen sulfide (H2S, an endogenous gaseous mediator) on the cytotoxicity caused by RAGE activation during the chronic oxidative stress. A beta(1-42) decreased cell viability and induced cell senescence in SH-SY5Y cells. Treatment with advanced glycation end products (AGEs) induced cell injury in HEK293 cells stably expressing RAGE (HEK293-RAGE) and stimulated inflammatory responses in SH-SY5Y cells. Pretreatment of SH-SY5Y cells with an H2S donor, NaHS, significantly attenuated the above harmful effects caused by A beta(1-42) or AGEs. Western blotting analysis shows that oxidative stress enhanced RAGE protein expression which was attenuated by either NaHS or over-expression of cystathionine beta-synthase (CBS), a critical enzyme for producing H2S in brain cells. Both Western blots and split GFP complementation analysis demonstrate that NaHS reduced H2O2-enhanced RAGE dimerization. Immunofluorescence analysis shows that H2O2 up-regulated the membrane expression of wild-type RAGE. However, H2O2 enhanced expression of the RAGE harboring C259S/C310S double mutation (DM-RAGE) was observed in the endoplasmic reticulum. Treatment with NaHS attenuated the effects of H2O2 on the protein expression of WT-RAGE, but not that of DM-RAGE. Cycloheximide chase and ubiquitination assays show that NaHS reduced the half-life of WT-RAGE to a similar level of DM-RAGE. Ssulfhydration assay with the tag-switch technique demonstrate that H2S may directly S-sulfhydrate the C259/ C301 residues. Our data suggest that H2S reduces RAGE dimer formation and impairs its membrane stability. The lowered plasma membrane abundance of RAGE therefore helps to protect cells against various RAGE mediated pathological effects. C1 [Zhou, Hong; Ding, Lei; Wu, Zhiyuan; Cao, Xu; Zhang, Qichun; Bian, Jin-Song] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pharmacol, 16 Med Dr,MD 3,04-01J, Singapore 117600, Singapore. [Wu, Zhiyuan] Natl Univ Singapore, Inst Life Sci, Singapore, Singapore. [Lin, Li] NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. RP Bian, JS (reprint author), Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pharmacol, 16 Med Dr,MD 3,04-01J, Singapore 117600, Singapore. EM phcbjs@nus.edu.sg FU NUHS B2B research grant [NUHSRO/2011/012/STB/B2B-08]; NMRC [NMRC/CIRG/1432/2015] FX This work was supported by NUHS B2B research grant (NUHSRO/2011/012/STB/B2B-08) and NMRC (NMRC/CIRG/1432/2015). NR 32 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD MAR PY 2017 VL 104 BP 262 EP 271 DI 10.1016/j.freeradbiomed.2017.01.026 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA EN4HJ UT WOS:000395968300021 PM 28108276 ER PT J AU Zhang, S Eitan, E Mattson, MP AF Zhang, Shi Eitan, Erez Mattson, Mark P. TI Early involvement of lysosome dysfunction in the degeneration of cerebral cortical neurons caused by the lipid peroxidation product 4-hydroxynonenal SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE apoptosis; autophagy; lipid peroxidation; lysosomes; mitophagy; ubiquitin ID AMYLOID BETA-PEPTIDE; CHAPERONE-MEDIATED AUTOPHAGY; ALZHEIMER-DISEASE BRAIN; OXIDATIVE STRESS; NEURODEGENERATIVE DISEASES; REDOX PROTEOMICS; PARKINSON DISEASE; PROTEASOME; VULNERABILITY; INHIBITION AB Free radical-mediated oxidative damage to proteins, lipids, and DNA occurs in neurons during acute brain injuries and in neurodegenerative disorders. Membrane lipid peroxidation contributes to neuronal dysfunction and death, in part by disrupting neuronal ion homeostasis and cellular bioenergetics. Emerging findings suggest that 4-hydroxynonenal (HNE), an aldehyde produced during lipid peroxidation, impairs the function of various proteins involved in neuronal homeostasis. Here we tested the hypothesis that HNE impairs the cellular system that removes damaged proteins and organelles, the autophagy-lysosome pathway in rat primary cortical neurons. We found that HNE, at a concentration that causes apoptosis over a 48 72 h period, increases protein levels of LC3 II and p62 and within 1 and 4 h of exposure, respectively; LC3 II and p62 immunoreactive puncta were observed in the cytoplasm of HNE-treated neurons at 6 h. The extent of up-regulation of p62 and LC3 II in response to HNE was not affected by co treatment with the lysosome inhibitor bafilomycin Al, suggesting that the effects of HNE on autophagy were secondary to lysosome inhibition. Indeed, we found that neurons exposed to HNE exhibit elevated pH levels, and decreased protein substrate hydrolysis and cathepsin B activity. Neurons exposed to HNE also exhibited the accumulation of K63 linked polyubiquitinated proteins, which are substrates targeted for lysosomal degradation. Moreover, we found that the levels of LAMP2a and constitutively active heat-shock protein 70, and numbers of LAMP2a-positive lysosomes, are decreased in neurons exposed to HNE. Our findings demonstrate that the lipid peroxidation product HNE causes early impairment of lysosomes which may contribute to the accumulation of damaged and dysfunctional proteins and organelles and consequent neuronal death. Because impaired lysosome function is increasingly recognized as an early event in the neuronal death that occurs in neurodegenerative disorders, our findings suggest a role for HNE in such lysosomal dysfunction. C1 [Zhang, Shi; Eitan, Erez; Mattson, Mark P.] NIA, Intramural Res Program, Neurosci Lab, BRC 5C214,251 Bayview Blvd, Baltimore, MD 21224 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Intramural Res Program, Neurosci Lab, BRC 5C214,251 Bayview Blvd, Baltimore, MD 21224 USA. EM mark.mattson@nih.gov FU Intramural Research Program of the National Institute on Aging FX This work was supported by the Intramural Research Program of the National Institute on Aging. The authors have no conflict of interest to declare. NR 59 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2017 VL 140 IS 6 BP 941 EP 954 DI 10.1111/jnc.13957 PG 14 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA EM8SM UT WOS:000395581400008 PM 28095639 ER PT J AU Coats, H Paganelli, T Starks, H Lindhorst, T Acosta, AS Mauksch, L Doorenbos, A AF Coats, Heather Paganelli, Tia Starks, Helene Lindhorst, Taryn Acosta, Anne Starks Mauksch, Larry Doorenbos, Ardith TI A Community Needs Assessment for the Development of an Interprofessional Palliative Care Training Curriculum SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article DE educational design; interprofessional curriculum; needs assessment; palliative care AB Background: There is a known shortage of trained palliative care professionals, and an even greater shortage of professionals who have been trained through interprofessional curricula. As part of an institutional Palliative Care Training Center grant, a core team of interprofessional palliative care academic faculty and staff completed a state-wide palliative care educational assessment to determine the needs for an interprofessional palliative care training program. Objective: The purpose of this article is to describe the process and results of our community needs assessment of interprofessional palliative care educational needs in Washington state. Design: We approached the needs assessment through a cross-sectional descriptive design by using mixed-method inquiry. Setting/Subjects: Each phase incorporated a variety of settings and subjects. Measurements: The assessment incorporated multiple phases with diverse methodological approaches: a preparatory phaseidentifying key informants; Phase Ikey informant interviews; Phase IIsurvey; and Phase IIIsteering committee endorsement. Results: The multiple phases of the needs assessment helped create a conceptual framework for the Palliative Care Training Center and developed an interprofessional palliative care curriculum. The input from key informants at multiple phases also allowed us to define priority needs and to refine an interprofessional palliative care curriculum. Conclusions: This curriculum will provide an interprofessional palliative care educational program that crosses disciplinary boundaries to integrate knowledge that is beneficial for all palliative care clinicians. The input from a range of palliative care clinicians and professionals at every phase of the needs assessment was critical for creating an interprofessional palliative care curriculum. C1 [Coats, Heather] Univ Washington, Cambia Palliat Care Ctr Excellence, NHLBI, NIH, Seattle, WA 98195 USA. [Paganelli, Tia; Doorenbos, Ardith] Univ Washington, Sch Nursing, Dept Biobehav Nursing & Hlth Syst, Seattle, WA 98195 USA. [Starks, Helene] Univ Washington, Dept Bioeth & Humanities, Seattle, WA 98195 USA. [Lindhorst, Taryn] Univ Washington, Sch Social Work, Seattle, WA 98195 USA. [Acosta, Anne Starks] Valora Consulting, Seattle, WA USA. [Mauksch, Larry] Univ Washington, Sch Med, Dept Family Med, Seattle, WA 98195 USA. [Doorenbos, Ardith] Univ Washington, Sch Med, Anesthesiol & Pain Med, Seattle, WA USA. RP Doorenbos, A (reprint author), Univ Washington, Dept Biobehav Nursing & Hlth Syst, Hlth Sci Bldg,1959 NE Pacific St,Off Box 357266, Seattle, WA 98195 USA. EM doorenbo@uw.edu FU Cambia Health Foundation; National Institute of Health; National Institute of Nursing Research [K24 NR015340]; National Heart, Blood, and Lung Institute [T32 HL125195] FX The authors would like to acknowledge the following: Cambia Palliative Center of Excellence; J. Randall Curtis, MD, MPH; Tony Back, MD; and Stu Farber, MD (deceased). Research reported in this article was supported by the Cambia Health Foundation, the National Institute of Health, the National Institute of Nursing Research under award number K24 NR015340, and the National Heart, Blood, and Lung Institute under award number T32 HL125195. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 12 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 EI 1557-7740 J9 J PALLIAT MED JI J. Palliat. Med. PD MAR PY 2017 VL 30 IS 3 BP 235 EP 240 DI 10.1089/jpm.2016.0321 PG 6 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EM6FC UT WOS:000395407200008 ER PT J AU Loo, CSN Lam, NSK Yu, DY Su, XZ Lu, FL AF Loo, Cecilia Shi Ni Lam, Nelson Siu Kei Yu, Deying Su, Xin-zhuan Lu, Fangli TI Artemisinin and its derivatives in treating protozoan infections beyond malaria SO PHARMACOLOGICAL RESEARCH LA English DT Review DE Artemisinin; Antiprotozoan activity; Leishmania spp; Trypanosoma spp; Toxoplasma gondii; Neospora caninum ID LEISHMANIA-DONOVANI PROMASTIGOTES; IN-VITRO EVALUATION; TOXOPLASMA-GONDII; NEOSPORA-CANINUM; VISCERAL LEISHMANIASIS; CHAGAS-DISEASE; AMEBIC MENINGOENCEPHALITIS; ANTILEISHMANIAL ACTIVITY; CUTANEOUS LEISHMANIASIS; FERRIPROTOPORPHYRIN-IX AB Parasitic protozoan diseases continue to rank among the world's greatest global health problems, which are also common among poor populations. Currently available drugs for treatment present drawbacks, urging the need for more effective, safer, and cheaper drugs. Artemisinin (ART) and its derivatives are some of the most important classes of antimalarial agents originally derived from Artemisia annua L. However, besides the outstanding antimalarial and antischistosomal activities, ART and its derivatives also possess activities against other parasitic protozoa. In this paper we review the activities of ART and its derivatives against protozoan parasites in vitro and in vivo, including Leishmania spp., Trypanosoma spp., Toxoplasma gondii, Neospora caninum, Eimeria tenella, Acanthamoeba castellanii, Naegleria fovyleri, Cryptosporidium parvum, Giardia lamblia, and Babesia spp. We conclude that ART and its derivatives may be good alternatives for treating other non-malarial protozoan infections in developing countries, although more studies are necessary before they can be applied clinically. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Loo, Cecilia Shi Ni; Lam, Nelson Siu Kei; Yu, Deying] Sun Yat Sen Univ, Zhongshan Sch Med, Bachelor Med & Bachelor Surg, Guangzhou 510080, Guangdong, Peoples R China. [Su, Xin-zhuan] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Su, Xin-zhuan] Xiamen Univ, State Key Lab Cellular Stress Biol, Xiamen 361005, Fujian, Peoples R China. [Su, Xin-zhuan] Xiamen Univ, Sch Life Sci, Xiamen 361005, Fujian, Peoples R China. [Lu, Fangli] Sun Yat Sen Univ, Zhongshan Sch Med, Dept Parasitol, Guangzhou 510080, Guangdong, Peoples R China. [Lu, Fangli] Sun Yat Sen Univ, Key Lab Trop Dis Control, Minist Educ, Guangzhou 510080, Guangdong, Peoples R China. RP Lu, FL (reprint author), Sun Yat Sen Univ, Zhongshan Sch Med, Dept Parasitol, Guangzhou 510080, Guangdong, Peoples R China.; Lu, FL (reprint author), Sun Yat Sen Univ, Key Lab Trop Dis Control, Minist Educ, Guangzhou 510080, Guangdong, Peoples R China. EM fanglilu@yahoo.com FU Natural Science Foundation of China [81471973, 81273643]; Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, National Institutes of Health; Science and Technology Planning Project of Guangdong Province, China [2014A020212108]; Project 111 of the State Bureau of Foreign Experts and Ministry of Education of China [B06016]; Education and Teaching Reform Project of Sun Yat-sen University, China FX This publication was supported in part by the Natural Science Foundation of China (nos. 81471973 and 81273643); the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, National Institutes of Health; the Science and Technology Planning Project of Guangdong Province, China (no. 2014A020212108); the Project 111 of the State Bureau of Foreign Experts and Ministry of Education of China (B06016), and the Education and Teaching Reform Project of Sun Yat-sen University, China (2016). The authors thank Cindy Clark, NIH Library Writing Center, for manuscript editing assistance. NR 102 TC 0 Z9 0 U1 2 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 2017 VL 117 BP 192 EP 217 DI 10.1016/j.phrs.2016.11.012 PG 26 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EN2MQ UT WOS:000395845000020 PM 27867026 ER PT J AU Goodyear, K Lee, MR Schwandt, ML Hodgkinson, CA Leggio, L AF Goodyear, Kimberly Lee, Mary R. Schwandt, Melanie L. Hodgkinson, Colin A. Leggio, Lorenzo TI Hepatic, lipid and genetic factors associated with obesity: crosstalk with alcohol dependence? SO WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY LA English DT Article DE Obesity; alcohol dependence; FTO; genetics; metabolism ID FTO GENE; METABOLIC SYNDROME; FAT MASS; CONSUMPTION; ADDICTION; GHRELIN; RISK; VARIANT; PREVALENCE; MECHANISMS AB Objectives: Alcohol dependence represents a leading cause of mortality and morbidity. Understanding the variables that contribute to this diagnosis and its severity is critical. An overlap between factors that may predispose people to become obese and those that may increase the risk of alcohol dependence may exist. However, data in the literature are not conclusive. Therefore, this study aimed to identify the association between alcohol dependence and obesity-related factors, including biochemical and genetic factors.Methods: In a case-control study with 829 participants, factors involved with metabolism and obesity were assessed, including biochemical lipid and liver markers, and the fat mass and obesity-associated (FTO) single nucleotide polymorphism (SNP) rs8050136.Results: Increased triglycerides, having one or two minor A alleles for rs8050136 and being a smoker were associated with increased risk of alcohol dependence, while increased low-density lipoprotein cholesterol was associated with decreased risk. In addition, having abnormal gamma-glutamyl transferase and being female were factors associated with an increased severity of alcohol dependence.Conclusions: Our preliminary findings suggest a link between alcohol dependence and obesity-related biochemical and genetic factors. Future studies are needed to better understand if these factors may play a predictive role and/or may act as biomarkers for treatment response. C1 [Goodyear, Kimberly; Lee, Mary R.; Leggio, Lorenzo] NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, 10 Ctr Dr 10CRC 15330, Bethesda, MD 20892 USA. [Goodyear, Kimberly; Lee, Mary R.; Leggio, Lorenzo] NIDA, 10 Ctr Dr 10CRC 15330, Bethesda, MD 20892 USA. [Goodyear, Kimberly; Leggio, Lorenzo] Brown Univ, Ctr Alcohol & Addict Studies, Dept Behav & Social Sci, Providence, RI 02912 USA. [Schwandt, Melanie L.] NIAAA, Off Clin Director, NIH, Bethesda, MD USA. [Hodgkinson, Colin A.] NIAAA, Lab Neurogenet, NIH, Rockville, MD 20852 USA. RP Leggio, L (reprint author), NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, 10 Ctr Dr 10CRC 15330, Bethesda, MD 20892 USA.; Leggio, L (reprint author), NIDA, 10 Ctr Dr 10CRC 15330, Bethesda, MD 20892 USA. EM lorenzo.leggio@nih.gov FU NIH [ZIA-AA000218]; Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA); Intramural Research Program of the National Institute on Drug Abuse (NIDA) FX This work was supported by NIH intramural funding ZIA-AA000218 (Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology; PI: Leggio), jointly supported by the Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the Intramural Research Program of the National Institute on Drug Abuse (NIDA). NR 46 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1562-2975 EI 1814-1412 J9 WORLD J BIOL PSYCHIA JI World J. Biol. Psychiatry PD MAR PY 2017 VL 18 IS 2 BP 120 EP 128 DI 10.1080/15622975.2016.1249952 PG 9 WC Psychiatry SC Psychiatry GA EM1UW UT WOS:000395103600003 PM 27905213 ER PT J AU Henderson, LA Shankar, LK AF Henderson, Lori A. Shankar, Lalitha K. TI Clinical Translation of the National Institutes of Health's Investments in Nanodrug Products and Devices SO AAPS JOURNAL LA English DT Review DE clinical trials; devices; nanodrugs; nanomedicine; nanotechnology ID FUTURE; STATE AB The National Institutes of Health (NIH), a part of the U.S. Department of Health and Human Services, is the primary Federal agency for conducting and supporting biomedical research. The NIH's mission is to seek fundamental knowledge about the nature and behavior of living systems and to apply that knowledge to enhance health, lengthen life, and reduce illness and disability. In support of this mission, NIH has invested about $4.4 billion since 2001 in nanotechnology (NT) research. This investment is leading to fundamental changes in understanding biological processes in health and disease, as well as enabling novel diagnostics and interventions for treating disease. NIH scientists are developing molecular agents and methods for earlier and more accurate diagnosis and therapies aimed directly and selectively at diseased cells, and are exploring root causes of common and rare diseases at the nanoscale. Work is also underway to move these research tools and devices into clinical practice. This particular investigative review examines the NIH NT portfolio linked to clinical trials from FY2008 to FY2015 to assess the progress of clinical translation. Among the subset of trials identified, 70% target drug or combination drug-device products used in treating cancer, AIDS, and other various diseases. The review also provides insight into trends observed from studying the clinical research portfolio. C1 [Henderson, Lori A.; Shankar, Lalitha K.] NCI, Diagnost Imaging Branch, Div Canc Treatment & Diag, NIH, 9609 Med Ctr Dr, Rockville, MD 20850 USA. RP Henderson, LA (reprint author), NCI, Diagnost Imaging Branch, Div Canc Treatment & Diag, NIH, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM hendersonlori@mail.nih.gov NR 14 TC 0 Z9 0 U1 0 U2 0 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 2017 VL 19 IS 2 BP 343 EP 359 DI 10.1208/s12248-016-9995-x PG 17 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EM0KA UT WOS:000395006000003 PM 27995455 ER PT J AU Carlier, J Diao, XX Sempio, C Huestis, MA AF Carlier, Jeremy Diao, Xingxing Sempio, Cristina Huestis, Marilyn A. TI Identification of New Synthetic Cannabinoid ADB-CHMINACA (MAB-CHMINACA) Metabolites in Human Hepatocytes SO AAPS JOURNAL LA English DT Article DE ADB-CHMINACA; hepatocyte metabolism; high resolution mass spectrometry; MAB-CHMINACA; synthetic cannabinoid ID RESOLUTION MASS-SPECTROMETRY; VIVO HUMAN METABOLISM; URINARY METABOLITES; RECEPTOR AGONIST; SOLID TISSUES; HUMAN CADAVER; AB-FUBINACA; IN-VITRO; AM-2201; 5F-AB-PINACA AB ADB-CHMINACA (MAB-CHMINACA) is a new synthetic cannabinoid with high potency and many reported adverse events and fatalities. The drug is currently scheduled in several countries in Europe and the USA. Analytical methods need to be developed to confirm ADB-CHMINACA intake for clinical and forensic programs. For many synthetic cannabinoids, parent compound is not detectable in biological samples after intake, making the detection of metabolites the only way to prove consumption. Therefore, detection of ADB-CHMINACA metabolites in biological specimens is critical. Since there are currently no published data on ADB-CHMINACA metabolism, we aimed to identify its major metabolites. Cryopreserved human hepatocytes were incubated with 10 mu mol/L ADB-CHMINACA for 3 h. Incubations were analyzed with liquid chromatography on a biphenyl column, high resolution tandem mass spectrometry (orbitrap), and metabolite identification software. A reference standard of six commercially available potential metabolites was simultaneously analyzed under the same conditions to allow correct assignment of isomers. We detected ten major metabolites. Biotransformations mainly occurred at the cyclohexylmethyl tail of the compound, as also observed with structural analogs' metabolism. Minor reactions also occurred at the tert-butyl chain. Only two analytical standards of potential metabolites matched an actual metabolite detected in hepatocyte incubations. We recommend A9 (ADB-CHMINACA hydroxycyclohexylmethyl), A4 (ADB-CHMINACA 4aEuro(3)-hydroxycyclohexyl), and A6 (ADB-CHMINACA hydroxycyclohexylmethyl) as metabolite targets to document ADB-CHMINACA intake in clinical and forensic cases. Additionally, these results will guide analytical standard manufacturers to better provide suitable references for further studies on ADB-CHMINACA metabolism. C1 [Carlier, Jeremy; Diao, Xingxing; Sempio, Cristina; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, Clin Pharmacol & Therapeut Res Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Diao, Xingxing] XenoBiotic Labs Inc, Plainsboro, NJ 08536 USA. [Sempio, Cristina] Univ Colorado, Clin Res & Dev IC42, Aurora, CO 80045 USA. [Huestis, Marilyn A.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab Sect, Clin Pharmacol & Therapeut Res Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA.; Huestis, MA (reprint author), Univ Maryland, Sch Med, Baltimore, MD 21201 USA. EM marilyn.huestis@gmail.com FU Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health FX The authors would like to thank Tim Moeller from BioreclamationIVT for his assistance with the incubations, and Caroline Ding, Helen Sun, and Thermo Scientific for providing LC-HRMS instrumentation, Compound Discoverer (R) software and training via a National Institute on Drug Abuse Materials Transfer Agreement. This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 41 TC 0 Z9 0 U1 0 U2 0 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 2017 VL 19 IS 2 BP 568 EP 577 DI 10.1208/s12248-016-0037-5 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EM0KA UT WOS:000395006000025 PM 28070717 ER PT J AU Kline-Simon, AH Litten, RZ Weisner, CM Falk, DE AF Kline-Simon, Andrea H. Litten, Raye Z. Weisner, Constance M. Falk, Daniel E. TI Posttreatment Low-Risk Drinking as a Predictor of Future Drinking and Problem Outcomes Among Individuals with Alcohol Use Disorders: A 9-Year Follow-Up SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Low-Risk Drinking; Long-Term Outcomes; Long-Term Psychosocial Functioning; Alcohol ID RANDOMIZED CONTROLLED-TRIAL; ADDICTION SEVERITY INDEX; DEPENDENCE; REMISSION; CARE; HMO AB Background: Treatment for alcohol use disorders (AUDs) has traditionally been abstinence oriented, but new research and regulatory guidelines suggest that low-risk drinking may also be an acceptable treatment outcome. However, little is known about long-term outcomes for patients who become low-risk drinkers posttreatment. This study explores a posttreatment low-risk drinking outcome as a predictor of future drinking and psychosocial outcomes over 9 years. Methods: Study participants were adults with AUDs at treatment entry who received follow-up interviews 6 months posttreatment intake (N - 1,061) in 2 large randomized studies conducted at Kaiser Permanente Northern California, a large private, nonprofit, integrated health system. Six-month drinking status was defined as abstinent, low-risk (nonabstinent, no 5+ drinking days), or heavy drinking (1 or more days of 5+ drinks). Using logistic regression models, we explored the relationship between past 30-day drinking status at 6 months and odds of being abstinent or a low-risk drinker (compared to heavy drinking), and positive Addiction Severity Index psychosocial outcomes over 9 years (9-year follow-up rate of 73%). Results: Abstainers and low-risk drinkers at 6 months had higher odds of recent abstinence/lowrisk drinking over 9 years than heavy drinkers; abstainers had better drinking outcomes than low-risk drinkers. Additionally, among those with interview data, 95% of abstainers and 94% of low-risk drinkers at 6 months were abstinent/low-risk drinkers at 9 years; surprisingly, 89% of heavy drinkers at 6 months were also abstinent/low-risk drinkers although still significantly fewer than the other groups. Abstainers and low-risk drinkers at 6 months had better psychiatric outcomes, and abstainers had better family/social outcomes than heavy drinkers; medical outcomes did not differ. Low-risk drinkers and abstainers showed no reliable differences across psychosocial measures. Conclusions: The findings suggest that a low-risk drinking outcome may be reasonable over the long-term for some alcohol-dependent individuals receiving addiction treatment. C1 [Kline-Simon, Andrea H.; Weisner, Constance M.] Kaiser Permanente Northern Calif, Div Res, 2000 Broadway, Oakland, CA 94612 USA. [Litten, Raye Z.; Falk, Daniel E.] NIAAA, Bethesda, MD USA. [Weisner, Constance M.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. RP Kline-Simon, AH (reprint author), Kaiser Permanente Northern Calif, Div Res, 2000 Broadway, Oakland, CA 94612 USA. EM Andrea.H.Kline-Simon@kp.org FU National Institute on Alcohol Abuse and Alcoholism Grant [R37 AA10359, 3R01AA016204-06S1]; National Institute on Drug Abuse [R37 DA10572] FX This study was supported by grants from the National Institute on Alcohol Abuse and Alcoholism Grant (R37 AA10359) and Supplement (3R01AA016204-06S1) and the National Institute on Drug Abuse (R37 DA10572). We thank Agatha Hinman, BA, for editorial assistance. The authors report no conflicts of interest. NR 24 TC 0 Z9 0 U1 0 U2 0 PU WILEY 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 2017 VL 41 IS 3 BP 653 EP 658 DI 10.1111/acer.13334 PG 6 WC Substance Abuse SC Substance Abuse GA EM0WM UT WOS:000395038400022 PM 28072453 ER PT J AU Takyar, V Etzion, O Heller, T Kleiner, DE Rotman, Y Ghany, MG Fryzek, N Williams, VH Rivera, E Auh, S Liang, TJ Hoofnagle, JH Koh, C AF Takyar, V. Etzion, O. Heller, T. Kleiner, D. E. Rotman, Y. Ghany, M. G. Fryzek, N. Williams, V. H. Rivera, E. Auh, S. Liang, T. J. Hoofnagle, J. H. Koh, C. TI Complications of percutaneous liver biopsy with Klatskin needles: a 36-year single-centre experience SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID NODULAR REGENERATIVE HYPERPLASIA; CHRONIC HEPATITIS-C; COAGULATION DISORDERS; NATIONWIDE SURVEY; DISEASE; CIRRHOSIS; RISK; MANAGEMENT; ARTICLE AB Background Liver biopsy is the gold standard in evaluating liver diseases but is susceptible to complications. Safety data on aspiration needle biopsies remain limited. Aim To evaluate the safety of percutaneous liver biopsy performed with Klatskin needle. Methods Clinical and biochemical data were retrospectively retrieved from sequential subjects who underwent liver biopsy with Klatskin needle from 1978 to 2015. Subjects with complications underwent thorough chart reviews for hospital course. Results Of 3357 biopsies performed, complications occurred in 135 (4%) biopsies with 33 (1%) resulting in major complications. Severe pain occurred in 78 (2.3%) subjects and bleeding occurred in 21 (0.6%) subjects. Biliary injury occurred in 8 (0.2%) biopsies. Three subjects died as a result of massive intraperitoneal bleeding. Compared to viral hepatitis, biopsies performed with certain diagnosis had significantly higher odds of major complications: NRH (OR: 17), DILI (OR: 20), GVHD (OR: 32) and HCC (OR: 34). Subjects with major complications had higher pre-biopsy median AP (153 vs. 78 U/L, P < 0.001), ALT (105 vs. 64 U/L, P < 0.05), AST (62 vs. 47 U/L, P < 0.02), along with marginally lower total bilirubin (1.0 vs. 0.7 mg/dL, P < 0.01) and albumin (3.7 vs. 4.0 g/dL, P < 0.001). By multivariate backward logistic regression, platelets <= 100 K mu/L and aPTT >35 were independent risk factors of post-biopsy bleeding. Conclusion Klatskin needle liver biopsies are safe with rare procedural morbidity. Our data suggests certain acutely ill subjects and those with systemic illnesses may be at higher risk of major complications. Clinicians should weigh the risks and benefits of liver biopsy in these patients with other alternative approaches. C1 [Takyar, V.; Etzion, O.; Heller, T.; Rotman, Y.; Ghany, M. G.; Fryzek, N.; Williams, V. H.; Rivera, E.; Liang, T. J.; Hoofnagle, J. H.; Koh, C.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Kleiner, D. E.] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Auh, S.] NIDDK, Off Director, NIH, Bethesda, MD USA. RP Koh, C (reprint author), NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. EM christopher.koh@nih.gov FU Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute of the National Institutes of Health FX This research was supported by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute of the National Institutes of Health. NR 39 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 EI 1365-2036 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD MAR PY 2017 VL 45 IS 5 BP 744 EP 753 DI 10.1111/apt.13939 PG 10 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA EL5WU UT WOS:000394693000016 PM 28074540 ER PT J AU Chitsaz, E AF Chitsaz, E. TI Letter: multivariate clinical model for eosinophilic oesophagitis - is this generalisable to general population SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Letter C1 [Chitsaz, E.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Chitsaz, E (reprint author), NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. EM ehsan.chitsaz@nih.gov NR 2 TC 1 Z9 1 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 EI 1365-2036 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD MAR PY 2017 VL 45 IS 6 BP 860 EP 860 DI 10.1111/apt.13919 PG 1 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA EL5XK UT WOS:000394694600013 PM 28211627 ER PT J AU Vilboux, T Malicdan, MCV Roney, JC Cullinane, AR Stephen, J Yildirimli, D Bryant, J Fischer, R Vemulapalli, M Mullikin, JC Steinbach, PJ Gahl, WA Gunay-Aygun, M AF Vilboux, Thierry Malicdan, May Christine V. Roney, Joseph C. Cullinane, Andrew R. Stephen, Joshi Yildirimli, Deniz Bryant, Joy Fischer, Roxanne Vemulapalli, Meghana Mullikin, James C. Steinbach, Peter J. Gahl, William A. Gunay-Aygun, Meral CA NISC Comparative Sequencing TI CELSR2, Encoding a Planar Cell Polarity Protein, Is a Putative Gene in Joubert Syndrome with Cortical Heterotopia, Microophthalmia, and Growth Hormone Deficiency SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Joubert syndrome; CELSR2; planar cell polarity; ciliopathy ID CILIOPATHIES; DISRUPTION; CADHERINS AB Joubert syndrome is a ciliopathy characterized by a specific constellation of central nervous system malformations that result in the pathognomonic molar tooth sign on imaging. More than 27 genes are associated with Joubert syndrome, but some patients do not have mutations in any of these genes. Celsr1, Celsr2, and Celsr3 are the mammalian orthologues of the drosophila planar cell polarity protein, flamingo; they play important roles in neural development, including axon guidance, neuronal migration, and cilium polarity. Here, we report bi-allelic mutations in CELSR2 in a Joubert patient with cortical heterotopia, microophthalmia, and growth hormone deficiency. (C) 2017 Wiley Periodicals, Inc. C1 [Vilboux, Thierry; Malicdan, May Christine V.; Roney, Joseph C.; Cullinane, Andrew R.; Stephen, Joshi; Yildirimli, Deniz; Bryant, Joy; Fischer, Roxanne; Gahl, William A.; Gunay-Aygun, Meral] NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. [Vilboux, Thierry] Inova Translat Med Inst, Falls Church, VA USA. [Malicdan, May Christine V.; Gahl, William A.] NIH, NIH Undiagnosed Dis Program, Common Fund, Off Director, Bldg 10, Bethesda, MD 20892 USA. [Cullinane, Andrew R.] Howard Univ, Coll Med, Dept Anat, Washington, DC USA. [Vemulapalli, Meghana; Mullikin, James C.; NISC Comparative Sequencing] NHGRI, NISC, NIH, Bethesda, MD 20892 USA. [Steinbach, Peter J.] NIH, Ctr Mol Modeling, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. [Gahl, William A.; Gunay-Aygun, Meral] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Malicdan, MCV (reprint author), NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM malicdanm@mail.nih.gov NR 21 TC 1 Z9 1 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD MAR PY 2017 VL 173 IS 3 BP 661 EP 666 DI 10.1002/ajmg.a.38005 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA EL8XN UT WOS:000394903800012 PM 28052552 ER PT J AU Jelovsek, JE AF Jelovsek, J. Eric TI A randomized trial of uterosacral ligament suspension or sacrospinous ligament fixation for apical pelvic organ prolapse: Five-year outcomes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 43rd Annual Scientific Meeting of the Society-of-Gynecologic-Surgeons (SGS) CY MAR 26-29, 2017 CL San Antonio, TX SP Soc Gynecol Surg C1 [Jelovsek, J. Eric] Cleveland Clin, Obstet Gynecol & Womens Hlth, Cleveland, OH 44106 USA. [Jelovsek, J. Eric] NICHD, Pelv Floor Disorders Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAR PY 2017 VL 216 IS 3 SU S MA 9 BP S566 EP S566 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EO9ZP UT WOS:000397046900011 ER PT J AU Zhu, LC Olsen, RJ Lee, JD Porter, AR Deleo, FR Musser, JM AF Zhu, Luchang Olsen, Randall J. Lee, Jessica D. Porter, Adeline R. Deleo, Frank R. Musser, James M. TI Contribution of Secreted NADase and Streptolysin 0 to the Pathogenesis of Epidemic Serotype M1 Streptococcus pyogenes Infections SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID GROUP-A STREPTOCOCCUS; HEMOLYTIC STREPTOCOCCI; VIRULENCE; GENE; GLYCOHYDROLASE; DISEASE; PURIFICATION; NUCLEOTIDE; EXPRESSION; SEPARATION AB Streptococcus pyogenes secretes many toxins that facilitate human colonization, invasion, and dissemination. NADase (SPN) and streptolysin O (SLO) are two toxins that play important roles in pathogenesis. We previously showed that increased production of SPN and SLO in epidemic serotype and M89 S. pyogenes strains is associated with rapid intercontinental spread and enhanced virulence. The biological functions of SPN and SLO have been extensively studied using eukaryotic cell lines, but the relative contribution of each of these two toxins to pathogenesis of epidemic M1. or M89 strains remains unexplored. Herein, using a genetically representative epidemic M1 strain and a panel of isogenic mutant derivative strains, we evaluated the relative contributions of SPN and SLO toxins to virulence in mouse models of necrotizing myositis, bacteremia, and skin and soft tissue infection. We found that isogenic mutants lacking SPN, SLO, and both toxins are equally impaired in ability to cause necrotizing myositis. In addition, mutants lacking either SPN or SLO are significantly attenuated in the bacteremia and soft tissue infection models, and the mutant strain lacking production of both toxins is further attenuated. The mutant strain lacking both SPN and SLO production is severely attenuated in ability to resist killing by human polymorphonuclear leukocytes. We conclude that both SPN and SLO contribute significantly to S. pyogenes pathogenesis in these virulence assays. C1 [Zhu, Luchang; Olsen, Randall J.; Musser, James M.] Houston Methodist Res Inst, Ctr Mol & Translat Human Infect Dis Res, Houston, TX USA. [Zhu, Luchang; Olsen, Randall J.; Musser, James M.] Houston Methodist Hosp, Dept Pathol & Genom Med, Houston, TX USA. [Lee, Jessica D.] Rice Univ, Dept Biosci, Houston, TX USA. [Porter, Adeline R.; Deleo, Frank R.] NIAID, Bacteriol Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. RP Musser, JM (reprint author), Houston Methodist Res Inst, Dept Pathol & Genom Med, 6565 Fannin St,Ste B490, Houston, TX 77030 USA. EM jmmusser@houstonmethodist.org RI Zhu, Luchang/C-9784-2017 OI Zhu, Luchang/0000-0002-4064-5781 FU Fondren Foundation; National Institute of Allergy and Infectious Diseases, NIH; Intramural Research Program; Rice University Century Scholar program FX Supported by the Fondren Foundation (J.M.M.) and in part by the National Institute of Allergy and Infectious Diseases, NIH, Intramural Research Program (F.R.D.). J.D.L. was supported by the Rice University Century Scholar program. NR 36 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 0002-9440 EI 1525-2191 J9 AM J PATHOL JI Am. J. Pathol. PD MAR PY 2017 VL 187 IS 3 BP 605 EP 613 DI 10.1016/j.ajpath.2016.11.003 PG 9 WC Pathology SC Pathology GA EL3ZC UT WOS:000394558200013 PM 28034602 ER PT J AU Lionakis, MS Albert, ND Swamydas, M Lee, CCR Loetscher, P Kontoyiannis, DP AF Lionakis, Michail S. Albert, Nathaniel D. Swamydas, Muthulekha Lee, Chyi-Chia R. Loetscher, Pius Kontoyiannis, Dimitrios P. TI Pharmacological Blockade of the Chemokine Receptor CCR1 Protects Mice from Systemic Candidiasis of Hematogenous Origin SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article DE CCR1; Candida; candidiasis; chemokine receptor ID INVASIVE CANDIDIASIS AB Systemic candidiasis is a leading cause of nosocomial bloodstream infection with a high mortality rate despite treatment. Immune-based strategies are needed to improve outcomes. We previously reported that genetic deficiency in the chemokine receptor CCR1 improves survival and ameliorates tissue damage in Candida-infected mice. Here, we found that treatment of immunocompetent Candida-infected mice with the CCR1-selective antagonist BL5923 improves survival, decreases the kidney fungal burden, and protects from renal tissue injury. C1 [Lionakis, Michail S.; Swamydas, Muthulekha] NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Albert, Nathaniel D.; Kontoyiannis, Dimitrios P.] Univ Texas MD Anderson Canc Ctr, Dept Infect Dis Infect Control & Employee Hlth, Houston, TX 77030 USA. [Lee, Chyi-Chia R.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Loetscher, Pius] Novartis Inst Biomed Res, Autoimmun Transplantat & Inflammat, Basel, Switzerland. RP Lionakis, MS (reprint author), NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Kontoyiannis, DP (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Infect Dis Infect Control & Employee Hlth, Houston, TX 77030 USA. EM lionakism@mail.nih.gov; dkontoyi@mdanderson.org FU Division of Intramural Research; National Institute of Allergy and Infectious Diseases; NIH FX D.P.K. acknowledges the Frances King Black Endowed Professorship for Cancer Research. This work was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. NR 17 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD MAR PY 2017 VL 61 IS 3 AR e02365-16 DI 10.1128/AAC.02365-16 PG 4 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA EL4QM UT WOS:000394605900033 ER PT J AU Chen, CX Mao, YS Foster, P Zhu, ZW Du, J Guo, CY AF Chen, Chang-Xi Mao, Yu-Shan Foster, Parker Zhu, Zhong-Wei Du, Juan Guo, Chuan-Yong TI Possible association between Helicobacter pylori infection and nonalcoholic fatty liver disease SO APPLIED PHYSIOLOGY NUTRITION AND METABOLISM LA English DT Article DE nonalcoholic fatty liver disease; Helicobacter pylori infection; ResNet Database; pathway enrichment analysis; network connectivity analysis ID GASTRIC EPITHELIAL-CELLS; INSULIN-RESISTANCE; MANAGEMENT; EPIDEMIOLOGY; GASTROENTEROLOGY; INFLAMMATION; PROGRESSION; POPULATION; PREVALENCE; HYPOTHESIS AB Possible association between Helicobacter pylori infection (HPI) and nonalcoholic fatty liver disease (NAFLD) has been proposed by several studies with inconsistent conclusions. Here, we studied the association between HPI and NAFLD at 3 levels: (i) genetic level; (ii) small molecular level; and (iii) clinical level. Relation data between diseases, genes, and small molecules were acquired from Pathway Studio ResNet Mammalian database. Clinical data were acquired from 2263 elderly South Chinese subjects, including 603 NAFLD patients and 1660 subjects without NAFLD. Results showed that HPI and NAFLD present significantly shared genetic bases (95 genes, p value = 2.5E-72), demonstrating multiple common genetic pathways (enrichment p value <= 4.38E-20 for the top 10 pathways). Genetic network analysis suggested that mutual regulation may exist between HPI and NAFLD through 21 out of 95 genes. Furthermore, 85 out of the 95 genes manifested strong interaction with 12 small molecules/drugs that demonstrate effectiveness in treating both diseases. Clinical results showed that HPI rate in the NAFLD group was significantly higher than that in the group without NAFLD (51.9% vs. 43.6%; p value = 4.9E-4). Multivariate logistic regression results supported the observations and suggested that HPI served as a risk factor for NAFLD in the experiment data studied (odds ratio: 1.387, p value = 0.018). Results from this study support the hypothesis that complex biological association may exist between HPI and NAFLD, which partially explains the significant clinical co-incidence in the elderly population of south China. C1 [Chen, Chang-Xi] Soochow Univ, Affiliated Hosp 1, Dept Gastroenterol, Suzhou 215006, Peoples R China. [Chen, Chang-Xi; Zhu, Zhong-Wei; Du, Juan] Zhenhai Lianhua Hosp, Dept Gastroenterol, Ningbo 315207, Zhejiang, Peoples R China. [Mao, Yu-Shan] Ningbo Univ, Coll Med, Affiliated Hosp, Dept Endocrinol, Ningbo 315020, Zhejiang, Peoples R China. [Foster, Parker] NIH, Dept Radiol & Imaging Sci, Bethesda, MD 20852 USA. [Guo, Chuan-Yong] Tongji Univ, Sch Med, Shanghai Peoples Hosp 10, Dept Gastroenterol, Shanghai 200072, Peoples R China. RP Guo, CY (reprint author), Tongji Univ, Sch Med, Shanghai Peoples Hosp 10, Dept Gastroenterol, Shanghai 200072, Peoples R China. EM c.guo@gousinfo.com FU Social Development Program of Ningbo, China [2013C50044, 2011C50021]; Social Development and Science & Technology Program of Zhenhai, Ningbo, China [2013S1002]; Medical Science & Technology Foundation of Zhenhai, Ningbo, China [2014020] FX This study was partly funded by the Social Development Program of Ningbo, China (no. 2013C50044, no. 2011C50021); The Social Development and Science & Technology Program of Zhenhai, Ningbo, China (no. 2013S1002); and Medical Science & Technology Foundation of Zhenhai, Ningbo, China (no. 2014020). NR 39 TC 0 Z9 0 U1 1 U2 1 PU CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS PI OTTAWA PA 65 AURIGA DR, SUITE 203, OTTAWA, ON K2E 7W6, CANADA SN 1715-5312 EI 1715-5320 J9 APPL PHYSIOL NUTR ME JI Appl. Physiol. Nutr. Metab. PD MAR PY 2017 VL 42 IS 3 BP 295 EP 301 DI 10.1139/apnm-2016-0499 PG 7 WC Nutrition & Dietetics; Physiology; Sport Sciences SC Nutrition & Dietetics; Physiology; Sport Sciences GA EM8DH UT WOS:000395541000010 PM 28177748 ER PT J AU Shi, N Li, CX Cui, XB Tomarev, SI Chen, SY AF Shi, Ning Li, Chen-Xiao Cui, Xiao-Bing Tomarev, Stanislav I. Chen, Shi-You TI Olfactomedin 2 Regulates Smooth Muscle Phenotypic Modulation and Vascular Remodeling Through Mediating Runt-Related Transcription Factor 2 Binding to Serum Response Factor SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE carotid arteries; contractile proteins; hyperplasia; neointima; vascular remodeling ID REDUCES NEOINTIMAL FORMATION; DIVISION CYCLE 7; GROWTH-FACTOR; GENE-EXPRESSION; CELL DIFFERENTIATION; IN-VIVO; INTIMAL HYPERPLASIA; MYOCARDIN; PROLIFERATION; PDGF AB Objective-The objective of this study is to investigate the role and underlying mechanism of Olfactomedin 2 (Olfm2) in smooth muscle cell (SMC) phenotypic modulation and vascular remodeling. Approach and Results-Platelet-derived growth factor-BB induces Olfm2 expression in primary SMCs while modulating SMC phenotype as shown by the downregulation of SMC marker proteins. Knockdown of Olfm2 blocks platelet-derived growth factor-BB-induced SMC phenotypic modulation, proliferation, and migration. Conversely, Olfm2 overexpression inhibits SMC marker expression. Mechanistically, Olfm2 promotes the interaction of serum response factor with the runt-related transcription factor 2 that is induced by platelet-derived growth factor-BB, leading to a decreased interaction between serum response factor and myocardin, causing a repression of SMC marker gene transcription and consequently SMC phenotypic modulation. Animal studies show that Olfm2 is upregulated in balloon-injured rat carotid arteries. Knockdown of Olfm2 effectively inhibits balloon injury-induced neointima formation. Importantly, knockout of Olfm2 in mice profoundly suppresses wire injury-induced neointimal hyperplasia while restoring SMC contractile protein expression, suggesting that Olfm2 plays a critical role in SMC phenotypic modulation in vivo. Conclusions-Olfm2 is a novel factor mediating SMC phenotypic modulation. Thus, Olfm2 may be a potential target for treating injury-induced proliferative vascular diseases. C1 [Shi, Ning; Li, Chen-Xiao; Cui, Xiao-Bing; Chen, Shi-You] Univ Georgia, Dept Physiol & Pharmacol, 501 DW Brooks Dr, Athens, GA 30602 USA. [Tomarev, Stanislav I.] NEI, Sect Retinal Gangl Cell Biol, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Chen, SY (reprint author), Univ Georgia, Dept Physiol & Pharmacol, 501 DW Brooks Dr, Athens, GA 30602 USA. EM sc229@uga.edu FU National Institutes of Health [HL123302, HL119053, HL135854] FX This work was supported by grants from National Institutes of Health (HL123302, HL119053, and HL135854). NR 47 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 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD MAR PY 2017 VL 37 IS 3 BP 446 EP + DI 10.1161/ATVBAHA.116.308606 PG 20 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA EL4DR UT WOS:000394572400015 PM 28062493 ER PT J AU Gao, SG Cui, XQ Wang, XJ Burg, MB Dmitrieva, NI AF Gao, Shouguo Cui, Xiangqin Wang, Xujing Burg, Maurice B. Dmitrieva, Natalia I. TI Cross-Sectional Positive Association of Serum Lipids and Blood Pressure With Serum Sodium Within the Normal Reference Range of 135-145 mmol/L SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE blood pressure; cardiovascular diseases; cholesterol; risk factors; stroke ID CORONARY-HEART-DISEASE; PLASMA SODIUM; CARDIOVASCULAR-DISEASE; ATHEROSCLEROSIS RISK; MULTIVARIABLE ANALYSIS; ENDOTHELIAL-CELLS; COMMUNITIES; PREDICTION; SALT; HOMEOSTASIS AB Objective-Serum sodium concentration is maintained by osmoregulation within normal range of 135 to 145 mmol/L. Previous analysis of data from the ARIC study (Atherosclerosis Risk in Communities) showed association of serum sodium with the 10-year risk scores of coronary heart disease and stroke. Current study evaluated the association of within-normal-range serum sodium with cardiovascular risk factors. Approach and Results-Only participants who did not take cholesterol or blood pressure medications and had sodium within normal 135 to 145 mmol/L range were included (n=8615), and the cohort was stratified based on race, sex, and smoking status. Multiple linear regression analysis of data from ARIC study was performed, with adjustment for age, blood glucose, insulin, glomerular filtration rate, body mass index, waist to hip ratio, and calorie intake. The analysis showed positive associations with sodium of total cholesterol, low-density lipoprotein cholesterol, and total cholesterol to high-density lipoprotein cholesterol ratio; apolipoprotein B; and systolic and diastolic blood pressure. Increases in lipids and blood pressure associated with 10 mmol/L increase in sodium are similar to the increases associated with 7 to 10 years of aging. Analysis of sodium measurements made 3 years apart demonstrated that it is stable within 2 to 3 mmol/L, explaining its association with long-term health outcomes. Furthermore, elevated sodium promoted lipid accumulation in cultured adipocytes, suggesting direct causative effects on lipid metabolism. Conclusions-Serum sodium concentration is a cardiovascular risk factor even within the normal reference range. Thus, decreasing sodium to the lower end of the normal range by modification of water and salt intake is a personalizable strategy for decreasing cardiovascular risks. C1 [Gao, Shouguo; Wang, Xujing] NHLBI, Bioinformat & Syst Biol Core, Syst Biol Ctr, Bldg 10, Bethesda, MD 20892 USA. [Burg, Maurice B.; Dmitrieva, Natalia I.] NHLBI, Renal Cellular & Mol Biol Sect, Syst Biol Ctr, Bldg 10, Bethesda, MD 20892 USA. [Dmitrieva, Natalia I.] NHLBI, Lab Cardiovasc & Regenerat Med, Ctr Mol Med, Bldg 10, Bethesda, MD 20892 USA. [Cui, Xiangqin] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL USA. RP Dmitrieva, NI (reprint author), NHLBI, Ctr Mol Med, 9000 Rockville Pike,10 CRC,Room 5E-3256, Bethesda, MD 20892 USA. EM dmitrien@nhlbi.nih.gov FU Intramural Program of the National Heart, Lung and Blood Institute FX This study was funded by the Intramural Program of the National Heart, Lung and Blood Institute. NR 54 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD MAR PY 2017 VL 37 IS 3 BP 598 EP + DI 10.1161/ATVBAHA.116.308413 PG 18 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA EL4DR UT WOS:000394572400031 PM 28062505 ER PT J AU Lee, H Gill, J Barr, T Yun, SJ Kim, H AF Lee, Hyunhwa Gill, Jessica Barr, Taura Yun, Sijung Kim, Hyungsuk TI Primer in Genetics and Genomics, Article 2-Advancing Nursing Research With Genomic Approaches: A Review of Methodological Considerations SO BIOLOGICAL RESEARCH FOR NURSING LA English DT Article DE epigenomics; genomics; nursing research ID DISCOVERY; SCIENCE; ASSOCIATION; MICROBIOME; BIOMARKERS; DISORDERS; PHENOTYPE; PATHWAYS AB Purpose: Nurses investigate reasons for variable patient symptoms and responses to treatments to inform how best to improve outcomes. Genomics has the potential to guide nursing research exploring contributions to individual variability. This article is meant to serve as an introduction to the novel methods available through genomics for addressing this critical issue and includes a review of methodological considerations for selected genomic approaches. Approach: This review presents essential concepts in genetics and genomics that will allow readers to identify upcoming trends in genomics nursing research and improve research practice. It introduces general principles of genomic research and provides an overview of the research process. It also highlights selected nursing studies that serve as clinical examples of the use of genomic technologies. Finally, the authors provide suggestions about how to apply genomic technology in nursing research along with directions for future research. Conclusions: Using genomic approaches in nursing research can advance the understanding of the complex pathophysiology of disease susceptibility and different patient responses to interventions. Nurses should be incorporating genomics into education, clinical practice, and research as the influence of genomics in health-care research and practice continues to grow. Nurses are also well placed to translate genomic discoveries into improved methods for patient assessment and intervention. C1 [Lee, Hyunhwa] Univ Nevada, Sch Nursing, 4505 S Maryland Pkwy,Box 453018, Las Vegas, NV 89154 USA. [Gill, Jessica; Kim, Hyungsuk] NINR, NIH, Bethesda, MD 20892 USA. [Barr, Taura] CereDx Inc, Morgantown, WV USA. [Yun, Sijung] Yotta Biomed LLC, Bethesda, MD USA. RP Lee, H (reprint author), Univ Nevada, Sch Nursing, 4505 S Maryland Pkwy,Box 453018, Las Vegas, NV 89154 USA. EM hyunhwa.lee@unlv.edu NR 43 TC 0 Z9 0 U1 1 U2 1 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 2017 VL 19 IS 2 SI SI BP 229 EP 239 DI 10.1177/1099800416689822 PG 11 WC Nursing SC Nursing GA EL7BF UT WOS:000394775400013 PM 28135824 ER PT J AU Morton, LM Saber, W Baker, KS Barrett, AJ Bhatia, S Engels, EA Gadalla, SM Kleiner, DE Pavletic, S Burns, LJ AF Morton, Lindsay M. Saber, Wael Baker, K. Scott Barrett, A. John Bhatia, Smita Engels, Eric A. Gadalla, Shahinaz M. Kleiner, David E. Pavletic, Steven Burns, Linda J. TI National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Subsequent Neoplasms Working Group Report SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Subsequent neoplasms; Second malignancies; Hematopoietic cell; transplantation; Long-term follow-up; Late effects ID BONE-MARROW-TRANSPLANTATION; ACUTE MYELOID-LEUKEMIA; CORD BLOOD TRANSPLANTATION; SEVERE APLASTIC-ANEMIA; LONG-TERM SURVIVORS; TOTAL-BODY IRRADIATION; VERSUS-HOST-DISEASE; THERAPY-RELATED LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; POPULATION-BASED COHORT AB Subsequent neoplasms (SN) after hematopoietic cell transplantation (HCT) cause significant patient morbidity and mortality. Risks for specific SN types vary substantially, with particularly elevated risks for post transplantation lymphoproliferative disorders, myelodysplastic syndrome/acute myeloid leukemia, and squamous cell malignancies. This document provides an overview of the current state of knowledge regarding SN after HCT and recommends priorities and approaches to overcome challenges and gaps in understanding. Numerous factors have been suggested to affect risk, including patient-related (eg, age), primary disease-related (eg, disease type, pre-HCT therapies), and HCT-related characteristics (eg, type and intensity of conditioning regimen, stem cell source, development of graft-versus-host disease). However, gaps in understanding remain for each of these risk factors, particularly for patients receiving HCT in the current era because of substantial advances in clinical transplantation practices. Additionally, the influence of nontransplantation-related risk factors (eg, germline genetic susceptibility, oncogenic viruses, lifestyle factors) is poorly understood. Clarification of the magnitude of SN risks and identification of etiologic factors will require large-scale, long-term, systematic follow-up of HCT survivors with detailed clinical data. Most investigations of the mechanisms of SN pathogenesis after HCT have focused on immune drivers. Expansion of our understanding in this area will require interdisciplinary laboratory collaborations utilizing measures of immune function and availability of archival tissue from SN diagnoses. Consensus based recommendations for optimal preventive, screening, and therapeutic approaches have been developed for certain SN after HCT, whereas for other SN, general population guidelines are recommended. Further evidence is needed to specifically tailor preventive, screening, and therapeutic guidelines for SN after HCT, particularly for unique patient populations. Accomplishment of this broad research agenda will require increased investment in systematic data collection with engagement from patients, clinicians, and interdisciplinary scientists to reduce the burden of SN in the rapidly growing population of HCT survivors. Published by Elsevier Inc. on behalf of the American Society for Blood and Marrow Transplantation. C1 [Morton, Lindsay M.] Natl Canc Inst, Natl Inst Hlth, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, Bethesda, MD USA. [Saber, Wael] Div Hematol Oncol, Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Depot Intent Med, Milwaukee, WI USA. [Baker, K. Scott] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA USA. [Barrett, A. John] Natl Inst Hlth, Natl Heart Lung & Blood Inst, Hematol Branch, Stem Cell Transplantation Section, Bethesda, MD USA. [Bhatia, Smita] Univ Alabama, Inst Canc Outcomes & Survivorship, Tuscaloosa, AL 35487 USA. [Engels, Eric A.] Natl Canc Inst, Natl Inst Hlth, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, Bethesda, MD USA. [Gadalla, Shahinaz M.] Natl Canc Inst, Natl Inst Hlth, Div Canc Epidemiol & Genet, Clin Genet Branch, Bethesda, MD USA. [Kleiner, David E.] Natl Canc Inst, Natl Inst Hlth, Ctr Canc Res, Pathol Lab, Bethesda, MD USA. [Pavletic, Steven] Natl Canc Inst, Natl Inst Hlth, Expt Transplantat & Immunol Branch, Ctr Canc Res, Bethesda, MD USA. [Burns, Linda J.] Match & Ctr Int Blood & Marrow Transplant Res, Natl Marrow Donor Program, Minneapolis, MN USA. RP Morton, LM (reprint author), Natl Canc Inst, Natl Inst Hlth, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, Bethesda, MD USA. EM mortonli@mail.nih.gov FU National Heart, Lung, and Blood Institute (NHLBI); National Cancer Institute (NCI) FX We thank the members of the National Institutes of Health Late Effects Initiative Steering Committee (Minoo Battiwalla, Shahrukh Hashmi, Navneet Majhail, Steven Pavletic, Bipin Savani, and Nonniekaye Shelburne) for their leadership of this initiative and critical review of the manuscript. We thank Mary Flowers and Gerard Socie for their critical review of the manuscript. We thank Barbara Brandys, National Institutes of Health Library, for conducting the literature database searches, and we thank Filip Pirsl for his assistance reviewing literature and preparing supplementary tables regarding GVHD. This initiative was sponsored jointly by the National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute (NCI). NR 200 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD MAR PY 2017 VL 23 IS 3 BP 367 EP 378 DI 10.1016/j.bbmt.2016.09.005 PG 12 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA EM5QL UT WOS:000395367300002 PM 27634019 ER PT J AU Heimall, J Puck, J Buckley, R Fleisher, TA Gennery, AR Neven, B Slatter, M Haddad, E Notarangelo, LD Baker, KS Dietz, AC Duncan, C Pulsipher, MA Cowan, MJ AF Heimall, Jennifer Puck, Jennifer Buckley, Rebecca Fleisher, Thomas A. Gennery, Andrew R. Neven, Benedicte Slatter, Mary Haddad, Elie Notarangelo, Luigi D. Baker, K. Scott Dietz, Andrew C. Duncan, Christine Pulsipher, Michael A. Cowan, Mort J. TI Current Knowledge and Priorities for Future Research in Late Effects after Hematopoietic Stem Cell Transplantation (HCT) for Severe Combined Immunodeficiency Patients: A Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric HCT SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Late effects; Pediatric allogeneic bone; marrow transplantation; Severe combined; immunodeficiency ID INTENSITY CONDITIONING REGIMEN; TERM IMMUNE RECONSTITUTION; SENSORINEURAL DEAFNESS; IMPROVED SURVIVAL; THYMIC OUTPUT; SINGLE-CENTER; CORD BLOOD; CHILDREN; DEFICIENCY; BUSULFAN AB Severe combined immunodeficiency (SCID) is 1 of the most common indications for pediatric hematopoietic cell transplantation (HCT) in patients with primary immunodeficiency. Historically, SCID was diagnosed in infants who presented with opportunistic infections within the first year of life. With newborn screening (NBS) for SCID in most of the United States, the majority of infants with SCID are now diagnosed and treated in the first 3.5 months of life; however, in the rest of the world, the lack of NBS means that most infants with SCID still present with infections. The average survival for SCID patients who have undergone transplantation currently is >70% at 3 years after transplantation, although this can vary significantly based on multiple factors, including age and infection status at the time of transplantation, type of donor source utilized, manipulation of graft before transplantation, graft-versus-host disease prophylaxis, type of conditioning (if any) utilized, and underlying genotype of SCID. In at least 1 study of SCID patients who received no conditioning, long-term survival was 77% at 8.7 years (range out to 26 years) after transplantation. Although a majority of patients with SCID will engraft T cells without any conditioning therapy, depending on genotype, donor source, HLA match, and presence of circulating maternal cells, a sizable percentage of these will fail to achieve full immune reconstitution. Without conditioning, T cell reconstitution typically occurs, although not always fully, whereas B cell engraftment does not, leaving some molecular types of SCID patients with intrinsically defective B cells, in most cases, dependent on regular infusions of immunoglobulin. Because of this, many centers have used conditioning with alkylating agents including busulfan or melphalan known to open marrow niches in attempts to achieve B cell reconstitution. Thus, it is imperative that we understand the potential late effects of these agents in this patient population. There are also nonimmunologic risks associated with HCT for SCID that appear to be dependent upon the genotype of the patient. In this report, we have evaluated the published data on late effects and attempted to summarize the known risks associated with conditioning and alternative donor sources. These data, while informative, are also a clear demonstration that there is still much to be learned from the SCID population in terms of their post-HCT outcomes. This paper will summarize current findings and recommend further research in areas considered high priority. Specific guidelines regarding a recommended approach to long-term follow-up, including laboratory and clinical monitoring, will be forthcoming in a subsequent paper. (C) 2017 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved. C1 [Heimall, Jennifer] Childrens Hosp Philadelphia, Univ Pennsylvania, Perelman Sch Med, Div Allergy & Immunol, Philadelphia, PA USA. [Puck, Jennifer; Cowan, Mort J.] Univ Calif San Francisco, Blood & Marrow Transplant Div, Dept Pediat, Allergy, San Francisco, CA USA. [Buckley, Rebecca] Duke Univ Med Ctr, Dept Pediat & Immunol, Durham, NC USA. [Fleisher, Thomas A.] Natl Inst Hlth, Dept Lab Med, Bethesda, MD USA. [Gennery, Andrew R.; Slatter, Mary] Univ Newcastle Tyne, United Kingdom Inst Cellular Med, Dept Paediat Immunol, Newcastle Tyne, Newcastle Upon Tyne, Tyne & Wear, England. [Neven, Benedicte] Dept Immunol, Bone Marrow Transplantat, Hop Necker Enfants Malades, Paris, France. [Haddad, Elie] Univ Montreal, Dept Microbiol, Dept Pediat, Infect & Immunol, Montreal, PQ, Canada. [Notarangelo, Luigi D.] Natl Inst Hlth, Lab Host Defenses, NIAID, Bethesda, MD USA. [Baker, K. Scott] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA USA. [Dietz, Andrew C.; Pulsipher, Michael A.] Childrens Hosp Angeles, Childrens Ctr Canc & Blood Dis, Los Angeles, CA USA. [Duncan, Christine] Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA. [Pulsipher, Michael A.] Childrens Hosp Angeles, USC Keck Sch Med, Div Hematol, Oncol & Blood & Marrow Transplantat, 4650 Sunset Blvd, Los Angeles, CA 90027 USA. RP Pulsipher, MA (reprint author), Childrens Hosp Angeles, USC Keck Sch Med, Div Hematol, Oncol & Blood & Marrow Transplantat, 4650 Sunset Blvd, Los Angeles, CA 90027 USA. EM mpulsipher@chla.usc.edu FU National Institutes of Health [1R13CA159788-01, U01HL069254, RO1 CA078938, U54AI082973, R13AI094943]; St. Baldrick's Foundation [2015 Consortium award] [360529] FX This work was supported in part by grants from the National Institutes of Health (1R13CA159788-01 [to M.P.], U01HL069254 [to M.P.], RO1 CA078938 [to S.B.], U54AI082973 L.N., J.P., and R.B.], R13AI094943 [M.J.C. and L.N.] and the St. Baldrick's Foundation [2015 Consortium award, ID: 360529] [to M.P]). The views expressed in this paper do not reflect the official policies of the Department of Health and Human Services, nor does mention of trade names, commercial practices, or organizations imply endorsement by the US Government. The content is solely the responsibility of the authors and does not necessarily represent the official views of those that provided funding. NR 54 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 2017 VL 23 IS 3 BP 379 EP 387 DI 10.1016/j.bbmt.2016.12.619 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA EM5QL UT WOS:000395367300003 PM 28068510 ER PT J AU Best, AF Wolfson, DB AF Best, Ana F. Wolfson, David B. TI Nested case-control study designs for left-truncated survival data SO CANADIAN JOURNAL OF STATISTICS-REVUE CANADIENNE DE STATISTIQUE LA English DT Article DE Canadian Longitudinal Study on Aging; left truncation; nested case-control; risk set sampling; study design; survival analysis ID CASE-COHORT DESIGN; EPIDEMIOLOGIC COHORT; DISEASE; MODEL AB The determination of risk factors for disease incidence has been the subject of much epidemiologic research. With this goal a common study design entails the follow-up of an initially disease-free cohort, keeping track of the dates of disease incidence (onset) and ascertaining covariate (putative risk factor) information on the full cohort. However, the collection of certain covariate information on all study subjects may be prohibitively expensive and, therefore, the nested case-control study has commonly been used. The high cost of full covariate information on all subjects also arises when determining risk factors for "failure," death say, "following" disease onset, in particular, in a prevalent cohort study with follow-up; in such a study a cohort of subjects with existing disease is followed. We here adapt nested case-control designs to the setting of a prevalent cohort study with follow-up, a topic previously not addressed in the literature. We provide the partial likelihood under risk set sampling and state the asymptotic properties of the estimated covariate effects and baseline cumulative hazard. We address the following design questions in the context of prevalent cohort studies with follow-up: How many subjects should be included in the sampled risk sets for efficient estimation? In what way is the proportion of censored subjects associated with the benefit of a nested case-control design? What proportion of overall variance is attributable to risk set sampling? This work is motivated by the anticipated analysis of data on survival with Parkinson's Disease, being collected as part of the ongoing Canadian Longitudinal Study on Aging. (C) 2017 Statistical Society of Canada C1 [Best, Ana F.] NCI, NIH, Div Canc Epidemiol & Genet, Biostat Branch, 9609 Med Ctr Dr,MSC 9776, Bethesda, MD 20892 USA. [Wolfson, David B.] McGill Univ, Dept Math & Stat, Burnside Hall Room 1005,805 Sherbrooke St West, Montreal, PQ H3A 0B9, Canada. RP Best, AF (reprint author), NCI, NIH, Div Canc Epidemiol & Genet, Biostat Branch, 9609 Med Ctr Dr,MSC 9776, Bethesda, MD 20892 USA. EM ana.best@nih.gov FU Schulich Graduate Fellowship; National Cancer Institute Intramural Research Program; National Sciences and Engineering Council of Canada Discovery Grant FX This research was funded in part by a Schulich Graduate Fellowship (Ana Best), the National Cancer Institute Intramural Research Program (Ana Best), and a National Sciences and Engineering Council of Canada Discovery Grant (David Wolfson). We thank an associate editor and reviewer for their suggestions that, we believe, led to a much improved article. NR 22 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0319-5724 EI 1708-945X J9 CAN J STAT JI Can. J. Stat.-Rev. Can. Stat. PD MAR PY 2017 VL 45 IS 1 BP 4 EP 28 DI 10.1002/cjs.11311 PG 25 WC Statistics & Probability SC Mathematics GA EM0WD UT WOS:000395037500001 ER PT J AU Romieu, I Dossus, L Barquera, S Blottiere, HM Franks, PW Gunter, M Hwalla, N Hursting, SD Leitzmann, M Margetts, B Nishida, C Potischman, N Seidell, J Stepien, M Wang, YF Westerterp, K Winichagoon, P Wiseman, M Willett, WC AF Romieu, Isabelle Dossus, Laure Barquera, Simon Blottiere, Herve M. Franks, Paul W. Gunter, Marc Hwalla, Nahla Hursting, Stephen D. Leitzmann, Michael Margetts, Barrie Nishida, Chizuru Potischman, Nancy Seidell, Jacob Stepien, Magdalena Wang, Youfa Westerterp, Klaas Winichagoon, Pattanee Wiseman, Martin Willett, Walter C. CA IARC Working Grp Energy Balance TI Energy balance and obesity: what are the main drivers? SO CANCER CAUSES & CONTROL LA English DT Article DE Energy intake; Energy expenditure; Energy balance; Obesity; Satiety; Diet ID BODY-MASS INDEX; SUGAR-SWEETENED BEVERAGES; RANDOMIZED CONTROLLED-TRIAL; ULTRA-PROCESSED FOODS; WEIGHT-GAIN; PHYSICAL-ACTIVITY; MEDITERRANEAN DIET; CHILDHOOD OBESITY; LIKELY IMPACT; VISCERAL FAT AB The aim of this paper is to review the evidence of the association between energy balance and obesity. In December 2015, the International Agency for Research on Cancer (IARC), Lyon, France convened a Working Group of international experts to review the evidence regarding energy balance and obesity, with a focus on Low and Middle Income Countries (LMIC). The global epidemic of obesity and the double burden, in LMICs, of malnutrition (coexistence of undernutrition and overnutrition) are both related to poor quality diet and unbalanced energy intake. Dietary patterns consistent with a traditional Mediterranean diet and other measures of diet quality can contribute to long-term weight control. Limiting consumption of sugar-sweetened beverages has a particularly important role in weight control. Genetic factors alone cannot explain the global epidemic of obesity. However, genetic, epigenetic factors and the microbiota could influence individual responses to diet and physical activity. Energy intake that exceeds energy expenditure is the main driver of weight gain. The quality of the diet may exert its effect on energy balance through complex hormonal and neurological pathways that influence satiety and possibly through other mechanisms. The food environment, marketing of unhealthy foods and urbanization, and reduction in sedentary behaviors and physical activity play important roles. Most of the evidence comes from High Income Countries and more research is needed in LMICs. C1 [Romieu, Isabelle; Dossus, Laure; Gunter, Marc; Stepien, Magdalena] Int Agcy Res Canc, Nutr & Metab Sect, 150 Cours Albert Thomas, F-69372 Lyon 08, France. [Barquera, Simon] Inst Nacl Salud Publ, Ctr Invest Nutr & Salud, Cuernavaca, Morelos, Mexico. [Blottiere, Herve M.] Univ Paris Saclay, Micalis Inst, MGP MetagenoPolis, INRA,AgroParisTech, Jouy En Josas, France. [Franks, Paul W.] Lund Univ, Univ Hosp Malmo, Genet & Mol Epidemiol Unit, Diabet Ctr,CRC, Malmo, Sweden. [Hwalla, Nahla] Amer Univ Beirut, Fac Agr & Food Sci, Beirut, Lebanon. [Hursting, Stephen D.] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. [Hursting, Stephen D.] Univ N Carolina, Inst Nutr Res, Chapel Hill, NC USA. [Leitzmann, Michael] Univ Regensburg, Dept Epidemiol & Prevent Med, Regensburg, Germany. [Margetts, Barrie] Univ Southampton, Southampton Gen Hosp, Fac Med, Southampton, Hants, England. [Nishida, Chizuru] WHO, Dept Nutr Hlth & Dev NHD, Nutr Policy & Sci Advice NPU, Geneva, Switzerland. [Potischman, Nancy] NCI, Off Associate Director, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Seidell, Jacob] Univ Amsterdam, Fac Earth & Life Sci, Dept Hlth Sci, Amsterdam, Netherlands. [Wang, Youfa] SUNY Buffalo, Dept Epidemiol & Environm Hlth, Sch Publ Hlth & Hlth Profess, Buffalo, NY USA. [Wang, Youfa] SUNY Buffalo, Sch Med & Biomed Sci, Buffalo, NY USA. [Westerterp, Klaas] Maastricht Univ, NUTRIM Sch Nutr & Translat Res Metab, Maastricht, Netherlands. [Winichagoon, Pattanee] Mahidol Univ Salaya, Inst Nutr, Nakhon Pathom, Thailand. [Wiseman, Martin] World Canc Res Fund Int, London, England. [Willett, Walter C.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. RP Romieu, I (reprint author), Int Agcy Res Canc, Nutr & Metab Sect, 150 Cours Albert Thomas, F-69372 Lyon 08, France. EM romieu@iarc.fr NR 111 TC 0 Z9 0 U1 5 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD MAR PY 2017 VL 28 IS 3 BP 247 EP 258 DI 10.1007/s10552-017-0869-z PG 12 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EM0CI UT WOS:000394986000008 PM 28210884 ER PT J AU Smith, C Parboosingh, JS Boycott, KM Bonnemann, CG Mah, JK Lamont, RE Innes, AM Bernier, FP AF Smith, C. Parboosingh, J. S. Boycott, K. M. Boennemann, C. G. Mah, J. K. Lamont, R. E. Innes, A. Micheil Bernier, F. P. CA Care4Rare Canada Consortium TI Expansion of the GLE1-associated arthrogryposis multiplex congenita clinical spectrum SO CLINICAL GENETICS LA English DT Article DE exome; infantile SMA; motor neuron disease; mRNA export; RNA metabolism; spinal muscular atrophy ID MESSENGER-RNA EXPORT; MOTONEURON DISEASE; SPLICING SIGNALS; NUCLEAR EXPORT; MUTATIONS; MEDIATOR AB Mutations in GLE1 cause two recessive subtypes of arthrogryposis multiplex congenita (AMC), a condition characterized by joint contractures at birth, and all previously reported patients died in the perinatal period. GLE1 related AMC has been almost exclusively reported in the Finnish population and is caused by a relatively common pathogenic splicing mutation in that population. Here, we report two non-Finnish brothers with novel compound heterozygous splicing mutations in GLE1, one of whom has survived to 12 years of age. We also demonstrate low levels of residual wild type transcript in fibroblasts from the surviving brother, suggesting that this residual wild-type transcript may contribute to the relatively longer-term survival in this family. We provide a detailed clinical report on the surviving patient, providing the first insight into the natural history of this rare neuromuscular disease. We also suggest that lethal congenital contracture syndrome 1 (LCCS1) and lethal arthrogryposis with anterior horn disease (LAAHD), the two AMC subtypes related to GLE1, do not have sufficient clinical or molecular differentiation to be considered allelic disorders. Rather, GLE1 mutations cause a variable spectrum of AMC severity including a non-lethal variant described herein. C1 [Smith, C.; Parboosingh, J. S.; Lamont, R. E.; Innes, A. Micheil; Bernier, F. P.] Univ Calgary, Cumming Sch Med, Dept Med Genet, 2888 Shaganappi Trail NW, Calgary, AB T3B 6A8, Canada. [Parboosingh, J. S.; Mah, J. K.; Lamont, R. E.; Innes, A. Micheil; Bernier, F. P.] Univ Calgary, Alberta Childrens Hosp Res Inst, Calgary, AB, Canada. [Boycott, K. M.] Univ Ottawa, Childrens Hosp Eastern Ontario Res Inst, Ottawa, ON, Canada. [Boennemann, C. G.] Natl Inst Hlth, Neuromuscular & Neurogenet Disorders Childhood S, Bethesda, MD USA. [Mah, J. K.] Univ Calgary, Cumming Sch Med, Dept Pediat, Div Neurol, Calgary, AB, Canada. RP Bernier, FP (reprint author), Univ Calgary, Cumming Sch Med, Dept Med Genet, 2888 Shaganappi Trail NW, Calgary, AB T3B 6A8, Canada. EM Francois.bernier@albertahealthservices.ca FU Genome Canada; Canadian Institutes of Health Research; Ontario Genomics Institute; Ontario Research Fund; Genome Quebec; Children's Hospital of Eastern Ontario Foundation; Alberta Children's Hospital Research Institute; Alberta Innovates Health Solutions FX We thank the patients and family for participating in our research. We would also like to thank Dr. Jennifer Gerritsen, Linda MacLaren, Rachelle Bistretzan, Dr. Jacek Majewski, Dr. Martine Tetreault and Sandra Donkervoort for their contributions to this project. This work was funded in part by Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, the Ontario Research Fund, Genome Quebec, the Children's Hospital of Eastern Ontario Foundation, Alberta Children's Hospital Research Institute, and Alberta Innovates Health Solutions. This work was selected for study by the Care4Rare (Enhanced Care for Rare Genetic Diseases in Canada) Consortium Gene Discovery Steering Committee: Kym Boycott (lead; University of Ottawa), Alex MacKenzie (co-lead; University of Ottawa), Jacek Majewski (McGillUniversity), Michael Brudno (University of Toronto), Dennis Bulman (University of Ottawa), and David Dyment (University of Ottawa). NR 19 TC 0 Z9 0 U1 2 U2 2 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9163 EI 1399-0004 J9 CLIN GENET JI Clin. Genet. PD MAR PY 2017 VL 91 IS 3 BP 426 EP 430 DI 10.1111/cge.12876 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA EM0KQ UT WOS:000395007600008 PM 27684565 ER PT J AU Ahn, J Albusaysi, S Alfonsi, J Ande, A Bank, P Barr, E Bezencon, J Bhagwat, S Borden, B Bos, J Brewer, J Bruckm, H Chanu, P Chen, XY Chen, H Chen, MQ Chowdhury, S Chu, LH Cooper, J Dhapare, S Freimuth, R Freise, K Hashida, T Hassan, O He, J Hoefman, S Hutchaleelaha, A Imai, S Jackson, I Job, K Kaspera, R Kleiber, N Klopp-Schulze, L Kramers, C Kumar, S Lai, E Lam, J Leibrand, C Lemmen, J Li, J Lo, A Lon, HK Maas, H Maass, C Marcath, L Marroum, P Morse, B Mostafa, N Mueck, W Mukherjee, D Ning, MR Oishi, M Pak, Y Park, WS Pasternak, A Piao, Z Poi, M Prasad, TN Prem, K Ramaiya, A Raut, A Rotter, C Salem, F Schmidt, K Seligson, N Shibata, K Shivva, V Suleiman, A Tanner, JA Tariq, B Trueman, S Wind, S Xia, C Xiong, H Yamada, T Yang, UO Yu, JJ Zhang, S Zhao, WH Zhou, JW AF Ahn, Jihye Albusaysi, Salwa Alfonsi, Jeffrey Ande, Anusha Bank, Paul Barr, Erin Bezencon, Jacqueline Bhagwat, Sharvari Borden, Brittany Bos, Jacqueline Brewer, Jamie Bruckm, Henrike Chanu, Pascal Chen, Xiaoying Chen, Heller Chen, Mingqing Chowdhury, Swapan Chu, Liang-Hui Cooper, Jennifer Dhapare, Sneha Freimuth, Robert Freise, Kevin Hashida, Tohru Hassan, Omar He, Jimmy Hoefman, Sven Hutchaleelaha, Athiwat Imai, Satoki Jackson, Isabel Job, Kathleen Kaspera, Rudiger Kleiber, Niina Klopp-Schulze, Lena Kramers, Cornelis Kumar, Shaun Lai, Eseng Lam, Justine Leibrand, Crystal Lemmen, Julia Li, Jerry Lo, Arthur Lon, Hoi Kei Maas, Hugo Maass, Christian Marcath, Lauren Marroum, Patrick Morse, Bridget Mostafa, Nael Mueck, Wolfgang Mukherjee, Dwaipavan Ning, Miaoran Oishi, Masayo Pak, Youngeen Park, Wan-Su Pasternak, Amy Piao, Zhenji Poi, Ming Prasad, Nagendra T. Prem, Komal Ramaiya, Atulkumar Raut, Anuja Rotter, Charles Salem, Farzaneh Schmidt, Keith Seligson, Nathan Shibata, Kaito Shivva, Vittal Suleiman, Ahmed Tanner, Julie-Anne Tariq, Bilal Trueman, Sheryl Wind, Sven Xia, Cindy Xiong, Hao Yamada, Takahiro Yang, Uan-Ou Yu, Jingjing Zhang, Steven Zhao, Weihan Zhou, Jiawei CA ASCPT Members TI 2017 Annual Meeting - What you need to know before you arrive SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material C1 [Ahn, Jihye] US FDA, Washington, DC 20204 USA. [Albusaysi, Salwa] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Alfonsi, Jeffrey] Univ Western Ontario, London, ON N6A 3K7, Canada. [Ande, Anusha] Univ Florida, Gainesville, FL 32611 USA. [Bank, Paul] Leiden Univ, Med Ctr, NL-2300 RA Leiden, Netherlands. [Barr, Erin; Borden, Brittany] Univ Chicago, Chicago, IL 60637 USA. [Bezencon, Jacqueline] Univ N Carolina, Chapel Hill, NC USA. [Bhagwat, Sharvari] Amgen Inc, Thousand Oaks, CA USA. [Bos, Jacqueline] Canisius Wilhelmina Hosp, Nijmegen, Netherlands. [Brewer, Jamie] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Bruckm, Henrike] Univ Hosp Schleswig Holstein, Kiel, Germany. [Chanu, Pascal] F Hoffmann La Roche Ltd, Basel, Switzerland. [Chen, Xiaoying] Pfizer Global Res & Dev, New London, CT USA. [Chen, Heller] Novartis Oncol, Basel, Switzerland. [Chen, Mingqing; Poi, Ming; Seligson, Nathan] Ohio State Univ, Columbus, OH 43210 USA. [Chowdhury, Swapan] Takeda Pharmaceut Co, Osaka, Japan. [Chu, Liang-Hui] Biogen, Cambridge, MA USA. [Cooper, Jennifer] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Dhapare, Sneha; Hassan, Omar; Leibrand, Crystal; Raut, Anuja] Virginia Commonwealth Univ, Richmond, VA 23284 USA. [Freimuth, Robert; Prem, Komal] Mayo Clin, Rochester, MN USA. [Freise, Kevin; Lon, Hoi Kei; Marroum, Patrick; Mostafa, Nael; Ning, Miaoran; Suleiman, Ahmed; Tariq, Bilal; Trueman, Sheryl; Xiong, Hao; Zhao, Weihan] AbbVie, N Chicago, IL USA. [Hashida, Tohru] Kobe City Med Ctr Gen Hosp, Kobe, Hyogo, Japan. [He, Jimmy] INC Res, Raleigh, NC USA. [Hoefman, Sven] Ablynx NV, Ghent, Belgium. [Hutchaleelaha, Athiwat] Global Blood Therapeut, San Francisco, CA USA. [Imai, Satoki] Sumitomo Dainippon Pharm, Osaka, Japan. [Jackson, Isabel] Univ Maryland, College Pk, MD 20742 USA. [Job, Kathleen; Kumar, Shaun] Univ Utah, Salt Lake City, UT 84112 USA. [Kaspera, Rudiger] Astellas Pharma Europe BV, Leiden, Netherlands. [Kleiber, Niina] Eramus MC Rotterdam, Rotterdam, Netherlands. [Klopp-Schulze, Lena] Free Univ Berlin, Berlin, Germany. [Kramers, Cornelis] Radboud Univ Nijmegen, Med Ctr, Nijmegen, Netherlands. [Lai, Eseng] Merck & Co Inc, Kenilworth, NJ USA. [Lam, Justine; Ramaiya, Atulkumar] Pfizer Inc, New York, NY USA. [Lemmen, Julia; Mueck, Wolfgang] Bayer AG, Leverkusen, Germany. [Li, Jerry; Marcath, Lauren; Pasternak, Amy] Univ Michigan, Ann Arbor, MI 48109 USA. [Lo, Arthur] Theravance Inc, San Francisco, CA USA. [Maas, Hugo] Boehringer Ingelheim GmbH & Co KG, Ingelheim, Germany. [Maass, Christian] MIT, Cambridge, MA 02139 USA. [Morse, Bridget] Eli Lilly, Indianapolis, IN USA. [Ning, Miaoran] Univ Illinois, Chicago, IL USA. [Oishi, Masayo] Pfizer Japan Inc, Tokyo, Japan. [Pak, Youngeen] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Park, Wan-Su] Catholic Univ Korea, Seoul, South Korea. [Piao, Zhenji] Seoul Natl Univ Hosp, Seoul, South Korea. [Prasad, Nagendra T.] Prestige Shantiniketan, Bangalore, Karnataka, India. [Rotter, Charles] Sekisui XenoTech LLC, Kansas City, KS USA. [Salem, Farzaneh] Simcyp Certara, Princeton, NJ USA. [Schmidt, Keith] NCI, Bethesda, MD 20892 USA. [Shibata, Kaito; Yamada, Takahiro] Hamamatsu Univ Sch Med, Hamamatsu, Shizuoka, Japan. [Shivva, Vittal] ORISE, Oak Ridge, TN USA. [Tanner, Julie-Anne] Univ Toronto, Toronto, ON M5S 1A1, Canada. [Wind, Sven] Boehringer Ingelheim Pharm GmbH & Co Kg, Ingelheim, Germany. [Xia, Cindy] Takeda Pharmaceut Int Co, Osaka, Japan. [Yang, Uan-Ou] Incyte, Wilmington, DE USA. [Yu, Jingjing] Univ Washington, Seattle, WA 98195 USA. [Zhang, Steven] Takeda Pharmaceut, Osaka, Japan. [Zhou, Jiawei] Tsinghua Univ, Beijing, Peoples R China. RP Ahn, J (reprint author), US FDA, Washington, DC 20204 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2017 VL 101 IS 3 BP 310 EP 316 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EO6ZJ UT WOS:000396840700004 ER PT J AU Warner, AW Moore, H Reinhard, D Ball, LA Knoppers, BM AF Warner, A. W. Moore, H. Reinhard, D. Ball, L. A. Knoppers, B. M. TI Harmonizing Global Biospecimen Consent Practices to Advance Translational Research: A Call to Action SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID CLINICAL-TRIALS AB One of the many challenges of translational medicine is working with research participants to donate biospecimens through an ethical informed consent framework. The increasingly complex ethical and regulatory differences across jurisdictions translates into limitations on use and potential value of biological specimens and their associated data in clinical research. We introduce a call to action for more uniform global standards for collection of biological specimen informed consent data to enable greater advancements in medical research. C1 [Warner, A. W.] Global Specimen Solut Inc, Raleigh, NC 27615 USA. [Moore, H.] NCI, NIH, Biorepositories & Biospecimen Res Branch, Rockville, MD USA. [Reinhard, D.] Bristol Myers Squibb, Clin Sample Strategy & Operat, Pennington, NJ USA. [Ball, L. A.] BioStorage Technol Inc, Indianapolis, IN USA. [Knoppers, B. M.] McGill Univ, Ctr Genom & Policy, Montreal, PQ, Canada. RP Warner, AW (reprint author), Global Specimen Solut Inc, Raleigh, NC 27615 USA. EM amelia.warner@globalspecimensolutions.com NR 5 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2017 VL 101 IS 3 BP 317 EP 319 DI 10.1002/cpt.461 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EO6ZJ UT WOS:000396840700005 PM 27558027 ER PT J AU Dietrich, C Singh, R AF Dietrich, Catharine Singh, Ram TI Circulating Endothelial Progenitor Cells in Crohn's Disease: An EPiC in the Making? SO DIGESTIVE DISEASES AND SCIENCES LA English DT Editorial Material ID INFLAMMATORY-BOWEL-DISEASE; PERIPHERAL-BLOOD; PATHOGENESIS C1 [Dietrich, Catharine; Singh, Ram] NCI, Stem Cell Regulat & Anim Aging Sect, Basic Res Lab, NIH, Frederick, MD 21702 USA. RP Singh, R (reprint author), NCI, Stem Cell Regulat & Anim Aging Sect, Basic Res Lab, NIH, Frederick, MD 21702 USA. EM singhshr@mail.nih.gov NR 13 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD MAR PY 2017 VL 62 IS 3 BP 567 EP 568 DI 10.1007/s10620-016-4445-2 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EL9YB UT WOS:000394974900003 PM 28078527 ER PT J AU Adjemian, J Frankland, TB Daida, YG Honda, JR Olivier, KN Zelazny, A Honda, S Prevots, DR AF Adjemian, Jennifer Frankland, Timothy B. Daida, Yihe G. Honda, Jennifer R. Olivier, Kenneth N. Zelazny, Adrian Honda, Stacey Prevots, D. Rebecca TI Epidemiology of Nontuberculous Mycobacterial Lung Disease and Tuberculosis, Hawaii, USA SO EMERGING INFECTIOUS DISEASES LA English DT Article ID HUMAN PULMONARY INFECTION; UNITED-STATES; CHANGING EPIDEMIOLOGY; PREVALENCE; TRENDS; VARIABLES; ONTARIO; KOREA AB Previous studies found Hawaiians and Asian-Americans/Pacific Islanders to be independently at increased risk for nontuberculous mycobacterial pulmonary disease (NTMPD) and tuberculosis (TB). To better understand NTM infection and TB risk patterns in Hawaii, USA, we evaluated data on a cohort of patients in Hawaii for 2005-2013. Period prevalence of NTMPD was highest among Japanese, Chinese, and Vietnamese patients (>300/100,000 persons) and lowest among Native Hawaiians. and Other Pacific Islanders (50/100,000). Japanese patients were twice as likely as all other racial/ethnic groups to have Mycobacterium abscessus isolated (adjusted odds ratio 2.0, 95% Cl 1.2-3.2) but were not at increased risk for infection with other mycobacteria species. In contrast, incidence of TB was stable and was lowest among Japanese patients (no cases) and highest among Filipino, Korean, and Vietnamese patients (>50/100,000). Substantial differences exist in the epidemiology of NTMPD by race/ethnicity, suggesting behavioral and biologic factors that affect disease susceptibility. C1 [Adjemian, Jennifer] US PHS, Commissioned Corps, Rockville, MD USA. [Adjemian, Jennifer; Zelazny, Adrian; Prevots, D. Rebecca] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Frankland, Timothy B.; Daida, Yihe G.; Honda, Jennifer R.] Kaiser Permanente, Honolulu, HI USA. [Honda, Jennifer R.] Univ Colorado, Anschutz Med Campus, Aurora, CO USA. [Honda, Jennifer R.] Natl Jewish Hlth, Denver, CO USA. [Olivier, Kenneth N.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Adjemian, Jennifer] NIAID, Epidemiol Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Adjemian, J (reprint author), NIAID, Epidemiol Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Adjemian, J (reprint author), NIAID, NIH, Qrts 15 B-1,8 West Dr,MSC 2665, Bethesda, MD 20892 USA. EM jennifer.adjemian@nih.gov FU Intramural Research Programs of the National Institute of Allergy and Infectious Diseases, National Heart, Lung, and Blood Institute, the National Institutes of Health Clinical Center, NIH; Cystic Fibrosis Foundation; Potts Foundation FX This work was supported in part by the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases, National Heart, Lung, and Blood Institute, the National Institutes of Health Clinical Center, NIH, and by grants from the Cystic Fibrosis Foundation and the Potts Foundation. NR 34 TC 0 Z9 0 U1 0 U2 0 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 2017 VL 23 IS 3 BP 439 EP 447 DI 10.3201/eid2303.161827 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EL7WB UT WOS:000394830900008 PM 28221128 ER PT J AU Powers, JF Pacak, K Tischler, AS AF Powers, James F. Pacak, Karel Tischler, Arthur S. TI Pathology of Human Pheochromocytoma and Paraganglioma Xenografts in NSG Mice SO ENDOCRINE PATHOLOGY LA English DT Article DE Paraganglioma; Pheochromocytoma; NSG mouse; Xenograft; PDX ID METASTATIC PHEOCHROMOCYTOMA; MALIGNANT PHEOCHROMOCYTOMA; NECK PARAGANGLIOMAS; ANIMAL-MODELS; CELLS; EXPRESSION; MUTATIONS; THERAPY; HEAD AB A major impediment to the development of effective treatments for metastatic or unresectable pheochromocytomas and paragangliomas has been the absence of valid models for pre-clinical testing. Attempts to establish cell lines or xenografts from human pheochromocytomas and paragangliomas have previously been unsuccessful. NOD-scid gamma (NSG) mice are a recently developed strain lacking functional B-cells, T-cells, and NK cells. We report here that xenografts of primary human paragangliomas will take in NSG mice while maintaining their architectural and immunophenotypic characteristics as expressed in the patients. In contrast to grafts of cell lines and of most common types of primary tumors, the growth rate of grafted paragangliomas is very slow, accurately representing the growth rate of most pheochromocytomas and paragangliomas even in metastases in humans. Although the model is therefore technically challenging, primary patient-derived xenografts of paragangliomas in NSG mice provide a potentially valuable new tool that could prove especially valuable for testing treatments aimed at eradicating the small tumor deposits that are often numerous in patients with metastatic paraganglioma. C1 [Powers, James F.; Tischler, Arthur S.] Tufts Med Ctr, Dept Pathol & Lab Med, 800 Washington St, Boston, MA 02111 USA. [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, Bethesda, MD USA. RP Powers, JF (reprint author), Tufts Med Ctr, Dept Pathol & Lab Med, 800 Washington St, Boston, MA 02111 USA. EM jpowers1@tuftsmedicalcenter.org FU Pheo Para Alliance; Intramural Research Program of the National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported by the Pheo Para Alliance and by the Intramural Research Program of the National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 20 TC 0 Z9 0 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1046-3976 EI 1559-0097 J9 ENDOCR PATHOL JI Endocr. Pathol. PD MAR PY 2017 VL 28 IS 1 BP 2 EP 6 DI 10.1007/s12022-016-9452-5 PG 5 WC Endocrinology & Metabolism; Pathology SC Endocrinology & Metabolism; Pathology GA EL9TL UT WOS:000394962900001 PM 27709415 ER PT J AU Xiong, YL Neifert, S Karuppagounder, SS Stankowski, JN Lee, BD Grima, JC Chen, GX Ko, HS Lee, Y Swing, D Tessarollo, L Dawson, TM Dawson, VL AF Xiong, Yulan Neifert, Stewart Karuppagounder, Senthilkumar S. Stankowski, Jeannette N. Lee, Byoung Dae Grima, Jonathan C. Chen, Guanxing Ko, Han Seok Lee, Yunjong Swing, Debbie Tessarollo, Lino Dawson, Ted M. Dawson, Valina L. TI Overexpression of Parkinson's Disease-Associated Mutation LRRK2 G2019S in Mouse Forebrain Induces Behavioral Deficits and alpha-Synuclein Pathology SO ENEURO LA English DT Article DE Parkinson's disease; LRRK2; transgenic mice; beta-synuclein ID MIDBRAIN DOPAMINERGIC-NEURONS; R1441C LRRK2; MICE; EXPRESSION; NEURODEGENERATION; MODEL; MOTOR; PHOSPHORYLATION; ABNORMALITIES; DEGENERATION AB Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified as an unambiguous cause of late-onset, autosomal-dominant familial Parkinson's disease (PD) and LRRK2 mutations are the strongest genetic risk factor for sporadic PD known to date. A number of transgenic mice expressing wild-type or mutant LRRK2 have been described with varying degrees of LRRK2-related abnormalities and modest pathologies. None of these studies directly addressed the role of the kinase domain in the changes observed and none of the mice present with robust features of the human disease. In an attempt to address these issues, we created a conditional LRRK2 G2019S (LRRK2 GS) mutant and a functionally negative control, LRRK2 G2019S/D1994A (LRRK2 GS/DA). Expression of LRRK2 GS or LRRK2 GS/DA was conditionally controlled using the tet-off system in which the presence of tetracycline-transactivator protein (tTA) with a CAMKII alpha promoter (CAMKII alpha-tTA) induced expression of TetP-LRRK2 GS or TetP-LRRK2 GS/DA in the mouse forebrain. Overexpression of LRRK2 GS in mouse forebrain induced behavioral deficits and alpha-synuclein pathology in a kinase-dependent manner. Similar to other genetically engineered LRRK2 GS mice, there was no significant loss of dopaminergic neurons. These mice provide an important new tool to study neurobiological changes associated with the increased kinase activity from the LRRK2 G2019S mutation, which may ultimately lead to a better understanding of not only the physiologic actions of LRRK2, but also potential pathologic actions that underlie LRRK2 GS-associated PD. C1 [Xiong, Yulan; Neifert, Stewart; Karuppagounder, Senthilkumar S.; Stankowski, Jeannette N.; Lee, Byoung Dae; Grima, Jonathan C.; Ko, Han Seok; Lee, Yunjong; Dawson, Ted M.; Dawson, Valina L.] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Neuroregenerat Program, Baltimore, MD 21205 USA. [Xiong, Yulan; Neifert, Stewart; Karuppagounder, Senthilkumar S.; Stankowski, Jeannette N.; Lee, Byoung Dae; Grima, Jonathan C.; Ko, Han Seok; Lee, Yunjong; Dawson, Ted M.; Dawson, Valina L.] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Stem Cell Program, Baltimore, MD 21205 USA. [Xiong, Yulan; Neifert, Stewart; Karuppagounder, Senthilkumar S.; Stankowski, Jeannette N.; Lee, Byoung Dae; Grima, Jonathan C.; Ko, Han Seok; Lee, Yunjong; Dawson, Ted M.; Dawson, Valina L.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Grima, Jonathan C.; Dawson, Ted M.; Dawson, Valina L.] Johns Hopkins Univ, Sch Med, Soloman H Snyder Dept Neurosci, Baltimore, MD 21205 USA. [Dawson, Valina L.] Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA. [Dawson, Ted M.] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. [Dawson, Ted M.; Dawson, Valina L.] Adrienne Helis Malvin Med Res Fdn, New Orleans, LA 70130 USA. [Dawson, Ted M.; Dawson, Valina L.] Diana Helis Henry Med Res Fdn, New Orleans, LA 70130 USA. [Xiong, Yulan; Chen, Guanxing] Kansas State Univ, Coll Vet Med, Dept Anat & Physiol, 212 Coles Hall, Manhattan, KS 66506 USA. [Swing, Debbie; Tessarollo, Lino] NCI, Neural Dev Sect, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. [Stankowski, Jeannette N.] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Lee, Byoung Dae] Kyung Hee Univ, Dept Neurosci, Age Related & Brain Dis Res Ctr, Seoul 130701, South Korea. [Lee, Yunjong] Sungkyunkwan Univ, Sch Med, Samsung Biomed Res Inst, Div Pharmacol,Dept Mol Cell Biol, Suwon 446746, South Korea. RP Xiong, YL (reprint author), Kansas State Univ, Coll Vet Med, Dept Anat & Physiol, 212 Coles Hall, Manhattan, KS 66506 USA.; Dawson, VL (reprint author), Johns Hopkins Univ, Sch Med, Inst Cell Engn, Neuroregenerat Program,Dept Neurol, 733 North Broadway,MRB 731, Baltimore, MD 21205 USA.; Dawson, VL (reprint author), Johns Hopkins Univ, Sch Med, Inst Cell Engn, Stem Cell Program,Dept Neurol, 733 North Broadway,MRB 731, Baltimore, MD 21205 USA. EM yulanxiong@ksu.edu; vdawson@jhmi.edu FU National Institutes of Health (NIH)/National Institute on Aging [K01-AG046366]; William N. & Bernice E. Bumpus Foundation Innovation Awards; Kansas State University College of Veterinary Medicine; National Science Foundation Graduate Research Fellowship Award; Thomas Shortman Training Fund Graduate Scholarship Award; Axol Science Scholarship Award; NIH/National Institute of Neurological Disorders and Stroke (NINDS) [NS-082205]; NIH/NINDS [NS-38377]; JPB Foundation FX This work was supported from National Institutes of Health (NIH)/National Institute on Aging Grant K01-AG046366 (Y.X.), the William N. & Bernice E. Bumpus Foundation Innovation Awards (Y.X.), start-up fund and SUCCESS-FYI Intramural Grant from Kansas State University College of Veterinary Medicine (Y.X.), National Science Foundation Graduate Research Fellowship Award (J.C.G.), the Thomas Shortman Training Fund Graduate Scholarship Award (J.C.G.), the Axol Science Scholarship Award (J.C.G.), NIH/National Institute of Neurological Disorders and Stroke (NINDS) Grant NS-082205 (H.S.K.), NIH/NINDS Grant NS-38377 (H.S.K., T.M.D., and V.L.D.), and the JPB Foundation (T.M.D.). T.M.D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases. The authors acknowledge the joint participation by the Adrienne Helis Malvin Medical Research Foundation and the Diana Helis Henry Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with The Johns Hopkins Hospital, the Johns Hopkins University School of Medicine, and the Foundation's Parkinson's Disease Programs. NR 34 TC 0 Z9 0 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 2373-2822 J9 ENEURO JI eNeuro PD MAR-APR PY 2017 VL 4 IS 2 AR UNSP e0004 DI 10.1523/ENEURO.0004-17.2017 PG 10 WC Neurosciences SC Neurosciences & Neurology GA EP7OU UT WOS:000397567900001 ER PT J AU Valeri, L Reese, SL Zhao, SS Page, CM Nystad, W Coull, BA London, SJ AF Valeri, Linda Reese, Sarah L. Zhao, Shanshan Page, Christian M. Nystad, Wenche Coull, Brent A. London, Stephanie J. TI Misclassified exposure in epigenetic mediation analyses. Does DNA methylation mediate effects of smoking on birthweight? SO EPIGENOMICS LA English DT Article DE DNA methylation; mediation analysis; misclassification ID MATERNAL SMOKING; CIGARETTE-SMOKING; MEASUREMENT-ERROR; GESTATIONAL-AGE; PREGNANCY; NEWBORNS; BIOMARKER; VARIABLES; PROFILE; COHORT AB Aims: Assessing whether epigenetic alterations mediate associations between environmental exposures and health outcomes is increasingly popular. We investigate the impact of exposure misclassification in such investigations. Materials & methods: We quantify bias and false-positive rates due to exposure misclassification in mediation analysis and assess the performance of the simulation extrapolation method (SIMEX). We evaluate whether DNA-methylation mediates smoking-birth weight relationship in the Norwegian Mother and Child Study birth cohort. Results: Ignoring exposure misclassification increases type I error in mediation analysis. The direct effect is underestimated and, when the mediator is a biomarker of the exposure, as is true for smoking, the indirect effect is overestimated. Conclusion: Misclassification correction plus cautious interpretation are recommended for mediation analyses in the presence of exposure misclassification. C1 [Valeri, Linda] Harvard Med Sch, Dept Psychiat, Boston, MA 02115 USA. [Valeri, Linda] McLean Hosp, Psychiatr Biostat Lab, Belmont, MA 02478 USA. [Reese, Sarah L.; Zhao, Shanshan; London, Stephanie J.] NIH, Nat Inst Environm Hlth Sci, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. [Page, Christian M.; Nystad, Wenche] Nat Inst Publ Hlth, Oslo, Norway. [Coull, Brent A.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Valeri, L (reprint author), Harvard Med Sch, Dept Psychiat, Boston, MA 02115 USA.; Valeri, L (reprint author), McLean Hosp, Psychiatr Biostat Lab, Belmont, MA 02478 USA. EM lvaleri@mclean.harvard.edu FU Intramural Research Program of NIH, National Institute of Environmental Health Sciences (NIEHS); Norwegian Ministry of Health; Ministry of Education and Research, NIH/NIEHS [N01-ES-75558, ZO1 ES-49019]; NIH/NINDS [1 UO1 NS 047537-01]; Norwegian Research Council/FUGE [151918/S10]; Norwegian Research Council/BIOBANK [221097] FX This work was supported in part by the Intramural Research Program of NIH, National Institute of Environmental Health Sciences (NIEHS). The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, NIH/NIEHS (contract number N01-ES-75558 and ZO1 ES-49019), NIH/NINDS (grant number 1 UO1 NS 047537-01) and the Norwegian Research Council/FUGE (grant number 151918/S10), and the present project by the Norwegian Research Council/BIOBANK (grant no 221097). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 46 TC 1 Z9 1 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1750-1911 EI 1750-192X J9 EPIGENOMICS-UK JI Epigenomics PD MAR PY 2017 VL 9 IS 3 SI SI BP 253 EP 265 DI 10.2217/epi-2016-0145 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA EN1ZC UT WOS:000395808100007 PM 28234025 ER PT J AU Richmond, RC Joubert, BR AF Richmond, Rebecca C. Joubert, Bonnie R. TI Contrasting the effects of intra-uterine smoking and one-carbon micronutrient exposures on offspring DNA methylation SO EPIGENOMICS LA English DT Review DE DNA methylation; epigenetic epidemiology; epigenome-wide association study (EWAS); folate; maternal smoking; micronutrients; one-carbon metabolism ID EPIGENOME-WIDE ASSOCIATION; NEURAL-TUBE DEFECTS; MATERNAL SMOKING; GENOME-WIDE; IN-UTERO; CIGARETTE-SMOKING; PRENATAL EXPOSURE; MENDELIAN RANDOMIZATION; GENE-EXPRESSION; TOBACCO-SMOKE AB Maternal smoking and micronutrient intake during pregnancy are two strong biological candidates for impacting the developing epigenome. The extent to which DNA methylation in offspring is modified by these intrauterine exposures has not been presented in parallel. In this review, we summarize human studies which have investigated genome-wide DNA methylation in the offspring in relation to maternal smoking and one-carbon micronutrient exposure during pregnancy. We contrast the primarily independent efforts for these two categories of exposure, and potential explanations for these differences. We emphasize methodological considerations such as power to detect methylation signals, exposure assessment, control of sources of variability, causal inference and the role of observed methylation changes in mediating downstream outcomes in the offspring. C1 [Richmond, Rebecca C.] Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England. [Joubert, Bonnie R.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Richmond, RC (reprint author), Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England. EM richmond@bristol.ac.uk FU NIEHS; University of Bristol; UK Medical Research Council [MC_UU_12013/2]; CRUK program [C18281/A19169] FX B Joubert is supported by the NIEHS as a federal employee. RC Richmond works in a unit that receives funds from the University of Bristol and the UK Medical Research Council (MC_UU_12013/2) and is funded by a CRUK program grant (C18281/A19169). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 81 TC 1 Z9 1 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1750-1911 EI 1750-192X J9 EPIGENOMICS-UK JI Epigenomics PD MAR PY 2017 VL 9 IS 3 SI SI BP 351 EP 369 DI 10.2217/epi-2016-0135 PG 18 WC Genetics & Heredity SC Genetics & Heredity GA EN1ZC UT WOS:000395808100013 PM 28234021 ER PT J AU Lin, FI Gonzalez, EM Kummar, S Do, K Shih, J Adler, S Kurdziel, KA Ton, A Turkbey, B Jacobs, PM Bhattacharyya, S Chen, AP Collins, JM Doroshow, JH Choyke, PL Lindenberg, ML AF Lin, Frank I. Gonzalez, E. M. Kummar, S. Do, K. Shih, J. Adler, S. Kurdziel, K. A. Ton, A. Turkbey, B. Jacobs, P. M. Bhattacharyya, S. Chen, A. P. Collins, J. M. Doroshow, J. H. Choyke, P. L. Lindenberg, M. L. TI Utility of F-18-fluoroestradiol (F-18-FES) PET/CT imaging as a pharmacodynamic marker in patients with refractory estrogen receptor-positive solid tumors receiving Z-endoxifen therapy SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article DE F-18-FES; Fluoroestradiol; Positron emission tomography (PET); Z-endoxifen; Pharmacodynamic marker ID POSITRON-EMISSION-TOMOGRAPHY; METASTATIC BREAST-CANCER; TOTAL LESION GLYCOLYSIS; STEROID-RECEPTORS; DESMOID TUMORS; IN-VIVO; EXPRESSION; BETA; TAMOXIFEN; METAANALYSIS AB Background Z-endoxifen is the most potent of the metabolites of tamoxifen, and has the potential to be more effective than tamoxifen because it bypasses potential drug resistance mechanisms attributable to patient variability in the expression of the hepatic microsomal enzyme CYP2D6. F-18-FES is a positron emission tomography (PET) imaging agent which selectively binds to estrogen receptor alpha (ER-a) and has been used for non-invasive in vivo assessment of ER activity in tumors. This study utilizes F-18-FES PET imaging as a pharmacodynamic biomarker in patients with ER+ tumors treated with Z-endoxifen. Methods Fifteen patients were recruited from a parent therapeutic trial of Z-endoxifen and underwent imaging with F-18-FES PET at baseline. Eight had positive lesions on the baseline scan and underwent follow-up imaging with F-18-FES 15 days post administration of Z-endoxifen. Results Statistically significant changes (p = 0.0078) in standard uptake value (SUV)-Max were observed between the baseline and follow-up scans as early as 1 day post drug administration. Conclusion F-FES PET imaging could serve as a pharmacodynamic biomarker for patients treated with ER-directed therapy. C1 [Lin, Frank I.; Jacobs, P. M.] NCI, Canc Imaging Program, NIH, Bethesda, MD 20892 USA. [Lin, Frank I.; Gonzalez, E. M.; Kurdziel, K. A.; Ton, A.; Turkbey, B.; Choyke, P. L.; Lindenberg, M. L.] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. [Kummar, S.; Do, K.; Collins, J. M.; Doroshow, J. H.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Kummar, S.; Do, K.; Collins, J. M.; Doroshow, J. H.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Shih, J.] NCI, Biometr Res Program, NIH, Bethesda, MD 20892 USA. [Adler, S.] Leidos Biomed Res Inc, Clin Res Directorate, Clin Monitoring Res Program, NCI Campus Frederick, Frederick, MD 21702 USA. [Bhattacharyya, S.] Leidos Biomed Res, Frederick Natl Lab Canc Res, Frederick, MD USA. [Chen, A. P.] NCI, Early Clin Trials Dev Program, DCTD, Bethesda, MD 20892 USA. RP Lin, FI (reprint author), NCI, Canc Imaging Program, NIH, Bethesda, MD 20892 USA.; Lin, FI (reprint author), NCI, Mol Imaging Program, Bethesda, MD 20892 USA. EM frank.lin2@nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. NR 36 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 EI 1619-7089 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD MAR PY 2017 VL 44 IS 3 BP 500 EP 508 DI 10.1007/s00259-016-3561-8 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EM0BZ UT WOS:000394985100019 PM 27872957 ER PT J AU Wassif, CA Kratz, L Sparks, SE Wheeler, C Bianconi, S Gropman, A Calis, KA Kelley, RI Tierney, E Porter, FD AF Wassif, Christopher A. Kratz, Lisa Sparks, Susan E. Wheeler, Courtney Bianconi, Simona Gropman, Andrea Calis, Karim A. Kelley, Richard I. Tierney, Elaine Porter, Forbes D. TI A placebo-controlled trial of simvastatin therapy in Smith-Lemli-Opitz syndrome SO GENETICS IN MEDICINE LA English DT Article DE Aberrant Behavior Checklist-Community; DHCR7; randomized, placebo-controlled trial; simvastatin; Smith-Lemli-Opitz syndrome ID CHOLESTEROL SUPPLEMENTATION; DIETARY-CHOLESTEROL; REDUCTASE GENE; SYNDROME SLOS; MUTATIONS; 7-DEHYDROCHOLESTEROL; FREQUENCY; CHILDREN; MODEL AB Background: Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation/cognitive impairment syndrome characterized by the accumulation of 7-dehydrocholesterol, a precursor sterol of cholesterol. Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor that crosses the blood-brain barrier, has been proposed for the treatment of SLOS based on in vitro and in vivo studies suggesting that simvastatin increases the expression of hypomorphic DHCR7 alleles. Methods: Safety and efficacy of simvastatin therapy in 23 patients with mild to typical SLOS were evaluated in a randomized, doubleblind, placebo-controlled trial. The crossover trial consisted of two 12-month treatment phases separated by a 2-month washout period. Results: No safety issues were identified in this study. Plasma dehydrocholesterol concentrations decreased significantly: 8.9 +/- 8.4% on placebo to 6.1 +/- 5.5% on simvastatin (P < 0.005); we observed a trend toward decreased cerebrospinal fluid dehydrocholesterol-concentrations. A significant improvement (P = 0.017, paired t-test) was observed on the irritability subscale of the Aberrant Behavior Checklist-C when subjects were taking simvastatin. Conclusion: This article reports what is, to our knowledge, the first randomized, placebo-controlled trial designed to test the safety and efficacy of simvastatin therapy in SLOS. Simvastatin seems to be-relatively safe in patients with SLOS, improves the serum-dehydrocholesterol-to-total sterol ratio, and significantly improves irritability symptoms in patients with mild to classic SLOS. C1 [Wassif, Christopher A.; Sparks, Susan E.; Bianconi, Simona; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Dept Hlth & Human Serv, Div Translat Med,Sect Mol Dysmorphol, Bethesda, MD 20892 USA. [Kratz, Lisa] Kennedy Krieger Inst, Dept Neurogenet, Baltimore, MD 21287 USA. [Sparks, Susan E.] Sanofi Genzyme, Cambridge, MA USA. [Wheeler, Courtney; Tierney, Elaine] Kennedy Krieger Inst, Dept Psychiat, Baltimore, MD 21287 USA. [Gropman, Andrea] Childrens Natl Med Ctr, Ctr Neuroscience & Behav Med, Dept Neurol, Washington, DC 20010 USA. [Calis, Karim A.] NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dept Hlth & Human Serv, Off Clin Director, Bethesda, MD 20892 USA. [Kelley, Richard I.] Boston Childrens Hosp, Dept Genet & Gen, Boston, MA 02215 USA. RP Porter, FD (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Dept Hlth & Human Serv, Div Translat Med,Sect Mol Dysmorphol, Bethesda, MD 20892 USA.; Tierney, E (reprint author), Kennedy Krieger Inst, Dept Psychiat, Baltimore, MD 21287 USA. EM tierney@kennedykrieger.org; fdporter@mail.nih.gov OI Wassif, Christopher/0000-0002-2524-1420 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; Autism Speaks; Johns Hopkins Institute for Clinical and Translational Research (ICTR); National Center for Advancing Translational Sciences (NCATS) - National Institutes of Health (NIH) [UL1 TR 001079]; NIH Roadmap for Medical Research FX This study was supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, by Autism Speaks, and by the Johns Hopkins Institute for Clinical and Translational Research (ICTR), which is funded in part by grant UL1 TR 001079 from the National Center for Advancing Translational Sciences (NCATS), which is a component of the National Institutes of Health (NIH), and the NIH Roadmap for Medical Research. The authors acknowledge clinical and supportive assistance by Halima Goodwin, Sandra Conley, Irena Bukelis, Geeta Sarphare, and Diane Lanham, as well as the laboratory assistance by Cynthia Toth. We also thank Judith Starling and George Grimes from the NIH Clinical Center Pharmaceutical Development Service for their assistance in the preparation of the simvastatin and placebo suspensions. We offer our greatest thanks to the individuals with SLOS and their family members who participated in this clinical study. NR 37 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD MAR PY 2017 VL 19 IS 3 BP 297 EP 305 DI 10.1038/gim.2016.102 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA EN1VZ UT WOS:000395799700005 PM 27513191 ER PT J AU Ng, D Hong, CS Singh, LN Johnston, JJ Mullikin, JC Biesecker, LG AF Ng, David Hong, Celine S. Singh, Larry N. Johnston, Jennifer J. Mullikin, James C. Biesecker, Leslie G. CA NISC Comparative Sequencing Progra TI Assessing the capability of massively parallel sequencing for opportunistic pharmacogenetic screening SO GENETICS IN MEDICINE LA English DT Article DE massively parallel sequencing; pharmacogenetic screening ID IMPLEMENTATION CONSORTIUM GUIDELINES; 2014 UPDATE; GENOTYPE; GENOME; GENES; MUTATIONS; VARIANTS; MEDICINE AB Purpose: The aim of the study was to assess exome data for preemptive pharmacogenetic screening for 203 clinically relevant pharmacogenetic variant positions from the Pharmacogenomics Knowledgebase and Clinical Pharmacogenetics Implementation Consortium and identify copy-number variants (CNVs) in CYP2D6. Methods: We examined the coverage and genotype quality of 203 pharmacogenetic variant positions in 973 exomes compared with five genomes and with five genotyping chip data sets. Then, we determined the agreement of exome and chip genotypes by evaluating concordance in a three-way comparison of exome, genome, and chip-based genotyping at 1,929 variant positions in five individuals. Finally, we evaluated the utility of exomes for detecting CYP2D6 CNVs. Results: For 5 individuals examined for 203 pharmacogenetic variants (5 x 203 = 1,015), 998/1,015 were identified by genome, 849/1,015 were identified by exome, and 295/1,015 by genotyping chip. Thirty-six pharmacogenetic star allele variants with moderate to strong Clinical Pharmacogenetics Implementation Consortium (CPIC) therapeutic recommendations were identified in 973 exomes. Exomes had high (98%) genotype concordance with chip-based genotyping. CYP2D6 CNVs were identified in 57/973 exomes. Conclusions: Exomes outperformed the current chip-based assay in detecting more important pharmacogenetic variant positions and CYP2D6 CNVs for preemptive pharmacogenetic screening. Tools should be developed to derive pharmacogenetic variants from exomes. C1 [Ng, David; Hong, Celine S.; Singh, Larry N.; Johnston, Jennifer J.; Biesecker, Leslie G.] NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA. [Mullikin, James C.; Biesecker, Leslie G.] NHGRI, Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. [Mullikin, James C.] NHGRI, Comparat Genom & Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA.; Biesecker, LG (reprint author), NHGRI, Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. EM lesb@mail.nih.gov FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health FX The authors are grateful for the contributions of the staff at the NIH Intramural Sequencing Center and NIH Clinical Center and of the ClinSeq(R) study participants. This study was funded by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 20 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD MAR PY 2017 VL 19 IS 3 BP 357 EP 361 DI 10.1038/gim.2016.105 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA EN1VZ UT WOS:000395799700013 PM 27537706 ER PT J AU Kulkarni, R Presley, RJ Lusher, JM Shapiro, AD Gill, JC Manco-Johnson, M Koerper, MA Abshire, TC Dimichele, D Hoots, WK Mathew, P Nugent, DJ Geraghty, S Evatt, BL Soucie, JM AF Kulkarni, R. Presley, R. J. Lusher, J. M. Shapiro, A. D. Gill, J. C. Manco-Johnson, M. Koerper, M. A. Abshire, T. C. Dimichele, D. Hoots, W. K. Mathew, P. Nugent, D. J. Geraghty, S. Evatt, B. L. Soucie, J. M. TI Complications of haemophilia in babies (first two years of life): a report from the Centers for Disease Control and Prevention Universal Data Collection System SO HAEMOPHILIA LA English DT Article DE babies; central venous access device; haemophilia; head trauma; inhibitors; intracranial hemorrhage ID AFFECTED INFANT; OPTIMAL-MODE; BLEEDING DISORDERS; CESAREAN DELIVERY; VAGINAL DELIVERY; FACTOR-VIII; DEFINITIONS; PROPHYLAXIS; DIAGNOSIS; BOYS AB Aim: To describe the prevalence and complications in babies <= 2 years with haemophilia. Methods: We used a standardized collection tool to obtain consented data on eligible babies aged <= 2 years with haemophilia enrolled in the Centers for Disease Control and Prevention Universal Data Collection System surveillance project at US Hemophilia Treatment Centers (HTCs). Results: Of 547 babies, 82% had haemophilia A, and 70% were diagnosed within one month of birth. Diagnosis was prompted by known maternal carrier status (40%), positive family history (23%), bleeding (35%) and unknown 2%; 81% bled during the first two years. The most common events were bleeding (circumcision, soft tissue, oral bleeding) and head injury. There were 46 episodes of intracranial haemorrhage (ICH) in 37 babies (7%): 18 spontaneous, 14 delivery related, 11 traumatic, 2 procedure related and 1 unknown cause. Of the 176 central venous access devices (CVADs) in 148 (27%) babies, there were 137 ports, 22 surgically inserted central catheters and 20 peripherally inserted central catheters. Ports had the lowest complication rates. Inhibitors occurred in 109 (20%) babies who experienced higher rates of ICH (14% vs. 5%; P = 0.002), CVAD placement (61% vs. 19%; P < 0.001) and CVAD complications (44% vs. 26%; P < 0.001). The most common replacement therapy was recombinant clotting factor concentrates. Conclusion: Bleeding events in haemophilic babies <= 2 years were common; no detectable difference in the rates of ICH by the mode of delivery was noted. Neonatal factor exposure did not affect the inhibitor rates. Minor head trauma, soft tissue and oropharyngeal bleeding were the leading indications for treatment. C1 [Kulkarni, R.] Michigan State Univ, Dept Pediat & Human Dev, B216 Clin Ctr, E Lansing, MI 48824 USA. [Presley, R. J.; Evatt, B. L.; Soucie, J. M.] Ctr Dis Control & Prevent, Div Blood Disorders, Atlanta, GA USA. [Lusher, J. M.] Childrens Hosp Michigan, Wayne State Med Ctr, Dept Pediat Hematol, Detroit, MI 48201 USA. [Shapiro, A. D.] Indiana Hemophilia & Thrombosis Ctr, Indianapolis, IN USA. [Gill, J. C.] Blood Ctr Wisconsin, Comprehens Ctr Bleeding Disorders, Milwaukee, WI USA. [Manco-Johnson, M.] Univ Colorado, Dept Pediat, Aurora, CO USA. [Koerper, M. A.] UCSF Med Ctr, San Francisco, CA USA. [Abshire, T. C.] Blood Ctr Wisconsin, Milwaukee, WI USA. [Dimichele, D.] Div Blood Dis & Resources, Bethesda, MD USA. [Hoots, W. K.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Mathew, P.] Univ New Mexico, Dept Pediat Hematol Oncol, Albuquerque, NM 87131 USA. [Nugent, D. J.] Childrens Hosp Orange Cty, Ctr Inherited Blood Disorders, Orange, CA 92668 USA. [Geraghty, S.] Univ Colorado Denver, Aurora, CO USA. RP Kulkarni, R (reprint author), Michigan State Univ, Dept Pediat & Human Dev, B216 Clin Ctr, E Lansing, MI 48824 USA. EM roshni.kulkarni@hc.msu.edu FU CDC; United States Hemophilia Treatment Center Network (US HTCN) FX The UDC project was funded by a cooperative agreement ('Prevention of Bleeding Disorder Complications through Regional Hemophilia Treatment Centers') between the CDC and the United States Hemophilia Treatment Center Network (US HTCN), which is comprised of >130 clinical centres located throughout the United States. The authors acknowledge with gratitude the staff of the US HTCN for recruiting patients to the UDC surveillance project and collecting the data. The authors also thank the regional coordinators, regional directors, patients and their families for their participation. The authors also thank the CDC Presentation and Publication Committee for their thorough review and very helpful comments and edits. NR 28 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-8216 EI 1365-2516 J9 HAEMOPHILIA JI Haemophilia PD MAR PY 2017 VL 23 IS 2 BP 207 EP 214 DI 10.1111/hae.13081 PG 8 WC Hematology SC Hematology GA EP5GC UT WOS:000397406000006 PM 27813214 ER PT J AU Huai, Y Guan, XH Liu, SL Uyeki, TM Jiang, H Klena, J Huang, JG Chen, MY Peng, YX Yang, H Luo, J Zheng, JD Peng, ZB Huo, XX Xiao, L Chen, H Zhang, YZ Xing, XS Feng, LZ Hu, DJ Yu, HJ Zhan, FX Varma, JK AF Huai, Yang Guan, Xuhua Liu, Shali Uyeki, Timothy M. Jiang, Hui Klena, John Huang, Jigui Chen, Maoyi Peng, Youxing Yang, Hui Luo, Jun Zheng, Jiandong Peng, Zhibin Huo, Xixiang Xiao, Lin Chen, Hui Zhang, Yuzhi Xing, Xuesen Feng, Luzhao Hu, Dale J. Yu, Hongjie Zhan, Faxian Varma, Jay K. TI Clinical characteristics and factors associated with severe acute respiratory infection and influenza among children in Jingzhou, China SO INFLUENZA AND OTHER RESPIRATORY VIRUSES LA English DT Article DE children; influenza; risk factors; severe acute respiratory infection ID SEASONAL INFLUENZA; TOBACCO-SMOKE; VACCINE; HOSPITALIZATIONS; PNEUMONIA; COMMUNITY; EXPOSURE; THERAPY; BURDEN AB Background: Influenza is an important cause of respiratory illness in children, but data are limited on hospitalized children with laboratory-confirmed influenza in China. Methods: We conducted active surveillance for severe acute respiratory infection (SARI; fever and at least one sign or symptom of acute respiratory illness) among hospitalized pediatric patients in Jingzhou, Hubei Province, from April 2010 to April 2012. Data were collected from enrolled SARI patients on demographics, underlying health conditions, clinical course of illness, and outcomes. Nasal swabs were collected and tested for influenza viruses by reverse transcription polymerase chain reaction. We described the clinical and epidemiological characteristics of children with influenza and analyzed the association between potential risk factors and SARI patients with influenza. Results: During the study period, 15 354 children aged <15 years with signs and symptoms of SARI were enrolled at hospital admission. severe acute respiratory infection patients aged 5-15 years with confirmed influenza (H3N2) infection were more likely than children without influenza to have radiographic diagnosis of pneumonia (11/31, 36% vs 15/105, 14%. P<.05). Only 16% (1116/7145) of enrolled patients had received seasonal trivalent influenza vaccination within 12 months of hospital admission. Non-vaccinated influenza cases were more likely than vaccinated influenza cases to have pneumonia (31/133, 23% vs 37/256, 15%, P<.05). severe acute respiratory infection cases aged 5-15 years diagnosed with influenza were also more likely to have a household member who smoked cigarettes compared with SARI cases without a smoking household member (54/208, 26% vs 158/960, 16%, P<.05). Conclusions: Influenza A (H3N2) virus infection was an important contributor to pneumonia requiring hospitalization. Our results highlight the importance of surveillance in identifying factors for influenza hospitalization, monitoring adherence to influenza prevention and treatment strategies, and evaluating the disease burden among hospitalized pediatric SARI patients. Influenza vaccination promotion should target children. C1 [Huai, Yang; Klena, John; Zhang, Yuzhi; Hu, Dale J.; Varma, Jay K.] Ctr Dis Control & Prevent, Ctr Global Hlth, China US Collaborat Program Emerging & Reemerging, Beijing, Peoples R China. [Guan, Xuhua; Huo, Xixiang; Chen, Hui; Xing, Xuesen; Zhan, Faxian] Hubei Prov Ctr Dis Control & Prevent, Wuhan, Peoples R China. [Liu, Shali; Huang, Jigui; Xiao, Lin] Jingzhou Cent Hosp, Jingzhou, Peoples R China. [Uyeki, Timothy M.] Natl Ctr Immunizat & Resp Dis, Influenza Div, Atlanta, GA USA. [Jiang, Hui; Zheng, Jiandong; Peng, Zhibin; Feng, Luzhao; Yu, Hongjie] Chinese Ctr Dis Control & Prevent, Div Infect Dis, Key Lab Surveillance & Early Warning Infect Dis, Beijing, Peoples R China. [Klena, John; Hu, Dale J.; Varma, Jay K.] Ctr Dis Control & Prevent, Global Dis Detect Branch, Div Global Hlth Protect, Ctr Global Hlth, Atlanta, GA USA. [Chen, Maoyi] Jingzhou Ctr Dis Control & Prevent, Jingzhou, Peoples R China. [Peng, Youxing] Jingzhou First Peoples Hosp, Jingzhou, Peoples R China. [Yang, Hui] Jingzhou Second Peoples Hosp, Jingzhou, Peoples R China. [Luo, Jun] Jingzhou Maternal & Childrens Hosp, Jingzhou, Peoples R China. [Hu, Dale J.] NIAID, Vaccine Clin Res Branch, Vaccine Res Program, Div AIDS,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Zhan, FX (reprint author), Hubei Prov Ctr Dis Control & Prevent, Wuhan, Peoples R China. EM zhanfx@163.com FU Centers for Disease Control and Prevention [5U2GGH000018] FX This study was supported by the Cooperative Agreement Number, 5U2GGH000018, funded by the Centers for Disease Control and Prevention. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention or the Department of Health and Human Services. NR 31 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1750-2640 EI 1750-2659 J9 INFLUENZA OTHER RESP JI Influenza Other Respir. Viruses PD MAR PY 2017 VL 11 IS 2 BP 148 EP 156 DI 10.1111/irv.12419 PG 9 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA EL9SW UT WOS:000394961400006 PM 27465959 ER PT J AU Weise, C Piaggi, P Reinhardt, M Chen, K Savage, C Krakoff, J Pleger, B AF Weise, C. M. Piaggi, P. Reinhardt, M. Chen, K. Savage, C. R. Krakoff, J. Pleger, B. TI The obese brain as a heritable phenotype: a combined morphometry and twin study SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article ID GRAY-MATTER VOLUME; BODY-MASS INDEX; ORBITOFRONTAL CORTEX; WHITE-MATTER; FOOD; REWARD; INDIVIDUALS; ACTIVATION; FAT; ASSOCIATION AB BACKGROUND: Body weight and adiposity are heritable traits. To date, it remains unknown whether obesity-associated brain structural alterations are under a similar level of genetic control. METHODS: For this study, we utilized magnetic resonance imaging data from the Human Connectome Project. Voxel-based morphometry was used to investigate associations between body mass index (BMI) and regional gray matter volume (GMV) in a sample of 875 young adults with a wide BMI range (386 males/489 females; age 28.8 +/- 3.7 years; BMI 26.6 +/- 5.3 kg m(-2)) that included 86 pairs of monozygotic twins and 82 pairs of dizygotic twins. Twin data were analyzed by applying the additive genetic, common environmental and residual effects model to determine heritability of brain regions that were associated with BMI. RESULTS: We observed positive associations between BMI and GMV in the ventromedial prefrontal cortex and the right cerebellum and widespread negative associations within the prefrontal cortex, cerebellum, temporal lobes and distinct subcortical structures. Varying degrees of heritability were found for BMI-associated brain regions, with the highest heritability estimates for cerebellar GMV and subcortical structures. CONCLUSIONS: These data indicate that brain regions associated with obesity are subject to differing levels of genetic control and environmental influences. Specific brain regions with high heritability might represent an inherent vulnerability factor for obesity. C1 [Weise, C. M.] Univ Leipzig, Dept Neurol, Liebigstr 20, D-04103 Leipzig, Germany. [Piaggi, P.; Krakoff, J.] NIDDK, Obes & Diabet Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. [Reinhardt, M.] Univ Leipzig, Dept Diagnost & Intervent Radiol, Leipzig, Germany. [Chen, K.; Savage, C. R.] Banner Alzheimers Inst, Phoenix, AZ USA. [Pleger, B.] Max Planck Inst Human Cognit & Brain Sci, Leipzig, Germany. [Pleger, B.] Ruhr Univ Bochum, BG Univ Clin Bergmannsheil, Dept Neurol, Bochum, Germany. RP Weise, C (reprint author), Univ Leipzig, Dept Neurol, Liebigstr 20, D-04103 Leipzig, Germany. EM christopher.weise@medizin.uni-leipzig.de FU 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research; McDonnell Center for Systems Neuroscience at Washington University; IFB AdiposityDiseases; Federal Ministry of Education and Research (BMBF), Germany [FKZ: 01E01001]; German Research Foundation within the framework of the CRC 1052 Obesity Mechanisms to Project A6 FX Data were provided (in part) by the Human Connectome Project, WU-Minn Consortium (Principal Investigators: David Van Essen and Kamil Ugurbil; 1U54MH091657) funded by the 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research and by the McDonnell Center for Systems Neuroscience at Washington University. This study was supported by the IFB AdiposityDiseases, Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01E01001 (http://www.bmbf.de) and the German Research Foundation (DFG;http://www.dfg.de), within the framework of the CRC 1052 Obesity Mechanisms to Project A6 (to BP). NR 49 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 EI 1476-5497 J9 INT J OBESITY JI Int. J. Obes. PD MAR PY 2017 VL 41 IS 3 BP 458 EP 466 DI 10.1038/ijo.2016.222 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA EN2CC UT WOS:000395816000013 PM 27916985 ER PT J AU Noriea, NF Clark, TR Mead, D Hackstadt, T AF Noriea, Nicholas F. Clark, Tina R. Mead, David Hackstadt, Ted TI Proteolytic Cleavage of the Immunodominant Outer Membrane Protein rOmpA in Rickettsia rickettsii SO JOURNAL OF BACTERIOLOGY LA English DT Article DE Rickettsia; autotransporter proteins ID ACTIN-BASED MOTILITY; SPOTTED-FEVER; AUTOTRANSPORTER PROTEINS; MONOCLONAL-ANTIBODIES; ANTIGEN; SURFACE; GENE; IDENTIFICATION; PROWAZEKII; SECRETION AB Rickettsia rickettsii, the causative agent of Rocky Mountain spotted fever, contains two immunodominant proteins, rOmpA and rOmpB, in the outer membrane. Both rOmpA and rOmpB are conserved throughout spotted fever group rickettsiae as members of a family of autotransporter proteins. Previously, it was demonstrated that rOmpB is proteolytically processed, with the cleavage site residing near the autotransporter domain at the carboxy-terminal end of the protein, cleaving the 168-kDa precursor into apparent 120-kDa and 32-kDa fragments. The 120and 32-kDa fragments remain noncovalently associated on the surface of the bacterium, with implications that the 32-kDa fragment functions as the membrane anchor domain. Here we present evidence for a similar posttranslational processing of rOmpA. rOmpA is expressed as a predicted 224-kDa precursor yet is observed on SDS-PAGE as a 190-kDa protein. A small rOmpA fragment of 32-kDa was discovered during surface proteome analysis and identified as the carboxyterminal end of the protein. A rabbit polyclonal antibody was generated to the autotransporter region of rOmpA and confirmed a 32-kDa fragment corresponding to the calculated mass of a proteolytically cleaved rOmpA autotransporter region. N-terminal amino acid sequencing revealed a cleavage site on the carboxy-terminal side of Ser-1958 in rOmpA. An avirulent strain of R. rickettsii Iowa deficient in rOmpB processing was also defective in the processing of rOmpA. The similarities of the cleavage sites and the failure of R. rickettsii Iowa to process either rOmpA or rOmpB suggest that a single enzyme may be responsible for both processing events. IMPORTANCE Members of the spotted fever group of rickettsiae, including R. rickettsii, the etiologic agent of Rocky Mountain spotted fever, express at least four autotransporter proteins that are protective antigens or putative virulence determinants. One member of this class of proteins, rOmpB, is proteolytically processed to a passenger domain and an autotransporter domain that remain associated on the rickettsial outer membrane. The protease responsible for this posttranslation processing remains unknown. Here we show that another autotransporter, rOmpA, is similarly processed by R. rickettsii. Similarities in sequence at the cleavage site and predicted secondary protein structure suggest that all four R. rickettsii autotransporters may be processed by the same outer membrane protease. C1 [Noriea, Nicholas F.; Clark, Tina R.; Mead, David; Hackstadt, Ted] NIAID, Host Parasite Interact Sect, Bacteriol Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Hackstadt, T (reprint author), NIAID, Host Parasite Interact Sect, Bacteriol Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. EM Ted_Hackstadt@nih.gov FU Intramural Research Program of the NIAID/NIH FX This work was supported by the Intramural Research Program of the NIAID/NIH. We thank Craig Martens and the RML Genomics Core/Research Technologies Section for the genomic sequencing and analysis. NR 51 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD MAR PY 2017 VL 199 IS 6 AR UNSP e00826 DI 10.1128/JB.00826-16 PG 13 WC Microbiology SC Microbiology GA EN1OQ UT WOS:000395780100006 ER PT J AU Nasab, MG Hassani, L Nejad, SM Norouzi, D AF Nasab, Maryam Ghahremani Hassani, Leila Nejad, Sara Mohammadi Norouzi, Davood TI Interaction of hemin with quadruplex DNA SO JOURNAL OF BIOLOGICAL PHYSICS LA English DT Article DE DNAzyme; Peroxidase; Quadruplex; Hemin; Interaction ID CIRCULAR-DICHROISM; TELOMERASE ACTIVITY; BINDING; DNAZYMES; PORPHYRINS; COMPLEXES; AFFINITY AB A DNA enzyme with peroxidase activity is a G-quadruplex-based DNAzyme formed by hemin and G-quadruplex DNA. Activity of peroxide DNAzymes can be influenced by the structure of quadruplex DNA. In this investigation, the interaction of hemin with T30695 G-quadruplex DNA is evaluated. Molecular dynamic simulation indicates that the binding mode of hemin to G-quadruplex DNA is end-stacking, which is consistent with absorption spectroscopy. Based on fluorescence spectroscopy, hemin ejects thiazole orange from bases of four-strand DNA. Circular dichroism spectra showed that no alteration occurs in this type of DNA structure. C1 [Nasab, Maryam Ghahremani; Hassani, Leila; Nejad, Sara Mohammadi] IASBS, Dept Biol Sci, Zanjan 451951159, Iran. [Norouzi, Davood] NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. RP Hassani, L (reprint author), IASBS, Dept Biol Sci, Zanjan 451951159, Iran. EM hasani@iasbs.ac.ir FU Research Council of Institute for Advanced Studies in Basic Sciences FX Financial support provided by the Research Council of Institute for Advanced Studies in Basic Sciences is gratefully acknowledged. NR 27 TC 0 Z9 0 U1 5 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0092-0606 EI 1573-0689 J9 J BIOL PHYS JI J. Biol. Phys. PD MAR PY 2017 VL 43 IS 1 BP 5 EP 14 DI 10.1007/s10867-016-9430-7 PG 10 WC Biophysics SC Biophysics GA EM1MC UT WOS:000395080700001 PM 27752804 ER PT J AU Laakso, M Kuusisto, J Stancakova, A Kuulasmaa, T Pajukanta, P Lusis, AJ Collins, FS Mohlke, KL Boehnke, M AF Laakso, Markku Kuusisto, Johanna Stancakova, Alena Kuulasmaa, Teemu Pajukanta, Paivi Lusis, Aldons J. Collins, Francis S. Mohlke, Karen L. Boehnke, Michael TI The Metabolic Syndrome in Men study: a resource for studies of metabolic and cardiovascular diseases SO JOURNAL OF LIPID RESEARCH LA English DT Article DE type 2 diabetes; cardiovascular risk factors; metabolic disease; coronary artery disease; METSIM ID TYPE-2 DIABETES SUSCEPTIBILITY; GENOME-WIDE ASSOCIATION; BODY-MASS INDEX; NONDIABETIC FINNISH MEN; INSULIN SENSITIVITY; GENETIC ARCHITECTURE; FASTING GLUCOSE; COMMON VARIANTS; BLOOD-PRESSURE; LOW-FREQUENCY AB The Metabolic Syndrome in Men (METSIM) study is a population-based study including 10,197 Finnish men examined in 2005-2010. The aim of the study is to investigate nongenetic and genetic factors associated with the risk of T2D and CVD, and with cardiovascular risk factors. The protocol includes a detailed phenotyping of the participants, an oral glucose tolerance test, fasting laboratory measurements including proton NMR measurements, mass spectometry metabolomics, adipose tissue biopsies from 1,400 participants, and a stool sample. In our ongoing follow-up study, we have, to date, reexamined 6,496 participants. Extensive genotyping and exome sequencing have been performed for essentially all METSIM participants, and > 2,000 METSIM participants have been whole-genome sequenced. We have identified several nongenetic markers associated with the development of diabetes and cardiovascular events, and participated in several genetic association studies to identify gene variants associated with diabetes, hyperglycemia, and cardiovascular risk factors.jlr The generation of a phenotype and genotype resource in the METSIM study allows us to proceed toward a "systems genetics" approach, which includes statistical methods to quantitate and integrate intermediate phenotypes, such as transcript, protein, or metabolite levels, to provide a global view of the molecular architecture of complex traits. C1 [Laakso, Markku; Kuusisto, Johanna; Stancakova, Alena; Kuulasmaa, Teemu] Univ Eastern Finland, Inst Clin Med, Internal Med, Kuopio, Finland. [Laakso, Markku; Kuusisto, Johanna] Kuopio Univ Hosp, Dept Med, Kuopio, Finland. [Lusis, Aldons J.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Lusis, Aldons J.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Pajukanta, Paivi] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90024 USA. [Collins, Francis S.] NHGRI, NIH, Bethesda, MD 20892 USA. [Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Boehnke, Michael] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Boehnke, Michael] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. RP Laakso, M (reprint author), Univ Eastern Finland, Inst Clin Med, Internal Med, Kuopio, Finland.; Laakso, M (reprint author), Kuopio Univ Hosp, Dept Med, Kuopio, Finland. EM markku.laakso@uef.fi FU National Institutes of Health; Academy of Finland; University of Eastern Finland; Juselius Foundation; Finnish Diabetes Research Foundation; Finnish Foundation for Cardiovascular Research FX The studies included in this work were funded by grants from the National Institutes of Health, the Academy of Finland, the University of Eastern Finland, the Juselius Foundation, the Finnish Diabetes Research Foundation, and the Finnish Foundation for Cardiovascular Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Manuscript received 11 October 2016 and in revised form 15 January 2017. NR 100 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 EI 1539-7262 J9 J LIPID RES JI J. Lipid Res. PD MAR PY 2017 VL 58 IS 3 BP 481 EP 493 DI 10.1194/jlr.O072629 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EM1YL UT WOS:000395113100001 PM 28119442 ER PT J AU Kannan, M Lahiri, S Liu, LK Choudhary, V Prinz, WA AF Kannan, Muthukumar Lahiri, Sujoy Liu, Li-Ka Choudhary, Vineet Prinz, William A. TI Phosphatidylserine synthesis at membrane contact sites promotes its transport out of the ER SO JOURNAL OF LIPID RESEARCH LA English DT Article DE endoplasmic reticulum; lipid transfer pro-teins; lipid biochemistry; mitochondria phospholipids/trafficking; lipid transport; phosphatidylethanolamine; phosphatidylserine synthase ID MITOCHONDRIA-ASSOCIATED MEMBRANES; YEAST SACCHAROMYCES-CEREVISIAE; HAMSTER OVARY CELLS; ENDOPLASMIC-RETICULUM; PHOSPHOLIPID-SYNTHESIS; ESCHERICHIA-COLI; MAMMALIAN-CELLS; PLASMA-MEMBRANE; LIPID TRANSPORT; TRITON X-100 AB Close contacts between organelles, often called membrane contact sites (MCSs), are regions where lipids are exchanged between organelles. Here, we identify a novel mechanism by which cells promote phospholipid exchange at MCSs. Previous studies have shown that phosphatidylserine (PS) synthase activity is highly enriched in portions of the endoplasmic reticulum (ER) in contact with mitochondria. The objective of this study was to determine whether this enrichment promotes PS transport out of the ER. We found that PS transport to mitochondria was more efficient when PS synthase was fused to a protein in the ER at ER- mitochondria contacts than when it was fused to a protein in all portions of the ER. Inefficient PS transport to mitochondria was corrected by increasing tethering between these organelles. PS transport to endosomes was similarly enhanced by PS production in regions of the ER in contact with endosomes. Together, these findings indicate that PS production at MCSs promotes PS transport out of the ER and suggest that phospholipid production at MCSs may be a general mechanism of channeling lipids to specific cellular compartments. C1 [Kannan, Muthukumar; Liu, Li-Ka; Choudhary, Vineet; Prinz, William A.] NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Lahiri, Sujoy] Univ Virginia, Sch Med, Dept Pharmacol, Charlottesville, VA 22908 USA. RP Prinz, WA (reprint author), NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. EM prinzw@helix.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 61 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 EI 1539-7262 J9 J LIPID RES JI J. Lipid Res. PD MAR PY 2017 VL 58 IS 3 BP 553 EP 562 DI 10.1194/jlr.M072959 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EM1YL UT WOS:000395113100008 PM 28119445 ER PT J AU Bann, CM Parker, CB Grobman, WA Willinger, M Simhan, HN Wing, DA Haas, DM Silver, RM Parry, S Saade, GR Wapner, RJ Elovitz, MA Miller, ES Reddy, UM AF Bann, Carla M. Parker, Corette B. Grobman, William A. Willinger, Marian Simhan, Hyagriv N. Wing, Deborah A. Haas, David M. Silver, Robert M. Parry, Samuel Saade, George R. Wapner, Ronald J. Elovitz, Michal A. Miller, Emily S. Reddy, Uma M. CA NuMoM2b Study TI Psychometric properties of stress and anxiety measures among nulliparous women SO JOURNAL OF PSYCHOSOMATIC OBSTETRICS & GYNECOLOGY LA English DT Article DE Anxiety; parity; psychometrics; stress ID LOW-BIRTH-WEIGHT; PREGNANCY-SPECIFIC STRESS; ANTENATAL ANXIETY; PERCEIVED STRESS; MATERNAL ANXIETY; PRENATAL STRESS; POSTPARTUM; DEPRESSION; OUTCOMES; HEALTH AB Objective: To examine the psychometric properties of three measures, the perceived stress scale (PSS), pregnancy experience scale (PES), and state trait anxiety inventory (STAI), for assessing stress and anxiety during pregnancy among a large sample of nulliparous women.Methods: The sample included 10,002 pregnant women participating in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nMoM2b). Internal consistency reliability was assessed with Cronbach's alpha and factorial validity with confirmatory factor analyses. Intraclass correlations (ICCs) were calculated to determine stability of PSS scales over time. Psychometric properties were examined for the overall sample, as well as subgroups based on maternal age, race/ethnicity and language.Results: All three scales demonstrated good internal consistency reliability. Confirmatory factor analyses supported the factor structures of the PSS and the PES. However, a one-factor solution of the trait-anxiety subscale from the STAI did not fit well; a two-factor solution, splitting the items into factors based on direction of item wording (positive versus negative) provided a better fit. Scores on the PSS were generally stable over time (ICC=0.60). Subgroup analyses revealed a few items that did not perform well on Spanish versions of the scales.Conclusion: Overall, the scales performed well, suggesting they could be useful tools for identifying women experiencing high levels of stress and anxiety during pregnancy and allowing for the implementation of interventions to help reduce maternal stress and anxiety. C1 [Bann, Carla M.] RTI Int, Div Stat & Data Sci, 3040 E Cornwallis Rd,POB 12194, Res Triangle Pk, NC 27709 USA. [Parker, Corette B.] RTI Int, Biostat & Epidemiol Div, Res Triangle Pk, NC USA. [Grobman, William A.] Northwestern Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Willinger, Marian; Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Simhan, Hyagriv N.] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Wing, Deborah A.] Univ Calif Irvine, Dept Obstet & Gynecol, Irvine, CA 92717 USA. [Haas, David M.] Indiana Univ, Dept Obstet & Gynecol, Indianapolis, IN 46204 USA. [Silver, Robert M.] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Parry, Samuel; Elovitz, Michal A.] Univ Penn, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Saade, George R.] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. [Wapner, Ronald J.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. [Miller, Emily S.] Northwestern Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Wing, Deborah A.] Miller Childrens Hosp, Long Beach Mem Med Ctr, Long Beach, CA USA. RP Bann, CM (reprint author), RTI Int, Div Stat & Data Sci, 3040 E Cornwallis Rd,POB 12194, Res Triangle Pk, NC 27709 USA. EM cmb@rti.org FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U10 HD063020, U10 HD063036, U10 HD063037, U10 HD063041, U10 HD063046, U10 HD063047, U10 HD063048, U10 HD063053, U10 HD063072] FX Eunice Kennedy Shriver National Institute of Child Health and Human Development, 10.13039/100009633 [U10 HD063020, U10 HD063036, U10 HD063037, U10 HD063041, U10 HD063046, U10 HD063047, U10 HD063048, U10 HD063053, U10 HD063072]. NR 28 TC 0 Z9 0 U1 1 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0167-482X EI 1743-8942 J9 J PSYCHOSOM OBST GYN JI J. Psychosomat. Obstet. Gynecol. PD MAR PY 2017 VL 38 IS 1 BP 53 EP 62 DI 10.1080/0167482X.2016.1252910 PG 10 WC Psychology, Clinical; Obstetrics & Gynecology; Psychiatry SC Psychology; Obstetrics & Gynecology; Psychiatry GA EM1GS UT WOS:000395066700008 PM 27830971 ER PT J AU Chang, LA Simon, SL Jorgensen, TJ Schauer, DA Lee, C AF Chang, Lienard A. Simon, Steven L. Jorgensen, Timothy J. Schauer, David A. Lee, Choonsik TI Dose coefficients for ICRP reference pediatric phantoms exposed to idealised external gamma fields SO JOURNAL OF RADIOLOGICAL PROTECTION LA English DT Article DE external photon; Monte Carlo radiation transport; organ dose; children ID DEPENDENT PROTECTION QUANTITIES; VOXEL PHANTOMS; COMPUTATIONAL MODELS; RADIATION PROTECTION; PHOTON IRRADIATION; ORGAN; DOSIMETRY; CHILDREN; RADIOLOGY; DIAMETER AB Organ and effective dose coefficients have been calculated for the International Commission on Radiological Protection (ICRP) reference pediatric phantoms externally exposed to mono-energetic photon radiation (x-and gamma-rays) from 0.01 to 20 MeV. Calculations used Monte Carlo radiation transport techniques. Organ dose coefficients, i.e., organ absorbed dose per unit air kerma (Gy/Gy), were calculated for 28 organs and tissues including the active marrow (or red bone marrow) for 10 phantoms (newborn, 1 year, 5 year, 10 year, and 15 year old male and female). Radiation exposure was simulated for 33 photon mono-energies (0.01-20 MeV) in six irradiation geometries: antero-posterior (AP), postero-anterior, right lateral, left lateral, rotational, and isotropic. Organ dose coefficients for different ages closely agree in AP geometry as illustrated by a small coefficient of variation (COV) (the ratio of the standard deviation to the mean) of 4.4% for the lungs. The small COVs shown for the effective dose and AP irradiation geometry reflect that most of the radiosensitive organs are located in the front part of the human body. In contrast, we observed differences in organ dose coefficients across the ages of the phantoms for lateral irradiation geometries. We also observed variation in dose coefficients across different irradiation geometries, where the COV ranges from 18% (newborn male) to 38% (15 year old male) across idealised whole body irradiation geometries for the major organs (active marrow, colon, lung, stomach wall, and breast) at the energy of 0.1 MeV. Effective dose coefficients were also derived for applicable situations, e.g., radiation protection or risk projection. Our results are the first comprehensive set of organ and effective dose coefficients applicable to children and adolescents based on the newly adopted ICRP pediatric phantom series. Our tabulated organ and effective dose coefficients for these next-generation phantoms should provide more accurate estimates of organ doses in children than earlier dosimetric models allowed. C1 [Chang, Lienard A.; Simon, Steven L.; Lee, Choonsik] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. [Jorgensen, Timothy J.] Georgetown Univ, Dept Radiat Med, Washington, DC 20057 USA. [Schauer, David A.] Int Commiss Radiat Units & Measurements ICRU, Bethesda, MD 20814 USA. RP Lee, C (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA. EM choonsik.lee@nih.gov FU National Cancer Institute Intramural Research Program; National Institute of Allergy and Infectious Diseases; National Institute of Allergy and Infectious Diseases, NIAID [Y2-Al-5077]; National Cancer Institute, NCI [Y3-CO-5117] FX This work was supported by the National Cancer Institute Intramural Research Program and by the Intra-Agency agreement between the National Institute of Allergy and Infectious Diseases and the National Cancer Institute, NIAID agreement Y2-Al-5077 and NCI agreement Y3-CO-5117. The authors would like to thank the members of the Task Group, Computational Phantom and Radiation Transport, of the International Commission on Radiological Protection for their invaluable comments and suggestions to develop the reference paediatric phantoms. NR 35 TC 0 Z9 0 U1 0 U2 0 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0952-4746 EI 1361-6498 J9 J RADIOL PROT JI J. Radiol. Prot. PD MAR PY 2017 VL 37 IS 1 BP 127 EP 144 DI 10.1088/1361-6498/aa559e PG 18 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA EM6DT UT WOS:000395403700001 PM 28118153 ER PT J AU Sylvetsky, AC Jin, YC Clark, EJ Welsh, JA Rother, KI Talegawkar, SA AF Sylvetsky, Allison C. Jin, Yichen Clark, Elena J. Welsh, Jean A. Rother, Kristina I. Talegawkar, Sameera A. TI Consumption of Low-Calorie Sweeteners among Children and Adults in the United States SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Article DE Artificial sweeteners; Beverages; Diabetes; Diet soda; Obesity ID NONNUTRITIVE SWEETENERS; BREAST-MILK; BEVERAGES; WEIGHT; HEALTH; TRENDS; PERSPECTIVE; NUTRITION; TRIAL; WATER AB Background Consumption of low-calorie sweeteners (LCSs) has increased markedly during the past several decades, yet the prevalence of LCS consumption in recent years is currently unknown. Objective The aim of this study was to describe LCS consumption in the United States and to characterize consumption by sociodemographic subgroups, source, frequency, eating occasion, and location. Design Cross-sectional study using National Health and Nutrition Examination Survey data from 2009 to 2012. The prevalence of LCS consumption was assessed using two 24 hour dietary recalls, while the frequency (number of times per day), occasion (meal vs snack vs alone), and location of LCS consumption (at home vs away from home) was assessed using data from the one, in-person, 24-hour dietary recall. Participants National Health and Nutrition Examination Survey participants (2 years old or older) either in 2009-2010 (n=9,047) or in 2011-2012 (n=7,939). After excluding participants with implausible energy intake (n=44), the final sample size was 16,942. Main outcome measures The primary outcome was the proportion of individuals consuming one or more foods, beverages, or packets containing LCSs during at least one of their two dietary recalls. Statistical analyses performed Data were weighted to provide national estimates and Stata frequency procedures for complex survey design were used for all analyses. Results Our findings were that 25.1% of children and 41.4% adults reported consuming LCSs. Most LCS consumers reported use once daily (80% of children, 56% of adults) and frequency of consumption increased with body weight in adults. LCS consumption was higher in females compared with males among adults, and in obese individuals, compared with overweight and normal-weight individuals. Individuals of non-Hispanic white race/ethnicity also had higher prevalence of consumption compared with non Hispanic blacks and Hispanics and those in the highest tertile of income had higher LCS consumption compared with individuals of middle or low income across LCS product categories in adults, and for LCS beverages and LCS foods in children. Most LCS consumers reported consuming LCS with meals (64% of adults, 62% of children) and the majority of LCS consumption occurred at home (71% and 72% among adults and children, respectively). Conclusions LCS consumption is highly prevalent in the United States, among both children and adults. Well-controlled, prospective trials are required to understand the health impact of this widespread LCS exposure. C1 [Sylvetsky, Allison C.; Jin, Yichen; Clark, Elena J.; Talegawkar, Sameera A.] George Washington Univ, Dept Exercise & Nutr Sci, Milken Inst Sch Publ Hlth, 950 New Hampshire Ave NW,Room 204, Washington, DC 20052 USA. [Sylvetsky, Allison C.; Talegawkar, Sameera A.] George Washington Univ, Milken Inst Sch Publ Hlth, Sumner M Redstone Global Ctr Prevent & Wellness, Washington, DC USA. [Sylvetsky, Allison C.; Rother, Kristina I.] NIDDK, Sect Pediat Diabet & Metab, NIH, Bethesda, MD 20892 USA. [Welsh, Jean A.] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. RP Sylvetsky, AC (reprint author), George Washington Univ, Dept Exercise & Nutr Sci, Milken Inst Sch Publ Hlth, 950 New Hampshire Ave NW,Room 204, Washington, DC 20052 USA. EM asylvets@gwu.edu NR 38 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 EI 2212-2680 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD MAR PY 2017 VL 117 IS 3 BP 441 EP 448 DI 10.1016/j.jand.2016.11.004 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EM7MH UT WOS:000395495400012 PM 28087414 ER PT J AU Espeland, MA Crimmins, EM Grossardt, BR Crandall, JP Gelfond, JAL Harris, TB Kritchevsky, SB Manson, JE Robinson, JG Rocca, WA Temprosa, M Thomas, F Wallace, R Barzilai, N AF Espeland, Mark A. Crimmins, Eileen M. Grossardt, Brandon R. Crandall, Jill P. Gelfond, Jonathan A. L. Harris, Tamara B. Kritchevsky, Stephen B. Manson, JoAnn E. Robinson, Jennifer G. Rocca, Walter A. Temprosa, Marinella Thomas, Fridtjof Wallace, Robert Barzilai, Nir CA Multimorbidity Clinical Trials TI Clinical Trials Targeting Aging and Age-Related Multimorbidity SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Clinical trial design; Geroscience; Chronic diseases ID INTERVENTIONS TESTING PROGRAM; COMPOSITE END-POINTS; LIFE EXPECTANCY; POPULATION; HEALTH; PRIORITIES; DESIGN; COHORT AB Background: There is growing interest in identifying interventions that may increase health span by targeting biological processes underlying aging. The design of efficient and rigorous clinical trials to assess these interventions requires careful consideration of eligibility criteria, outcomes, sample size, and monitoring plans. Methods: Experienced geriatrics researchers and clinical trialists collaborated to provide advice on clinical trial design. Results: Outcomes based on the accumulation and incidence of age-related chronic diseases are attractive for clinical trials targeting aging. Accumulation and incidence rates of multimorbidity outcomes were developed by selecting at-risk subsets of individuals from three large cohort studies of older individuals. These provide representative benchmark data for decisions on eligibility, duration, and assessment protocols. Monitoring rules should be sensitive to targeting aging-related, rather than disease-specific, outcomes. Conclusions: Clinical trials targeting aging are feasible, but require careful design consideration and monitoring rules. C1 [Espeland, Mark A.] Wake Forest Sch Med, Dept Biostat Sci, One Med Ctr Blvd, Winston Salem, NC 28157 USA. [Crimmins, Eileen M.] Univ Southern Calif, Davis Sch Gerontol, Los Angeles, CA USA. [Grossardt, Brandon R.] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA. [Crandall, Jill P.] Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Gelfond, Jonathan A. L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Kritchevsky, Stephen B.] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA. [Manson, JoAnn E.] Harvard Med Sch, Brigham & Womens Hosp, Div Prevent Med, Boston, MA USA. [Robinson, Jennifer G.; Wallace, Robert] Univ Iowa, Carver Coll Med, Iowa City, IA 52242 USA. [Rocca, Walter A.] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA. [Rocca, Walter A.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Temprosa, Marinella] George Washington Univ, Biostat Ctr, Rockville, MD USA. [Thomas, Fridtjof] Univ Tennessee, Dept Prevent Med, Hlth Sci Ctr, Memphis, TN USA. [Barzilai, Nir] Albert Einstein Coll Med, Inst Aging Res, Bronx, NY 10467 USA. RP Espeland, MA (reprint author), Wake Forest Sch Med, Dept Biostat Sci, One Med Ctr Blvd, Winston Salem, NC 28157 USA. EM mespelan@wakehealth.edu FU National Institute on Aging (NIA) [U01 AG09740]; National Institutes of Health [R01AR030582, R01AG034676]; National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services; American Federation for Aging Research; Nathan Shock Center of Excellence for the Biology of Aging [P30AG038072]; Glenn Center for the Biology of Human Aging (Paul Glenn Foundation for Medical Research); NIA [1R24AG044396, P30 AG021332]; HHS [HHSN26801100004C] FX The Health and Retirement Study was funded by the National Institute on Aging (NIA; U01 AG09740). The Rochester Epidemiology Project infrastructure is funded by the National Institutes of Health (R01AR030582 and R01AG034676; PI: W.A.R., MD, MPH). The Womens Health Initiative was funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services. The American Federation for Aging Research has provided support for this work (J.P.C. and N.B.). Additional support has been provided by the Nathan Shock Center of Excellence for the Biology of Aging (P30AG038072, N.B.), the Glenn Center for the Biology of Human Aging (Paul Glenn Foundation for Medical Research) (N.B.), grant 1R24AG044396 from the NIA (PI: Kirkland; co-PI: N.B.), grant P30 AG021332 from the NIA to the Wake Forest Older Americans Independence Center (S.B.K.), and HHS contract HHSN26801100004C (PI: Shumaker; co-PI: M.A.E). NR 37 TC 1 Z9 1 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAR PY 2017 VL 72 IS 3 BP 355 EP 361 DI 10.1093/gerona/glw220 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EP2EM UT WOS:000397195800008 PM 28364543 ER PT J AU Nadkami, NK Lopez, OL Perera, S Studenski, SA Snitz, BE Erickson, KI Mathis, CA Nebes, RD Redfern, M Klunk, WE AF Nadkami, Neelesh K. Lopez, Oscar L. Perera, Subashan Studenski, Stephanie A. Snitz, Beth E. Erickson, Kirk I. Mathis, Chester A. Nebes, Robert D. Redfern, Mark Klunk, William E. TI Cerebral Amyloid Deposition and Dual-Tasking in Cognitively Normal, Mobility Unimpaired Older Adults SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Cognition; Gait; Alzheimer's disease ID FUNCTIONAL CONNECTIVITY; ALZHEIMERS-DISEASE; WORKING-MEMORY; GAIT VELOCITY; WALKING; RISK; BURDEN; HYPERINTENSITIES; INTERFERENCE; ASSOCIATION AB Background: We examined relationships between cerebral amyloid-beta (A beta) and cognitive-gait dual-task performance in 27 cognitively normal, mobility unimpaired elders. Methods: We assessed A beta on Pittsburgh Compound B (PiB)-PET. We measured gait speed separately and while performing working-memory, response-inhibition, motor-sequencing, and phone-dialing tasks. We compared dual-task costs on gait and cognitive performance in high-A beta (PiB(+)) and low-A beta (PiB(-)) groups and examined the association between A beta and dual-task performance decrements. Results: PiB(+) (n = 16) were comparable with the PiB(-) (n = 11) individuals on demographics, general cognitive and physical performance, and key brain MRI characteristics. PiB(+) group demonstrated greater dual-task costs on gait speed on all cognitive tasks (p <.05) except on response inhibition. Dual-task costs on cognition were similar between groups. Overall, A beta was associated with dual-task decrement on gait speed but not on dual-task decrement on cognitive performance. Conclusions: Preliminary evidence indicates that cerebral A beta is associated with gait slowing on dual-tasking in healthy older adults. C1 [Nadkami, Neelesh K.; Perera, Subashan] Univ Pittsburgh, Dept Med Geriatr Med, 500-3471 5th Ave, Pittsburgh, PA 15213 USA. [Nadkami, Neelesh K.; Lopez, Oscar L.; Snitz, Beth E.; Klunk, William E.] Univ Pittsburgh, Alzheimers Dis Res Ctr, 500-3471 5th Ave, Pittsburgh, PA 15213 USA. [Lopez, Oscar L.; Snitz, Beth E.; Klunk, William E.] Univ Pittsburgh, Dept Neurol, 500-3471 5th Ave, Pittsburgh, PA 15213 USA. [Lopez, Oscar L.; Nebes, Robert D.; Klunk, William E.] Univ Pittsburgh, Dept Psychiat, 500-3471 5th Ave, Pittsburgh, PA 15213 USA. [Perera, Subashan] Univ Pittsburgh, Dept Biostat, 500-3471 5th Ave, Pittsburgh, PA 15213 USA. [Studenski, Stephanie A.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Erickson, Kirk I.] Univ Pittsburgh, Dept Psychol, 500-3471 5th Ave, Pittsburgh, PA 15213 USA. [Mathis, Chester A.] Univ Pittsburgh, Dept Radiol, 500-3471 5th Ave, Pittsburgh, PA 15213 USA. [Redfern, Mark] Univ Pittsburgh, Swanson Sch Engn, 500-3471 5th Ave, Pittsburgh, PA 15213 USA. RP Nadkami, NK (reprint author), Univ Pittsburgh, Dept Med Geriatr Med, 500-3471 5th Ave, Pittsburgh, PA 15213 USA. EM nkn3@pitt.edu FU National Institute on Aging [RF1AG025516, K23AG049945]; Pittsburgh Pepper OAIC [P30AG024827]; Pittsburgh Alzheimer's Disease Research Center [P50AG005133] FX This research was supported by the National Institute on Aging (RF1AG025516 and K23AG049945), the Pittsburgh Pepper OAIC (P30AG024827), and the Pittsburgh Alzheimer's Disease Research Center (P50AG005133). NR 33 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAR PY 2017 VL 72 IS 3 BP 431 EP 437 DI 10.1093/gerona/glw211 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EP2EM UT WOS:000397195800019 PM 27803098 ER PT J AU Ramachandran, R Jha, J Paulsson, J Chattoraj, D AF Ramachandran, Revathy Jha, Jyoti Paulsson, Johan Chattoraj, Dhruba TI Random versus Cell Cycle-Regulated Replication Initiation in Bacteria: Insights from Studying Vibrio cholerae Chromosome 2 SO MICROBIOLOGY AND MOLECULAR BIOLOGY REVIEWS LA English DT Review DE cell cycle control of replication timing; plasmid replication; Vibrio cholerae ID P1 PLASMID REPLICATION; ESCHERICHIA-COLI CHROMOSOME; COPY-NUMBER CONTROL; DNA-REPLICATION; BACILLUS-SUBTILIS; PROTEIN DNAA; CAULOBACTER-CRESCENTUS; RESPONSE REGULATOR; NEGATIVE CONTROL; ORIGIN AB Bacterial chromosomes initiate replication at a fixed time in the cell cycle, whereas there is generally no particular time for plasmid replication initiation or chromosomal replication initiation from integrated plasmids. In bacteria with divided genomes, the replication system of one of the chromosomes typically resembles that of bacteria with undivided genomes, whereas the remaining chromosomes have plasmid-like replication systems. For example, in Vibrio cholerae, a bacterium with two chromosomes (chromosome 1 [Chr1] and Chr2), the Chr1 system resembles that of the Escherichia coli chromosome, and the Chr2 system resembles that of iteron-based plasmids. However, Chr2 still initiates replication at a fixed time in the cell cycle and thus offers an opportunity to understand the molecular basis for the difference between random and cell cycleregulated modes of replication. Here we review studies of replication control in Chr2 and compare it to those of plasmids and chromosomes. We argue that although the Chr2 control mechanisms in many ways are reminiscent of those of plasmids, they also appear to combine more regulatory features than are found on a typical plasmid, including some that are more typical of chromosomes. One of the regulatory mechanisms is especially novel, the coordinated timing of replication initiation of Chr1 and Chr2, providing the first example of communication between chromosomes for replication initiation. C1 [Ramachandran, Revathy; Jha, Jyoti; Chattoraj, Dhruba] NCI, Lab Biochem & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Paulsson, Johan] Harvard Med Sch, Dept Syst Biol, Longwood, MA USA. RP Chattoraj, D (reprint author), NCI, Lab Biochem & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM chattoraj@nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health; National Institutes of Health [GM081563] FX This research was supported (in part) by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, and a National Institutes of Health grant (GM081563) to J.P. NR 99 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1092-2172 EI 1098-5557 J9 MICROBIOL MOL BIOL R JI Microbiol. Mol. Biol. Rev. PD MAR PY 2017 VL 81 IS 1 AR e00033 DI 10.1128/MMBR.00033-16 PG 18 WC Microbiology SC Microbiology GA EP6KI UT WOS:000397488000001 ER PT J AU Ames, NJ Ranucci, A Moriyama, B Wallen, GR AF Ames, Nancy J. Ranucci, Alexandra Moriyama, Brad Wallen, Gwenyth R. TI The Human Microbiome and Understanding the 16S rRNA Gene in Translational Nursing Science SO NURSING RESEARCH LA English DT Review DE 16S rRNA sequencing; human microbiome; nursing research; translational research ID GUT-BRAIN AXIS; VENTILATOR-ASSOCIATED PNEUMONIA; INTENSIVE-CARE-UNIT; CHLORHEXIDINE GLUCONATE; RESPIRATORY PATHOGENS; LUNG MICROBIOME; DENTAL PLAQUE; GASTROINTESTINAL MICROBIOTA; NOSOCOMIAL INFECTIONS; ANTIBIOTIC USE AB Background: As more is understood regarding the human microbiome, it is increasingly important for nurse scientists and healthcare practitioners to analyze these microbial communities and their role in health and disease. 16S rRNA sequencing is a key methodology in identifying these bacterial populations that has recently transitioned from use primarily in research to having increased utility in clinical settings. Objectives: The objectives of this review are to (a) describe 16S rRNA sequencing and its role in answering research questions important to nursing science; (b) provide an overview of the oral, lung, and gut microbiomes and relevant research; and (c) identify future implications for microbiome research and 16S sequencing in translational nursing science. Discussion: Sequencing using the 16S rRNA gene has revolutionized research and allowed scientists to easily and reliably characterize complex bacterial communities. This type of research has recently entered the clinical setting, one of the best examples involving the use of 16S sequencing to identify resistant pathogens, thereby improving the accuracy of bacterial identification in infection control. Clinical microbiota research and related requisite methods are of particular relevance to nurse scientists-individuals uniquely positioned to utilize these techniques in future studies in clinical settings. C1 [Ames, Nancy J.; Ranucci, Alexandra; Wallen, Gwenyth R.] NIH, Dept Nursing, Ctr Clin, Bldg 10,Room 2B10,10 Ctr Dr, Bethesda, MD 20892 USA. [Ranucci, Alexandra] Tulane Univ, Sch Med, 1430 Tulane Ave, New Orleans, LA 70112 USA. [Moriyama, Brad] NIH, Dept Pharm, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Ames, NJ (reprint author), NIH, Dept Nursing, Ctr Clin, Bldg 10,Room 2B10,10 Ctr Dr, Bethesda, MD 20892 USA. EM names@nih.gov FU Clinical Center Nursing Department, National Institutes for Health FX The authors acknowledge that this work was supported by the Clinical Center Nursing Department, National Institutes for Health. NR 121 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 2017 VL 66 IS 2 BP 184 EP 197 DI 10.1097/NNR.0000000000000212 PG 14 WC Nursing SC Nursing GA EN1YF UT WOS:000395805700369 PM 28252578 ER PT J AU Lea, D Henderson, W Lingler, J Ren, DX Morrow, L Erlen, J AF Lea, Dawn Henderson, Wendy Lingler, Jennifer Ren, Dianxu Morrow, Lisa Erlen, Judith TI Medication Discrepancies and Community Dwelling Older Adults with Diabetes Mellitus in Primary Care SO NURSING RESEARCH LA English DT Meeting Abstract C1 [Lea, Dawn] 3M Hlth Informat Syst, Salt Lake City, UT USA. [Henderson, Wendy] NINR, Bethesda, MD 20892 USA. [Lingler, Jennifer; Ren, Dianxu; Morrow, Lisa; Erlen, Judith] Univ Pittsburgh, Pittsburgh, PA 15260 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 2017 VL 66 IS 2 BP E127 EP E127 PG 1 WC Nursing SC Nursing GA EN1YF UT WOS:000395805700334 ER PT J AU Weaver, K Melkus, G Fletcher, J Henderson, W AF Weaver, Kristen Melkus, Gail Fletcher, Jason Henderson, Wendy TI Stress Perceptions, Physiological Correlates and Quality of Life, in Patients with Irritable Bowel Syndrome SO NURSING RESEARCH LA English DT Meeting Abstract C1 [Weaver, Kristen] NYU, Natl Inst Nursing Res, Rory Meyers Coll Nursing, New York, NY 10003 USA. [Melkus, Gail; Fletcher, Jason] NYU, Rory Meyers Coll Nursing, New York, NY 10003 USA. [Henderson, Wendy] NINR, Bethesda, MD 20892 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 2017 VL 66 IS 2 BP E10 EP E10 PG 1 WC Nursing SC Nursing GA EN1YF UT WOS:000395805700026 ER PT J AU Xu, WL Cong, XM Henderson, W AF Xu, Wanli Cong, Xiaomei Henderson, Wendy TI The Role of Chronic Pain in Modulating Preterm Infants' Gut Microbiome SO NURSING RESEARCH LA English DT Meeting Abstract C1 [Xu, Wanli; Cong, Xiaomei] Univ Connecticut, Storrs, CT USA. [Henderson, Wendy] NINR, Bethesda, MD 20892 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 2017 VL 66 IS 2 BP E106 EP E107 PG 2 WC Nursing SC Nursing GA EN1YF UT WOS:000395805700278 ER PT J AU Xu, WL Cong, XM McGrath, J Henderson, W AF Xu, Wanli Cong, Xiaomei McGrath, Jacqueline Henderson, Wendy TI The Impact of Cumulative Pain/Stress on Neurodevelopment of Preterm Infants in the NICU SO NURSING RESEARCH LA English DT Meeting Abstract C1 [Xu, Wanli; Cong, Xiaomei; McGrath, Jacqueline] Univ Connecticut, Storrs, CT USA. [Henderson, Wendy] NINR, Biobehav Branch, Div Intramural Res, NIH,DHHS, Bethesda, MD 20892 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 2017 VL 66 IS 2 BP E26 EP E27 PG 2 WC Nursing SC Nursing GA EN1YF UT WOS:000395805700070 ER PT J AU Xue, Z Chen, JX Zhao, Y Medvar, B Knepper, MA AF Xue, Zhe Chen, Jia-Xu Zhao, Yue Medvar, Barbara Knepper, Mark A. TI Data integration in physiology using Bayes' rule and minimum Bayes' factors: deubiquitylating enzymes in the renal collecting duct SO PHYSIOLOGICAL GENOMICS LA English DT Article DE systems biology; collecting duct; kidney; ubiquitin ID EPITHELIAL SODIUM-CHANNEL; DEUBIQUITINATING ENZYMES; TRANSCRIPTIONAL ACTIVITY; NA+ CHANNEL; LC-MS/MS; CELLS; UBIQUITINATION; AQUAPORIN-2; DEGRADATION; NEDD4-2 AB A major challenge in physiology is to exploit the many large-scale data sets available from "-omic" studies to seek answers to key physiological questions. In previous studies, Bayes' theorem has been used for this purpose. This approach requires a means to map continuously distributed experimental data to probabilities (likelihood values) to derive posterior probabilities from the combination of prior probabilities and new data. Here, we introduce the use of minimum Bayes' factors for this purpose and illustrate the approach by addressing a physiological question, "Which deubiquitylating enzymes (DUBs) encoded by mammalian genomes are most likely to regulate plasma membrane transport processes in renal cortical collecting duct principal cells?" To do this, we have created a comprehensive online database of 110 DUBs present in the mammalian genome (https://hpcwebapps.cit.nih.gov/ESBL/Database/DUBs/). We used Bayes' theorem to integrate available information from large-scale data sets derived from proteomic and transcriptomic studies of renal collecting duct cells to rank the 110 known DUBs with regard to likelihood of interacting with and regulating transport processes. The top-ranked DUBs were OTUB1, USP14, PSMD7, PSMD14, USP7, USP9X, OTUD4, USP10, and UCHL5. Among these USP7, USP9X, OTUD4, and USP10 are known to be involved in endosomal trafficking and have potential roles in endosomal recycling of plasma membrane proteins in the mammalian cortical collecting duct. C1 [Zhao, Yue; Medvar, Barbara; Knepper, Mark A.] NIH, Syst Biol Ctr, Natl Heart Lung & Blood Inst, Epithelial Syst Biol Lab, Bldg 10, Bethesda, MD 20892 USA. [Xue, Zhe; Chen, Jia-Xu] Beijing Univ, Chinese Med, Sch Basic Med Sci, Beijing, Peoples R China. [Medvar, Barbara] Cathol Univ Amer, Washington, DC USA. RP Knepper, MA (reprint author), NIH, Bldg 10,Rm 6N307,10 Ctr Dr,MSC 1603, Bethesda, MD 20892 USA. EM knepperm@nhlbi.nih.gov FU [HL-001285]; [HL006129] FX The study was carried out in the Division of Intramural Research of the National Heart, Lung, and Blood Institute (projects HL-001285 and HL006129, M.A. Knepper). NR 42 TC 0 Z9 0 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 EI 1531-2267 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD MAR PY 2017 VL 49 IS 3 BP 151 EP 159 DI 10.1152/physiolgenomics.00120.2016 PG 9 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA EN1TQ UT WOS:000395793400005 PM 28039431 ER PT J AU Pongpiachan, S Hattayanone, M Pinyakong, O Viyakarn, V Chavanich, SA Bo, C Khumsup, C Kittikoon, I Hirunyatrakul, P AF Pongpiachan, S. Hattayanone, M. Pinyakong, O. Viyakarn, V. Chavanich, S. A. Bo, C. Khumsup, C. Kittikoon, I. Hirunyatrakul, P. TI Quantitative ecological risk assessment of inhabitants exposed to polycyclic aromatic hydrocarbons in terrestrial soils of King George Island, Antarctica SO POLAR SCIENCE LA English DT Article DE PAHs; Cancer risk; King George Island; Antarctica; Terrestrial soils ID PERSISTENT ORGANIC POLLUTANTS; FRASER-RIVER BASIN; SOURCE IDENTIFICATION; VERTICAL-DISTRIBUTION; CONTAMINATED SOILS; URBAN ATMOSPHERE; MARINE ORGANISMS; DIESEL-ENGINE; HEAVY-METALS; BOUND PAHS AB This study aims to conduct a quantitative ecological risk assessment of human exposure to polycyclic aromatic hydrocarbons (PAHs) in terrestrial soils of King George Island, Antarctica. Generally, the average PAH concentrations detected in King George Terrestrial Soils (KGS) were appreciably lower than those of World Marine Sediments (WMS) and World Terrestrial Soils (WTS), highlighting the fact that Antarctica is one of the most pristine continents in the world. The total concentrations of twelve probably carcinogenic PAHs (Sigma PAHs: a sum of Phe, An, Fluo, Pyr, B[a] A, Chry, B[b] F, B[k] F, B[a] P, Ind, D[a, h] A and B[g,h,i] P) were 3.21 +/- 1.62 ng g +/- 1, 5749 +/- 4576 ng g +/- 1, and 257,496 +/- 291,268 ng g +/- 1, for KGS, WMS and WTS, respectively. In spite of the fact that KGS has extremely low SPAHs in comparison with others, the percentage contribution of Phe is exceedingly high with the value of 50%. By assuming that incidental ingestion and dermal contact are two major exposure pathways responsible for the adverse human health effects, the cancer and non-cancer risks from environmental exposure to PAHs were carefully evaluated based on the "Role of the Baseline Risk Assessment in Superfund Remedy Selection Decisions" memorandum provided by US-EPA. The logarithms of cancer risk levels of PAH contents in KGS varied from -11.1 to -7.18 with an average of -7.96 +/- 7.73, which is 1790 times and 80,176 times lower than that of WMS and WTS, respectively. All cancer risk levels of PAH concentrations observed in KGS are significantly (p < 0.001) lower than those of WMS and WTS. Despite the Comandante Ferraz Antarctic Station fire occurred in February 25th, 2012, both the cancer and non-cancer risks of environmental exposure to PAHs were found in " acceptable level". (C) 2016 Elsevier B.V. and NIPR. All rights reserved. C1 [Pongpiachan, S.] NIDA, Sch Social & Environm Dev, Bangkok, Thailand. [Hattayanone, M.] Prince Songkla Univ, Fac Environm Management, Hat Yai, Songkhla, Thailand. [Pinyakong, O.] Chulalongkorn Univ, Dept Microbiol, Bioremediat Res Unit, Fac Sci, Bangkok, Thailand. [Viyakarn, V.; Chavanich, S. A.] Chulalongkorn Univ, Dept Marine Sci, Reef Biol Res Grp, Fac Sci, Bangkok, Thailand. [Bo, C.] Polar Res Inst China, Polar Biol Sci Div, Shanghai, Peoples R China. [Khumsup, C.; Kittikoon, I.; Hirunyatrakul, P.] Bara Sci Co Ltd, Bangkok, Thailand. RP Pongpiachan, S (reprint author), NIDA, Sch Social & Environm Dev, Bangkok, Thailand. EM pongpiajun@gmail.com OI Pinyakong, Onruthai/0000-0003-0014-1690 FU Information Technology Foundation under the Initiative of Her Royal Highness Princess Maha Chakri Sirindhorn; Polar Research Project under the Initiatives of Her Royal Highness Princess Maha Chakri Sirindhorn; National Science and Technology Development Agency; Chinese Arctic and Antarctic Administration; T. C. Pharmaceutical Industries Co., Ltd FX The authors acknowledge the Information Technology Foundation under the Initiative of Her Royal Highness Princess Maha Chakri Sirindhorn, Polar Research Project under the Initiatives of Her Royal Highness Princess Maha Chakri Sirindhorn, National Science and Technology Development Agency, Chinese Arctic and Antarctic Administration, and T. C. Pharmaceutical Industries Co., Ltd for supporting this study. The authors would also like to thank all members of CHINARE 30 for their kind assistances. NR 93 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1873-9652 EI 1876-4428 J9 POLAR SCI JI Polar Sci. PD MAR PY 2017 VL 11 BP 19 EP 29 DI 10.1016/j.polar.2016.12.001 PG 11 WC Ecology; Geosciences, Multidisciplinary SC Environmental Sciences & Ecology; Geology GA EM6XL UT WOS:000395455800003 ER PT J AU Olaku, OO Taylor, EA AF Olaku, Oluwadamilola O. Taylor, Emmanuel A. TI Cancer in the Medically Underserved Population SO PRIMARY CARE LA English DT Article DE Cancer; Incidence; Mortality; Underserved; Screening; Prevention; Health disparities; Global health ID RACIAL DISPARITIES; SOCIOECONOMIC-STATUS; RADIATION-EXPOSURE; LOW-INCOME; HEALTH; PREVENTION; MORTALITY; RISK; OUTCOMES; RACE AB Cancer is characterized by uncontrolled growth and spread of abnormal cells. It is the second most common cause of death in the United States, and a significant proportion can be prevented. Underrepresented and underserved populations are less likely to receive routine medical procedures and experience a lower quality of health services. Despite the increase in cancer screening, there are disparities in the incidence and mortality of various cancers. These disparities are not fully explained by the correlations between minority race and lower socioeconomic status or minority race and insurance status. Considerations for global cancer control in low-resource settings are presented. C1 [Olaku, Oluwadamilola O.] Natl Canc Inst, Off Canc Complementary & Alternat Med, 9609 Med Ctr Dr,5-W622,MSC 9743, Bethesda, MD 20892 USA. [Olaku, Oluwadamilola O.] Kelly Serv, Kelly Govt Solut, 6101 Executive Blvd,Suite 392, Rockville, MD 20852 USA. [Taylor, Emmanuel A.] Natl Canc Inst, Ctr Reduce Canc Hlth Dispar, 9609 Med Ctr Dr,6-W104,MSC 9746, Rockville, MD 20850 USA. RP Olaku, OO (reprint author), Natl Canc Inst, Off Canc Complementary & Alternat Med, 9609 Med Ctr Dr,5-W622,MSC 9743, Bethesda, MD 20892 USA. EM Olakuo@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 38 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0095-4543 EI 1558-299X J9 PRIMARY CARE JI Primary Care PD MAR PY 2017 VL 44 IS 1 BP 87 EP + DI 10.1016/j.pop.2016.09.020 PG 12 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA EM5OX UT WOS:000395362600010 PM 28164822 ER PT J AU Pantik, C Cho, YE Hathaway, D Tolley, E Cashion, A AF Pantik, Catherine Cho, Young-Eun Hathaway, Donna Tolley, Elizabeth Cashion, Ann TI Characterization of Body Composition and Fat Mass Distribution 1 Year After Kidney Transplantation SO PROGRESS IN TRANSPLANTATION LA English DT Article DE kidney transplant; obesity; weight gain; body fat mass; BMI ID VISCERAL ADIPOSE-TISSUE; AFFECTING WEIGHT-GAIN; RENAL-TRANSPLANTATION; NUTRITIONAL-STATUS; RISK-FACTORS; RECIPIENTS; OBESITY; INDEX; DISEASE; HEMODIALYSIS AB Purpose: In some recipients, significant weight gain occurs after kidney transplantation. Weight gain is associated with poor outcomes, particularly increased cardiovascular risk. In this study, we characterized changes in body mass index and body fat mass and compared them based on gender and race. Methods: Fifty-two kidney transplant recipients (aged >= 18 years old, 50% men, 58% African American) were enrolled into a prospective study. Body mass index and body fat mass were measured at baseline and 12 months posttransplant. Body fat mass was determined by dual-energy X-ray absorptiometry. Results: The mean increase in body weight was 3.7kg at 12 months; 36.5% (n=19) gained at least 10% of their baseline body weight. Body mass index, percentage of total body fat, and trunk fat were significantly increased. In subgroups, women and African American showed significant increases in body mass index and body fat measures. More participants were classified as obese based on total body fat compared to body mass index. Calories from fat were significantly increased at 12 months and associated with increased body mass index, total body fat, and trunk fat. Days of physical activity were significantly increased. Conclusion: Both body mass index and total body fat mass were significantly increased at 12 months following kidney transplantation, especially for women and African Americans. Importantly, more participants were classified as obese based on total body fat compared to body mass index. Relevant nutrition and physical intervention should be provided, and both body mass index and body fat mass should be evaluated when monitoring weight gain. C1 [Pantik, Catherine; Hathaway, Donna] Univ Tennessee, Coll Nursing, Hlth Sci Ctr, Memphis, TN USA. [Cho, Young-Eun; Cashion, Ann] NINR, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Tolley, Elizabeth] Univ Tennessee, Dept Prevent Med, Hlth Sci Ctr, Memphis, TN USA. RP Cashion, A (reprint author), NINR, NIH, 3 Ctr Dr,Bldg 3,Room 5E26, Bethesda, MD 20892 USA. EM ann.cashion@nih.gov FU National Institutes of Health [R01 NR009270]; National Institute of Nursing Research Intramural Program FX The author(s) disclosed receipt of the following financial support for the research and/or authorship of this article: Funding was made possible through National Institutes of Health grant number R01 NR009270 and the National Institute of Nursing Research Intramural Program. NR 33 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1526-9248 EI 2164-6708 J9 PROG TRANSPLANT JI Prog. Transplant. PD MAR PY 2017 VL 27 IS 1 BP 10 EP 15 DI 10.1177/1526924816681007 PG 6 WC Surgery; Transplantation SC Surgery; Transplantation GA EL5SC UT WOS:000394680100003 ER PT J AU Hickey, JM Sahni, N Chaudhuri, R D'Souza, A Metters, A Joshi, SB Middaugh, CR Volkin, DB AF Hickey, John M. Sahni, Neha Chaudhuri, Rajoshi D'Souza, Ajit Metters, Andrew Joshi, Sangeeta B. Middaugh, C. Russell Volkin, David B. TI Effect of acrylodan conjugation and forced oxidation on the structural integrity, conformational stability, and binding activity of a glucose binding protein SM4 used in a prototype continuous glucose monitor SO PROTEIN SCIENCE LA English DT Article DE acrylodan; chemical modification; glucose; mass spectrometry; oxidation; stability ID DIABETES-MELLITUS; BLOOD-GLUCOSE; MANAGEMENT; DISEASE AB Continuous glucose monitoring (CGM) devices offer diabetes patients a convenient approach to assist in controlling blood glucose levels. A prototype CGM has been developed that uses the emission profile of a polarity-sensitive fluorophore (acrylodan) conjugated to a glucose/galactose-binding protein (SM4-AC) to measure the concentration of glucose in vivo. During development, a decrease in the devices signal intensity was observed in vivo over time, which was postulated to be result of oxidative degradation of SM4-AC. A comprehensive physicochemical analysis of SM4-AC was pursued to identify potential mechanisms of signal intensity loss in this CGM during in vitro forced oxidation studies. An assessment of the structural integrity and conformational stability of SM4-AC indicated a relatively decreased polarity and lower tertiary structure stability compared to unconjugated protein (SM4). The stability and polarity of SM4-AC was also altered in the presence of H2O2. Furthermore, a time-dependent loss in the fluorescence signal of SM4-AC was observed when incubated with H2O2. An LC-MS peptide mapping analysis of these protein samples indicated that primarily two Met residues in SM4-AC were susceptible to oxidation. When these two residues were genetically altered to an amino acid not prone to oxidation, the glucose binding ability of the protein was retained and no loss of acrylodan fluorescence was observed in the presence of H2O2. Genetic alteration of these two residues is proposed as an effective approach to increase the long-term stability of SM4-AC within this prototype CGM in vivo. C1 [Hickey, John M.; Sahni, Neha; Chaudhuri, Rajoshi; Joshi, Sangeeta B.; Middaugh, C. Russell; Volkin, David B.] Univ Kansas, Dept Pharmaceut Chem, Macromol & Vaccine Stabilizat Ctr, Lawrence, KS 66047 USA. [D'Souza, Ajit; Metters, Andrew] BD Med Diabet Care, Andover, MA 01810 USA. [Chaudhuri, Rajoshi] NIAID, Vaccine Prod Program, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Volkin, DB (reprint author), 2030 Becker Dr, Lawrence, KS 66047 USA. EM volkin@ku.edu FU BD Medical-Diabetes Care FX The authors would like to acknowledge Dr. Philip Gao in the COBRE Protein Production Group at the University of Kansas for production of SM4-AC mutant proteins, and Dr. Doug Sherman at BD Technologies (Research Triangle Park, North Carolina) for assistance in labeling the SM4 mutants with acrylodan and for careful review of this manuscript. This study was funded by BD Medical-Diabetes Care. Ajit D'Souza and Andrew Metters are employees of BD Medical-Diabetes Care. NR 19 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD MAR PY 2017 VL 26 IS 3 BP 527 EP 535 DI 10.1002/pro.3102 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EM0EX UT WOS:000394992700013 PM 27997712 ER PT J AU Grayson, PC Ahlman, MA Marinelli, KC Borchin, R Carette, S Khalidi, N Langford, C McAlear, C Monach, PA Pagnoux, C Ytterberg, S Merkel, PA AF Grayson, Peter C. Ahlman, Mark A. Marinelli, Kathleen C. Borchin, Renee Carette, Simon Khalidi, Nader Langford, Carol McAlear, Carol Monach, Paul A. Pagnoux, Christian Ytterberg, Steven Merkel, Peter A. CA Vasculitis Clin Res Consortium TI DISCREPANCIES BETWEEN CLINICAL- AND IMAGING-BASED ASSESSMENTS OF DISEASE ACTIVITY IN TAKAYASU'S ARTERITIS SO RHEUMATOLOGY LA English DT Meeting Abstract CT 18th International Vasculitis and ANCA Workshop CY MAR 25-28, 2017 CL Univ Tokyo, Tokyo, JAPAN HO Univ Tokyo C1 [Grayson, Peter C.; Ahlman, Mark A.; Marinelli, Kathleen C.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Carette, Simon; Pagnoux, Christian] Mt Sinai Hosp, Toronto, ON, Canada. [Khalidi, Nader] McMaster Univ, Hamilton, ON, Canada. [Langford, Carol] Cleveland Clin, Cleveland, OH 44106 USA. [Monach, Paul A.] Boston Univ, Boston, MA 02215 USA. [Ytterberg, Steven] Mayo Clin, Rochester, MN USA. [McAlear, Carol; Merkel, Peter A.] Univ Penn, Philadelphia, PA 19104 USA. [Borchin, Renee] Univ S Florida, Tampa, FL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 EI 1462-0332 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD MAR PY 2017 VL 56 SU 3 MA P1_7 BP 45 EP 45 PG 1 WC Rheumatology SC Rheumatology GA EP0CR UT WOS:000397054900093 ER PT J AU Rhee, RL Grayson, PC Merkel, PA Tomasson, G AF Rhee, Rennie L. Grayson, Peter C. Merkel, Peter A. Tomasson, Gunnar TI INFECTIONS AND THE RISK OF INCIDENT GIANT CELL ARTERITIS: A POPULATION-BASED CASE-CONTROL STUDY SO RHEUMATOLOGY LA English DT Meeting Abstract CT 18th International Vasculitis and ANCA Workshop CY MAR 25-28, 2017 CL Univ Tokyo, Tokyo, JAPAN HO Univ Tokyo C1 [Rhee, Rennie L.; Merkel, Peter A.] Univ Penn, Rheumatol, Philadelphia, PA 19104 USA. [Grayson, Peter C.] NIAMSD, Syst Autoimmun Branch, Bethesda, MD 20892 USA. [Tomasson, Gunnar] Univ Iceland, Dept Publ Hlth Sci, Reykjavik, Iceland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 EI 1462-0332 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD MAR PY 2017 VL 56 SU 3 MA P1_29 BP 52 EP 53 PG 2 WC Rheumatology SC Rheumatology GA EP0CR UT WOS:000397054900114 ER PT J AU Robson, JC Grayson, PC Suppiah, R Ponte, C Craven, A Khalid, S Judge, A Hutchings, A Morgan, AM Gray, D Rosa, J Barrett, J Watts, RA Merkel, PA Luqmani, RA AF Robson, Joanna C. Grayson, Peter C. Suppiah, Ravi Ponte, Cristina Craven, Anthea Khalid, Sara Judge, Andrew Hutchings, Andrew Morgan, Ann-Marie Gray, David Rosa, Joe Barrett, Joe Watts, Richard A. Merkel, Peter A. Luqmani, Raashid A. TI AMERICAN COLLEGE OF RHEUMATOLOGY AND EUROPEAN LEAGUE AGAINST RHEUMATISM 2017 PROVISIONAL CLASSIFICATION CRITERIA FOR GRANULOMATOSIS WITH POLYANGIITIS SO RHEUMATOLOGY LA English DT Meeting Abstract CT 18th International Vasculitis and ANCA Workshop CY MAR 25-28, 2017 CL Univ Tokyo, Tokyo, JAPAN HO Univ Tokyo C1 [Robson, Joanna C.] Univ West England, Acad Rheumatol Unit, Bristol, Avon, England. [Grayson, Peter C.] NIAHMs, System Autoimmun Branch, NIH, Bethesda, MD USA. [Suppiah, Ravi] Auckland Dist Hlth Board, Dept Rheumatol, Auckland, New Zealand. [Ponte, Cristina] Lisbon Acad Med Ctr, Dept Rheumatol, Lisbon, Portugal. [Craven, Anthea; Khalid, Sara; Judge, Andrew; Morgan, Ann-Marie; Gray, David; Rosa, Joe; Barrett, Joe; Luqmani, Raashid A.] Univ Oxford, Musculoskeletal Biomed Res Unit, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Oxford, England. [Hutchings, Andrew] London Sch Hyg & Trop Med, Dept Hlth Serv Res & Policy, London, England. [Watts, Richard A.] Univ East Anglia, Norwich Med Sch, Norwich, Norfolk, England. [Merkel, Peter A.] Univ Penn, Div Rheumatol, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 EI 1462-0332 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD MAR PY 2017 VL 56 SU 3 MA P2_16 BP 108 EP + PG 2 WC Rheumatology SC Rheumatology GA EP0CR UT WOS:000397054900284 ER PT J AU Rhee, RL Sreih, A Grayson, PC Collman, RG Merkel, PA AF Rhee, Rennie L. Sreih, Antoine Grayson, Peter C. Collman, Ronald G. Merkel, Peter A. TI NASAL MICROBIOTA IN PATIENTS WITH GRANULOMATOSIS WITH POLYANGIITIS SO RHEUMATOLOGY LA English DT Meeting Abstract CT 18th International Vasculitis and ANCA Workshop CY MAR 25-28, 2017 CL Univ Tokyo, Tokyo, JAPAN HO Univ Tokyo C1 [Rhee, Rennie L.; Sreih, Antoine; Collman, Ronald G.; Merkel, Peter A.] Univ Penn, Philadelphia, PA 19104 USA. [Grayson, Peter C.] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 EI 1462-0332 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD MAR PY 2017 VL 56 SU 3 MA P2_20 BP 110 EP + PG 2 WC Rheumatology SC Rheumatology GA EP0CR UT WOS:000397054900288 ER PT J AU Grayson, PC Eddy, S Taroni, JN Nair, V Parikh, H Lindenmeyer, M Mariani, L Huang, H Ju, W Greene, CS Cohen, C Krischer, J Kretzler, M Eichinger, FH Merkel, PA AF Grayson, Peter C. Eddy, Sean Taroni, Jaclyn N. Nair, Viji Parikh, Hemang Lindenmeyer, Maja Mariani, Laura Huang, Huateng Ju, Wenjun Greene, Casey S. Cohen, Clemens Krischer, Jeffrey Kretzler, Matthias Eichinger, Felix H. Merkel, Peter A. TI IMMUNOMETABOLISM IN ANCA-ASSOCIATED GLOMERULONEPHRITIS SO RHEUMATOLOGY LA English DT Meeting Abstract CT 18th International Vasculitis and ANCA Workshop CY MAR 25-28, 2017 CL Univ Tokyo, Tokyo, JAPAN HO Univ Tokyo C1 [Grayson, Peter C.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Eddy, Sean; Nair, Viji; Mariani, Laura; Huang, Huateng; Ju, Wenjun; Kretzler, Matthias; Eichinger, Felix H.] Univ Michigan, Div Nephrol, Ann Arbor, MI 48109 USA. [Taroni, Jaclyn N.; Greene, Casey S.] Univ Penn, Syst Pharmacol & Translat Therapeut, Philadelphia, PA 19104 USA. [Parikh, Hemang; Krischer, Jeffrey] Univ S Florida, Tampa, FL USA. [Lindenmeyer, Maja; Cohen, Clemens] Univ Munich, Munich, Germany. [Merkel, Peter A.] Univ Penn, Div Rheumatol, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 EI 1462-0332 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD MAR PY 2017 VL 56 SU 3 MA P2_46 BP 119 EP 119 PG 1 WC Rheumatology SC Rheumatology GA EP0CR UT WOS:000397054900314 ER PT J AU Rhee, RL Davis, JC Ding, L Fervenza, FC Hoffman, GS Kallenberg, CGM Langford, CA McCune, WJ Monach, PA Seo, P Spiera, R St Clair, EW Specks, U Stone, JH Merkel, PA AF Rhee, Rennie L. Davis, John C. Ding, Linna Fervenza, Fernando C. Hoffman, Gary S. Kallenberg, Cees G. M. Langford, Carol A. McCune, W. Joseph Monach, Paul A. Seo, Philip Spiera, Robert St Clair, E. William Specks, Ulrich Stone, John H. Merkel, Peter A. TI THE UTILITY OF URINALYSIS IN DETERMINING THE RISK OF RENAL RELAPSE IN ANCA-ASSOCIATED VASCULITIS SO RHEUMATOLOGY LA English DT Meeting Abstract CT 18th International Vasculitis and ANCA Workshop CY MAR 25-28, 2017 CL Univ Tokyo, Tokyo, JAPAN HO Univ Tokyo C1 [Rhee, Rennie L.; Merkel, Peter A.] Univ Penn, Philadelphia, PA 19104 USA. [Davis, John C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Ding, Linna] NIH, Bldg 10, Bethesda, MD 20892 USA. [Fervenza, Fernando C.; Specks, Ulrich] Mayo Clin, Rochester, MN USA. [Hoffman, Gary S.; Langford, Carol A.] Cleveland Clin, Cleveland, OH 44106 USA. [Kallenberg, Cees G. M.] Univ Groningen, Groningen, Netherlands. [McCune, W. Joseph] Univ Michigan, Ann Arbor, MI 48109 USA. [Monach, Paul A.] Boston Univ, Boston, MA 02215 USA. [Seo, Philip] Johns Hopkins Univ, Baltimore, MD USA. [Spiera, Robert] Hosp Special Surg, 535 E 70th St, New York, NY 10021 USA. [St Clair, E. William] Duke Univ, Med Ctr, Durham, NC USA. [Stone, John H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 EI 1462-0332 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD MAR PY 2017 VL 56 SU 3 MA P2_76 BP 128 EP 129 PG 2 WC Rheumatology SC Rheumatology GA EP0CR UT WOS:000397054900344 ER PT J AU Selvaraj, P Xiao, L Lee, C Murthy, SRK Cawley, NX Lane, M Merchenthaler, I Ahn, S Loh, YP AF Selvaraj, Prabhuanand Xiao, Lan Lee, Cheol Murthy, Saravana R. K. Cawley, Niamh X. Lane, Malcolm Merchenthaler, Istvan Ahn, Sohyun Loh, Y. Peng TI Neurotrophic Factor-alpha 1: A Key Wnt-beta-Catenin Dependent Anti-Proliferation Factor and ERK-Sox9 Activated Inducer of Embryonic Neural Stem Cell Differentiation to Astrocytes in Neurodevelopment SO STEM CELLS LA English DT Article DE Carboxypeptidase E; Neurotrophic factor-1; Astrocytes; Stem cell; Wnt pathway ID REGULATED SECRETORY PATHWAY; LEUKEMIA INHIBITORY FACTOR; CARBOXYPEPTIDASE-E; NEURONAL DIFFERENTIATION; RAT-BRAIN; SIGNALING PATHWAY; MESSENGER-RNA; SELF-RENEWAL; RADIAL GLIA; IN-VITRO AB Embryonic neurodevelopment involves inhibition of proliferation of multipotent neural stem cells (NSCs) followed by differentiation into neurons, astrocytes and oligodendrocytes to form the brain. We have identified a new neurotrophic factor, NF-1, which inhibits proliferation and promotes differentiation of NSC/progenitors derived from E13.5 mouse cortex. Inhibition of proliferation of these cells was mediated through negatively regulating the Wnt pathway and decreasing -catenin. NF-1 induced differentiation of NSCs to astrocytes by enhancing Glial Fibrillary Acidic Protein (GFAP) expression through activating the ERK1/2-Sox9 signaling pathway. Cultured E13.5 cortical stem cells from NF-1-knockout mice showed decreased astrocyte numbers compared to wild-type mice, which was rescued by treatment with NF-1. In vivo, immunocytochemistry of brain sections and Western blot analysis of neocortex of mice showed a gradual increase of NF-1 expression from E14.5 to P1 and a surge of GFAP expression at P1, the time of increase in astrogenesis. Importantly, NF-1-Knockout mice showed approximate to 49% fewer GFAP positive astrocytes in the neocortex compared to WT mice at P1. Thus, NF-1 is critical for regulating antiproliferation and cell fate determination, through differentiating embryonic stem cells to GFAP-positive astrocytes for normal neurodevelopment. C1 [Selvaraj, Prabhuanand; Xiao, Lan; Murthy, Saravana R. K.; Cawley, Niamh X.; Loh, Y. Peng] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Neurobiol, NIH, Bethesda, MD USA. [Lee, Cheol; Ahn, Sohyun] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Dev Neurogenet, NIH, Bethesda, MD USA. [Lane, Malcolm; Merchenthaler, Istvan] Univ Maryland, Dept Epidemiol & Publ Hlth & Anat & Neurobiol, Baltimore, MD 21201 USA. RP Loh, YP (reprint author), NIH, Bldg 49,Room 5A22,49 Convent Dr, Bethesda, MD 20892 USA. EM lohp@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institutes of Health, USA FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, USA. We thank Dr. Marianne Bronner (CALTECH, Pasadena, Ca.) for her critical reading of this manuscript, and Lynn Holtzclaw and Dr. Vincent Schram (NICHD Microscopy Core Facility) for their assistance in microscopy. NR 80 TC 0 Z9 0 U1 0 U2 0 PU WILEY 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 2017 VL 35 IS 3 BP 557 EP 571 DI 10.1002/stem.2511 PG 15 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA EM0UH UT WOS:000395032700003 PM 27709799 ER PT J AU Uchida, N Haro-Mora, JJ Fujita, A Lee, DY Winkler, T Hsieh, MM Tisdale, JF AF Uchida, Naoya Haro-Mora, Juan J. Fujita, Atsushi Lee, Duck-Yeon Winkler, Thomas Hsieh, Matthew M. Tisdale, John F. TI Efficient Generation of beta-Globin-Expressing Erythroid Cells Using Stromal Cell-Derived Induced Pluripotent Stem Cells from Patients with Sickle Cell Disease SO STEM CELLS LA English DT Article DE Pluripotent stem cells; Erythroid differentiation; Primitive and definitive hematopoiesis; Hemogenic endothelium ID HUMAN EMBRYONIC STEM; FETAL-HEMOGLOBIN PRODUCTION; HUMAN SOMATIC-CELLS; RED-BLOOD-CELLS; IN-VITRO; YOLK-SAC; DEFINITIVE HEMATOPOIESIS; VASCULAR ENDOTHELIUM; LENTIVIRAL VECTOR; PERIPHERAL-BLOOD AB Human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells represent an ideal source for in vitro modeling of erythropoiesis and a potential alternative source for red blood cell transfusions. However, iPS cell-derived erythroid cells predominantly produce epsilon- and -globin without -globin production. We recently demonstrated that ES cell-derived sacs (ES sacs), known to express hemangioblast markers, allow for efficient erythroid cell generation with -globin production. In this study, we generated several iPS cell lines derived from bone marrow stromal cells (MSCs) and peripheral blood erythroid progenitors (EPs) from sickle cell disease patients, and evaluated hematopoietic stem/progenitor cell (HSPC) generation after iPS sac induction as well as subsequent erythroid differentiation. MSC-derived iPS sacs yielded greater amounts of immature hematopoietic progenitors (VEGFR2+GPA-), definitive HSPCs (CD34+CD45+), and megakaryoerythroid progenitors (GPA+CD41a+), as compared to EP-derived iPS sacs. Erythroid differentiation from MSC-derived iPS sacs resulted in greater amounts of erythroid cells (GPA+) and higher -globin (and S-globin) expression, comparable to ES sac-derived cells. These data demonstrate that human MSC-derived iPS sacs allow for more efficient erythroid cell generation with higher -globin production, likely due to heightened emergence of immature progenitors. Our findings should be important for iPS cell-derived erythroid cell generation. C1 [Uchida, Naoya; Haro-Mora, Juan J.; Fujita, Atsushi; Hsieh, Matthew M.; Tisdale, John F.] NHLBI, Mol & Clin Hematol Branch, NIDDK, NIH, Bldg 10, Bethesda, MD 20892 USA. [Lee, Duck-Yeon] NHLBI, Biochem Core, NIH, Bldg 10, Bethesda, MD 20892 USA. [Winkler, Thomas] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Uchida, N (reprint author), Mol & Clin Hematol Branch, 9000 Rockville Pike,Bldg 10,9N112, Bethesda, MD 20892 USA. EM uchidan@nhlbi.nih.gov FU intramural research program of the National Heart, Lung, and Blood Institute (NHLBI); National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH) FX This work was supported by the intramural research program of the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH). We thank Kayo Uchida for statistical analysis. NR 55 TC 0 Z9 0 U1 1 U2 1 PU WILEY 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 2017 VL 35 IS 3 BP 586 EP 596 DI 10.1002/stem.2517 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA EM0UH UT WOS:000395032700005 PM 27739611 ER PT J AU Cramer, SC Wolf, SL Adams, HP Chen, DF Dromerick, AW Dunning, K Ellerbe, C Grande, A Janis, S Lansberg, MG Lazar, RM Palesch, YY Richards, L Roth, E Savitz, SI Wechsler, LR Wintermark, M Broderick, JP AF Cramer, Steven C. Wolf, Steven L. Adams, Harold P., Jr. Chen, Daofen Dromerick, Alexander W. Dunning, Kari Ellerbe, Caitlyn Grande, Andrew Janis, Scott Lansberg, Maarten G. Lazar, Ronald M. Palesch, Yuko Y. Richards, Lorie Roth, Elliot Savitz, Sean I. Wechsler, Lawrence R. Wintermark, Max Broderick, Joseph P. TI Stroke Recovery and Rehabilitation Research Issues, Opportunities, and the National Institutes of Health StrokeNet SO STROKE LA English DT Article ID DEPENDENT NEURAL PLASTICITY; RANDOMIZED CLINICAL-TRIAL; UPPER EXTREMITY FUNCTION; STANDARDIZED APPROACH; ISCHEMIC-STROKE; BRAIN; BLIND; POSTSTROKE; CHALLENGES; ANATOMY C1 [Cramer, Steven C.] Univ Calif Irvine, Dept Neurol Anat & Neurobiol, Irvine, CA USA. [Cramer, Steven C.] Univ Calif Irvine, Dept Phys Med & Rehabil, Irvine, CA USA. [Cramer, Steven C.] Univ Calif Irvine, Sue & Bill Gross Stem Cell Res Ctr, Irvine, CA USA. [Wolf, Steven L.] Emory Univ, Sch Med, Dept Rehabil Med, Div Phys Therapy, Atlanta, GA USA. [Wolf, Steven L.] Atlanta VA Ctr Visual & Neurocognit Rehabil, Decatur, GA USA. [Adams, Harold P., Jr.] Univ Iowa, Dept Neurol, Iowa City, IA 52242 USA. [Chen, Daofen] NINDS, Extramural Res Program, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Dromerick, Alexander W.] Georgetown Univ, MedStar Natl Rehabil Hosp, Dept Rehabil Med, Washington, DC USA. [Dromerick, Alexander W.] Washington DC VA Med Ctr, Washington, DC USA. [Dunning, Kari] Univ Cincinnati, Dept Rehabil Sci, Cincinnati, OH 45221 USA. [Ellerbe, Caitlyn; Palesch, Yuko Y.] Med Univ South Carolina, Dept Publ Hlth Sci, Data Coordinat Unit, Charleston, SC USA. [Grande, Andrew] Univ Minnesota, Dept Neurosurg, Minneapolis, MN 55455 USA. [Janis, Scott] NINDS, Off Clin Res, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Lansberg, Maarten G.] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford Stroke Ctr, Stanford, CA 94305 USA. [Lazar, Ronald M.] Columbia Univ Coll Phys & Surg, Dept Neurol, Stroke Div, New York, NY 10032 USA. [Richards, Lorie] Univ Utah, Dept Occupat Therapy, Salt Lake City, UT USA. [Roth, Elliot] Northwestern Feinberg Sch Med, Dept Phys Med & Rehabil, Chicago, IL USA. [Savitz, Sean I.] Univ Texas Houston, Dept Neurol, Houston, TX USA. [Wechsler, Lawrence R.] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15260 USA. [Wintermark, Max] Stanford Healthcare & Sch Med, Dept Radiol, Neuroradiol Sect, Stanford, CA USA. [Broderick, Joseph P.] Univ Cincinnati, Gardner Neurosci Inst, Cincinnati, OH 45221 USA. [Broderick, Joseph P.] Univ Cincinnati, Dept Neurol & Rehabil Med, Cincinnati, OH 45221 USA. RP Cramer, SC (reprint author), Univ Calif Irvine, Med Ctr, 200 S Manchester Ave,Suite 206, Orange, CA 92868 USA. EM scramer@uci.edu FU NIH [U01NS086872, K24 HD074722]; [U01NS087748] FX The National Institutes of Health (NIH) StrokeNet National Clinical Coordinating Center is supported by NIH U01NS086872, and National Data Management Center is supported by U01NS087748. Dr Cramer is supported by NIH K24 HD074722. NR 52 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 2017 VL 48 IS 3 BP 813 EP 819 DI 10.1161/STROKEAHA.116.015501 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA EM8HF UT WOS:000395551400058 PM 28174324 ER PT J AU Murata, T Iwadate, M Takizawa, Y Miyakoshi, M Hayase, S Yang, WJ Cai, Y Yokoyama, S Nagashima, K Wakabayashi, Y Zhu, J Kimura, S AF Murata, Tsubasa Iwadate, Manabu Takizawa, Yoshinori Miyakoshi, Masaaki Hayase, Suguru Yang, Wenjing Cai, Yan Yokoyama, Shigetoshi Nagashima, Kunio Wakabayashi, Yoshiyuki Zhu, Jun Kimura, Shioko TI An Adult Mouse Thyroid Side Population Cell Line that Exhibits Enriched Epithelial-Mesenchymal Transition SO THYROID LA English DT Article DE thyroid stem cells; thyroid cancer; RNA seq analysis; thyroid side population; epithelial-to-mesenchymal transition ID EMBRYONIC STEM-CELLS; GENE-EXPRESSION DATA; DIFFERENTIAL EXPRESSION; MOLECULAR-MECHANISMS; IN-VIVO; REGENERATION; PROLIFERATION; TRANSCRIPTION; ENHANCER; PROTEIN AB Background: Studies of thyroid stem/progenitor cells have been hampered due to the small organ size and lack of tissue, which limits the yield of these cells. A continuous source that allows the study and characterization of thyroid stem/progenitor cells is desired to push the field forward. Method: A cell line was established from Hoechst-resistant side population cells derived from mouse thyroid that were previously shown to contain stem/progenitor-like cells. Characterization of these cells were carried out by using in vitro two- and three-dimensional cultures and in vivo reconstitution of mice after orthotopic or intravenous injection, in conjunction with quantitative reverse transcription polymerase chain reaction, Western blotting, immunohisto(cyto)chemistry/immunofluorescence, and RNA seq analysis. Results: These cells were named SPTL (side population cell-derived thyroid cell line). Under low serum culturing conditions, SPTL cells expressed the thyroid differentiation marker NKX2-1, a transcription factor critical for thyroid differentiation and function, while no expression of other thyroid differentiation marker genes were observed. SPTL cells formed follicle-like structures in Matrigel (R) cultures, which did not express thyroid differentiation marker genes. In mouse models of orthotopic and intravenous injection, the latter following partial thyroidectomy, a few SPTL cells were found in part of the follicles, most of which expressed NKX2-1. SPTL cells highly express genes involved in epithelial-mesenchymal transition, as demonstrated by RNA seq analysis, and exhibit a gene-expression pattern similar to anaplastic thyroid carcinoma. Conclusion: These results demonstrate that SPTL cells have the capacity to differentiate into thyroid to a limited degree. SPTL cells may provide an excellent tool to study stem cells, including cancer stem cells of the thyroid. C1 [Murata, Tsubasa; Iwadate, Manabu; Takizawa, Yoshinori; Miyakoshi, Masaaki; Hayase, Suguru; Cai, Yan; Yokoyama, Shigetoshi; Kimura, Shioko] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Yang, Wenjing; Wakabayashi, Yoshiyuki] NHLBI, DNA Sequencing & Genom Core, Bldg 10, Bethesda, MD 20892 USA. [Zhu, Jun] NHLBI, Syst Biol Ctr, Bldg 10, Bethesda, MD 20892 USA. [Nagashima, Kunio] Leidos Biomed Res Inc, Electron Microscope Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. [Murata, Tsubasa] Tomakomai City Hosp, Dent & Oral Surg, Tomakomai, Hokkaido, Japan. [Miyakoshi, Masaaki] Hokkaido Univ, Grad Sch Dent Med, Dept Oral Pathobiol Sci, Sapporo, Hokkaido, Japan. [Hayase, Suguru] Fukushima Med Univ, Dept Organ Regulatory Surg, Sch Med, Fukushima, Japan. [Cai, Yan] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. RP Kimura, S (reprint author), NIH, Bldg 37,Rm 3106,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kimuras@mail.nih.gov FU Intramural Research Program of National Cancer Institute, Center for Cancer Research [ZIABC005522]; National Heart Lung and Blood Institute [1ZICHL006058]; National Cancer Institute, National Institutes of Health [HHSN26120080001E]; Japan Society for the Promotion of Science Research Fellowship for Japanese Biomedical and Behavioral Researchers at NIH FX This work was supported by an Intramural Research Program of National Cancer Institute, Center for Cancer Research ZIABC005522 (to S.K.), National Heart Lung and Blood Institute 1ZICHL006058 (to J.Z.), Federal funds from the National Cancer Institute, National Institutes of Health under contract HHSN26120080001E (to K.N.), and Japan Society for the Promotion of Science Research Fellowship for Japanese Biomedical and Behavioral Researchers at NIH (to T.M.). NR 52 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD MAR PY 2017 VL 27 IS 3 BP 460 EP 474 DI 10.1089/thy.2016.0130 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EN1QS UT WOS:000395785500013 PM 28125936 ER PT J AU Fulkerson, CM Dhawan, D Jones, DR Marquez, VE Jones, PA Wang, Z Wu, Q Klaunig, JE Fourez, LM Bonney, PL Knapp, DW AF Fulkerson, C. M. Dhawan, D. Jones, D. R. Marquez, V. E. Jones, P. A. Wang, Z. Wu, Q. Klaunig, J. E. Fourez, L. M. Bonney, P. L. Knapp, D. W. TI Pharmacokinetics and toxicity of the novel oral demethylating agent zebularine in laboratory and tumor bearing dogs SO VETERINARY AND COMPARATIVE ONCOLOGY LA English DT Article DE demethylating agent; DNA methylation; dog pharmacokinetics and toxicity; epigeneitcs; zebularine ID DNA METHYLTRANSFERASE INHIBITOR; ALDEHYDE OXIDASE; METHYLATION INHIBITOR; IN-VITRO; EPIGENETIC THERAPY; CANCER-CELLS; APOPTOSIS; DECITABINE; METABOLISM; CYTOSOL AB The purpose of this study was to determine the plasma pharmacokinetics (PK) and toxicity of zebularine, an oral cytidine analog with demethylating activity, in dogs. Plasma zebularine concentrations were determined by HPLC-MS/MS following an oral zebularine dose of 8 or 4mg kg(-1). Plasma zebularine clearance was constant. Mean maximum concentration (C-max) was 23 +/- 4.8 and 8.6 +/- 1.4 mu M following 8 and 4mgkg-1, respectively. Mean half-life was 5.7 +/- 0.84 and 7.1 +/- 2.1 following 8 and 4mg kg(-1), respectively. A single 8mgkg(-1) dose was well tolerated. Daily 4mg kg(-1) treatment in three laboratory dogs resulted in grade 4 neutropenia (n= 3), grade 1 anorexia (n= 2) and grade 1 or 2 dermatologic changes (n= 2). All adverse events resolved with supportive care. A 4mgkg-1 dose every 21 days was well tolerated. A follow-up dose escalation study is in progress with a lower starting dose. C1 [Fulkerson, C. M.; Dhawan, D.; Fourez, L. M.; Bonney, P. L.; Knapp, D. W.] Purdue Univ Coll Vet Med, Dept Vet Clin Sci, W Lafayette, IN USA. [Jones, D. R.] Indiana Univ Sch Med, Div Clin Pharmacol, Indianapolis, IN USA. [Marquez, V. E.] Natl Canc Inst, Ctr Canc Res, Biol Chem Lab, Frederick, MD USA. [Jones, P. A.] Van Adel Res Inst, Grand Rapids, MI USA. [Wang, Z.; Wu, Q.; Klaunig, J. E.] Indiana Univ, Sch Publ Hlth, Dept Environm Hlth, Bloomington, IN USA. [Knapp, D. W.] Purdue Univ, Ctr Canc Res, W Lafayette, IN USA. RP Knapp, DW (reprint author), Purdue Univ Coll Vet Med, Dept Vet Clin Sci, W Lafayette, IN USA.; Knapp, DW (reprint author), Purdue Univ, Ctr Canc Res, W Lafayette, IN USA. EM knappd@purdue.edu FU Purdue University Canine Disease Research Fund; National Cancer Institute [P30 CA082709] FX This study was supported by a grant from the Purdue University Canine Disease Research Fund and private donations to the Purdue Comparative Oncology Program. The generous gift of the NCI drug zebularine by Dr James H. Doroshow, Director of Division of Cancer Treatment and Diagnosis, National Cancer Institute, is gratefully acknowledged. The authors wish to thank Ms Cheryl Anderson, Ms Lee Ann Grote and Ms Jennifer Pope for care of laboratory animals provided by the Purdue Clinical Discovery Laboratory. Analytical work was performed by the Clinical Pharmacology Analytical Core laboratory, a core laboratory of the Indiana University Melvin and Bren Simon Cancer Center supported by the National Cancer Institute grant P30 CA082709. NR 28 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1476-5810 EI 1476-5829 J9 VET COMP ONCOL JI Vet. Comp. Oncol. PD MAR PY 2017 VL 15 IS 1 BP 226 EP 236 DI 10.1111/vco.12159 PG 11 WC Veterinary Sciences SC Veterinary Sciences GA EM0GB UT WOS:000394995700021 PM 26178438 ER PT J AU White, LA Sexton, JM Shive, HR AF White, L. A. Sexton, J. M. Shive, H. R. TI Histologic and Immunohistochemical Analyses of Soft Tissue Sarcomas From brca2-Mutant/tp53-Mutant Zebrafish Are Consistent With Neural Crest (Schwann Cell) Origin SO VETERINARY PATHOLOGY LA English DT Article DE cancer; Danio rerio; immunohistochemistry; malignant peripheral nerve sheath tumor; sarcoma; zebrafish ID NERVE SHEATH TUMORS; FIBRILLARY ACIDIC PROTEIN; EXPRESSION; TUMORIGENESIS AB The zebrafish (Danio rerio) provides a powerful model for analyzing genetic contributors to cancer. Multiple zebrafish lines with cancer-associated genetic mutations develop soft tissue sarcomas that are histologically consistent with malignant peripheral nerve sheath tumor (MPNST). The goal of this study was to determine the phenotype of soft tissue sarcomas in a brca2-mutant/tp53-mutant zebrafish line using immunohistochemical markers that are commonly expressed in mammalian MPNST. We classified 70 soft tissue sarcomas from a brca2-mutant/tp53-mutant zebrafish cohort as MPNST, undifferentiated sarcoma, or other tumor based on histologic features. The expression of S100, CD57, and glial fibrillary acidic protein (GFAP) was analyzed in nonneoplastic neural tissues and tumor specimens by immunohistochemistry. Each marker was expressed in nonneoplastic neural tissues. In MPNST, S100 and CD57 were widely expressed in neoplastic cells, with greater consistency observed for CD57 expression. In undifferentiated sarcomas, results were variable and correlated to anatomic location. Coelomic undifferentiated sarcomas often exhibited widespread CD57 expression but limited S100 expression. In comparison, ocular undifferentiated sarcomas exhibited limited expression of both CD57 and S100. Overall, CD57 and S100 expression was significantly higher in MPNST than in undifferentiated sarcomas. GFAP was not expressed in any of the tumors. This study identified commercially available antibodies that are useful for analyzing S100, CD57, and GFAP expression in zebrafish. This study further shows a correlation between degree of histologic differentiation and expression of these markers in soft tissue sarcomas from brca2-mutant/tp53-mutant zebrafish and suggests that these cancers are derived from the neural crest with differentiation toward myelinating Schwann cells. C1 [White, L. A.; Shive, H. R.] North Carolina State Univ, Coll Vet Med, Raleigh, NC USA. [Sexton, J. M.] NCI, NIH, Bethesda, MD 20892 USA. RP Shive, HR (reprint author), 1060 William Moore Dr,RB 248, Raleigh, NC 27607 USA. EM hrshive@ncsu.cvm FU US National Institutes of Health, National Cancer Institute, Center for Cancer Research; North Carolina State University, College of Veterinary Medicine FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research, and the North Carolina State University, College of Veterinary Medicine. NR 32 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0300-9858 EI 1544-2217 J9 VET PATHOL JI Vet. Pathol. PD MAR PY 2017 VL 54 IS 2 BP 320 EP 327 DI 10.1177/0300985816669406 PG 8 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA EL8AJ UT WOS:000394842200019 PM 27879444 ER PT J AU Huang, HX Falgout, B Takeda, K Yamada, KM Dhawan, S AF Huang, Hanxia Falgout, Barry Takeda, Kazuyo Yamada, Kenneth M. Dhawan, Subhash TI Nrf2-dependent induction of innate host defense via heme oxygenase-1 inhibits Zika virus replication SO VIROLOGY LA English DT Article DE Zika; Monocytes; Macrophages; Heme oxygenase-1; Nuclear factor erythroid-related factor 2 ID INFECTION; MALARIA; HCV AB We identified primary human monocyte-derived macrophages (MDM) as vulnerable target cells for Zika virus (ZIKV) infection. We demonstrate dramatic effects of hemin, the natural inducer of the heme catabolic enzyme heme oxygenase-1 (HO-1), in the reduction of ZIKV replication in vitro. Both LLC-MK2 monkey kidney cells and primary MDM exhibited hemin-induced HO-1 expression with major reductions of > 90% in ZIKV replication, with little toxicity to infected cells. Silencing expression of HO-1 or its upstream regulatory gene, nuclear factor erythroid-related factor 2 (Nrf2), attenuated hemin-induced suppression of ZIKV infection, suggesting an important role for induction of these intracellular mediators in retarding ZIKV replication. The inverse correlation between hemin-induced HO-1 levels and ZIKV replication provides a potentially useful therapeutic modality based on stimulation of an innate cellular response against Zika virus infection. C1 [Huang, Hanxia; Falgout, Barry; Takeda, Kazuyo; Dhawan, Subhash] US FDA, Silver Spring, MD 20993 USA. [Yamada, Kenneth M.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Dhawan, S (reprint author), US FDA, Silver Spring, MD 20993 USA. EM subhash.dhawan@fda.hhs.gov FU NIDCR Intramural Research Program; FDA Intramural Research Program FX We thank Dr. Rana Nagarkatti and Dr. Sreenivas Gannavaram for critical review of the manuscript. The findings and conclusions in this paper have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any agency determination or policy. This work was supported by FDA and NIDCR Intramural Research Programs. NR 25 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR PY 2017 VL 503 BP 1 EP 5 DI 10.1016/j.virol.2016.12.019 PG 5 WC Virology SC Virology GA EM5MR UT WOS:000395356200001 PM 28068513 ER PT J AU Molkov, YI Rubin, JE Rybak, IA Smith, JC AF Molkov, Yaroslav I. Rubin, Jonathan E. Rybak, Ilya A. Smith, Jeffrey C. TI Computational models of the neural control of breathing SO WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE LA English DT Review ID RESPIRATORY RHYTHM GENERATION; PRE-BOTZINGER COMPLEX; CENTRAL PATTERN GENERATOR; SPINAL-CORD PREPARATIONS; MAMMALIAN BRAIN-STEM; NEWBORN RAT; EXPIRATORY ACTIVITY; CONTROL-SYSTEM; IN-VIVO; FUNCTIONAL ARCHITECTURE AB The ongoing process of breathing underlies the gas exchange essential for mammalian life. Each respiratory cycle ensues from the activity of rhythmic neural circuits in the brainstem, shaped by various modulatory signals, including mechanoreceptor feedback sensitive to lung inflation and chemoreceptor feedback dependent on gas composition in blood and tissues. This paper reviews a variety of computational models designed to reproduce experimental findings related to the neural control of breathing and generate predictions for future experimental testing. The review starts from the description of the core respiratory network in the brainstem, representing the central pattern generator (CPG) responsible for producing rhythmic respiratory activity, and progresses to encompass additional complexities needed to simulate different metabolic challenges, closed-loop feedback control including the lungs, and interactions between the respiratory and autonomic nervous systems. The integrated models considered in this review share a common framework including a distributed CPG core network responsible for generating the baseline three-phase pattern of rhythmic neural activity underlying normal breathing. (C) 2016 Wiley Periodicals, Inc. C1 [Molkov, Yaroslav I.] Georgia State Univ, Dept Math & Stat, Atlanta, GA 30303 USA. [Rubin, Jonathan E.] Univ Pittsburgh, Dept Math, Pittsburgh, PA USA. [Rybak, Ilya A.] Drexel Univ, Coll Med, Dept Neurobiol & Anat, Philadelphia, PA 19104 USA. [Smith, Jeffrey C.] NINDS, Cellular & Syst Neurobiol Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Rybak, IA (reprint author), Drexel Univ, Coll Med, Dept Neurobiol & Anat, Philadelphia, PA 19104 USA. EM rybak@drexel.edu FU National Institutes of Health (NIH) [R01 NS069220, R01 AT008632]; National Science Foundation [DMS-1312508, DMS-1612913]; Intramural Research Program of NIH; National Institute of Neurological Disorders and Stroke FX This study was supported by the National Institutes of Health (NIH): R01 NS069220 (Ilya A. Rybak) and R01 AT008632 (Yaroslav I. Molkov), National Science Foundation, DMS-1312508 and DMS-1612913 (Jonathan E. Rubin), and in part by the Intramural Research Program of NIH, National Institute of Neurological Disorders and Stroke (Jeffrey C. Smith). The authors have declared no conflicts of interest for this article. NR 93 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1939-5094 EI 1939-005X J9 WIRES SYST BIOL MED JI Wiley Interdiscip. Rev.-Syst. Biol PD MAR-APR PY 2017 VL 9 IS 2 AR UNSP e1371 DI 10.1002/wsbm.1371 PG 22 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EL8VN UT WOS:000394898500004 ER PT J AU Smith, SS Cannon, DL Fagan, K Weis, CP AF Smith, Stephanie Sayre Cannon, Dawn L. Fagan, Kathleen Weis, Christopher P. TI Occupational Hydrogen Sulfide Fatalities and Thiosulfate Levels SO AMERICAN JOURNAL OF FORENSIC MEDICINE AND PATHOLOGY LA English DT Letter ID INHALATION; EXPOSURE; DEATH C1 [Smith, Stephanie Sayre] Ft Belvoir Community Hosp, Ft Belvoir, VA 22060 USA. [Cannon, Dawn L.; Fagan, Kathleen] Occupat Safety & Hlth Adm, Washington, DC USA. [Weis, Christopher P.] NIEHS, Bethesda, MD USA. RP Smith, SS (reprint author), Ft Belvoir Community Hosp, Ft Belvoir, VA 22060 USA. EM steph.sayre@gmail.com FU National Institutes of Health FX Dr: Christopher P Weis is the Toxicology liaison and Senior Science Advisor for the Director of the National Institute of Environmental Health Sciences. This work was supported in part by the National Institutes of Health. NR 10 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 0195-7910 EI 1533-404X J9 AM J FOREN MED PATH JI Am. J. Forensic Med. Pathol. PD MAR PY 2017 VL 38 IS 1 BP 47 EP 48 PG 2 WC Medicine, Legal; Pathology SC Legal Medicine; Pathology GA EL1WK UT WOS:000394411900014 PM 28002071 ER PT J AU Boyer, DF McKelvie, PA de Leval, L Edlefsen, KL Ko, YH Aberman, ZA Kovach, AE Masih, A Nishino, HT Weiss, LM Meeker, AK Nardi, V Palisoc, M Shao, L Pittaluga, S Ferry, JA Harris, NL Sohani, AR AF Boyer, Daniel F. McKelvie, Penelope A. de Leval, Laurence Edlefsen, Kerstin L. Ko, Young-Hyeh Aberman, Zachary A. Kovach, Alexandra E. Masih, Aneal Nishino, Ha T. Weiss, Lawrence M. Meeker, Alan K. Nardi, Valentina Palisoc, Maryknoll Shao, Lina Pittaluga, Stefania Ferry, Judith A. Harris, Nancy Lee Sohani, Aliyah R. TI Fibrin-associated EBV-positive Large B-Cell Lymphoma An Indolent Neoplasm With Features Distinct From Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE diffuse large B-cell lymphoma; fibrin; microscopic; chronic inflammation; Epstein-Barr virus ID EPSTEIN-BARR-VIRUS; PYOTHORAX-ASSOCIATED LYMPHOMA; CHRONIC SUBDURAL-HEMATOMA; OF-THE-LITERATURE; CHRONIC INFLAMMATION; LYMPHOPROLIFERATIVE DISORDER; METALLIC IMPLANT; ATRIAL-MYXOMA; DLBCL; TELOMERASE AB Incidental cases of localized fibrin-associated Epstein-Barr virus (EBV)+ large B-cell proliferations have been described at unusual anatomic sites and have been included in the category of diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) in the WHO Classification. We describe 12 cases and review the literature to define their clinicopathologic spectrum and compare features with typical cases of DLBCL-CI. Median age was 55.5 years with a M:F ratio of 3. In all 12 cases, the lymphoma was an incidental microscopic finding involving atrial myxomas (n=3), thrombi associated with endovascular grafts (n=3), chronic hematomas (n=2), and pseudocysts (n=4). All cases tested were non-germinal center B-cell origin, type III EBV latency, and were negative for MYC rearrangements and alternative lengthening of telomeres by FISH. Most showed high CD30, Ki67, and PDL1, and low to moderate MYC and p53 expression. Among 11 patients with detailed follow-up, 6 were treated surgically, 3 with cardiac or vascular lesions had persistent/recurrent disease at intravascular sites, and 4 died of causes not directly attributable to lymphoma. Reports of previously published fibrin-associated cases showed similar features, whereas traditional DLBCL-CI cases with a mass lesion had significantly higher lymphoma-associated mortality. Fibrin-associated EBV+ large B-cell lymphoma is clinicopathologically distinct from DLBCL-CI, warranting separate classification. Most cases, particularly those associated with pseudocysts, behave indolently with the potential for cure by surgery alone and may represent a form of EBV+ lymphoproliferative disease rather than lymphoma. However, primary cardiac or vascular disease may have a higher risk of recurrence despite systemic chemotherapy. C1 [Boyer, Daniel F.; Shao, Lina] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI USA. [McKelvie, Penelope A.; Nardi, Valentina; Ferry, Judith A.; Harris, Nancy Lee; Sohani, Aliyah R.] Harvard Med Sch, Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Dept Pathol, Boston, MA USA. [Nishino, Ha T.] North Shore Med Ctr, Dept Pathol, Salem, MA USA. [McKelvie, Penelope A.] St Vincents Hosp, Dept Anat Pathol, Melbourne, Vic, Australia. [de Leval, Laurence] CHU Vaudois, Inst Univ Pathol, Lausanne, Switzerland. [Edlefsen, Kerstin L.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Ko, Young-Hyeh] Sungkyunkwan Univ, Samsung Med Ctr, Dept Pathol, Seoul, South Korea. [Aberman, Zachary A.] Florida Int Univ, Herbert Wertheim Coll Med, Miami, FL 33199 USA. [Kovach, Alexandra E.] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN USA. [Masih, Aneal] Holmes Reg Med Ctr, Dept Pathol, Melbourne, Vic, Australia. [Weiss, Lawrence M.] NeoGenom Labs, Aliso Viejo, CA USA. [Meeker, Alan K.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Palisoc, Maryknoll; Pittaluga, Stefania] NCI, Pathol Lab, Hematopathol Sect, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Sohani, AR (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,WRN 219, Boston, MA 02114 USA. EM arsohani@mgh.harvard.edu FU NCI Cancer Center Support Grant [NIH 5 P30 CA06516] FX The authors thank Dr Elaine S. Jaffe for providing valuable comments on the manuscript, Drs Ali Ansari-Lari, Benjamin Bricks, Sara Edward, Boris Havkin, Naomi Montague, Daniel Rubin, Vitaly Siomin and Ann Toran for providing clinical follow-up details, and Dr Amy Chadburn, Dr Jonathan Said, and the organizers of the Society of Hematopathology 2015 Workshop on Immunodeficiency and Dysregulation for sharing results of EBV-related stains on case 3. The authors also thank the technical staff of the immunohistochemistry laboratories at the University of Michigan School of Medicine, the Massachusetts General Hospital, and the Dana-Farber/Harvard Cancer Center (supported in part by NCI Cancer Center Support Grant # NIH 5 P30 CA06516) for performing additional immunohistochemical studies. NR 57 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 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD MAR PY 2017 VL 41 IS 3 BP 299 EP 312 PG 14 WC Pathology; Surgery SC Pathology; Surgery GA EL2LW UT WOS:000394452200002 PM 28195879 ER PT J AU Traylor, M Malik, R Nalls, MA Cotlarciuc, I Radmanesh, F Thorleifsson, G Hanscombe, KB Langefeld, C Saleheen, D Rost, NS Yet, I Spector, TD Bell, JT Hannon, E Mill, J Chauhan, G Debette, S Bis, JC Longstreth, WT Ikram, MA Launer, LJ Seshadri, S Hamilton-Bruce, MA Jimenez-Conde, J Cole, JW Schmidt, R Slowik, A Lemmens, R Lindgren, A Melander, O Grewal, RP Sacco, RL Rundek, T Rexrode, K Arnett, DK Johnson, JA Benavente, OR Wasssertheil-Smoller, S Lee, JM Pulit, SL Wong, Q Rich, SS de Bakker, PIW McArdle, PF Woo, D Anderson, CD Xu, HC Heitsch, L Fornage, M Jern, C Stefansson, K Thorsteinsdottir, U Gretarsdottir, S Lewis, CM Sharma, P Sudlow, CLM Rothwell, PM Boncoraglio, GB Thijs, V Levi, C Meschia, JF Rosand, J Kittner, SJ Mitchell, BD Dichgans, M Worrall, BB Markus, HS AF Traylor, Matthew Malik, Rainer Nalls, Mike A. Cotlarciuc, Ioana Radmanesh, Farid Thorleifsson, Gudmar Hanscombe, Ken B. Langefeld, Carl Saleheen, Danish Rost, Natalia S. Yet, Idil Spector, Tim D. Bell, Jordana T. Hannon, Eilis Mill, Jonathan Chauhan, Ganesh Debette, Stephanie Bis, Joshua C. Longstreth, W. T., Jr. Ikram, M. Arfan Launer, Lenore J. Seshadri, Sudha Hamilton-Bruce, Monica Anne Jimenez-Conde, Jordi Cole, John W. Schmidt, Reinhold Slowik, Agnieszka Lemmens, Robin Lindgren, Arne Melander, Olle Grewal, Raji P. Sacco, Ralph L. Rundek, Tatjana Rexrode, Kathryn Arnett, Donna K. Johnson, Julie A. Benavente, Oscar R. Wasssertheil-Smoller, Sylvia Lee, Jin-Moo Pulit, Sara L. Wong, Quenna Rich, Stephen S. de Bakker, Paul I. W. McArdle, Patrick F. Woo, Daniel Anderson, Christopher D. Xu, Huichun Heitsch, Laura Fornage, Myriam Jern, Christina Stefansson, Kari Thorsteinsdottir, Unnur Gretarsdottir, Solveig Lewis, Cathryn M. Sharma, Pankaj Sudlow, Cathie L. M. Rothwell, Peter M. Boncoraglio, Giorgio B. Thijs, Vincent Levi, Chris Meschia, James F. Rosand, Jonathan Kittner, Steven J. Mitchell, Braxton D. Dichgans, Martin Worrall, Bradford B. Markus, Hugh S. CA METASTROKE UK Young Lacunar DNA Study NINDS Stroke Genetics Network Neurology Working Grp CHARGE Conso Int Stroke Genetics Consortium TI Genetic Variation at 16q24.2 Is Associated With Small Vessel Stroke SO ANNALS OF NEUROLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; WHITE-MATTER HYPERINTENSITIES; ISCHEMIC-STROKE; DNA METHYLATION; METASTROKE COLLABORATION; FAMILY-HISTORY; DISEASE; METAANALYSIS; RISK; SUBTYPES AB Objective: Genome-wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger-onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age-at-onset informed GWAS metaanalysis, including a large younger-onset SVS population, to identify novel associations with stroke. Methods: We used a three-stage age-at-onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain. Results: We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10-1.22]; p=3.2x10(-9)). The lead single-nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05-1.16]; p=5.3x10(-5); N=3,670), but not intracerebral hemorrhage (OR [95% CI] 50.97 [0.84-1.12]; p=0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p=9.4x10(-7)) and DNA methylation at probe cg16596957 in whole blood (p=5.3x10(-6)). Interpretation: 16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. C1 [Traylor, Matthew; Hanscombe, Ken B.; Lewis, Cathryn M.] Kings Coll London, Dept Med & Mol Genet, London, England. [Malik, Rainer; Dichgans, Martin] Univ Munich, Klinikum Univ Munchen, Inst Stroke & Dementia Res, Munich, Germany. [Nalls, Mike A.] NIA, Neurogenet Lab, Bethesda, MD USA. [Cotlarciuc, Ioana; Sharma, Pankaj] Inst Cardiovasc Res Royal Holloway Univ London IC, London, England. [Radmanesh, Farid; Anderson, Christopher D.; Rosand, Jonathan] Massachusetts Gen Hosp, Div Neurocrit Care & Emergency Neurol, Boston, MA 02114 USA. [Radmanesh, Farid; Rost, Natalia S.; Anderson, Christopher D.; Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, Boston, MA USA. [Radmanesh, Farid; Anderson, Christopher D.; Rosand, Jonathan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA USA. [Thorleifsson, Gudmar; Stefansson, Kari; Thorsteinsdottir, Unnur] deCODE Genet AMGEN, Reykjavik, Iceland. [Langefeld, Carl; Gretarsdottir, Solveig] Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC USA. [Langefeld, Carl; Gretarsdottir, Solveig] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Saleheen, Danish] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA USA. [Yet, Idil; Spector, Tim D.; Bell, Jordana T.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Hannon, Eilis; Mill, Jonathan] Univ Exeter, Univ Exeter Med Sch, Exeter, Devon, England. [Mill, Jonathan; Lewis, Cathryn M.] Kings Coll London, Inst Psychiat Psychol & Neurosci, Social Genet & Dev Psychiat Ctr, London, England. [Chauhan, Ganesh; Debette, Stephanie] INSERM, Res Ctr Epidemiol & Biostat U897, Team Neuroepidemiol, Bordeaux, France. [Chauhan, Ganesh; Debette, Stephanie] Univ Bordeaux, Bordeaux, France. [Bis, Joshua C.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Longstreth, W. T., Jr.] Univ Washington, Dept Neurol & Epidemiol, Seattle, WA USA. [Ikram, M. Arfan] Erasmus MC Univ Med Ctr, Dept Neurol Epidemiol & Radiol, Rotterdam, Netherlands. [Launer, Lenore J.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD USA. [Seshadri, Sudha] Boston Univ, Sch Med, Boston, MA USA. [Seshadri, Sudha; Thijs, Vincent] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Hamilton-Bruce, Monica Anne; Thijs, Vincent] Royal Adelaide Hosp, Dept Neurol, Adelaide, SA, Australia. [Jimenez-Conde, Jordi] Inst Hosp Mar Invest Med, Dept Neurol, Neurovasc Res Grp NEUVAS, Barcelona, Spain. [Cole, John W.; Kittner, Steven J.] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD USA. [Cole, John W.; Kittner, Steven J.] Baltimore VAMC, Baltimore, MD USA. [Schmidt, Reinhold] Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, Graz, Austria. [Slowik, Agnieszka] Jagiellonian Univ, Dept Neurol, Krakow, Poland. [Lemmens, Robin] KU Leuven Univ Leuven, Dept Neurosci, Expt Neurol, Leuven, Belgium. [Lemmens, Robin] Leuven Res Inst Neurosci & Dis LIND, Leuven, Belgium. [Lemmens, Robin] VIB, Vesalius Res Ctr, Neurobiol Lab, Dept Neurol, Leuven, Belgium. [Lemmens, Robin] Univ Hosp Leuven, Dept Neurol, Leuven, Belgium. [Lindgren, Arne] Lund Univ, Dept Clin Sci Lund, Neurol, Lund, Sweden. [Lindgren, Arne] Skane Univ Hosp, Dept Neurol & Rehabil Med, Lund, Sweden. [Melander, Olle] Lund Univ, Dept Clin Sci, Malmo, Sweden. [Grewal, Raji P.] Seton Hall Univ, Sch Hlth & Med Sci, St Francis Med Ctr, Inst Neurosci, S Orange, NJ USA. [Sacco, Ralph L.; Rundek, Tatjana] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL USA. [Rexrode, Kathryn] Harvard Med Sch, Boston, MA USA. [Rexrode, Kathryn] Brigham & Womens Hosp, Ctr Fac Dev & Divers, 75 Francis St, Boston, MA 02115 USA. [Arnett, Donna K.] Univ Kentucky, Coll Publ Hlth, Lexington, KY USA. [Johnson, Julie A.] Univ Florida, Dept Pharmacotherapy & Translat Res, Coll Pharm, Gainesville, FL USA. [Johnson, Julie A.] Univ Florida, Ctr Pharmacogenom, Coll Pharm, Gainesville, FL USA. [Johnson, Julie A.] Univ Florida, Coll Med, Div Cardiovasc Med, Gainesville, FL USA. [Benavente, Oscar R.] Univ British Columbia, Dept Neurol, Vancouver, BC, Canada. [Wasssertheil-Smoller, Sylvia] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA. [Lee, Jin-Moo] Univ Washington, Sch Med, Dept Neurol, Stroke Ctr, Seattle, WA USA. [Pulit, Sara L.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [Wong, Quenna] Univ Washington, Dept Biostat, Seattle, WA USA. [Rich, Stephen S.] Univ Virginia, Sch Med, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Ctr Mol Med, Dept Med Genet, Utrecht, Netherlands. [McArdle, Patrick F.] Univ Maryland, Sch Med, Dept Med, College Pk, MD 20742 USA. [Woo, Daniel; Rosand, Jonathan] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Anderson, Christopher D.] Broad Inst, Program Med & Populat Genet, Boston, MA USA. [Xu, Huichun] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD USA. [Heitsch, Laura] Washington Univ, Sch Med, Div Emergency Med, St Louis, MO USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Jern, Christina] Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Gothenburg, Sweden. [Stefansson, Kari; Thorsteinsdottir, Unnur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Sudlow, Cathie L. M.] Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland. [Sudlow, Cathie L. M.] Univ Edinburgh, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Rothwell, Peter M.] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford, England. [Boncoraglio, Giorgio B.] Fdn IRCCS Ist Neurol Carlo Besta, Dept Cardiovasc Dis, Milan, Italy. [Thijs, Vincent] Austin Hlth & Florey Inst Neurosci & Mental Hlth, Dept Neurol, Heidelberg, Australia. [Levi, Chris] John Hunter Hosp, Hunter Med Res Inst, Newcastle, NSW, Australia. [Levi, Chris] Univ Newcastle, Newcastle, NSW, Australia. [Meschia, James F.] Mayo Clin Jacksonville, Dept Neurol, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. [Mitchell, Braxton D.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Mitchell, Braxton D.] Baltimore Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD USA. [Dichgans, Martin] Munich Cluster Syst Neurol SyNergy, Munich, Germany. [Worrall, Bradford B.] Univ Virginia, Sch Med, Dept Neurol, Charlottesville, VA 22908 USA. [Worrall, Bradford B.] Univ Virginia, Sch Med, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. [Markus, Hugh S.] Univ Cambridge, Div Clin Neurosci, Stroke Res Grp, Cambridge, England. RP Traylor, M (reprint author), Kings Coll London, Guys Hosp, Dept Med & Mol Genet, 8th Floor,Tower Wing, London SE1 9RT, England. EM matthew.traylor@kcl.ac.uk OI Hannon, Eilis/0000-0001-6840-072X FU NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London; NIHR Senior Investigator award; NIHR Comprehensive Biomedical Research Unit; National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London; Maudsley NHS Foundation Trust and King's College London; Wellcome Trust [Wellcome Trust (WT072952]; Stroke Association [TSA 2010/01]; Stroke Association Grant [TSA 2013/01]; DFG [CRC 1123]; EU [666881]; European Research Council [ERC 250157]; TwinsUK resource; National Institute for Health Research (NIHR); US National Institute of Neurological Disorders and Stroke, National Institutes of Health [U01 NS069208] FX Matthew Traylor is funded by the NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. Hugh Markus is supported by an NIHR Senior Investigator award and his work is supported by NIHR Comprehensive Biomedical Research Unit funding awarded to Cambridge University Hospitals Trust. Cathryn Lewis receives salary support from the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. Collection of the UK Young Lacunar Stroke DNA Study (DNA Lacunar) was primarily supported by the Wellcome Trust (WT072952) with additional support from the Stroke Association (TSA 2010/01). Genotyping of the DNA Lacunar samples was supported by a Stroke Association Grant (TSA 2013/01). Robin Lemmens is a senior clinical investigator of FWO Flanders. Martin Dichgans received funding from the DFG (CRC 1123, B3) and an EU Horizon 2020 grant (agreement No. 666881 SVDs@target). The TwinsUK study was funded, in part, by the European Research Council (ERC 250157), and from the TwinsUK resource, which receives support from the Wellcome Trust and the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. SNP Genotyping was performed by The Wellcome Trust Sanger Institute and National Eye Institute through NIH/CIDR. The SiGN study was funded by a cooperative agreement grant from the US National Institute of Neurological Disorders and Stroke, National Institutes of Health (U01 NS069208). NR 51 TC 0 Z9 0 U1 2 U2 2 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD MAR PY 2017 VL 81 IS 3 BP 383 EP 394 DI 10.1002/ana.24840 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EP3KB UT WOS:000397280100008 PM 27997041 ER PT J AU Glauser, TA Holland, K O'Brien, VP Keddache, M Martin, LJ Clark, PO Cnaan, A Dlugos, D Hirtz, DG Shinnar, S Grabowski, G AF Glauser, Tracy A. Holland, Katherine O'Brien, Valerie P. Keddache, Mehdi Martin, Lisa J. Clark, Peggy O. Cnaan, Avital Dlugos, Dennis Hirtz, Deborah G. Shinnar, Shlomo Grabowski, Gregory CA Childhood Absence Epilepsy Study TI Pharmacogenetics of Antiepileptic Drug Efficacy in Childhood Absence Epilepsy SO ANNALS OF NEUROLOGY LA English DT Article ID P-GLYCOPROTEIN; VALPROIC ACID; CALCIUM-CHANNELS; ASSOCIATION; RESISTANCE; ETHOSUXIMIDE; METAANALYSIS; LAMOTRIGINE; TRANSPORTER; POPULATION AB Objective: To determine whether common polymorphisms in CACNA1G, CACNA1H, CACNA1I, and ABCB1 are associated with differential short-term seizure outcome in childhood absence epilepsy (CAE). Methods: Four hundred forty-six CAE children in a randomized double-blind trial of ethosuximide, lamotrigine, and valproate had short-term seizure outcome determined. Associations between polymorphisms (minor allele frequency >= 15%) in 4 genes and seizure outcomes were assessed. In vitro electrophysiology on transfected CACNA1H channels determined impact of 1 variant on T-type calcium channel responsiveness to ethosuximide. Results: Eighty percent (357 of 446) of subjects had informative short-term seizure status (242 seizure free, 115 not seizure free). In ethosuximide subjects, 2 polymorphisms (CACNA1H rs61734410/P640L, CACNA1I rs3747178) appeared more commonly among not-seizure-free participants (p50.011, odds ratio [OR] 52.63, 95% confidence limits [CL] 51.25-5.56; p50.026, OR52.38, 95% CL51.11-5.00). In lamotrigine subjects, 1 ABCB1 missense polymorphism (rs2032582/S893A; p50.015, OR52.22, 95% CL51.16-4.17) was more common in not-seizure-free participants, and 2 CACNA1H polymorphisms (rs2753326, rs2753325) were more common in seizure-free participants (p50.038, OR50.52, 95% CL50.28-0.96). In valproate subjects, no common polymorphisms were associated with seizure status. In vitro electrophysiological studies showed no effect of the P640L polymorphism on channel physiology in the absence of ethosuximide. Ethosuximide's effect on rate of decay of CaV3.2 was significantly less for P640L channel compared to wild-type channel. Interpretation: Four T-type calcium channel variants and 1 ABCB1 transporter variant were associated with differential drug response in CAE. The in vivo P640L variant's ethosuximide effect was confirmed by in vitro electrophysiological studies. This suggests that genetic variation plays a role in differential CAE drug response. C1 [Glauser, Tracy A.; Holland, Katherine; O'Brien, Valerie P.; Clark, Peggy O.] Cincinnati Childrens Hosp Med Ctr, Div Neurol, Comprehens Epilepsy Ctr, MLC 2015,3333 Burnet Ave, Cincinnati, OH 45229 USA. [Glauser, Tracy A.; Holland, Katherine; O'Brien, Valerie P.; Keddache, Mehdi; Martin, Lisa J.; Clark, Peggy O.; Grabowski, Gregory] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Keddache, Mehdi; Martin, Lisa J.; Grabowski, Gregory] Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA. [Cnaan, Avital] Childrens Natl Hlth Syst, Div Biostat & Study Methodol, Washington, DC USA. [Dlugos, Dennis] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Div Neurol, Philadelphia, PA 19104 USA. [Hirtz, Deborah G.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Shinnar, Shlomo] Albert Einstein Coll Med, Montefiore Med Ctr, Div Neurol, New York, NY USA. RP Glauser, TA (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Neurol, Comprehens Epilepsy Ctr, MLC 2015,3333 Burnet Ave, Cincinnati, OH 45229 USA. EM tracy.glauser@cchmc.org FU NIH [NINDS U01NS 045911, NINDS U01NS045803, NINDS R01NS062756, NICHD 5U10HD031318, NICHD 5U10HD037249, NCRR M01RR008084, NICHD P30HD26979, NICHD P30HD040677, NCATS UL1TR000075] FX The work was supported by the NIH (NINDS U01NS 045911, NINDS U01NS045803, NINDS R01NS062756, NICHD 5U10HD031318, NICHD 5U10HD037249, NCRR M01RR008084, NICHD P30HD26979, NICHD P30HD040677, NCATS UL1TR000075). NR 36 TC 0 Z9 0 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD MAR PY 2017 VL 81 IS 3 BP 444 EP 453 DI 10.1002/ana.24886 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EP3KB UT WOS:000397280100013 PM 28165634 ER PT J AU van Vollenhoven, R Voskuyl, A Bertsias, G Aranow, C Aringer, M Arnaud, L Askanase, A Balazova, P Bonfa, E Bootsma, H Boumpas, D Bruce, I Cervera, R Clarke, A Coney, C Costedoat-Chalumeau, N Czirjak, L Derksen, R Doria, A Dorner, T Fischer-Betz, R Fritsch-Stork, R Gordon, C Graninger, W Gyori, N Houssiau, F Isenberg, D Jacobsen, S Jayne, D Kuhn, A Le Guern, V Lerstrom, K Levy, R Machado-Ribeiro, F Mariette, X Missaykeh, J Morand, E Mosca, M Inanc, M Navarra, S Neumann, I Olesinska, M Petri, M Rahman, A Rekvig, OP Rovensky, J Shoenfeld, Y Smolen, J Tincani, A Urowitz, M van Leeuw, B Vasconcelos, C Voss, A Werth, VP Zakharova, H Zoma, A Schneider, M Ward, M AF van Vollenhoven, Ronald Voskuyl, Alexandre Bertsias, George Aranow, Cynthia Aringer, Martin Arnaud, Laurent Askanase, Anca Balazova, Petra Bonfa, Eloisa Bootsma, Hendrika Boumpas, Dimitrios Bruce, Ian Cervera, Ricard Clarke, Ann Coney, Cindy Costedoat-Chalumeau, Nathalie Czirjak, Laszlo Derksen, Ronald Doria, Andrea Doerner, Thomas Fischer-Betz, Rebecca Fritsch-Stork, Ruth Gordon, Caroline Graninger, Winfried Gyori, Noemi Houssiau, Frederic Isenberg, David Jacobsen, Soren Jayne, David Kuhn, Annegret Le Guern, Veronique Lerstrom, Kirsten Levy, Roger Machado-Ribeiro, Francinne Mariette, Xavier Missaykeh, Jamil Morand, Eric Mosca, Marta Inanc, Murat Navarra, Sandra Neumann, Irmgard Olesinska, Marzena Petri, Michelle Rahman, Anisur Rekvig, Ole Petter Rovensky, Jozef Shoenfeld, Yehuda Smolen, Josef Tincani, Angela Urowitz, Murray van Leeuw, Bernadette Vasconcelos, Carlos Voss, Anne Werth, Victoria P. Zakharova, Helena Zoma, Asad Schneider, Matthias Ward, Michael TI A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS) SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; DISEASE-ACTIVITY; RETROSPECTIVE ANALYSIS; INITIAL VALIDATION; NEPHRITIS PATIENTS; AMERICAN-COLLEGE; CHINESE PATIENTS; RENAL FLARES; PREDICTORS; OUTCOMES AB Objectives Treat-to-target recommendations have identified `remission' as a target in systemic lupus erythematosus (SLE), but recognise that there is no universally accepted definition for this. Therefore, we initiated a process to achieve consensus on potential definitions for remission in SLE. Methods An international task force of 60 specialists and patient representatives participated in preparatory exercises, a face-to-face meeting and follow-up electronic voting. The level for agreement was set at 90%. Results The task force agreed on eight key statements regarding remission in SLE and three principles to guide the further development of remission definitions: 1. Definitions of remission will be worded as follows: remission in SLE is a durable state characterised by ... (reference to symptoms, signs, routine labs). 2. For defining remission, a validated index must be used, for example, clinical systemic lupus erythematosus disease activity index (SLEDAI)=0, British Isles lupus assessment group (BILAG) 2004 D/E only, clinical European consensus lupus outcome measure (ECLAM)=0; with routine laboratory assessments included, and supplemented with physician's global assessment. 3. Distinction is made between remission off and on therapy: remission off therapy requires the patient to be on no other treatment for SLE than maintenance antimalarials; and remission on therapy allows patients to be on stable maintenance antimalarials, low-dose corticosteroids (prednisone <= 5 mg/day), maintenance immunosuppressives and/or maintenance biologics. The task force also agreed that the most appropriate outcomes (dependent variables) for testing the prognostic value (construct validity) of potential remission definitions are: death, damage, flares and measures of health-related quality of life. Conclusions The work of this international task force provides a framework for testing different definitions of remission against long-term outcomes. C1 [van Vollenhoven, Ronald; Voskuyl, Alexandre] D100 Karolinska Univ Hosp, Karolinska Inst, Inflammatory Dis ClinTRID, Unit Clin Therapy Res,Dept Med, Stockholm, Sweden. [Bertsias, George] Vrije Univ Amsterdam Med Ctr, Amsterdam Rheumatol & Immunol Ctr, Amsterdam, Netherlands. [Aranow, Cynthia] Univ Crete, Sch Med, Dept Rheumatol Clin Immunol & Allergy, Iraklion, Greece. [Aringer, Martin] Feinstein Inst Med Res, Manhasset, NY USA. [Askanase, Anca] Tech Univ Dresden, Univ Med Ctr, Dept Med 3, Dresden, Germany. [Balazova, Petra] NYU, New York, NY USA. [Bonfa, Eloisa] LPRe SR Klub Motylik, Bratislava, Slovakia. [Bootsma, Hendrika] Univ Sao Paulo, Fac Med, Div Rheumatol, Sao Paulo, Brazil. [Boumpas, Dimitrios] Univ Groningen, Univ Med Ctr Groningen, Dept Rheumatol & Clin Immunol, Groningen, Netherlands. [Boumpas, Dimitrios] Univ Athens, Dept Med, Athens, Greece. [Bruce, Ian] Univ Athens, Joint Acad Rheumatol Program, Sch Med, Athens, Greece. [Cervera, Ricard] Univ Manchester & Cent Manchester Fdn Trust, NIHR Manchester Biomed Res Unit, Manchester, Lancs, England. [Clarke, Ann] Hosp Clin Barcelona, Dept Autoimmune Dis, Barcelona, Catalonia, Spain. [Coney, Cindy] Univ Calgary, Cumming Sch Med, Arthrit Soc Chair Rheumat Dis, Div Rheumatol, Calgary, AB, Canada. [Costedoat-Chalumeau, Nathalie; Le Guern, Veronique] Lupus Fdn Amer, Washington, DC USA. [Costedoat-Chalumeau, Nathalie; Le Guern, Veronique] Univ Paris Decartes, Paris, France. [Czirjak, Laszlo] Hop Cochin, AP HP, Serv Med Interne, Ctr Reference Malad Auto Immunes & Syst Rares, Paris, France. [Czirjak, Laszlo] Univ Pecs, Inst Family Med, Inst Bioanal, Dept Rheumatol & Immunol, Pecs, Hungary. [Fritsch-Stork, Ruth] Semmelweis Univ, Dept Internal Med 3, Budapest, Hungary. [Doria, Andrea] Univ Med Ctr, Dept Rheumatol & Clin Immunol, Utrecht, Netherlands. [Doerner, Thomas] Univ Padua, Dept Med, Rheumatol Unit, Padua, Italy. [Fischer-Betz, Rebecca; Schneider, Matthias] Charite, Dept Med Rheumatol & Clin Immunol, Berlin, Germany. [Gordon, Caroline] Univ Dusseldorf, Univ Clin Duesseldorf, Hiller Res Unit, Polyclin Rheumatol, Dusseldorf, Germany. [Graninger, Winfried] Univ Birmingham, Coll Med & Dent Sci, Inst Inflammat & Ageing, Rheumatol Res Grp, Birmingham, W Midlands, England. [Houssiau, Frederic] Med Univ Graz, Div Rheumatol, Graz, Austria. [Isenberg, David; Rahman, Anisur] Catholic Univ Louvain, Inst Rech Expt & Clin, Pole Pathol Rhumatism Inflammatoires & Syst, Serv Rhumatol,Clin Univ St Luc, Brussels, Belgium. [Jacobsen, Soren] UCL, Ctr Rheumatol, Dept Med, London, England. [Jayne, David] Ctr Rheumatol & Spine Dis, Copenhagen Lupus & Vasculitis Clin, Copenhagen, Denmark. [Kuhn, Annegret] Univ Cambridge, Dept Med, Cambridge, England. [Lerstrom, Kirsten; van Leeuw, Bernadette] Univ Med Ctr Mainz, Interdisciplinary Ctr Clin Trials IZKS, Mainz, Germany. [Levy, Roger; Machado-Ribeiro, Francinne] LUPUS EUROPE, Romford, Essex, England. [Mariette, Xavier] Univ Estado Rio de Janeiro, Dept Rheumatol, Rio De Janeiro, Brazil. [Missaykeh, Jamil] Univ Paris 11, Hop Univ Paris Sud, AP HP, INSERM,U1184, Le Kremlin Bicetre, France. [Morand, Eric] Monla Hosp, Bone Densitometry Unit, Tripoli, Libya. [Inanc, Murat] Monash Univ, Monash Med Ctr, Fac Med Nursing & Hlth Sci, Clayton, Vic, Australia. [Navarra, Sandra] Univ Pisa, Dept Clin & Expt Med, Rheumatol Unit, Pisa, Italy. [Neumann, Irmgard] Istanbul Univ, Istanbul Fac Med, Div Rheumatol, Dept Internal Med, Istanbul, Turkey. [Olesinska, Marzena] Univ Santo Tomas, Manila, Philippines. [Petri, Michelle] Vasculitis At, Vienna, Austria. [Petri, Michelle] Natl Inst Geriatr Rheumatol & Rehabil, Dept Connect Tissues Dis, Warsaw, Poland. [Rekvig, Ole Petter] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Rovensky, Jozef] Univ Tromso, Fac Hlth Sci, Inst Med Biol, RNA & Mol Pathol Res Grp, Tromso, Norway. [Shoenfeld, Yehuda] Natl Inst Rheumat Dis, Piestany, Slovakia. [Smolen, Josef] Tel Aviv Univ, Sheba Med Ctr, Zabludowicz Ctr Autoimmune Dis, Tel Aviv, Israel. [Smolen, Josef] Med Univ Vienna, Dept Med 3, Div Rheumatol, Vienna, Austria. [Tincani, Angela] Hietzing Hosp, Dept Med 2, Vienna, Austria. [Urowitz, Murray] Univ Brescia, Dipartimento Sci Clin & Sperimentali, Spedali Civ Brescia, UO Reumatol Immunol Clin, Brescia, Italy. [Vasconcelos, Carlos] Univ Toronto, Toronto Western Hosp, Ctr Prognosis Studies Rheumat Dis, Senior Scientist Krembil Res Inst,Med, Toronto, ON, Canada. [Voss, Anne] Univ Porto, UMIB, Inst Ciencias Biomed Abel Salazar, Hosp Santo Antonio,Ctr Hosp Porto,Unidade Imunol, Oporto, Portugal. [Werth, Victoria P.] Univ Southern Denmark, Odense Univ Hosp, Dept Rheumatol, Odense, Denmark. [Werth, Victoria P.] Corporal Michael J Crescenz VA Med Ctr Philadelph, Philadelphia, PA USA. [Zakharova, Helena] Univ Penn, Perelman Sch Med, Dept Dermatol, Philadelphia, PA 19104 USA. [Zoma, Asad] City Clin Hosp Na S P Botkin, Nephrol Unit, Moscow, Russia. [Ward, Michael] Hairmyres Hosp, Lanarkshire Ctr Rheumatol, Glasgow, Lanark, Scotland. [Schneider, Matthias] NIAMSD, NIH, Bethesda, MD 20892 USA. RP van Vollenhoven, R (reprint author), Amsterdam Rheumatol & Immunol Ctr ARC, NL-1100 DD Amsterdam, Netherlands. EM r.f.vanvollenhoven@amc.uva.nl OI , nathalie/0000-0002-1555-9021 FU AbbVie; Amgen; BMS; GSK; Pfizer; Roche; UCB; Adelphivalues; Eli Lilly; LFB; Menarini France; MSD; Raison de sante FX RvVreports having received Research Support and Grants from AbbVie, Amgen, BMS, GSK, Pfizer, Roche, UCB, and Consultancy or honoraria from AbbVie, Biotest, BMS, Celgene, Crescendo, GSK, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB, Vertex. LAreports having received travel grants, consultancy or honoraria from Adelphivalues, Amgen, Eli Lilly, GSK, LFB, Menarini France, MSD, Raison de sante. NR 42 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD MAR PY 2017 VL 76 IS 3 BP 554 EP 561 DI 10.1136/annrheumdis-2016-209519 PG 8 WC Rheumatology SC Rheumatology GA EL3IR UT WOS:000394513300015 PM 27884822 ER PT J AU Smith, CK Seto, NL Vivekanandan-Giri, A Yuan, WM Playford, MP Manna, Z Hasni, SA Kuai, R Mehta, NN Schwendeman, A Pennathur, S Kaplan, MJ AF Smith, Carolyne K. Seto, Nickie L. Vivekanandan-Giri, Anuradha Yuan, Wenmin Playford, Martin P. Manna, Zerai Hasni, Sarfaraz A. Kuai, Rui Mehta, Nehal N. Schwendeman, Anna Pennathur, Subramaniam Kaplan, Mariana J. TI Lupus high-density lipoprotein induces proinflammatory responses in macrophages by binding lectin-like oxidised low-density lipoprotein receptor 1 and failing to promote activating transcription factor 3 activity SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID APOLIPOPROTEIN-A-I; CORONARY-ARTERY-DISEASE; RHEUMATOID-ARTHRITIS; CHOLESTEROL EFFLUX; ERYTHEMATOSUS; ATHEROSCLEROSIS; MYELOPEROXIDASE; MECHANISMS; FRAMINGHAM; REGULATOR AB Objectives Recent evidence indicates that high-density lipoprotein (HDL) exerts vasculoprotective activities by promoting activating transcription factor 3 (ATF3), leading to downregulation of toll-like receptor (TLR)induced inflammatory responses. Systemic lupus erythematosus (SLE) is associated with increased cardiovascular disease risk not explained by the Framingham risk score. Recent studies have indicated oxidised HDL as a possible contributor. We investigated the potential mechanisms by which lupus HDL may lose its anti-inflammatory effects and promote immune dysregulation. Methods Control macrophages were challenged with control and SLE HDL in vitro and examined for inflammatory markers by real-time qRT-PCR, confocal microscopy, ELISA and flow cytometry. Lupus-prone mice were treated with an HDL mimetic (ETC-642) in vivo and inflammatory cytokine levels measured by real-time qRTPCR and ELISA. Results Compared with control HDL, SLE HDL activates NF kappa B, promotes inflammatory cytokine production and fails to block TLR-induced inflammation in control macrophages. This failure of lupus HDL to block inflammatory responses is due to an impaired ability to promote ATF3 synthesis and nuclear translocation. This inflammation is dependent on lectin-like oxidised low-density lipoprotein receptor 1 (LOX1R) binding and rho-associated, coiled-coil containing protein kinase 1 and 2 (ROCK1/2) kinase activity. HDL mimetic-treated lupus mice showed significant ATF3 induction and proinflammatory cytokine abrogation. Conclusions Lupus HDL promotes proinflammatory responses through NF kappa B activation and decreased ATF3 synthesis and activity in an LOX1R-dependent and ROCK1/2-dependent manner. HDL mimetics should be explored as potential therapies for inflammation and SLE cardiovascular risk. C1 [Smith, Carolyne K.; Seto, Nickie L.; Kaplan, Mariana J.] NIAMSD, Syst Autoimmun Branch, NIH, 10 Ctr Dr,Room 6D47C, Bethesda, MD 20892 USA. [Vivekanandan-Giri, Anuradha; Pennathur, Subramaniam] Univ Michigan, Dept Internal Med, Div Nephrol, Ann Arbor, MI 48109 USA. [Yuan, Wenmin; Kuai, Rui; Schwendeman, Anna] Univ Michigan, Dept Med Chem, Biointerfaces Inst, Ann Arbor, MI 48109 USA. [Playford, Martin P.; Mehta, Nehal N.] NHLBI, Sect Inflammat & Cardiometab Dis, NIH, Bldg 10, Bethesda, MD 20892 USA. [Manna, Zerai; Hasni, Sarfaraz A.] NIAMS, Lupus Clin Res Program, Off Clin Director, NIH, Bethesda, MD USA. RP Kaplan, MJ (reprint author), NIAMSD, Syst Autoimmun Branch, NIH, 10 Ctr Dr,Room 6D47C, Bethesda, MD 20892 USA. EM mariana.kaplan@nih.gov FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases [ZIA AR041199]; Lupus Research Institute; NIH [HL006193-01]; AHA [13SDG17230049, R01 GM113832] FX This work was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (project ZIA AR041199), the Lupus Research Institute and also by the NIH through grants: HL006193-01 (MP and NNM), AHA 13SDG17230049 and R01 GM113832 (AS and WY). NR 27 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD MAR PY 2017 VL 76 IS 3 BP 602 EP 611 DI 10.1136/annrheumdis-2016-209683 PG 10 WC Rheumatology SC Rheumatology GA EL3IR UT WOS:000394513300021 PM 27543414 ER PT J AU Le Grice, SFJ Sztuba-Solinska, J Maccioni, E Purzycka, KJ Parolin, C Tramontano, E AF Le Grice, Stuart F. J. Sztuba-Solinska, Joanna Maccioni, Elias Purzycka, Katarzyna J. Parolin, Cristina Tramontano, Enzo TI Meeting report: Third Summer School on Innovative Approaches for Identification of Antiviral Agents (IAAASS) SO ANTIVIRAL RESEARCH LA English DT Article DE Antiviral therapies; Summer school; Emerging infections; Antiviral drugs; Medicinal chemistry AB The third Summer School on Innovative Approaches for Identification of Antiviral Agents (IAAASS) was held from September 28th to October 2nd, 2016 at the Sardegna Ricerche Research Park in Santa Margherita di Pula, Sardinia, Italy. The school brought together graduate students and postdoctoral fellows early in their careers with a faculty of internationally recognized experts, to encourage the sharing of knowledge and experience in virology research and drug development in an informal and interactive environment. The first IAAASS was held in Sardinia in 2012 and the second in 2014. The meetings provide a unique combination of plenary lectures on topics in virology, biochemistry, molecular modeling, crystallography and medicinal chemistry with small group sessions, in which students have the opportunity to ask questions and put forward their own ideas, and senior researchers offer advice, based on their own experience. This report summarizes presentations and presentations at the 3rd IAAASS. Published by Elsevier B.V. C1 [Le Grice, Stuart F. J.; Sztuba-Solinska, Joanna] NCI, Basic Res Lab, Frederick, MD 21701 USA. [Maccioni, Elias; Tramontano, Enzo] Univ Cagliari, Dept Life & Environm Sci, Cittadella Univ SS554, I-09042 Monserrato, Italy. [Purzycka, Katarzyna J.] Polish Acad Sci, Inst Bioorgan Chem, PL-61704 Poznan, Poland. [Parolin, Cristina] Univ Padua, Dept Mol Med, Via Gabelli 63, I-35121 Padua, Italy. RP Le Grice, SFJ (reprint author), NCI, Basic Res Lab, Frederick, MD 21701 USA. EM legrices@mail.nih.gov OI Tramontano, Enzo/0000-0002-4849-0980 FU Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services; Regione Sardegna LR07 - grant [CRP-78711]; Foundation for Polish Science (FNP) [HOMING PLUS/2012-6/12]; Ministry of Science and Higher Education Poland (MNiSW); University of Padova; ANRS [13018] FX SFJ Le G and J S-S are supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. ET is supported by Regione Sardegna LR07 - grant CRP-78711. KJP is supported by Foundation for Polish Science (FNP, HOMING PLUS/2012-6/12) and the Ministry of Science and Higher Education Poland (MNiSW, fellowship for outstanding young scientists). CP is supported by the University of Padova and ANRS Agreement n. 13018. NR 0 TC 0 Z9 0 U1 1 U2 1 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 2017 VL 139 BP 13 EP 17 DI 10.1016/j.antiviral.2016.12.004 PG 5 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA EL1QW UT WOS:000394397100002 PM 27939841 ER PT J AU Wang, RS Ward, MM AF Wang, Runsheng Ward, Michael M. TI Low rate of progression to ankylosing spondylitis among patients with presumed nonradiographic axial spondyloarthritis: comment on the article by Wang et al Reply SO ARTHRITIS & RHEUMATOLOGY LA English DT Letter ID BACK-PAIN; CRITERIA C1 [Wang, Runsheng; Ward, Michael M.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Wang, Runsheng] Columbia Univ, Med Ctr, New York, NY 10027 USA. RP Wang, RS (reprint author), NIAMSD, NIH, Bethesda, MD 20892 USA.; Wang, RS (reprint author), Columbia Univ, Med Ctr, New York, NY 10027 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU WILEY 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 2017 VL 69 IS 3 BP 677 EP 678 DI 10.1002/art.40006 PG 2 WC Rheumatology SC Rheumatology GA EM0VF UT WOS:000395035100024 PM 27875629 ER PT J AU Fay, MP Kim, S AF Fay, Michael P. Kim, Sungwook TI Confidence intervals for directly standardized rates using mid-p gamma intervals SO BIOMETRICAL JOURNAL LA English DT Article DE Age-adjusted rates; Directly standardized rates; Gamma confidence interval; Mid-p confidence interval; Weighted sum of Poisson variates ID SURVIVAL; CANCER AB Directly standardized rates continue to be an integral tool for presenting rates for diseases that are highly dependent on age, such as cancer. Statistically, these rates are modeled as a weighted sum of Poisson random variables. This is a difficult statistical problem, because there are k observed Poisson variables and k unknown means. The gamma confidence interval has been shown through simulations to have at least nominal coverage in all simulated scenarios, but it can be overly conservative. Previous modifications to that method have closer to nominal coverage on average, but they do not achieve the nominal coverage bound in all situations. Further, those modifications are not central intervals, and the upper coverage error rate can be substantially more than half the nominal error. Here we apply a mid-p modification to the gamma confidence interval. Typical mid-p methods forsake guaranteed coverage to get coverage that is sometimes higher and sometimes lower than the nominal coverage rate, depending on the values of the parameters. The mid-p gamma interval does not have guaranteed coverage in all situations; however, in the (not rare) situations where the gamma method is overly conservative, the mid-p gamma interval often has at least nominal coverage. The mid-p gamma interval is especially appropriate when one wants a central interval, since simulations show that in many situations both the upper and lower coverage error rates are on average less than or equal to half the nominal error rate. C1 [Fay, Michael P.; Kim, Sungwook] NIAID, Biostat Res Branch, 5601 Fishers Lane, Bethesda, MD 20892 USA. [Kim, Sungwook] Univ Sci, Philadelphia, PA 19104 USA. RP Fay, MP (reprint author), NIAID, Biostat Res Branch, 5601 Fishers Lane, Bethesda, MD 20892 USA. EM mfay@niaid.nih.gov NR 13 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0323-3847 EI 1521-4036 J9 BIOMETRICAL J JI Biom. J. PD MAR PY 2017 VL 59 IS 2 BP 377 EP 387 DI 10.1002/bimj.201600111 PG 11 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA EO1IR UT WOS:000396452500011 PM 28008645 ER PT J AU Barel, O Malicdan, MCV Ben-Zeev, B Kandel, J Pri-Chen, H Stephen, J Castro, IG Metz, J Atawa, O Moshkovitz, S Ganelin, E Barshack, I Polak-Charcon, S Nass, D Marek-Yagel, D Amariglio, N Shalva, N Vilboux, T Ferreira, C Pode-Shakked, B Heimer, G Hoffmann, C Yardeni, T Nissenkorn, A Avivi, C Eyal, E Kol, N Saar, EG Wallace, DC Gahl, WA Rechavi, G Schrader, M Eckmann, DM Anikster, Y AF Barel, Ortal Malicdan, May Christine V. Ben-Zeev, Bruria Kandel, Judith Pri-Chen, Hadass Stephen, Joshi Castro, Ines G. Metz, Jeremy Atawa, Osama Moshkovitz, Sharon Ganelin, Eti Barshack, Iris Polak-Charcon, Sylvie Nass, Dvora Marek-Yagel, Dina Amariglio, Ninette Shalva, Nechama Vilboux, Thierry Ferreira, Carlos Pode-Shakked, Ben Heimer, Gali Hoffmann, Chen Yardeni, Tal Nissenkorn, Andreea Avivi, Camila Eyal, Eran Kol, Nitzan Saar, Efrat Glick Wallace, Douglas C. Gahl, William A. Rechavi, Gideon Schrader, Michael Eckmann, David M. Anikster, Yair TI Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy SO BRAIN LA English DT Article DE TRAK1; mitochondria transport; rare diseases; early-onset epilepsy; neurodegeneration ID KINESIN HEAVY-CHAIN; HEREDITARY SPASTIC PARAPLEGIA; AXONAL-TRANSPORT; GABA(A) RECEPTOR; PARTIALIS CONTINUA; RESPIRATORY-CHAIN; TRAFFICKING; DISORDERS; SYNAPSES; EPILEPSY AB Cellular distribution and dynamics of mitochondria are regulated by several motor proteins and a microtubule network. In neurons, mitochondrial trafficking is crucial because of high energy needs and calcium ion buffering along axons to synapses during neurotransmission. The trafficking kinesin proteins (TRAKs) are well characterized for their role in lysosomal and mitochondrial trafficking in cells, especially neurons. Using whole exome sequencing, we identified homozygous truncating variants in TRAK1 (NM_001042646:c.287-2A>C), in six lethal encephalopathic patients from three unrelated families. The pathogenic variant results in aberrant splicing and significantly reduced gene expression at the RNA and protein levels. In comparison with normal cells, TRAK1-deficient fibroblasts showed irregular mitochondrial distribution, altered mitochondrial motility, reduced mitochondrial membrane potential, and diminished mitochondrial respiration. This study confirms the role of TRAK1 in mitochondrial dynamics and constitutes the first report of this gene in association with a severe neurodevelopmental disorder. C1 [Barel, Ortal; Moshkovitz, Sharon; Amariglio, Ninette; Eyal, Eran; Kol, Nitzan; Saar, Efrat Glick; Rechavi, Gideon] Sheba Med Ctr, Sheba Canc Res Ctr, Tel Hashomer, Israel. [Barel, Ortal; Ben-Zeev, Bruria; Moshkovitz, Sharon; Marek-Yagel, Dina; Amariglio, Ninette; Eyal, Eran; Kol, Nitzan; Saar, Efrat Glick; Rechavi, Gideon; Anikster, Yair] Sheba Med Ctr, Wohl Inst Translat Med, Tel Hashomer, Israel. [Malicdan, May Christine V.; Pri-Chen, Hadass; Stephen, Joshi; Vilboux, Thierry; Ferreira, Carlos; Gahl, William A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Malicdan, May Christine V.] NHGRI, NIH Undiagnosed Dis Program, NIH, Bethesda, MD 20892 USA. [Ben-Zeev, Bruria; Pri-Chen, Hadass; Marek-Yagel, Dina; Shalva, Nechama; Pode-Shakked, Ben; Heimer, Gali; Hoffmann, Chen; Nissenkorn, Andreea; Rechavi, Gideon; Anikster, Yair] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel. [Ben-Zeev, Bruria; Ganelin, Eti; Heimer, Gali] Edmond & Lily Safra Childrens Hosp, Sheba Med Ctr, Pediat Neurol Unit, Tel Hashomer, Israel. [Kandel, Judith] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA. [Kandel, Judith] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA. [Metz, Jeremy] Palestenian Red Crescent Soc Hosp, Dept Pediat, Hebron City, Palestine. [Atawa, Osama] Sheba Med Ctr, Dept Pathol, Tel Hashomer, Israel. [Marek-Yagel, Dina; Shalva, Nechama; Pode-Shakked, Ben; Anikster, Yair] Edmond & Lily Safra Childrens Hosp, Sheba Med Ctr, Metab Dis Unit, IL-52621 Tel Hashomer, Israel. [Vilboux, Thierry] Inova Hlth Syst, Inova Translat Med Inst, Falls Church, VA USA. [Ferreira, Carlos] Childrens Natl Hlth Syst, Div Genet & Metab, Washington, DC USA. [Pode-Shakked, Ben; Heimer, Gali] Sheba Med Ctr, Dr Pinchas Borenstein Talpiot Med Leadership Prog, Tel Hashomer, Israel. [Hoffmann, Chen] Sheba Med Ctr, Dept Radiol, Tel Hashomer, Israel. [Yardeni, Tal] Childrens Hosp Philadelphia, Ctr Mitochondrial & Epigen Med, Philadelphia, PA 19104 USA. [Nissenkorn, Andreea] Edmond & Lily Safra Childrens Hosp, Sheba Med Ctr, Pediat Neurol Unit, Serv Rare Disorders, Tel Hashomer, Israel. [Eckmann, David M.] Perelman Sch Med, Dept Anesthesiol & Crit Care, Philadelphia, PA USA. [Eckmann, David M.] Univ Penn, Inst Med & Engn, Philadelphia, PA 19104 USA. [Kandel, Judith] Complete Healthcare Commun Inc, One Dickinson Dr, Chadds Ford, PA USA. RP Anikster, Y (reprint author), Edmond & Lily Safra Childrens Hosp, Sheba Med Ctr, Metab Dis Unit, IL-52621 Tel Hashomer, Israel.; Malicdan, MCV (reprint author), NHGRI, NIH Undiagnosed Dis Program, 10C-103 10 Ctr Dr, Bethesda, MD 20892 USA.; Malicdan, MCV (reprint author), Common Fund, 10C-103 10 Ctr Dr, Bethesda, MD 20892 USA. EM maychristine.malicdan@nih.gov; yair.anikster@sheba.health.gov.il FU Office of Naval Research (ONR) [N000141410538]; BBSRC [BB/K006231/1]; Wellcome Trust [WT097835MF, WT105618MA]; Marie Curie Initial Training Network (ITN) action PerFuMe [316723]; NGHRI Intramural Research Program; Kahn Family Foundation; Israeli Centers of Excellence (I-CORE) Program (ISF) [41/11] FX D.M.E. and J.K. are supported by the Office of Naval Research (ONR) Grant N000141410538. M.S. is supported by the BBSRC (BB/K006231/1), a Wellcome Trust Institutional Strategic Support Award (WT097835MF, WT105618MA), and a Marie Curie Initial Training Network (ITN) action PerFuMe (316723). M.C.V.M., J.S., H.P., C.F., T.V. and W.A.G. are supported by the NGHRI Intramural Research Program. G.R. is supported by the Kahn Family Foundation and the Israeli Centers of Excellence (I-CORE) Program (ISF grant no. 41/11). NR 51 TC 0 Z9 0 U1 1 U2 1 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 PY 2017 VL 140 BP 568 EP 581 DI 10.1093/brain/awx002 PN 3 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EP3YH UT WOS:000397317100016 PM 28364549 ER PT J AU Chapeton, JI Inati, SK Zaghloul, KA AF Chapeton, Julio I. Inati, Sara K. Zaghloul, Kareem A. TI Stable functional networks exhibit consistent timing in the human brain SO BRAIN LA English DT Article DE neuroanatomy; temporal lobe; clinical neurophysiology; EEG; intracranial EEG ID MUTUAL INFORMATION ANALYSIS; WHITE-MATTER; EEG; CONNECTIVITY; TIME; MRI; ELECTROENCEPHALOGRAPHY; COMMUNICATION; FEEDFORWARD; EMERGENCE AB Despite many advances in the study of large-scale human functional networks, the question of timing, stability, and direction of communication between cortical regions has not been fully addressed. At the cellular level, neuronal communication occurs through axons and dendrites, and the time required for such communication is well defined and preserved. At larger spatial scales, however, the relationship between timing, direction, and communication between brain regions is less clear. Here, we use a measure of effective connectivity to identify connections between brain regions that exhibit communication with consistent timing. We hypothesized that if two brain regions are communicating, then knowledge of the activity in one region should allow an external observer to better predict activity in the other region, and that such communication involves a consistent time delay. We examine this question using intracranial electroencephalography captured from nine human participants with medically refractory epilepsy. We use a coupling measure based on time-lagged mutual information to identify effective connections between brain regions that exhibit a statistically significant increase in average mutual information at a consistent time delay. These identified connections result in sparse, directed functional networks that are stable over minutes, hours, and days. Notably, the time delays associated with these connections are also highly preserved over multiple time scales. We characterize the anatomic locations of these connections, and find that the propagation of activity exhibits a preferred posterior to anterior temporal lobe direction, consistent across participants. Moreover, networks constructed from connections that reliably exhibit consistent timing between anatomic regions demonstrate features of a small-world architecture, with many reliable connections between anatomically neighbouring regions and few long range connections. Together, our results demonstrate that cortical regions exhibit functional relationships with well-defined and consistent timing, and the stability of these relationships over multiple time scales suggests that these stable pathways may be reliably and repeatedly used for large-scale cortical communication. C1 [Chapeton, Julio I.; Zaghloul, Kareem A.] NINDS, Surg Neurol Branch, NIH, 10,Room 3D20 10 Ctr Dr, Bethesda, MD 20892 USA. [Inati, Sara K.] NINDS, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Zaghloul, KA (reprint author), NINDS, Surg Neurol Branch, NIH, 10,Room 3D20 10 Ctr Dr, Bethesda, MD 20892 USA. EM kareem.zaghloul@nih.gov FU National Institutes of Health FX This work was supported by the Intramural Research Program at the National Institutes of Health. The authors declare no competing financial interests. NR 57 TC 0 Z9 0 U1 1 U2 1 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 PY 2017 VL 140 BP 628 EP 640 DI 10.1093/brain/aww337 PN 3 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EP3YH UT WOS:000397317100020 PM 28364547 ER PT J AU Crimins, JL Wang, ACJ Yuk, F Puri, R Janssen, WGM Hara, Y Rapp, PR Morrison, JH AF Crimins, Johanna L. Wang, Athena Ching-Jung Yuk, Frank Puri, Rishi Janssen, William G. M. Hara, Yuko Rapp, Peter R. Morrison, John H. TI Diverse Synaptic Distributions of G Protein-coupled Estrogen Receptor 1 in Monkey Prefrontal Cortex with Aging and Menopause SO CEREBRAL CORTEX LA English DT Article DE Area 46; delayed response; estradiol; GPER1; synapse ID FEMALE RHESUS-MONKEYS; SPATIAL-LEARNING TASK; BREAST-CANCER CELLS; DENDRITIC SPINES; NONHUMAN-PRIMATES; OVARIECTOMIZED RATS; LUTEINIZING-HORMONE; MACACA-FASCICULARIS; COGNITIVE DECLINE; GPR30 ANTAGONIST AB Age-and menopause-related impairment in working memory mediated by the dorsolateral prefrontal cortex (dlPFC) occurs in humans and nonhuman primates. Long-term cyclic 17 beta-estradiol treatment rescues cognitive deficits in aged ovariectomized rhesus monkeys while restoring highly plastic synapses. Here we tested whether distributions of G protein-coupled estrogen receptor 1 (GPER1) within monkey layer III dlPFC synapses are sensitive to age and estradiol, and coupled to cognitive function. Ovariectomized young and aged monkeys administered vehicle or estradiol were first tested on a delayed response test of working memory. Then, quantitative serial section immunoelectron microscopy was used to determine the distributions of synaptic GPER1. GPER1-containing nonperforated axospinous synapse density was reduced with age, and partially restored with estrogen treatment. The majority of synapses expressed GPER1, which was predominately localized to presynaptic cytoplasm and mitochondria. GPER1 was also abundant at plasmalemmas, and within cytoplasmic and postsynaptic density (PSD) domains of dendritic spines. GPER1 levels did not differ with age or treatment, and none of the variables examined were tightly associated with cognitive function. However, greater representation of GPER1 subjacent to the PSD accompanied higher synapse density. These data suggest that GPER1 is positioned to support diverse functions key to synaptic plasticity in monkey dlPFC. C1 [Crimins, Johanna L.; Yuk, Frank; Puri, Rishi; Janssen, William G. M.; Hara, Yuko; Morrison, John H.] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USA. [Crimins, Johanna L.; Yuk, Frank; Puri, Rishi; Janssen, William G. M.; Hara, Yuko; Morrison, John H.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Morrison, John H.] Icahn Sch Med Mt Sinai, Dept Geriatr & Palliat Med, New York, NY 10029 USA. [Morrison, John H.] Icahn Sch Med Mt Sinai, Grad Sch Biomed Sci, New York, NY 10029 USA. [Morrison, John H.] Calif Natl Primate Res Ctr, Davis, CA 95616 USA. [Morrison, John H.] Univ Calif Davis, Sch Med, Dept Neurol, Davis, CA 95616 USA. [Wang, Athena Ching-Jung] Univ Colorado, Sch Med, Linda Crnic Inst Syndrome, Aurora, CO 80045 USA. [Rapp, Peter R.] NIA, Lab Behav Neurosci, Baltimore, MD 21224 USA. RP Morrison, JH (reprint author), Univ Calif Davis, Calif Natl Primate Res Ctr, One Shields Ave, Davis, CA 95616 USA. EM jhmorrison@ucdavis.edu FU National Institutes of Health [R37 AG06647, P01 AG16765]; National Institute on Aging FX This work was supported by National Institutes of Health grants R37 AG06647 and P01 AG16765 to J. H. M., and in part by the Intramural Research Program of the National Institute on Aging. NR 75 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 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD MAR PY 2017 VL 27 IS 3 BP 2022 EP 2033 DI 10.1093/cercor/bhw050 PG 12 WC Neurosciences SC Neurosciences & Neurology GA EP8PF UT WOS:000397636600026 ER PT J AU Wei, SM Eisenberg, DP Nabel, KG Kohn, PD Kippenhan, JS Dickinson, D Kolachana, B Berman, KF AF Wei, Shau-Ming Eisenberg, Daniel P. Nabel, Katherine G. Kohn, Philip D. Kippenhan, J. Shane Dickinson, Dwight Kolachana, Bhaskar Berman, Karen F. TI Brain-Derived Neurotrophic Factor Val(66)Met Polymorphism Affects the Relationship Between an Anxiety-Related Personality Trait and Resting Regional Cerebral Blood Flow SO CEREBRAL CORTEX LA English DT Article DE BDNF genotype; frontolimbic circuitry; harm avoidance; PET; resting rCBF ID FACTOR VAL66MET POLYMORPHISM; ACTIVITY-DEPENDENT SECRETION; MAJOR DEPRESSIVE DISORDER; FACTOR MESSENGER-RNA; BEHAVIORAL-MODELS; CHARACTER TRAITS; HUMAN-MEMORY; BDNF; TEMPERAMENT; ALTERS AB Brain-derived neurotrophic factor (BDNF) is an important modulator of constitutive stress responses mediated by limbic frontotemporal circuits, and its gene contains a functional polymorphism (Val(66)Met)that may influence trait stress sensitivity. Reports of an association of this polymorphism with anxiety-related personality traits have been controversial and without clear neurophysiological support. We, therefore, determined the relationship between resting regional cerebral blood flow (rCBF) and a well-validated measure of anxiety-related personality, the TPQ Harm Avoidance (HA) scale, as a function of BDNF Val(66)Met genotype. Sixty-four healthy participants of European ancestry underwent resting (H2O)-O-15 positron emission tomography scans. For each genotype group separately, we first determined the relationship between participants' HA scores and their resting rCBF values in each voxel across the entire brain, and then directly compared these HA-rCBF relationships between Val(66)Met genotype groups. HA-rCBF relationships differed between Val homozygotes and Met carriers in several regions relevant to stress regulation: subgenual cingulate, orbital frontal cortex, and the hippocampal/parahippocampal region. In each of these areas, the relationship was positive in Val homozygotes and negative in Met carriers. These data demonstrate a coupling between trait anxiety and basal resting blood flow in frontolimbic neurocircuitry that may be determined in part by genetically mediated BDNF signaling. C1 [Wei, Shau-Ming; Eisenberg, Daniel P.; Nabel, Katherine G.; Kohn, Philip D.; Kippenhan, J. Shane; Berman, Karen F.] NIH, Sect Integrat Neuroimaging, Bldg 10, Bethesda, MD 20892 USA. [Wei, Shau-Ming; Eisenberg, Daniel P.; Nabel, Katherine G.; Kohn, Philip D.; Kippenhan, J. Shane; Dickinson, Dwight; Kolachana, Bhaskar; Berman, Karen F.] NIH, NIMH IRP, Clin & Translat Neurosci Branch, Bldg 10, Bethesda, MD 20892 USA. RP Berman, KF (reprint author), NIH, CTNB NIMH IRP, Sect Integrat Neuroimaging, 10 Ctr Dr,Bldg 10,Room 3C209, Bethesda, MD 20892 USA. EM bermank@mail.nih.gov FU National Institute of Mental Health; National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health. NR 55 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD MAR PY 2017 VL 27 IS 3 BP 2175 EP 2182 DI 10.1093/cercor/bhw072 PG 8 WC Neurosciences SC Neurosciences & Neurology GA EP8PF UT WOS:000397636600038 ER PT J AU Gibson, WS Cho, S Abulseoud, OA Gorny, KR Felmlee, JP Welker, KM Klassen, BT Min, HK Lee, KH AF Gibson, William S. Cho, Shinho Abulseoud, Osama A. Gorny, Krzysztof R. Felmlee, Joel P. Welker, Kirk M. Klassen, Bryan T. Min, Hoon-Ki Lee, Kendall H. TI The Impact of Mirth-Inducing Ventral Striatal Deep Brain Stimulation on Functional and Effective Connectivity SO CEREBRAL CORTEX LA English DT Article DE DBS; fMRI; mood; nucleus accumbens; obsessive compulsive disorder ID OBSESSIVE-COMPULSIVE DISORDER; ANTERIOR CINGULATE CORTEX; NUCLEUS-ACCUMBENS REGION; EVENT-RELATED FMRI; NEURONAL-ACTIVITY; BASAL GANGLIA; NEGATIVE BOLD; INTEROCEPTIVE INFERENCE; ELECTRICAL-STIMULATION; FACIAL EXPRESSIONS AB Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) is an investigational therapy for treatmentresistant obsessive-compulsive disorder. The ability of VC/VS DBS to evoke spontaneous mirth in patients, often accompanied by smiling and laughter, is clinically well documented. However, the neural correlates of DBS-evoked mirth remain poorly characterized. Patients undergoing VC/VS DBS surgery underwent intraoperative evaluation in which mirth-inducing and nonmirth-inducing stimulation localizations were identified. Using dynamic causal modeling (DCM) for fMRI, the effect of mirthinducing DBS on functional and effective connectivity among established nodes in limbic cortico-striato-thalamo-cortical (CSTC) circuitry was investigated. Both mirth-inducing and non-mirth-inducing VC/VS DBS consistently resulted (conjunction, global null, family-wise error-corrected P < 0.05) in activation of amygdala, ventral striatum, and mediodorsal thalamus. However, only mirth-inducing DBS resulted in functional inhibition of anterior cingulate cortex. Dynamic causal modeling revealed that mirth-inducing DBS enhanced effective connectivity from anterior cingulate to ventral striatum, while attenuating connectivity from thalamus to ventral striatum relative to non-mirth-inducing stimulation. These results suggest that DBS-evoked mood elevation is accompanied by distinct patterns of limbic thalamocortical connectivity. Using the novel combination of DBS-evoked mood alteration and functional MRI in human subjects, we provide new insights into the networklevel mechanisms that influence affect. C1 [Gibson, William S.; Cho, Shinho; Min, Hoon-Ki; Lee, Kendall H.] Mayo Clin, Dept Neurol Surg, Rochester, MN 55905 USA. [Gorny, Krzysztof R.; Felmlee, Joel P.; Welker, Kirk M.; Min, Hoon-Ki] Mayo Clin, Dept Radiol, Rochester, MN 55905 USA. [Klassen, Bryan T.] Mayo Clin, Dept Neurol, Rochester, MN 55905 USA. [Min, Hoon-Ki; Lee, Kendall H.] Mayo Clin, Dept Physiol & Biomed Engn, Rochester, MN 55905 USA. [Abulseoud, Osama A.] Mayo Clin, Dept Psychiat & Psychol, Rochester, MN 55906 USA. [Abulseoud, Osama A.] Natl Inst Drug Abuse, Baltimore, MD 21224 USA. RP Lee, KH (reprint author), Dept Neurol Surg, 200 1st St SW, Rochester, MN 55905 USA.; Lee, KH (reprint author), Dept Physiol & Biomed Engn, 200 1st St SW, Rochester, MN 55905 USA. EM min.paul@mayo.edu; Lee.Kendall@mayo.edu FU National Institutes of Health [R01 NS 70872]; The Grainger Foundation FX This work was supported by the National Institutes of Health (R01 NS 70872 awarded to K.H.L.) and by The Grainger Foundation. NR 88 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD MAR PY 2017 VL 27 IS 3 BP 2183 EP 2194 DI 10.1093/cercor/bhw074 PG 12 WC Neurosciences SC Neurosciences & Neurology GA EP8PF UT WOS:000397636600039 ER PT J AU McNeil, NE Padilla-Nash, HM Buishand, FO Hue, Y Ried, T AF McNeil, Nicole E. Padilla-Nash, Hesed M. Buishand, Floryne O. Hue, Yue Ried, Thomas TI Novel Mouse Model Recapitulates Genome and Transcriptome Alterations in Human Colorectal Carcinomas SO GENES CHROMOSOMES & CANCER LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; COLON-CANCER; SPONTANEOUS TRANSFORMATION; CENTROSOME AMPLIFICATION; TUMOR PROGRESSION; INSTABILITY; CELLS; CARCINOGENESIS; TUMORIGENESIS; METASTASIS AB Human colorectal carcinomas are defined by a nonrandom distribution of genomic imbalances that are characteristic for this disease. Often, these imbalances affect entire chromosomes. Understanding the role of these aneuploidies for carcinogenesis is of utmost importance. Currently, established transgenic mice do not recapitulate the pathognonomic genome aberration profile of human colorectal carcinomas. We have developed a novel model based on the spontaneous transformation of murine colon epithelial cells. During this process, cells progress through stages of pre-immortalization, immortalization and, finally, transformation, and result in tumors when injected into immunocompromised mice. We analyzed our model for genome and transcriptome alterations using ArrayCGH, spectral karyotyping (SKY), and array based gene expression profiling. ArrayCGH revealed a recurrent pattern of genomic imbalances. These results were confirmed by SKY. Comparing these imbalances with orthologous maps of human chromosomes revealed a remarkable overlap. We observed focal deletions of the tumor suppressor genes Trp53 and Cdkn2a/p16. High-level focal genomic amplification included the locus harboring the oncogene Mdm2, which was confirmed by FISH in the form of double minute chromosomes. Array-based global gene expression revealed distinct differences between the sequential steps of spontaneous transformation. Gene expression changes showed significant similarities with human colorectal carcinomas. Pathways most prominently affected included genes involved in chromosomal instability and in epithelial to mesenchymal transition. Our novel mouse model therefore recapitulates the most prominent genome and transcriptome alterations in human colorectal cancer, and might serve as a valuable tool for understanding the dynamic process of tumorigenesis, and for preclinical drug testing. (C) 2016 Wiley Periodicals, Inc. C1 [McNeil, Nicole E.; Padilla-Nash, Hesed M.; Buishand, Floryne O.; Hue, Yue; Ried, Thomas] NCI, Genet Branch, Ctr Canc Res, NIH, Bldg 50,Room 1408,50 South Dr, Bethesda, MD 20892 USA. [Buishand, Floryne O.] Univ Utrecht, Fac Med Vet, Dept Clin Sci Compan Anim, Utrecht, Netherlands. RP Ried, T (reprint author), NCI, Genet Branch, Ctr Canc Res, NIH, Bldg 50,Room 1408,50 South Dr, Bethesda, MD 20892 USA. EM riedt@mail.nih.gov FU Intramural Research Program of the National Institutes of Health; National Cancer Institute; Center for Cancer Research, Bethesda, MD; Rubicon grant of the Netherlands Organization for Scientific Research FX Supported by: Intramural Research Program of the National Institutes of Health; National Cancer Institute; Center for Cancer Research, Bethesda, MD; Rubicon grant of the Netherlands Organization for Scientific Research. NR 47 TC 0 Z9 0 U1 2 U2 2 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1045-2257 EI 1098-2264 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD MAR PY 2017 VL 56 IS 3 BP 199 EP 213 DI 10.1002/gcc.22426 PG 15 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA EL2CE UT WOS:000394426900003 PM 27750367 ER PT J AU Xia, ZQ Steele, SU Bakshi, A Clarkson, SR White, CC Schindler, MK Nair, G Dewey, BE Price, LR Ohayon, J Chibnik, LB Cortese, ICM De Jager, PL Reich, DS AF Xia, Zongqi Steele, Sonya U. Bakshi, Anshika Clarkson, Sarah R. White, Charles C. Schindler, Matthew K. Nair, Govind Dewey, Blake E. Price, Lauren R. Ohayon, Joan Chibnik, Lori B. Cortese, Irene C. M. De Jager, Philip L. Reich, Daniel S. TI Assessment of Early Evidence of Multiple Sclerosis in a Prospective Study of Asymptomatic High-Risk Family Members SO JAMA NEUROLOGY LA English DT Article ID RADIOLOGICALLY ISOLATED SYNDROME; DIGIT MODALITIES TEST; ABNORMALITIES; PERFORMANCE; IMPAIRMENT; DISABILITY; RELATIVES AB IMPORTANCE Subclinical inflammatory demyelination and neurodegeneration often precede symptom onset in multiple sclerosis (MS). OBJECTIVE To investigate the prevalence of brain magnetic resonance imaging (MRI) and subclinical abnormalities among asymptomatic individuals at risk for MS. DESIGN, SETTING, AND PARTICIPANTS The Genes and Environment in Multiple Sclerosis (GEMS) project is a prospective cohort study of first-degree relatives of people with MS. Each participant's risk for MS was assessed using a weighted score (Genetic and Environmental Risk Score for Multiple Sclerosis Susceptibility [GERS(MS)]) comprising an individual's genetic burden and environmental exposures. The study dates were August 2012 to July 2015. MAIN OUTCOMES AND MEASURES Participants in the top and bottom 10% of the risk distribution underwent standard and quantitative neurological examination, including disability status, visual, cognitive, motor, and sensory testing, as well as qualitative and quantitative neuroimaging with 3-T brain MRI and optical coherence tomography. RESULTS This study included 100 participants at risk for MS, with 41 at higher risk (40 women [98%]) and 59 at lower risk (25 women [42%]), at a mean (SD) age of 35.1 (8.7) years. Given the unequal sex distribution between the 2 groups, the analyses were restricted to women (n = 65). When considering all measured outcomes, higher-risk women differed from lower-risk women (P =.01 by omnibus test). Detailed testing with a vibration sensitivity testing device in a subgroup of 47 women showed that higher-risk women exhibited significantly poorer vibration perception in the distal lower extremities (P =.008, adjusting for age, height, and testing date). Furthermore, 5 of 65 women (8%) (4 at higher risk and 1 at lower risk) met the primary neuroimaging outcome of having T2-weighted hyperintense brain lesions consistent with the 2010 McDonald MRI criteria for dissemination in space. A subset of participants harbor many different neuroimaging features associated with MS, including perivenous T2-weighted hyperintense lesions and focal leptomeningeal enhancement, consistent with the hypothesis that these individuals are at higher risk of developing clinical symptoms of MS than the general population. CONCLUSIONS AND RELEVANCE Higher-risk asymptomatic family members of patients with MS are more likely to have early subclinical manifestations of MS. These findings underscore the importance of early detection in high-risk individuals. C1 [Xia, Zongqi; Clarkson, Sarah R.; White, Charles C.; Chibnik, Lori B.; De Jager, Philip L.] Brigham & Womens Hosp, Ann Romney Ctr Neurol Dis, Dept Neurol, Program Translat Neuropsychiat Genom, Boston, MA 02115 USA. [Xia, Zongqi; Clarkson, Sarah R.; White, Charles C.; Chibnik, Lori B.; De Jager, Philip L.] Brigham & Womens Hosp, Ann Romney Ctr Neurol Dis, Partners Multiple Sclerosis Ctr, Dept Neurol, Boston, MA 02115 USA. [Xia, Zongqi; Chibnik, Lori B.; De Jager, Philip L.] Harvard Med Sch, Boston, MA USA. [Xia, Zongqi; White, Charles C.; Chibnik, Lori B.; De Jager, Philip L.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Xia, Zongqi] Univ Pittsburgh, Pittsburgh Inst Neurodegenerat Dis, Pittsburgh, PA USA. [Xia, Zongqi] Univ Pittsburgh, Inst Multiple Sclerosis Care & Res, Dept Neurol, Pittsburgh, PA USA. [Steele, Sonya U.; Bakshi, Anshika; Schindler, Matthew K.; Nair, Govind; Dewey, Blake E.; Price, Lauren R.; Ohayon, Joan; Cortese, Irene C. M.; Reich, Daniel S.] NINDS, Div Neuroimmunol & Neurovirol, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Reich, DS (reprint author), Natl Inst Neurol Dis & Stroke, Div Neuroimmunol & Neurovirol, Room 5C103,10 Ctr Dr,MSC 1400,Bldg 10,Room 5C103, Bethesda, MD 20892 USA. EM reichds@ninds.nih.gov FU National Institutes of Health and the National Multiple Sclerosis Society; National Multiple Sclerosis Society [RG-5003-A-2]; National Institute of Neurological Disorders and Stroke [K08-NS079493]; National Institute of Neurological Disorders and Stroke Division of Intramural Research FX This study was supported by the National Institutes of Health and the National Multiple Sclerosis Society. The Genes and Environment in Multiple Sclerosis (GEMS) project is supported by grant RG-5003-A-2 from the National Multiple Sclerosis Society (Dr DeJager), by grant K08-NS079493 from the National Institute of Neurological Disorders and Stroke (Dr Xia), and by the National Institute of Neurological Disorders and Stroke Division of Intramural Research (Dr Reich). NR 34 TC 1 Z9 1 U1 2 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD MAR 1 PY 2017 VL 74 IS 3 BP 291 EP 298 DI 10.1001/jamaneurol.2016.5056 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EP8BW UT WOS:000397601900010 ER PT J AU Notarangelo, LD Fleisher, TA AF Notarangelo, Luigi D. Fleisher, Thomas A. TI Targeted strategies directed at the molecular defect: Toward precision medicine for select primary immunodeficiency disorders SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Review DE Personalized medicine; primary immunodeficiency disorders; immune dysregulation; autoimmunity; therapy mutation ID CHRONIC MUCOCUTANEOUS CANDIDIASIS; OF-FUNCTION MUTATIONS; CXCR4 ANTAGONIST PLERIXAFOR; STEM-CELL TRANSPLANTATION; FUNCTION STAT1 MUTATIONS; FUNCTION SIGNAL TRANSDUCER; WHIM-SYNDROME; IMMUNE DYSREGULATION; LRBA DEFICIENCY; GERMLINE MUTATIONS AB Primary immunodeficiency disorders (PIDs) represent a range of genetically determined diseases that typically have increased susceptibility to infections and in many cases also have evidence of immune dysregulation that often presents as autoimmunity. Most recently, the concept of gain-of-function mutations associated with PIDs has become well recognized and adds a new dimension to the understanding of this group of disorders, moving beyond the more commonly seen loss-of-function mutations. The rapidly expanding genetic defects that have been identified in patients with previously uncharacterized PIDs has opened up the potential for targeted therapy directed at the specific disease-causing abnormality. This has been driven by linking PID-specific genetic defects to the associated unique abnormalities in cellular signaling pathways amenable to directed therapies. These include agents that either block overactive or enhance underresponsive cellular pathways. Selected primary immunodeficiencies were chosen, the genetic defects of which have been recently characterized and are amenable to targeted therapy, as a reflection of the power of precision medicine. C1 [Notarangelo, Luigi D.] NIAID, Clin Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Fleisher, Thomas A.] NIH, Ctr Clin, Dept Lab Med, Serv Immunol, Bldg 10, Bethesda, MD 20892 USA. RP Fleisher, TA (reprint author), Dept Lab Med, CC, Ctr Dr,MSC 1508,Bldg 10,Room 2C306, Bethesda, MD 20892 USA. EM tfleishe@mail.nih.gov FU Intramural Research Program of the National Institutes of Allergy and Infectious Diseases; National Institutes of Health Clinical Center FX Supported by the Intramural Research Program of the National Institutes of Allergy and Infectious Diseases and the National Institutes of Health Clinical Center. NR 67 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAR PY 2017 VL 139 IS 3 BP 715 EP 725 DI 10.1016/j.jaci.2017.01.004 PG 11 WC Allergy; Immunology SC Allergy; Immunology GA EP3QC UT WOS:000397295800001 PM 28270363 ER PT J AU Tangye, SG Pillay, B Randall, KL Avery, DT Phan, TG Gray, P Ziegler, JB Smart, JM Peake, J Arkwright, PD Hambleton, S Orange, J Goodnow, CC Uzel, G Casanova, JL Reyes, SOL Freeman, AF Su, HC Ma, CS AF Tangye, Stuart G. Pillay, Bethany Randall, Katrina L. Avery, Danielle T. Tri Giang Phan Gray, Paul Ziegler, John B. Smart, Joanne M. Peake, Jane Arkwright, Peter D. Hambleton, Sophie Orange, Jordan Goodnow, Christopher C. Uzel, Gulbu Casanova, Jean-Laurent Lugo Reyes, Saul Oswaldo Freeman, Alexandra F. Su, Helen C. Ma, Cindy S. TI Dedicator of cytokinesis 8-deficient CD4(+) T cells are biased to a T(H)2 effector fate at the expense of T(H)1 and T(H)17 cells SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Dedicator of cytokinesis 8; CD4(+) T-cell differentiation; T(H)2 skewing; allergy; atopic disease; chronic mucocutaneous candidiasis; viral immunity ID HYPER-IGE SYNDROME; CHRONIC MUCOCUTANEOUS CANDIDIASIS; LINKED LYMPHOPROLIFERATIVE DISEASE; BONE-MARROW-TRANSPLANTATION; HUMAN B-CELLS; DOCK8 DEFICIENCY; ATOPIC-DERMATITIS; TH17 CELLS; MUTATIONS; MEMORY AB Background: Dedicator of cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency caused by autosomal recessive loss-of- function mutations in DOCK8. This disorder is characterized by recurrent cutaneous infections, increased serum IgE levels, and severe atopic disease, including food-induced anaphylaxis. However, the contribution of defects in CD4(+) T cells to disease pathogenesis in these patients has not been thoroughly investigated. Objective: We sought to investigate the phenotype and function of DOCK8-deficient CD4(+) T cells to determine (1) intrinsic and extrinsic CD4 1 T-cell defects and (2) how defects account for the clinical features of DOCK8 deficiency. Methods: We performed in-depth analysis of the CD4(+) T-cell compartment of DOCK8-deficient patients. We enumerated subsets of CD4(+) T helper cells and assessed cytokine production and transcription factor expression. Finally, we determined the levels of IgE specific for staple foods and house dust mite allergens in DOCK8-deficient patients and healthy control subjects. Results: DOCK8-deficient memory CD4 1 T cells were biased toward a T(H)2 type, and this was at the expense of T(H)1 and T(H)17 cells. In vitro polarization of DOCK8-deficient naive CD4(+) T cells revealed the TH2 bias and TH17 defect to be T-cell intrinsic. Examination of allergen-specific IgE revealed plasma IgE from DOCK8-deficient patients is directed against staple food antigens but not house dust mites. Conclusion: Investigations into the DOCK8-deficient CD4(+) T cells provided an explanation for some of the clinical features of this disorder: the T(H)2 bias is likely to contribute to atopic disease, whereas defects in T(H)1 and T(H)17 cells compromise antiviral and antifungal immunity, respectively, explaining the infectious susceptibility of DOCK8-deficient patients. C1 [Tangye, Stuart G.; Pillay, Bethany; Avery, Danielle T.; Tri Giang Phan; Goodnow, Christopher C.; Ma, Cindy S.] Garvan Inst Med Res, Div Immunol, Darlinghurst, NSW, Australia. [Tangye, Stuart G.; Pillay, Bethany; Tri Giang Phan; Goodnow, Christopher C.; Ma, Cindy S.] Univ New South Wales, St Vincents Clin Sch, Darlinghurst, NSW, Australia. [Randall, Katrina L.] John Curtin Sch Med Res, Dept Immunol, Acton, ACT, Australia. [Randall, Katrina L.] Australian Natl Univ, Sch Med, Acton, ACT, Australia. [Gray, Paul; Ziegler, John B.] Univ New South Wales, Sch Womens & Childrens Hlth, Randwick, NSW, Australia. [Smart, Joanne M.] Royal Childrens Hosp Melbourne, Dept Allergy & Immunol, Parkville, Vic, Australia. [Peake, Jane] Univ Queensland, Brisbane, Qld, Australia. [Peake, Jane] Lady Cilento Childrens Hosp, Brisbane, Qld, Australia. [Arkwright, Peter D.] Univ Manchester, Royal Manchester Childrens Hosp, Manchester M13 9PL, Lancs, England. [Hambleton, Sophie] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England. [Hambleton, Sophie] Great North Childrens Hosp, Newcastle Upon Tyne, Tyne & Wear, England. [Orange, Jordan] Texas Childrens Hosp, Baylor Coll Med, Dept Pediat, Ctr Human Immunobiol, Houston, TX 77030 USA. [Orange, Jordan] Baylor Coll Med, Dept Pediat, Div Immunol Allergy & Rheumatol, Houston, TX 77030 USA. [Orange, Jordan] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Orange, Jordan] Texas Childrens Hosp, Houston, TX 77030 USA. [Uzel, Gulbu; Freeman, Alexandra F.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Su, Helen C.] NIAID, Lab Host Def, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Casanova, Jean-Laurent] Univ Paris 05, Lab Human Genet Infect Dis, Necker Branch, INSERM,U1163,Inst IMAGINE,Necker Med Sch, Paris, France. [Casanova, Jean-Laurent] Necker Hosp Sick Children, AP HP, Pediat Hematol & Immunol Unit, Paris, France. [Casanova, Jean-Laurent] Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USA. [Casanova, Jean-Laurent] Howard Hughes Med Inst, New York, NY USA. [Lugo Reyes, Saul Oswaldo] Natl Inst Pediat, Immunodeficiencies Res Unit, Mexico City, DF, Mexico. RP Tangye, SG; Ma, CS (reprint author), Garvan Inst Med Res, Div Immunol, 384 Victoria St, Darlinghurst, NSW 2010, Australia. EM tangye@garvan.org.au; c.ma@garvan.org.au FU National Health and Medical Research Council (NHMRC) of Australia [1060303, 596813, 1016953, 1022922]; Rockefeller University Center for Clinical and Translational Science [5UL1RR024143]; Intramural Research Program of the National Institutes of Health/National Institute of Allergy and Infectious Diseases; NHMRC of Australia [1008820, 1042925] FX Supported by research grants awarded by the National Health and Medical Research Council (NHMRC) of Australia (to C.S.M. and S.G.T.: 1060303, 596813, and 1016953; to K.L.R.: 1022922), and Rockefeller University Center for Clinical and Translational Science (5UL1RR024143 to J.-L.C.). This research was supported in part by the Intramural Research Program of the National Institutes of Health/National Institute of Allergy and Infectious Diseases. C.S.M. is a recipient of a Career Development Fellowship (1008820), and S.G.T. is a Principal Research Fellowship (1042925) from the NHMRC of Australia and a Fulbright Senior Scholar. NR 71 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 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAR PY 2017 VL 139 IS 3 BP 933 EP 949 DI 10.1016/j.jaci.2016.07.016 PG 17 WC Allergy; Immunology SC Allergy; Immunology GA EP3QC UT WOS:000397295800026 PM 27554822 ER PT J AU Ogburn, RN Randall, TA Xu, YR Roberts, JH Mebrahtu, B Karnuta, JM Rider, SD Kissling, GE London, RE Pomes, A Arlian, L Fitzgerald, MC Mueller, GA AF Ogburn, Ryenne N. Randall, Thomas A. Xu, Yingrong Roberts, Julia H. Mebrahtu, Betelihem Karnuta, Jaret M. Rider, S. Dean Kissling, Grace E. London, Robert E. Pomes, Anna Arlian, Larry Fitzgerald, Michael C. Mueller, Geoffrey A. TI Are dust mite allergens more abundant and/or more stable than other Dermatophagoides pteronyssinus proteins? SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter C1 [Ogburn, Ryenne N.; Xu, Yingrong; Roberts, Julia H.; Mebrahtu, Betelihem; Karnuta, Jaret M.; Fitzgerald, Michael C.] Duke Univ, Dept Chem, Durham, NC 27706 USA. [Randall, Thomas A.; Kissling, Grace E.; London, Robert E.; Mueller, Geoffrey A.] NIEHS, Intramural Program, POB 12233, Res Triangle Pk, NC 27709 USA. [Rider, S. Dean; Arlian, Larry] Wright State Univ, Fairbornc, OH USA. [Pomes, Anna] Indoor Biotechnol, Charlottesville, VA USA. RP Mueller, GA (reprint author), NIEHS, Intramural Program, POB 12233, Res Triangle Pk, NC 27709 USA. EM Geoffrey.Mueller@nih.gov FU Intramural Research Program of the National Institute of Environmental Health Sciences [Z01-ES102906-01]; Extramural Research Program of the National Institute of General Medical Sciences [2R01-GM08174]; National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R01AI077653]; National Science Foundation [CHE-1308093] FX This study was supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences (grant no. Z01-ES102906-01 to R.E.L.), the Extramural Research Program of the National Institute of General Medical Sciences (grant no. 2R01-GM08174 to M.C.F.), the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (grant no. R01AI077653 to A.P.), and the National Science Foundation (grant no. CHE-1308093 to M.C.F.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 11 TC 0 Z9 0 U1 2 U2 2 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 2017 VL 139 IS 3 BP 1030 EP 1032 DI 10.1016/j.jaci.2016.08.016 PG 4 WC Allergy; Immunology SC Allergy; Immunology GA EP3QC UT WOS:000397295800035 PM 27771129 ER PT J AU Florea, AED Braylan, RC Schafernak, KT Williams, KW Daub, J Goyal, RK Puck, JM Rao, VK Pittaluga, S Holland, SM Uzel, G Calvo, KR AF Florea, Alina E. Dulau Braylan, Raul C. Schafernak, Kristian T. Williams, Kelli W. Daub, Janine Goyal, Rakesh K. Puck, Jennifer M. Rao, V. Koneti Pittaluga, Stefania Holland, Steven M. Uzel, Gulbu Calvo, Katherine R. TI Abnormal B-cell maturation in the bone marrow of patients with germline mutations in PIK3CD SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID DUST-MITE ALLERGENS; PHOSPHOINOSITIDE 3-KINASE; DERMATOPHAGOIDES-FARINAE; THERMODYNAMIC ANALYSIS; PI3K; TRANSCRIPTOME; HEMATOGONES; STABILITY; GENOME C1 [Florea, Alina E. Dulau; Braylan, Raul C.; Calvo, Katherine R.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Schafernak, Kristian T.] Ann & Robert H Lurie Childrens Hosp Chicago, Dept Pathol & Lab Med, Chicago, IL 60611 USA. [Schafernak, Kristian T.] Phoenix Childrens Hosp, Div Pathol & Lab Med, Phoenix, AZ USA. [Williams, Kelli W.; Rao, V. Koneti; Holland, Steven M.; Uzel, Gulbu] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Goyal, Rakesh K.] UPMC, Childrens Hosp Pittsburgh, Pediat Hematol Oncol, Pittsburgh, PA USA. [Puck, Jennifer M.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Pittaluga, Stefania] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Calvo, KR (reprint author), NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. EM calvok@mail.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Cancer Institute; National Institutes of Health Clinical Center FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Cancer Institute, and National Institutes of Health Clinical Center. The content of this letter does not necessarily reflect the views or policies of the Department of Health and Human Services. NR 18 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 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAR PY 2017 VL 139 IS 3 BP 1032 EP 1035 DI 10.1016/j.jaci.2016.08.028 PG 6 WC Allergy; Immunology SC Allergy; Immunology GA EP3QC UT WOS:000397295800036 ER PT J AU Chandrakasan, S Marsh, RA Uzel, G Holland, SM Shah, KN Bleesing, J AF Chandrakasan, Shanmuganathan Marsh, Rebecca A. Uzel, Gulbu Holland, Steven M. Shah, Kara N. Bleesing, Jack TI Outcome of patients with NEMO deficiency following allogeneic hematopoietic cell transplant SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID CORD BLOOD TRANSPLANTATION; ECTODERMAL DYSPLASIA; MUTATION; IMMUNODEFICIENCY C1 [Chandrakasan, Shanmuganathan] Emory Univ, Aflac Canc & Blood Disorder Ctr, Sch Med, Dept Pediat,Div Bone Marrow Transplantat, Atlanta, GA 30322 USA. [Marsh, Rebecca A.; Bleesing, Jack] Cincinnati Childrens Hosp Med Ctr, Div Bone Marrow Transplantat & Immune Def, Cincinnati, OH 45229 USA. [Uzel, Gulbu; Holland, Steven M.] NIAID, Lab Clin Infect Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Shah, Kara N.] Cincinnati Childrens Hosp Med Ctr, Div Dermatol, Cincinnati, OH 45229 USA. RP Chandrakasan, S (reprint author), Emory Univ, Aflac Canc & Blood Disorder Ctr, Sch Med, Dept Pediat,Div Bone Marrow Transplantat, Atlanta, GA 30322 USA. EM Shanmuganathan.chandrakasan@emory.edu FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 10 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAR PY 2017 VL 139 IS 3 BP 1040 EP 1043 DI 10.1016/j.jaci.2016.08.039 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA EP3QC UT WOS:000397295800040 PM 27744027 ER PT J AU Krouse, RZ Sorkness, CA Wildfire, JJ Calatroni, A Gruchalla, R Hershey, GKK Kattan, M Liu, AH Makhija, M Teach, SJ West, JB Wood, RA Zoratti, EM Gergen, PJ AF Krouse, Rebecca Z. Sorkness, Christine A. Wildfire, Jeremy J. Calatroni, Agustin Gruchalla, Rebecca Hershey, Gurjit K. Khurana Kattan, Meyer Liu, Andrew H. Makhija, Melanie Teach, Stephen J. West, Joseph B. Wood, Robert A. Zoratti, Edward M. Gergen, Peter J. TI Minimally important differences and risk levels for the Composite Asthma Severity Index SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID INNER-CITY CHILDREN; MATRIX MICROFIBRILLAR PROTEIN; MYASTHENIA-GRAVIS; MOLECULAR-CLONING; AUTOANTIBODIES; CELLS; OSTEOPROTEGERIN; TRANSCRIPTOMES; IDENTIFICATION; AUTOANTIGENS C1 [Krouse, Rebecca Z.; Wildfire, Jeremy J.; Calatroni, Agustin] Rho Fed Syst Div Inc, Chapel Hill, NC 27517 USA. [Sorkness, Christine A.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Gruchalla, Rebecca] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. [Hershey, Gurjit K. Khurana] Cincinnati Childrens Hosp, Cincinnati, OH USA. [Kattan, Meyer] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Liu, Andrew H.] Natl Jewish Hlth, Denver, CO USA. [Liu, Andrew H.] Childrens Hosp Colorado, Aurora, CO USA. [Liu, Andrew H.] Univ Colorado, Sch Med, Aurora, CO USA. [Makhija, Melanie] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. [Teach, Stephen J.] Childrens Natl Hlth Syst, Washington, DC USA. [West, Joseph B.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Wood, Robert A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Zoratti, Edward M.] Henry Ford Hlth Syst, Detroit, MI USA. [Gergen, Peter J.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Krouse, RZ (reprint author), Rho Fed Syst Div Inc, Chapel Hill, NC 27517 USA. EM Rebecca_Krouse@rhoworld.com FU National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Department of Health and Human Services [HHSN272200900052C, HHSN272201000052I, 1UM1AI114271-01]; National Center for Advancing Translational Sciences, NIH [NCRR/NIH UL1TR000451, UL1RR025780, UL1TR000075, UL1TR000154, UL1TR001082, UL1TR000077-04, UL1TR000040, UL1TR000150, UL1TR001105]; National Center for Research Resources FX This project has been funded in whole or in part with federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Department of Health and Human Services (contract nos. HHSN272200900052C, HHSN272201000052I, and 1UM1AI114271-01). Additional support was provided by the National Center for Research Resources, and National Center for Advancing Translational Sciences, NIH (grant nos. NCRR/NIH UL1TR000451, UL1RR025780, UL1TR000075, UL1TR000154, UL1TR001082, UL1TR000077-04, UL1TR000040, UL1TR000150, and UL1TR001105). Glaxo SmithKline (GSK) provided Ventolin, Flovent, Advair, and Flonase under a clinical trial agreement with NIH-NIAID; GSK did not have a role in the development or approval of the protocol, conduct of the trial, data analysis, manuscript preparation, or the decision to submit the manuscript for publication. NR 35 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAR PY 2017 VL 139 IS 3 BP 1052 EP 1055 DI 10.1016/j.jaci.2016.08.041 PG 17 WC Allergy; Immunology SC Allergy; Immunology GA EP3QC UT WOS:000397295800044 PM 27744028 ER PT J AU Wang, SH Sekiguchi, R Daley, WP Yamada, KM AF Wang, Shaohe Sekiguchi, Rei Daley, William P. Yamada, Kenneth M. TI Patterned cell and matrix dynamics in branching morphogenesis SO JOURNAL OF CELL BIOLOGY LA English DT Review ID EPITHELIUM IN-VITRO; PLANE ILLUMINATION MICROSCOPY; SUPERNUMERARY TRACHEAL BUDS; MAMMARY-GLAND DEVELOPMENT; BIOENGINEERED ORGAN GERM; URETERAL BUD; LUNG DEVELOPMENT; SUBMANDIBULAR-GLAND; BASEMENT-MEMBRANE; BLOOD-VESSELS AB Many embryonic organs undergo branching morphogenesis to maximize their functional epithelial surface area. Branching morphogenesis requires the coordinated interplay of multiple types of cells with the extracellular matrix (ECM). During branching morphogenesis, new branches form by "budding" or "clefting." Cell migration, proliferation, rearrangement, deformation, and ECM dynamics have varied roles in driving budding versus clefting in different organs. Elongation of the newly formed branch and final maturation of the tip involve cellular mechanisms that include cell elongation, intercalation, convergent extension, proliferation, and differentiation. New methodologies such as high-resolution live imaging, tension sensors, and force-mapping techniques are providing exciting new opportunities for future research into branching morphogenesis. C1 [Wang, Shaohe; Sekiguchi, Rei; Daley, William P.; Yamada, Kenneth M.] Natl Inst Dent & Craniofacial Res, Cell Biol Sect, NIH, Bethesda, MD 20892 USA. RP Wang, SH; Yamada, KM (reprint author), Natl Inst Dent & Craniofacial Res, Cell Biol Sect, NIH, Bethesda, MD 20892 USA. EM shaohe.wang@nih.gov; kenneth.yamada@nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research [ZIA DE000524, ZIA DE000525] FX Work in the authors' laboratory is supported by the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research (ZIA DE000524 and ZIA DE000525). NR 129 TC 0 Z9 0 U1 1 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD MAR PY 2017 VL 216 IS 3 BP 559 EP 570 DI 10.1083/jcb.201610048 PG 12 WC Cell Biology SC Cell Biology GA EN2FV UT WOS:000395826200011 PM 28174204 ER PT J AU Valansi, C Moi, D Leikina, E Matveev, E Grana, M Chernomordik, LV Romero, H Aguilar, PS Podbilewicz, B AF Valansi, Clari Moi, David Leikina, Evgenia Matveev, Elena Grana, Martin Chernomordik, Leonid V. Romero, Hector Aguilar, Pablo S. Podbilewicz, Benjamin TI Arabidopsis HAP2/GCS1 is a gamete fusion protein homologous to somatic and viral fusogens SO JOURNAL OF CELL BIOLOGY LA English DT Article ID CELL-CELL FUSION; MEMBRANE-FUSION; STRUCTURE SIMILARITY; WEB SERVER; C-ELEGANS; MECHANISMS; HAP2; FERTILIZATION; CHLAMYDOMONAS; SIMULATIONS AB Cell-cell fusion is inherent to sexual reproduction. Loss of HAPLESS 2/GENERATIVE CELL SPECIFIC 1 (HAP2/GCS1) proteins results in gamete fusion failure in diverse organisms, but their exact role is unclear. In this study, we show that Arabidopsis thaliana HAP2/GCS1 is sufficient to promote mammalian cell-cell fusion. Hemifusion and complete fusion depend on HAP2/GCS1 presence in both fusing cells. Furthermore, expression of HAP2 on the surface of pseudotyped vesicular stomatitis virus results in homotypic virus-cell fusion. We demonstrate that the Caenorhabditis elegans Epithelial Fusion Failure 1 (EFF-1) somatic cell fusogen can replace HAP2/GCS1 in one of the fusing membranes, indicating that HAP2/GCS1 and EFF-1 share a similar fusion mechanism. Structural modeling of the HAP2/GCS1 protein family predicts that they are homologous to EFF-1 and viral class II fusion proteins (e.g., Zika virus). We name this superfamily Fusexins: fusion proteins essential for sexual reproduction and exoplasmic merger of plasma membranes. We suggest a common origin and evolution of sexual reproduction, enveloped virus entry into cells, and somatic cell fusion. C1 [Valansi, Clari; Matveev, Elena; Podbilewicz, Benjamin] Technion Israel Inst Technol, Dept Biol, IL-32000 Haifa, Israel. [Moi, David; Aguilar, Pablo S.] Univ Nacl San Martin, Inst Invest Biotecnol Dr Rodolfo A Ugald, Lab Biol Celular Membranas, RA-1650 Buenos Aires, DF, Argentina. [Leikina, Evgenia; Chernomordik, Leonid V.] NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Membrane Biol, Bethesda, MD 20892 USA. [Grana, Martin] Inst Pasteur Montevideo, Unidad Bioinformat, Montevideo 11400, Uruguay. [Romero, Hector] Univ Republic, Fac Ciencias, Dept Ecol & Evoluc,Ctr Univ Reg Este, Unidad Genom Evolut,Lab Org & Evolucion Genoma, Montevideo 11400, Uruguay. RP Podbilewicz, B (reprint author), Technion Israel Inst Technol, Dept Biol, IL-32000 Haifa, Israel.; Aguilar, PS (reprint author), Univ Nacl San Martin, Inst Invest Biotecnol Dr Rodolfo A Ugald, Lab Biol Celular Membranas, RA-1650 Buenos Aires, DF, Argentina. EM paguilar@iib.unsam.edu.ar; podbilew@technion.ac.il FU International Centre for Genetic Engineering and Biotechnology [CRP/URU11-01]; Fondo para la Investigacion Cientifica y Tecnologica, Argentina [PICT-2014-3034]; Israel Science Foundation [826/08]; H European Research Council [ELEGANSFUSION 268843]; United States-Israel Binational Science Foundation [2013151]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Agencia Nacional de Investigacion e Innovacion; Programa de Desarrollo de las Ciencias Basicas FX This work was supported by the International Centre for Genetic Engineering and Biotechnology (grant CRP/URU11-01 to P.S. Aguilar), the Fondo para la Investigacion Cientifica y Tecnologica, Argentina (grant PICT-2014-3034 to P.S. Aguilar), Israel Science Foundation (grant 826/08 to B. Podbilewicz), the H2020 European Research Council (Advanced grant ELEGANSFUSION 268843 to B. Podbilewicz), and the United States-Israel Binational Science Foundation (grant 2013151 to L.V. Chernomordik and B. Podbilewicz). The research in the laboratory of L.V. Chernomordik was also supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. D. Moi is a fellow from the Consejo Nacional de Investigaciones Cientificas y Tecnicas, Argentina. M. Grana and H. Romero acknowledge support from Agencia Nacional de Investigacion e Innovacion and Programa de Desarrollo de las Ciencias Basicas. NR 46 TC 0 Z9 0 U1 1 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD MAR PY 2017 VL 216 IS 3 BP 571 EP 581 DI 10.1083/jcb.201610093 PG 11 WC Cell Biology SC Cell Biology GA EN2FV UT WOS:000395826200012 PM 28137780 ER PT J AU Guidry, VT Kinlaw, AC Johnston, J Hall, D Wing, S AF Guidry, Virginia T. Kinlaw, Alan C. Johnston, Jill Hall, Devon Wing, Steve TI Hydrogen sulfide concentrations at three middle schools near industrial livestock facilities SO JOURNAL OF EXPOSURE SCIENCE AND ENVIRONMENTAL EPIDEMIOLOGY LA English DT Article DE air pollution; animal feeding operations; children's health; hydrogen sulfide; livestock ID ANIMAL FEEDING OPERATIONS; SWINE OPERATIONS; AIR-POLLUTION; NEIGHBORING RESIDENTS; CHILDRENS HEALTH; EXPOSURE; ASTHMA; PREVALENCE; STUDENTS; COHORT AB Safe school environments are essential for healthy development, yet some schools are near large-scale livestock facilities that emit air pollution. Hydrogen sulfide ( H2S) from decomposing manure is an indicator of livestock-related air pollution. We measured outdoor concentrations of H2S at three public middle schools near livestock facilities in North Carolina. We used circular graphs to relate H2S detection and wind direction to geospatial distributions of nearby livestock barns. We also used logistic and linear regression to model H2S in relation to upwind, distance-weighted livestock barn area. Circular graphs suggested an association between upwind livestock barns and H2S detection. The log-odds of H2S detection per 1000 m(2) increased with upwind weighted swine barn area (School A: beta-coefficient (beta) = 0.43, SE = 0.06; School B: beta = 0.64, SE = 0.24) and upwind weighted poultry barn area (School A: beta = 0.05, SE = 0.01), with stronger associations during periods of atmospheric stability than atmospheric instability (School A stable: beta = 0.69, SE = 0.11; School A unstable: beta = 0.32, SE = 0.09). H2S concentration also increased linearly with upwind swine barn area, with greater increases during stable atmospheric conditions (stable: beta = 0.16 parts per billion (p.p.b.), SE = 0.01; unstable: beta = 0.05 p.p.b., SE = 0.01). Off-site migration of pollutants from industrial livestock operations can decrease air quality at nearby schools. C1 [Guidry, Virginia T.; Kinlaw, Alan C.; Wing, Steve] Univ North Carolina Chapel Hill, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Johnston, Jill] Univ Southern Calif, Keck Sch Med, Div Environm Hlth, Los Angeles, CA USA. [Hall, Devon] Rural Empowerment Assoc Community Help, Warsaw, NC USA. RP Guidry, VT (reprint author), NIEHS, Off Commun & Publ Liaison, POB 12233, Res Triangle Pk, NC 27709 USA. EM virginia.guidry@nih.gov FU The Johns Hopkins Center for a Livable Future at the Bloomberg School of Public Health; National Institute of Environmental Health Sciences Training [T32ES007018] FX David Leith, Maryanne Boundy, and Karin Yeatts helped to design the study and contributed to field work. William H Frederick, Lenon Hickman, Patricia Mason, Revenda Ross, Bryce Koukopoulos, Eileen Gregory, Steve Hutton, and Christopher Heaney provided essential study support during data collection. Sean Fitzsimmons, Ambient Air Monitoring Group, Air Quality Bureau, and Iowa Department of Natural Resources loaned us the Thermo H2S monitor used in this study. Brian Eder classified our meteorological data into atmospheric stability classes and provided a preliminary review of our manuscript. Nathaniel MacHardy developed the initial program in R for the circular plots. David Leith and Maryanne Boundy also reviewed the manuscript. Funding support for this research was provided by The Johns Hopkins Center for a Livable Future at the Bloomberg School of Public Health and the National Institute of Environmental Health Sciences Training Grant T32ES007018. The funding sources had no involvement in any phase of research or the preparation for publication. NR 42 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1559-0631 EI 1559-064X J9 J EXPO SCI ENV EPID JI J. Expo. Sci. Environ. Epidemiol. PD MAR-APR PY 2017 VL 27 IS 2 BP 167 EP 174 DI 10.1038/jes.2016.7 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA EL2NM UT WOS:000394456500003 PM 27094997 ER PT J AU Kong, HH Andersson, B Clavel, T Common, JE Jackson, SA Olson, ND Segre, JA Traidl-Hoffmann, C AF Kong, Heidi H. Andersson, Bjorn Clavel, Thomas common, John E. Jackson, Scott A. Olson, Nathan D. Segre, Julia A. Traidl-Hoffmann, Claudia TI Performing Skin Microbiome Research: A Method to the Madness SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Review ID 16S RIBOSOMAL-RNA; ATOPIC-DERMATITIS; ANTIMICROBIAL DEFENSE; CUTANEOUS BACTERIAL; MINIMUM INFORMATION; FUNGAL POPULATIONS; MOLECULAR ANALYSIS; SEQUENCING DATA; BODY HABITATS; DIVERSITY AB Growing interest in microbial contributions to human health and disease has increasingly led investigators to examine the microbiome in both healthy skin and cutaneous disorders, including acne, psoriasis, and atopic dermatitis. The need for common language, effective study design, and validated methods is critical for high-quality standardized research. Features, unique to skin, pose particular challenges when conducting microbiome research. This review discusses microbiome research standards and highlights important factors to consider, including clinical study design, skin sampling, sample processing, DNA sequencing, control inclusion, and data analysis. C1 [Kong, Heidi H.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Andersson, Bjorn] Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden. [Clavel, Thomas] Tech Univ Munich, ZIEL Inst Food & Hlth, Core Facil NGS Microbiome, Freising Weihenstephan, Germany. [common, John E.] ASTAR, Inst Med Biol, Singapore, Singapore. [Jackson, Scott A.; Olson, Nathan D.] NIST, Biosyst & Biomat Div, Gaithersburg, MD 20899 USA. [Segre, Julia A.] NHGRI, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. [Traidl-Hoffmann, Claudia] Tech Univ Munich, UNIKA T, Inst Environm Med, Augsburg, Germany. [Traidl-Hoffmann, Claudia] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Augsburg, Germany. [Traidl-Hoffmann, Claudia] Christine Kuhne Ctr Allergy Res & Educ, Davos, Switzerland. RP Kong, HH (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM konghe@mail.nih.gov OI Kong, Heidi/0000-0003-4424-064X; Clavel, Thomas/0000-0002-7229-5595; Traidl-Hoffmann, Claudia/0000-0001-5085-5179 NR 105 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2017 VL 137 IS 3 BP 561 EP 568 DI 10.1016/j.jid.2016.10.033 PG 8 WC Dermatology SC Dermatology GA EL9IJ UT WOS:000394933600011 PM 28063650 ER PT J AU O'Connor, J Vjecha, MJ Phillips, AN Angus, B Cooper, D Grinsztejn, B Lopardo, G Das, S Wood, R Wilkin, A Klinker, H Kantipong, P Klingman, KL Jilich, D Herieka, E Denning, E Abubakar, I Gordin, F Lundgren, JD AF O'Connor, Jemma Vjecha, Michael J. Phillips, Andrew N. Angus, Brian Cooper, David Grinsztejn, Beatriz Lopardo, Gustavo Das, Satyajit Wood, Robin Wilkin, Aimee Klinker, Hartwig Kantipong, Pacharee Klingman, Karin L. Jilich, David Herieka, Elbushra Denning, Eileen Abubakar, Ibrahim Gordin, Fred Lundgren, Jens D. CA INSIGHT START Study Grp TI Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with CD4 cell counts of more than 500 cells per mu L: secondary outcome results from a randomised controlled trial SO LANCET HIV LA English DT Article ID COMMUNITY-ACQUIRED PNEUMONIA; BODY-MASS INDEX; NEUTROPHILS; TUBERCULOSIS; ADULTS; PREVENTION; MORTALITY; IMMUNITY; DISEASES; COHORT AB Background The effects of antiretroviral therapy on risk of severe bacterial infections in people with high CD4 cell counts have not been well described. In this study, we aimed to quantify the effects of immediate versus deferred ART on the risk of severe bacterial infection in people with high CD4 cell counts in a preplanned analysis of the START trial. Methods The START trial was a randomised controlled trial in ART-naive HIV-positive patients with CD4 cell count of more than 500 cells per mu L assigned to immediate ART or deferral until their CD4 cell counts were lower than 350 cells per mu L. We used Cox proportional hazards regression to model time to severe bacterial infection, which was defined as a composite endpoint of bacterial pneumonia (confirmed by the endpoint review committee), pulmonary or extrapulmonary tuberculosis, or any bacterial infectious disorder of grade 4 severity, that required unscheduled hospital admissions, or caused death. This study is registered with ClinicalTrials.gov, number NCT00867048. Findings Patients were recruited from April 15, 2009, to Dec 23, 2013. The data cutoff for follow-up was May 26, 2015. Of 4685 HIV-positive people enrolled, 120 had severe bacterial infections (immediate-initiation group n=34, deferredinitiation group n=86; median 2 . 8 years of follow-up). Immediate ART was associated with a reduced risk of severe bacterial infection compared with deferred ART (hazard ratio [HR] 0.39, 95% CI 0. 26-0 . 57, p < 0.0001). In the immediate-initiation group, average neutrophil count over follow-up was 321 cells per mu L\higher, and average CD4 cell count 194 cells per mu L higher than the deferred-initiation group (p < 0 . 0001). In univariable analysis, higher timeupdated CD4 cell count (0 . 78, 0 . 71-0-85, p=0.0001) was associated with reduced risk of severe bacterial infection. Time-updated neutrophil count was not associated with severe bacterial infection. After adjustment for time-updated factors in multivariable analysis, particularly the CD4 cell count, the HR for immediate-initiation group moved closer to 1 (HR 0. 84, 0. 50-1.41, p=0.52). These results were consistent when subgroups of the severe bacterial infection composite were analysed separately. Interpretation Immediate ART reduces the risk of several severe bacterial infections in HIV- positive people with high CD4 cell count. This is partly explained by ART-induced increases in CD4 cell count, but not by increases in neutrophil count. Funding National Institute of Allergy and Infectious Diseases National Institutes of Health, Agence Nationale de Recherches sur le SIDA et les Hepatites Virales, Bundesministerium f-r Bildung und Forschung, European AIDS Treatment Network, Australian National Health and Medical Research Council, UK National Institute for Health Research and Medical Research Council, Danish National Research Foundation. Copyright (C) The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. C1 [O'Connor, Jemma; Phillips, Andrew N.] UCL, Res Dept Infect & Populat Hlth, London, England. [Abubakar, Ibrahim] UCL, Inst Global Hlth, London, England. [Vjecha, Michael J.; Gordin, Fred] Vet Affairs Med Ctr, Washington, DC USA. [Gordin, Fred] George Washington Univ, Washington, DC USA. [Angus, Brian] Univ Oxford, Oxford Ctr Clin Trop Med, Nuffield Dept Med, Oxford, England. [Cooper, David] Univ New South Wales, Kirby Inst, Sydney, NSW, Australia. [Grinsztejn, Beatriz] Evandro Chagas Clin Res Inst IPEC, STD & AIDS Clin Res Lab, Rio De Janeiro, Brazil. [Lopardo, Gustavo] Fundacion Ctr Estudios Infectol, Buenos Aires, DF, Argentina. [Das, Satyajit] Univ Warwick, Coventry & Warwickshire Partnership Trust, HIV & GU Med, Coventry, W Midlands, England. [Wood, Robin] Univ Cape Town, Desmond Tutu HIV Ctr, Inst Infect Dis & Mol Med, Cape Town, South Africa. [Wilkin, Aimee] Wake Forest Univ, Sch Med, Infect Dis Sect, Winston Salem, NC USA. [Klinker, Hartwig] Univ Wurzburg, Med Ctr, Dept Internal Med II, Wurzburg, Germany. [Kantipong, Pacharee] Chaingrai Hosp, Chaingrai, Thailand. [Klingman, Karin L.] Natl Inst Hlth, Natl Inst Allergy & Infect Dis, Div Aids, Bethesda, MD USA. [Jilich, David] Charles Univ Prague, First Fac Med, Dept Infect & Trop Dis, CR-11636 Prague 1, Czech Republic. [Jilich, David] Na Baulovce Hosp, Prague, Czech Republic. [Herieka, Elbushra] Royal Bournemouth Hosp, Bournemouth, Dorset, England. [Denning, Eileen] Univ Minnesota, Div Biostatist, Minneapolis, MN USA. [Lundgren, Jens D.] Univ Copenhagen, Dept Infect Dis Rigshospitalet, Copenhagen, Denmark. RP Phillips, AN (reprint author), Dept Infect & Populat Hlth, Univ Coll London Royal Free Campus,Rowland Hill s, London NW3 2PF, England. EM andrew.phillips@ucl.ac.uk FU National Institute of Allergy and Infectious Diseases; National Institutes of Health Clinical Center; National Cancer Institute; National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Agence Nationale de Recherches sur le SIDA et les Hepatites Virales (France); National Health and Medical Research Council (Australia); National Research Foundation (Denmark); Bundesministerium fur Bildung und Forschung (Germany); European AIDS Treatment Network; Medical Research Council (United Kingdom); National Institute for Health Research; National Health Service (United Kingdom); University of Minnesota FX This study was supported by the National Institute of Allergy and Infectious Diseases; National Institutes of Health Clinical Center; National Cancer Institute; National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Agence Nationale de Recherches sur le SIDA et les Hepatites Virales (France); National Health and Medical Research Council (Australia); National Research Foundation (Denmark); Bundesministerium fur Bildung und Forschung (Germany); European AIDS Treatment Network; Medical Research Council (United Kingdom); National Institute for Health Research; National Health Service (United Kingdom); and University of Minnesota. Antiretroviral drugs were donated to the central drug repository by AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline-ViiV Healthcare, Janssen Scientific Affairs, and Merck. We thank all the patients who participated in this study. NR 32 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 2352-3018 J9 LANCET HIV JI Lancet HIV PD MAR PY 2017 VL 4 IS 3 BP E105 EP E112 DI 10.1016/S2352-3018(16)30216-8 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EP3FB UT WOS:000397267100011 PM 28063815 ER PT J AU Kerr, J Marinac, CR Ellis, K Godbole, S Hipp, A Glanz, K Mitchell, J Laden, F James, P Berrigan, D AF Kerr, Jacqueline Marinac, Catherine R. Ellis, Katherine Godbole, Suneeta Hipp, Aaron Glanz, Karen Mitchell, Jonathan Laden, Francine James, Peter Berrigan, David TI Comparison of Accelerometry Methods for Estimating Physical Activity SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE ACTIGRAPH; ACCELEROMETER; WRIST; HIP; MACHINE LEARNING; SEDENTARY BEHAVIOR ID SEDENTARY BEHAVIORS; ENERGY-EXPENDITURE; UNITED-STATES; WRIST; HIP; MONITORS; ISSUES; WOMEN AB Purpose: This study aimed to compare physical activity estimates across different accelerometer wear locations, wear time protocols, and data processing techniques. Methods: A convenience sample of middle-age to older women wore a GT3X+ accelerometer at the wrist and hip for 7 d. Physical activity estimates were calculated using three data processing techniques: single-axis cut points, raw vector magnitude thresholds, and machine learning algorithms applied to the raw data from the three axes. Daily estimates were compared for the 321 women using generalized estimating equations. Results: A total of 1420 d were analyzed. Compliance rates for the hip versus wrist location only varied by 2.7%. All differences between techniques, wear locations, and wear time protocols were statistically different (P < 0.05). Mean minutes per day in physical activity varied from 22 to 67 depending on location and method. On the hip, the 1952-count cut point found at least 150 min.wk(-1)of physical activity in 22% of participants, raw vector magnitude found 32%, and the machine-learned algorithm found 74% of participants with 150 min of walking/running per week. The wrist algorithms found 59% and 60% of participants with 150 min of physical activity per week using the raw vector magnitude and machine-learned techniques, respectively. When the wrist device was worn overnight, up to 4% more participants met guidelines. Conclusion: Estimates varied by 52% across techniques and by as much as 41% across wear locations. Findings suggest that researchers should be cautious when comparing physical activity estimates from different studies. Efforts to standardize accelerometry-based estimates of physical activity are needed. A first step might be to report on multiple procedures until a consensus is achieved. C1 [Kerr, Jacqueline; Marinac, Catherine R.; Godbole, Suneeta] Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA. [Marinac, Catherine R.] San Diego State Univ, Grad Sch Publ Hlth, San Diego, CA 92182 USA. [Ellis, Katherine] Univ Calif San Diego, Dept Elect & Comp Engn, La Jolla, CA 92093 USA. [Hipp, Aaron] North Carolina State Univ, Dept Pk Recreat & Tourism Management, Ctr Geospatial Analyt, Ctr Human Hlth & Environm, Raleigh, NC USA. [Glanz, Karen] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Glanz, Karen] Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. [Mitchell, Jonathan] Childrens Hosp Philadelphia, Div Gastroenterol Hepatol & Nutr, Philadelphia, PA 19104 USA. [Mitchell, Jonathan] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Laden, Francine] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Laden, Francine] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Laden, Francine; James, Peter] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Laden, Francine; James, Peter] Harvard Med Sch, Boston, MA USA. [Berrigan, David] NCI, NIH, Bethesda, MD 20892 USA. RP Kerr, J (reprint author), Univ Calif San Diego, 9500 Gilman Dr,0811, La Jolla, CA 92093 USA. EM jkerr@ucsd.edu FU NCI Centers for Transdisciplinary Research on Energetics and Cancer (Transdisciplinary Research in Energetics and Cancer) [U01 CA116850, U54 CA155496, U54 CA155626, U54 CA155435, U54 CA155850]; National Institutes of Health [UM1 CA176726, R01 ES017017]; Harvard Cardiovascular Epidemiology Program [NHLBI] [T32HL098048]; Harvard Cardiovascular Epidemiology Program [NCI] [K99CA201542]; NCI [F32CA162847, F31CA183125]; NHLBI [K01HL123612] FX This work was supported by the NCI Centers for Transdisciplinary Research on Energetics and Cancer (Transdisciplinary Research in Energetics and Cancer) (grant nos. U01 CA116850, U54 CA155496, U54 CA155626, U54 CA155435, and U54 CA155850) and the National Institutes of Health (grant nos. UM1 CA176726 and R01 ES017017). Dr. James was supported by the Harvard Cardiovascular Epidemiology Program (grant nos. T32HL098048 [NHLBI] and K99CA201542 [NCI]). Dr. Mitchell was supported by Award Numbers F32CA162847 (NCI) and K01HL123612 (NHLBI). Dr. Marinac was supported by Award Number F31CA183125 (NCI). The opinions or assertions contained herein are the private ones of the authors and are not considered as official or reflecting the views of the National Institutes of Health. Results of this study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. None of the authors have conflicts of interest, and the results of this study do not constitute endorsement by the American College of Sports Medicine. NR 36 TC 1 Z9 1 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0195-9131 EI 1530-0315 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAR PY 2017 VL 49 IS 3 BP 617 EP 624 DI 10.1249/MSS.0000000000001124 PG 8 WC Sport Sciences SC Sport Sciences GA EL2IR UT WOS:000394443800028 PM 27755355 ER PT J AU Xie, YJ Anson, ER Simonsick, EM Studenski, SA Agrawal, Y AF Xie, Yanjun Anson, Eric R. Simonsick, Eleanor M. Studenski, Stephanie A. Agrawal, Yuri TI Compensatory Saccades Are Associated With Physical Performance in Older Adults: Data From the Baltimore Longitudinal Study of Aging SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Aging; Head impulse test; Physical performance; Saccade; Vestibulo; ocular reflex ID UNILATERAL VESTIBULAR DEAFFERENTATION; LOWER-EXTREMITY FUNCTION; VESTIBULOOCULAR REFLEX; VIDEO-OCULOGRAPHY; EYE-MOVEMENTS; WALKING; AGE; CONSISTENCY; DISABILITY; BATTERY AB Objective: To determine whether compensatory saccade metrics observed in the video head impulse test, specifically saccade amplitude and latency, predict physical performance. Study Design: Cross-sectional analysis of the Baltimore Longitudinal Study of Aging, a prospective cohort study. Setting: National Institute on Aging Intramural Research Program Clinical Research Unit in Baltimore, Maryland. Patients: Community-dwelling older adults. Intervention(s): Video head impulse testing was performed, and compensatory saccades and horizontal vestibulo-ocular reflex (VOR) gain were measured. Physical performance was assessed using the Short Physical Performance Battery (SPPB), which included the feet side-by-side, semitandem, tandem, and single-leg stance; repeated chair stands; and usual gait speed measurements. Main Outcome Measure( s): Compensatory saccade amplitude and latency, VOR gain, and SPPB performance. Results: In 183 participants who underwent vestibular and SPPB testing (mean age 71.8 yr; 53% females), both higher mean saccade amplitude (odds ratio [OR] = 1.62, p = 0.010) and shorter mean saccade latency (OR = 0.88, p = 0.004) were associated with a higher odds of failing the tandem stand task. In contrast, VOR gain was not associated with any physical performance measure. Conclusion: We observed in a cohort of healthy older adults that compensatory saccade amplitude and latency were associated with tandem stance performance. Compensatory saccade metrics may provide insights into capturing the impact of vestibular loss on physical function in older adults. C1 [Xie, Yanjun; Anson, Eric R.; Agrawal, Yuri] Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, 601 North Caroline St 6th Floor, Baltimore, MD 21287 USA. [Simonsick, Eleanor M.; Studenski, Stephanie A.] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. RP Xie, YJ (reprint author), Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, 601 North Caroline St 6th Floor, Baltimore, MD 21287 USA. EM johnny@jhmi.edu FU National Institute of Health (NIH) [T32-DC000023]; NIH [NIDCD K23-DC013056] FX E.R.A. receives funding support from the National Institute of Health (NIH) grant T32-DC000023. Y.A. receives funding support from the NIH grant NIDCD K23-DC013056. NR 30 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1531-7129 EI 1537-4505 J9 OTOL NEUROTOL JI Otol. Neurotol. PD MAR PY 2017 VL 38 IS 3 BP 373 EP 378 DI 10.1097/MAO.0000000000001301 PG 6 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA EL1FW UT WOS:000394366900011 PM 28192379 ER PT J AU Peterson, LX Kim, H Esquivel-Rodriguez, J Roy, A Han, XS Shin, WH Zhang, J Terashi, G Lee, M Kihara, D AF Peterson, Lenna X. Kim, Hyungrae Esquivel-Rodriguez, Juan Roy, Amitava Han, Xusi Shin, Woong-Hee Zhang, Jian Terashi, Genki Lee, Matt Kihara, Daisuke TI Human and server docking prediction for CAPRI round 30-35 using LZerD with combined scoring functions SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE CAPRI; protein docking prediction; protein-protein docking; protein structure prediction; computational methods; prediction accuracy; structure modeling ID PROTEIN-PROTEIN DOCKING; 3D ZERNIKE DESCRIPTORS; COMPLEX INTERFACES; STRUCTURE MODELS; POTENTIALS; SELECTION; SURFACE; RECOGNITION; DATABASE; PROGRAM AB We report the performance of protein-protein docking predictions by our group for recent rounds of the Critical Assessment of Prediction of Interactions (CAPRI), a community-wide assessment of state-of-the-art docking methods. Our prediction procedure uses a protein-protein docking program named LZerD developed in our group. LZerD represents a protein surface with 3D Zernike descriptors (3DZD), which are based on a mathematical series expansion of a 3D function. The appropriate soft representation of protein surface with 3DZD makes the method more tolerant to conformational change of proteins upon docking, which adds an advantage for unbound docking. Docking was guided by interface residue prediction performed with BindML and cons-PPISP as well as literature information when available. The generated docking models were ranked by a combination of scoring functions, including PRESCO, which evaluates the native-likeness of residues' spatial environments in structure models. First, we discuss the overall performance of our group in the CAPRI prediction rounds and investigate the reasons for unsuccessful cases. Then, we examine the performance of several knowledge-based scoring functions and their combinations for ranking docking models. It was found that the quality of a pool of docking models generated by LZerD, that is whether or not the pool includes near-native models, can be predicted by the correlation of multiple scores. Although the current analysis used docking models generated by LZerD, findings on scoring functions are expected to be universally applicable to other docking methods. (C) 2016 Wiley Periodicals, Inc. C1 [Peterson, Lenna X.; Kim, Hyungrae; Roy, Amitava; Han, Xusi; Shin, Woong-Hee; Zhang, Jian; Terashi, Genki; Kihara, Daisuke] Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. [Esquivel-Rodriguez, Juan; Kihara, Daisuke] Purdue Univ, Dept Comp Sci, W Lafayette, IN 47907 USA. [Roy, Amitava] Purdue Univ, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. [Roy, Amitava] NIAID, Bioinformat & Computat Biosci Branch, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Terashi, Genki] Kitasato Univ, Sch Pharm, Minato Ku, Tokyo 1088641, Japan. [Lee, Matt] Lilly Biotechnol Ctr San Diego, 10300 Campus Point Dr, San Diego, CA USA. RP Kihara, D (reprint author), Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. EM dkihara@purdue.edu FU National Institute of General Medical Sciences of the National Institutes of Health [R01GM097528]; National Science Foundation [IIS1319551, DBI1262189, IOS1127027] FX Grant sponsor: National Institute of General Medical Sciences of the National Institutes of Health; Grant number: R01GM097528; Grant sponsor: National Science Foundation; Grant numbers: IIS1319551, DBI1262189, IOS1127027. NR 72 TC 0 Z9 0 U1 1 U2 1 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-3585 EI 1097-0134 J9 PROTEINS JI Proteins PD MAR PY 2017 VL 85 IS 3 SI SI BP 513 EP 527 DI 10.1002/prot.25165 PG 15 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA EL3LY UT WOS:000394521800016 PM 27654025 ER PT J AU Lau, MWL Trachman, RJ Ferre-D'Amare, AR AF Lau, Matthew W. L. Trachman, Robert J., III Ferre-D'Amare, Adrian R. TI A divalent cation-dependent variant of the glmS ribozyme with stringent Ca2+ selectivity co-opts a preexisting nonspecific metal ion-binding site SO RNA LA English DT Article DE catalytic RNA; in vitro selection; phosphorothioate interference; SAXS; molecular exaptation ID IN-VITRO; ABSOLUTE ELECTRONEGATIVITY; CATALYTIC COFACTOR; STRUCTURAL BASIS; SELF-CLEAVAGE; RNA; COENZYME; GLUCOSAMINE; RIBOSWITCH; MAGNESIUM AB Ribozymes use divalent cations for structural stabilization, as catalytic cofactors, or both. Because of the prominent role of Ca2+ in intracellular signaling, engineered ribozymes with stringent Ca2+ selectivity would be important in biotechnology. Thewild-type glmS ribozyme (glmS(WT)) requires glucosamine-6-phosphate (GlcN6P) as a catalytic cofactor. Previously, a glmS ribozyme variant with three adenosine mutations (glmS(AAA)) was identified, which dispenses with GlcN6P and instead uses, with little selectivity, divalent cations as cofactors for site-specific RNA cleavage. We now report a Ca2+-specific ribozyme (glmS(Ca)) evolved from glmS(AAA) that is >10,000 times more active in Ca2+ than Mg2+, is inactive in even 100 mM Mg2+, and is not responsive to GlcN6P. This stringent selectivity, reminiscent of the protein nuclease from Staphylococcus, allows rapid and selective ribozyme inactivation using a Ca2+ chelator such as EGTA. Because glmS(Ca) functions in physiologically relevant Ca2+ concentrations, it can form the basis for intracellular sensors that couple Ca2+ levels to RNA cleavage. Biochemical analysis of glmSCa reveals that it has co-opted for selective Ca2+ binding a nonspecific cation-binding site responsible for structural stabilization in glmSWT and glmS(AAA). Fine-tuning of the selectivity of the cation site allows repurposing of this preexisting molecular feature. C1 [Lau, Matthew W. L.; Trachman, Robert J., III; Ferre-D'Amare, Adrian R.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. RP Ferre-D'Amare, AR (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. EM adrian.ferre@nih.gov FU Intramural Program of the National Heart, Lung and Blood Institute, National Institutes of Health (NIH) FX We thank J. Sellers for access to rapid-quench instrumentation, X. Zuo and the staff at beamline 12-ID-C of the Advanced Photon Source (APS), Argonne National Laboratory (ANL) for SAXS data collection support, S. Bachas, N. Baird, M. Chen, T. Dever, J. Hogg, C. Jones, J. Posakony, K. Warner, and J. Zhang for discussions, and two anonymous referees for motivating the SAXS experiments and suggesting the inclusion of Table 2. M.W.L. was a Croucher Foundation Postdoctoral Fellow. SAXS data were collected in a core facility of the Center for Cancer Research, US National Cancer Institute (NCI), allocated under an agreement between NCI and ANL (PUP-24152). Use of APS was supported by the US Department of Energy. This work was supported in part by the Intramural Program of the National Heart, Lung and Blood Institute, National Institutes of Health (NIH). NR 52 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 1355-8382 EI 1469-9001 J9 RNA JI RNA PD MAR PY 2017 VL 23 IS 3 BP 355 EP 364 DI 10.1261/rna.059824.116 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EL2RQ UT WOS:000394467500009 PM 27932587 ER PT J AU Edmiston, E Ashwood, P Van de Water, J AF Edmiston, Elizabeth Ashwood, Paul Van de Water, Judy TI Autoimmunity, Autoantibodies, and Autism Spectrum Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Review DE Autism; Autoimmunity; Immune; Maternal autoantibodies; Neurodevelopmental; Pregnancy ID RESPONSE MEDIATOR PROTEINS; FETAL-BRAIN PROTEINS; MATERNAL AUTOANTIBODIES; TOURETTE SYNDROME; ANTIBRAIN AUTOANTIBODIES; FAMILY-HISTORY; IMMUNE INVOLVEMENT; BEHAVIORAL-CHANGES; INFANTILE-AUTISM; INCREASED RISK AB Auism spectrum disorder (ASD) now affects one in 68 births in the United States and is the fastest growing neurodevelopmental disability worldwide. Alarmingly, for the majority of cases, the causes of ASD are largely unknown, but it is becoming increasingly accepted that ASD is no longer defined simply as a behavioral disorder, but rather as a highly complex and heterogeneous biological disorder. Although research has focused on the identification of genetic abnormalities, emerging studies increasingly suggest that immune dysfunction is a viable risk factor contributing to the neurodevelopmental deficits observed in ASD. This review summarizes the investigations implicating autoimmunity and autoantibodies in ASD. C1 [Edmiston, Elizabeth; Van de Water, Judy] Univ Calif Davis, Dtivis Rheumatol Allergy & Clin Immunol, Davis, CA 95616 USA. [Edmiston, Elizabeth; Ashwood, Paul; Van de Water, Judy] Univ Calif Davis, MIND Inst, Davis, CA 95616 USA. [Ashwood, Paul; Van de Water, Judy] Univ Calif Davis, NIEHS Ctr Childrens Environm Hlth, Davis, CA 95616 USA. [Ashwood, Paul] Univ Calif Davis, Dept Med Microbiol & Immunol, Davis, CA 95616 USA. RP Van de Water, J (reprint author), Univ Calif Davis, Div Rheumatol Allergy & Clin Immunol, 451 E Hlth Sci Dr,Suite 6510, Davis, CA 95616 USA. EM javandewater@ucdavis.edu FU National Institute of Environmental Health Sciences (NIEHS) Center [2P01ES011269-11, 83543201]; NIEHS [R01ES015359]; National Institute of Child Health and Human Development [U54HD079125]; Pediatric Bioscience FX This study was funded by the National Institute of Environmental Health Sciences (NIEHS) Center for Children's Environmental Health and Environmental Protection Agency (Grant Nos. 2P01ES011269-11 and 83543201, respectively, to JV as PI), the NIEHS-funded CHARGE study (Grant No. R01ES015359 to JV and PA as Co- I), and the National Institute of Child Health and Human Development-funded Intellectual and Developmental Disabilities Research Center 054 (Grant No. U54HD079125 to JV as Co-PI).; There are three patents associated with the work at University of California, Davis noted in this review: A provisional 'Maternal Diagnostic Marker for Autism Risk and Therapeutic Intervention' UC Case No. 2014467-1. There are two issued patents: The US patent Methods of Diagnosing and Treating Autism, U. S. Patent No. 8,383,360 B2 or Pat. 8,383,360 was filed August 12, 2010, and issued February 26, 2013. The client reference number for this patent is 2009-737-2US. This patent is currently in the process of national filing. The first issued patent is Diagnostic Methods for Detection of Autism Spectrum Disorder, U. S. Patent No. US 7,452,681 B2. This patent was filed May 5, 2006, and was issued November 18, 2008. This patent was filed in the United States only. JVdW received consulting fees from Pediatric Bioscience from January 1, 2015, until October 2015. EE and PA report no biomedical financial interests or potential conflicts of interest. NR 97 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAR 1 PY 2017 VL 81 IS 5 SI SI BP 383 EP 390 DI 10.1016/j.biopsych.2016.08.031 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EP3RO UT WOS:000397299600005 PM 28340985 ER PT J AU Chowell, G Viboud, C Simonsen, L Merler, S Vespignani, A AF Chowell, Gerardo Viboud, Cecile Simonsen, Lone Merler, Stefano Vespignani, Alessandro TI Perspectives on model forecasts of the 2014-2015 Ebola epidemic in West Africa: lessons and the way forward SO BMC MEDICINE LA English DT Article DE Ebola; West Africa; Epidemic model; Lessons learned; Disease forecast; Exponential growth; Sub-exponential growth; Polynomial growth; Data sharing ID VIRUS DISEASE OUTBREAK; TRANSMISSION DYNAMICS; GROWTH; INTERVENTIONS; IMPACT; CHARACTERIZE; INFECTION; LIBERIA; CONGO AB The unprecedented impact and modeling efforts associated with the 2014-2015 Ebola epidemic in West Africa provides a unique opportunity to document the performances and caveats of forecasting approaches used in near-real time for generating evidence and to guide policy. A number of international academic groups have developed and parameterized mathematical models of disease spread to forecast the trajectory of the outbreak. These modeling efforts often relied on limited epidemiological data to derive key transmission and severity parameters, which are needed to calibrate mechanistic models. Here, we provide a perspective on some of the challenges and lessons drawn from these efforts, focusing on (1) data availability and accuracy of early forecasts; (2) the ability of different models to capture the profile of early growth dynamics in local outbreaks and the importance of reactive behavior changes and case clustering; (3) challenges in forecasting the long-term epidemic impact very early in the outbreak; and (4) ways to move forward. We conclude that rapid availability of aggregated population-level data and detailed information on a subset of transmission chains is crucial to characterize transmission patterns, while ensemble-forecasting approaches could limit the uncertainty of any individual model. We believe that coordinated forecasting efforts, combined with rapid dissemination of disease predictions and underlying epidemiological data in shared online platforms, will be critical in optimizing the response to current and future infectious disease emergencies. C1 [Chowell, Gerardo] Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA. [Chowell, Gerardo; Viboud, Cecile] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Simonsen, Lone] Univ Copenhagen, Dept Publ Hlth, Copenhagen, Denmark. [Simonsen, Lone] George Washington Univ, Dept Global Hlth, Washington, DC USA. [Merler, Stefano] Bruno Kessler Fdn, Trento, Italy. [Vespignani, Alessandro] Northeastern Univ, Lab Modeling Biol & Sociotech Syst, Boston, MA 02115 USA. RP Chowell, G (reprint author), Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA.; Chowell, G (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM gchowell@gsu.edu FU NSF [1414374, 1518939, 1318788, 1610429]; UK Biotechnology and Biological Sciences Research Council [BB/M008894/1]; RAPIDD Program of the Science & Technology Directorate; Division of International Epidemiology and Population Studies; The Fogarty International Center; US National Institutes of Health; European Commission; Lundbeck Foundation; NIH [MIDAS-U54GM111274] FX GC acknowledges financial support from the NSF grant 1414374 as part of the joint NSF-NIH-USDA Ecology and Evolution of Infectious Diseases program, UK Biotechnology and Biological Sciences Research Council grant BB/M008894/1, NSF grants # 1518939, # 1318788, and # 1610429, and the in-house research program Division of International Epidemiology and Population Studies, The Fogarty International Center, US National Institutes of Health. This work was made possible by workshops funded by the RAPIDD Program of the Science & Technology Directorate and the Division of International Epidemiology and Population Studies, The Fogarty International Center, US National Institutes of Health. LS also acknowledges support from the European Commission (Marie Curie fellowship) and the Lundbeck Foundation. AV acknowledges support from the NIH MIDAS-U54GM111274. NR 49 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD MAR 1 PY 2017 VL 15 DI 10.1186/s12916-017-0811-y PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA EN5VE UT WOS:000396073000001 PM 28245814 ER PT J AU Tamma, PD Avdic, E Keenan, JF Zhao, Y Anand, G Cooper, J Dezube, R Hsu, S Cosgrove, SE AF Tamma, Pranita D. Avdic, Edina Keenan, John F. Zhao, Yuan Anand, Gobind Cooper, James Dezube, Rebecca Hsu, Steven Cosgrove, Sara E. TI What Is the More Effective Antibiotic Stewardship Intervention: Preprescription Authorization or Postprescription Review With Feedback? SO CLINICAL INFECTIOUS DISEASES LA English DT Review DE antibiotics; ASP; days of therapy; antimicrobial stewardship ID ACADEMIC-MEDICAL-CENTER; TIME-SERIES ANALYSIS; INTENSIVE-CARE-UNIT; ANTIMICROBIAL STEWARDSHIP; PROSPECTIVE AUDIT; CLINICAL-OUTCOMES; PROGRAM; HOSPITALS; IMPACT AB Background. The optimal approach to conducting antibiotic stewardship interventions has not been defined. We compared days of antibiotic therapy (DOT) using preprescription authorization (PPA) vs postprescription review with feedback (PPRF) strategies. Methods. A quasi-experimental, crossover trial comparing PPA and PPRF for adult inpatients prescribed any antibiotic was conducted. For the first 4 months, 2 medicine teams were assigned to the PPA arm and the other 2 teams to the PPRF arm. The teams were then assigned to the alternate arm for an additional 4 months. Appropriateness of antibiotic use was adjudicated by at least 2 infectious diseases-trained clinicians and according to institutional guidelines. Results. There were 2686 and 2693 patients admitted to the PPA and PPRF groups, with 29% and 27% of patients prescribed antibiotics, respectively. Initially, antibiotic DOTs remained relatively unchanged in the PPA arm. When changed to the PPRF arm, antibiotic use decreased (-2.45 DOT per 1000 patient-days [PD]). In the initial PPRF arm, antibiotic use decreased (slope of -5.73 DOT per 1000 PD) but remained constant when changed to the PPA arm. Median patient DOTs in the PPA and PPRF arms were 8 and 6 DOT per 1000 PD, respectively (P = .03). Antibiotic therapy was guideline-noncompliant in 34% and 41% of patients on days 1 and 3 in the PPA group (P < .01) and in 57% and 36% of patients on days 1 and 3 in the PPRF group (P = .03). Conclusions. PPRF may have more of an impact on decreasing antibiotic DOTs compared with PPA. This information may be useful for institutions without sufficient resources to incorporate both stewardship approaches. C1 [Tamma, Pranita D.] Johns Hopkins Univ, Sch Med, Dept Pediat, Div Infect Dis, 200 N Wolfe St,Ste 3149, Baltimore, MD 21287 USA. [Avdic, Edina] Johns Hopkins Univ Hosp, Dept Pharm, Baltimore, MD USA. [Keenan, John F.] Lynchburg Gen & Virginia Baptist Hosp, Dept Family Med, Lynchburg, VA USA. [Zhao, Yuan] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Anand, Gobind] Univ Calif San Diego, Dept Med, Div Gastroenterol, San Diego, CA USA. [Cooper, James] Natl Inst Hlth, Dept Med, Div Hematol, Baltimore, MD USA. [Dezube, Rebecca] Johns Hopkins Univ, Sch Med, Div Pulmonary & Crit Care Med, Baltimore, MD USA. [Hsu, Steven] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD USA. [Cosgrove, Sara E.] Johns Hopkins Univ, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD USA. RP Tamma, PD (reprint author), Johns Hopkins Univ, Sch Med, Dept Pediat, Div Infect Dis, 200 N Wolfe St,Ste 3149, Baltimore, MD 21287 USA. EM ptamma1@jhmi.edu FU Pfizer Independent Grants for Learning and Change; The Joint Commission FX This study was made by possible by an investigator-initiated grant from Pfizer Independent Grants for Learning and Change and The Joint Commission. 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 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAR 1 PY 2017 VL 64 IS 5 BP 537 EP 543 DI 10.1093/cid/ciw780 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP3TA UT WOS:000397303400001 PM 27927861 ER PT J AU Cranston, RD Lama, JR Richardson, BA Carballo-Dieguez, A Ayudhya, RPKN Liu, K Patterson, KB Leu, CS Galaska, B Jacobson, CE Parikh, UM Marzinke, MA Hendrix, CW Johnson, S Piper, JM Grossman, C Ho, KS Lucas, J Pickett, J Bekker, LG Chariyalertsak, S Chitwarakorn, A Gonzales, P Holtz, TH Liu, AY Mayer, KH Zorrilla, C Schwartz, JL Rooney, J McGowan, I AF Cranston, Ross D. Lama, Javier R. Richardson, Barbra A. Carballo-Dieguez, Alex Ayudhya, Ratiya Pamela Kunjara Na Liu, Karen Patterson, Karen B. Leu, Cheng-Shiun Galaska, Beth Jacobson, Cindy E. Parikh, Urvi M. Marzinke, Mark A. Hendrix, Craig W. Johnson, Sherri Piper, Jeanna M. Grossman, Cynthia Ho, Ken S. Lucas, Jonathan Pickett, Jim Bekker, Linda-Gail Chariyalertsak, Suwat Chitwarakorn, Anupong Gonzales, Pedro Holtz, Timothy H. Liu, Albert Y. Mayer, Kenneth H. Zorrilla, Carmen Schwartz, Jill L. Rooney, James McGowan, Ian CA MTN-017 Protocol Team TI MTN-017: A Rectal Phase 2 Extended Safety and Acceptability Study of Tenofovir Reduced-Glycerin 1% Gel SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE rectal; microbicide; HIV; prevention; tenofovir ID PREEXPOSURE PROPHYLAXIS; TRANSGENDER WOMEN; MEN; HIV; SEX; MICROBICIDES; INFECTION; RISK AB Background. Human immunodeficiency virus (HIV) disproportionately affects men who have sex with men (MSM) and transgender women (TGW). Safe and acceptable topical HIV prevention methods that target the rectum are needed. Methods. MTN-017 was a phase 2, 3-period, randomized sequence, open-label, expanded safety and acceptability crossover study comparing rectally applied reduced-glycerin (RG) 1% tenofovir (TFV) and oral emtricitabine/TFV disoproxil fumarate (FTC/ TDF). In each 8-week study period participants were randomized to RG-TFV rectal gel daily, or RG-TFV rectal gel before and after receptive anal intercourse (RAI; or at least twice weekly in the event of no RAI), or daily oral FTC/TDF. Results. MSM and TGW (n = 195) were enrolled from 8 sites in the United States, Thailand, Peru, and South Africa with mean age of 31.1 years (range 18-64). There were no differences in = grade 2 adverse event rates between daily gel (incidence rate ratio [IRR], 1.09; P = .59) or RAI gel (IRR, 0.90; P = .51) compared to FTC/TDF. High adherence (>= 80% of prescribed doses assessed by unused product return and Short Message System reports) was less likely in the daily gel regimen (odds ratio [OR], 0.35; P < .001), and participants reported less likelihood of future daily gel use for HIV protection compared to FTC/TDF (OR, 0.38; P < .001). Conclusions. Rectal application of RG TFV gel was safe in MSM and TGW. Adherence and product use likelihood were similar for the intermittent gel and daily oral FTC/TDF regimens, but lower for the daily gel regimen. C1 [Cranston, Ross D.; Parikh, Urvi M.; Ho, Ken S.; McGowan, Ian] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Lama, Javier R.; Gonzales, Pedro] Asociac Civil Impacta Salud Educ, Lima, Peru. [Richardson, Barbra A.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Richardson, Barbra A.; Liu, Karen; Patterson, Karen B.] Fred Hutchinson Canc Res Center, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA USA. [Carballo-Dieguez, Alex; Galaska, Beth] Columbia Univ, New York State Psychiat Inst, New York, NY USA. [Ayudhya, Ratiya Pamela Kunjara Na; Galaska, Beth] Magee Womens Res Inst, Pittsburgh, PA USA. [Hendrix, Craig W.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Johnson, Sherri; Lucas, Jonathan] FHI 360, Durham, NC USA. [Piper, Jeanna M.] Nat Inst Allergy & Infect Disease, Bethesda, MD USA. [Grossman, Cynthia] Natl Inst Mental Hlth, Bethesda, MD USA. [Pickett, Jim] AIDS Fdn Chicago, Chicago, IL USA. [Bekker, Linda-Gail] Univ Cape Town, Desmond Tutu HIV Ctr, Cape Town, South Africa. [Chariyalertsak, Suwat] Chiang Mai Univ, Res Inst Hlth Sci, Chiang Mai, Thailand. [Chitwarakorn, Anupong; Holtz, Timothy H.] US Ctr Dis Control & Prevent Collaborat, Thailand Minist Publ Hlth, Bangkok, Thailand. [Holtz, Timothy H.] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Atlanta, GA USA. [Liu, Albert Y.] Bridge HIV, San Francisco Dept Publ Hlth, San Francisco, CA USA. [Mayer, Kenneth H.] Fenway Inst, Boston, MA USA. [Zorrilla, Carmen] Univ Puerto Rico, Sch Med, Dept Obstet & Gynecol, San Juan, PR USA. [Schwartz, Jill L.] CONRAD Eastern Virginia Med Sch, Arlington, VA USA. [Rooney, James] Gilead Sci, Foster City, CA USA. RP Cranston, RD (reprint author), Hosp Univ Germans Trias Pujol, Fundacio Lluita Sida, Badalona 08916, Spain. EM rdcranston@outlook.com FU National Institute of Allergy and Infectious Diseases of the NIH [UM1AI068633, UM1AI068615, UM1AI106707]; Eunice Kennedy Shriver National Institute of Child Health and Human Development of the NIH; National Institute of Mental Health of the NIH FX This work was supported by the National Institute of Allergy and Infectious Diseases (UM1AI068633, UM1AI068615, UM1AI106707), with cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the NIH. NR 19 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAR 1 PY 2017 VL 64 IS 5 BP 614 EP 620 DI 10.1093/cid/ciw832 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP3TA UT WOS:000397303400011 PM 27986684 ER PT J AU Portugal, S Tran, TM Ongoiba, A Bathily, A Li, S Doumbo, S Skinner, J Doumtabe, D Kone, Y Sangala, J Jain, A Davies, DH Hung, C Liang, L Ricklefs, S Homann, MV Felgner, PL Porcella, SF Faernert, A Doumbo, OK Kayentao, K Greenwood, BM Traore, B Crompton, PD AF Portugal, Silvia Tran, Tuan M. Ongoiba, Aissata Bathily, Aboudramane Li, Shanping Doumbo, Safiatou Skinner, Jeff Doumtabe, Didier Kone, Younoussou Sangala, Jules Jain, Aarti Davies, D. Huw Hung, Christopher Liang, Li Ricklefs, Stacy Homann, Manijeh Vafa Felgner, Philip L. Porcella, Stephen F. Faernert, Anna Doumbo, Ogobara K. Kayentao, Kassoum Greenwood, Brian M. Traore, Boubacar Crompton, Peter D. TI Treatment of Chronic Asymptomatic Plasmodium falciparum Infection Does Not Increase the Risk of Clinical Malaria Upon Reinfection SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE Plasmodium falciparum; malaria; asymptomatic; malaria/drug therapy; mass drug administration ID ACQUIRED-IMMUNITY; ARTEMETHER-LUMEFANTRINE; GAMETOCYTE CARRIAGE; PREDICT PROTECTION; CHILDREN; CARRIERS; DISEASE; TRIAL; TRANSMISSION; POPULATION AB Background. Chronic asymptomatic Plasmodium falciparum infections are common in endemic areas and are thought to contribute to the maintenance of malaria immunity. Whether treatment of these infections increases the subsequent risk of clinical episodes of malaria is unclear. Methods. In a 3-year study in Mali, asymptomatic individuals with or without P. falciparum infection at the end of the 6-month dry season were identified by polymerase chain reaction (PCR), and clinical malaria risk was compared during the ensuing 6-month malaria transmission season. At the end of the second dry season, 3 groups of asymptomatic children were identified: (1) children infected with P. falciparum as detected by rapid diagnostic testing (RDT) who were treated with antimalarials (n = 104), (2) RDT-negative children whose untreated P. falciparum infections were detected retrospectively by PCR (n = 55), and (3) uninfected children (RDT/PCR negative) (n = 434). Clinical malaria risk during 2 subsequent malaria seasons was compared. Plasmodium falciparum-specific antibody kinetics during the dry season were compared in children who did or did not harbor asymptomatic P. falciparum infections. Results. Chronic asymptomatic P. falciparum infection predicted decreased clinical malaria risk during the subsequent malaria season(s); treatment of these infections did not alter this reduced risk. Plasmodium falciparum-specific antibodies declined similarly in children who did or did not harbor chronic asymptomatic P. falciparum infection during the dry season. Conclusions. These findings challenge the notion that chronic asymptomatic P. falciparum infection maintains malaria immunity and suggest that mass drug administration during the dry season should not increase the subsequent risk of clinical malaria. C1 [Portugal, Silvia; Tran, Tuan M.; Li, Shanping; Skinner, Jeff; Crompton, Peter D.] Natl Inst Allergy & Infect Dis, Natl Inst Hlth, Immunogenet Lab, Rockville, MD USA. [Tran, Tuan M.] Indiana Univ, Sch Med, Dept Med, Div Infect Dis, Bloomington, IN 47405 USA. [Ongoiba, Aissata; Bathily, Aboudramane; Doumbo, Safiatou; Doumtabe, Didier; Kone, Younoussou; Sangala, Jules; Kayentao, Kassoum; Traore, Boubacar] Univ Sci Tech & Technol Bamako, Int Ctr Excellence Res, Malaria Res & Training Ctr, Dept Epidemiol Parasit Dis, Bamako, Mali. [Jain, Aarti; Davies, D. Huw; Hung, Christopher; Felgner, Philip L.] Univ Calif Irvine, Irvine, CA USA. [Ricklefs, Stacy] Natl Inst Allergy & Infect Dis, Natl Inst Hlth, Genom Unit, Rocky Mt Lab Res Technol Sect, Hamilton, MT USA. [Homann, Manijeh Vafa; Faernert, Anna] Karolinska Inst, Dept Med Solna, Dept Infect Dis, Solna, Sweden. [Faernert, Anna] Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden. [Greenwood, Brian M.] London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London, England. [Portugal, Silvia] Heidelberg Univ Hosp, Ctr Infect Dis Parasitol, Im Neuenheimer Feld 324, Heidelberg, Germany. RP Portugal, S (reprint author), Heidelberg Univ Hosp, Ctr Infect Dis Parasitol, Im Neuenheimer Feld 324, Heidelberg, Germany. EM silvia.portugal@med.uni-heidelberg.de FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; NIAID [U19AI089686, R01AI095916] FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Protein microarray experiments were funded by NIAID grants (award numbers U19AI089686 and R01AI095916 to A. J., D. H. D., C. H., L. L., and P. L. F.). NR 45 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 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAR 1 PY 2017 VL 64 IS 5 BP 645 EP 653 DI 10.1093/cid/ciw849 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EP3TA UT WOS:000397303400015 PM 28362910 ER PT J AU Lim, JA Li, LS Shirihai, OS Trudeau, KM Puertollano, R Raben, N AF Lim, Jeong-A Li, Lishu Shirihai, Orian S. Trudeau, Kyle M. Puertollano, Rosa Raben, Nina TI Modulation of mTOR signaling as a strategy for the treatment of Pompe disease SO EMBO MOLECULAR MEDICINE LA English DT Article DE autophagy; lysosomal storage disorders; mTOR; myopathy; Pompe disease ID ACID-ALPHA-GLUCOSIDASE; ENZYME REPLACEMENT THERAPY; VACUOLAR H+-ATPASE; LYSOSOMAL STORAGE DISEASE; SKELETAL-MUSCLE; AMINO-ACIDS; TRANSLATION INITIATION; LEUCINE SUPPLEMENTATION; MAMMALIAN TARGET; AUTOPHAGY AB Mechanistic target of rapamycin (mTOR) coordinates biosynthetic and catabolic processes in response to multiple extracellular and intracellular signals including growth factors and nutrients. This serine/threonine kinase has long been known as a critical regulator of muscle mass. The recent finding that the decision regarding its activation/inactivation takes place at the lysosome undeniably brings mTOR into the field of lysosomal storage diseases. In this study, we have examined the involvement of the mTOR pathway in the pathophysiology of a severe muscle wasting condition, Pompe disease, caused by excessive accumulation of lysosomal glycogen. Here, we report the dysregulation of mTOR signaling in the diseased muscle cells, and we focus on potential sites for therapeutic intervention. Reactivation of mTOR in the whole muscle of Pompe mice by TSC knockdown resulted in the reversal of atrophy and a striking removal of autophagic buildup. Of particular interest, we found that the aberrant mTOR signaling can be reversed by arginine. This finding can be translated into the clinic and may become a paradigm for targeted therapy in lysosomal, metabolic, and neuromuscular diseases. C1 [Lim, Jeong-A; Li, Lishu; Raben, Nina] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. [Lim, Jeong-A; Puertollano, Rosa] NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Shirihai, Orian S.; Trudeau, Kyle M.] Boston Univ, Sch Med, Evans Biomed Res Ctr, Dept Med Obes & Nutr Sect, Boston, MA 02118 USA. RP Li, LS; Raben, N (reprint author), NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA.; Puertollano, R (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM lishuli1@hotmail.com; puertolr@mail.nih.gov; rabenn@mail.nih.gov FU National Institute of Arthritis and Musculoskeletal and Skin diseases of the National Institutes of Health; CRADA; Acid Maltase Deficiency Association FX We would like to thank Kristien Zaal and Evelyn Ralston (Light Imaging Section, Office of Science and Technology, NIAMS, NIH) for their help with the imaging. We are grateful to Dr. Markus A. Ruegg (Biozentrum, University of Basel) for the generous gift of shRNA-TSC1/2 plasmid. This research was supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin diseases of the National Institutes of Health. Dr. Lim and Dr. Li are supported in part by a CRADA between NIH and Genzyme Corporation and from the Acid Maltase Deficiency Association. NR 75 TC 0 Z9 0 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1757-4676 EI 1757-4684 J9 EMBO MOL MED JI EMBO Mol. Med. PD MAR PY 2017 VL 9 IS 3 BP 353 EP 370 DI 10.15252/emmm.201606547 PG 18 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EP3QE UT WOS:000397296000008 PM 28130275 ER PT J AU Snyder, HM Ahles, T Calderwood, S Carrillo, MC Chen, HL Chang, CCH Craft, S De Jager, P Driver, JA Fillit, H Knopmann, D Lotze, M Tierney, MC Petanceska, S Saykin, A Seshadri, S Shineman, D Ganguli, M AF Snyder, Heather M. Ahles, Tim Calderwood, Stuart Carrillo, Maria C. Chen, Honglei Chang, Chung-Chou H. Craft, Suzanne De Jager, Philip Driver, Jane A. Fillit, Howard Knopmann, David Lotze, Michael Tierney, Mary C. Petanceska, Suzana Saykin, Andrew Seshadri, Sudha Shineman, Diana Ganguli, Mary TI Exploring the nexus of Alzheimer's disease and related dementias with cancer and cancer therapies: A convening of the Alzheimer's Association. & Alzheimer's Drug Discovery Foundation SO ALZHEIMERS & DEMENTIA LA English DT Review DE Alzheimer's disease; Oncology; Cancer; Repurpose therapy; Epidemiology; Biological mechanisms; Genetics ID AMYOTROPHIC-LATERAL-SCLEROSIS; ANDROGEN DEPRIVATION THERAPY; US ELDERLY ADULTS; PARKINSON DISEASE; BREAST-CANCER; PROSTATE-CANCER; NEURODEGENERATIVE DISEASE; COGNITIVE FUNCTION; MOUSE MODELS; RISK AB Recent population studies suggest an intriguing inverse relationship between several types of cancer and neurodegenerative diseases, including Alzheimer's disease. Understanding the intersection of the underlying biology for these two distinct families of diseases with one another may offer novel approaches to identify iiew therapeutic approaches and possible opportunities to repurpose existing drug candidates. The Alzheimer's Association and the Alzheimer's Drug Discovery Foundation convened a one-day workshop todelve into this discussion. Workshop participants outlined research focus areas, potential collaboratiOns, and partnerships for future action. (C) 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved. C1 [Snyder, Heather M.; Carrillo, Maria C.] Alzheimers Assoc, Div Med & Sci Relat, Chicago, IL 60631 USA. [Ahles, Tim] Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, New York, NY USA. [Calderwood, Stuart] Harvard Univ, Sch Med, Radiat Oncol, Boston, MA USA. [Chen, Honglei] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Chang, Chung-Chou H.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. [Chang, Chung-Chou H.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Chang, Chung-Chou H.] Univ Pittsburgh, Sch Med, Dept Biostat, Pittsburgh, PA USA. [Chang, Chung-Chou H.] Univ Pittsburgh, Sch Med, Clin & Translat Sci, Pittsburgh, PA USA. [Craft, Suzanne] Wake Forest Univ Med, Dept Internal Med, Div Gerontol & Geriatr Med, Winston Salem, NC USA. [De Jager, Philip] VA Boston HealthCare Syst, Geriatr Res Educ & Clin Ctr, Boston, MA USA. [Driver, Jane A.] Brigham & Womens Hosp, Div Aging, 75 Francis St, Boston, MA 02115 USA. [Driver, Jane A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Fillit, Howard; Shineman, Diana] Alzheimers Drug Discovery Fdn, Sci Affairs, New York, NY USA. [Knopmann, David] Mayo Clin, Dept Neurol, Rochester, MN USA. [Lotze, Michael] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA USA. [Lotze, Michael] Univ Pittsburgh, Sch Med, Dept Immunol, Pittsburgh, PA USA. [Lotze, Michael] Univ Pittsburgh, Sch Med, Dept Bioengn, Pittsburgh, PA USA. [Tierney, Mary C.] Sunnybrook Hlth Sci Ctr, Dept Family & Community Med, Toronto, ON, Canada. [Petanceska, Suzana] NIA, Div Neurosci, NIH, Bethesda, MD 20892 USA. [Saykin, Andrew] Indiana Univ Sch Med, Dept Radiol, Indianapolis, IN 46202 USA. [Seshadri, Sudha] Boston Univ, Sch Med, Div Neurol, Boston, MA 02118 USA. [Ganguli, Mary] Univ Pittsburgh, Sch Med, Psychiat Neurol & Epidemiol, Pittsburgh, PA USA. [Ganguli, Mary] Grad Sch Publ Hlth, Pittsburgh, PA USA. [Driver, Jane A.; Lotze, Michael] Lion Biotechnol Inc, Tampa, FL USA. RP Snyder, HM (reprint author), Alzheimers Assoc, Div Med & Sci Relat, Chicago, IL 60631 USA. EM hsnyder@alz.org NR 64 TC 0 Z9 0 U1 4 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1552-5260 EI 1552-5279 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD MAR PY 2017 VL 13 IS 3 BP 267 EP 273 DI 10.1016/jalz.2016.11.002 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA EN4HI UT WOS:000395968200008 PM 27998721 ER PT J AU Xia, Y Carpentier, A Cheng, XM Block, PD Zhao, Y Zhang, ZS Protzer, U Liang, TJ AF Xia, Yuchen Carpentier, Arnaud Cheng, Xiaoming Block, Peter Daniel Zhao, Yao Zhang, Zhensheng Protzer, Ulrike Liang, T. Jake TI Human stem cell-derived hepatocytes as a model for hepatitis B virus infection, spreading and virus-host interactions SO JOURNAL OF HEPATOLOGY LA English DT Article DE Hepatitis B virus; Stem cell; Model; Antivirals; Antiviral agents; Hepatocytes; DNA; Viral ID CLOSED CIRCULAR DNA; IN-VITRO; RECEPTOR; DEDIFFERENTIATION; ENTRY; TRANSPORTER; PERSISTENCE; INHIBITION; MEMBRANE; PROTEIN AB Background & Aims: One major obstacle of hepatitis B virus (HBV) research is the lack of efficient cell culture system permissive for viral infection and replication. The aim of our study was to establish a robust HBV infection model by using hepatocytelike cells (HLCs) derived from human pluripotent stem cells. Methods: HLCs were differentiated from human embryonic stem cells and induced pluripotent stem cells. Maturation of hepatocyte functions was determined. After HBV infection, total viral DNA, cccDNA, total viral RNA, pgRNA, HBeAg and HBsAg were measured. Results: More than 90% of the HLCs expressed strong signals of human hepatocyte markers, like albumin, as well as known host factors required for HBV infection, suggesting that these cells possessed key features of mature hepatocytes. Notably, HLCs expressed the viral receptor sodium-taurocholate cotransporting polypeptide more stably than primary human hepatocytes (PHHs). HLCs supported robust infection and some spreading of HBV. Finally, by using this model, we identified two host targeting agents, genistin and PA452, as novel antivirals. Conclusions: Stem cell-derived HLCs fully support HBV infection. This novel HLC HBV infection model offers a unique opportunity to advance our understanding of the molecular details of the HBV life cycle; to further characterize virus-host interactions and to define new targets for HBV curative treatment. Lay summary: Our study used human pluripotent stem cells to develop hepatocyte-like cells (HLCs) capable of expressing hepatocyte markers and host factors important for HBV infection. These cells fully support HBV infection and virus-host interactions, allowing for the identification of two novel antiviral agents. Thus, stem cell-derived HLCs provide a highly physiologically relevant system to advance our understanding of viral life cycle and provide a new tool for antiviral drug screening and development. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. C1 [Xia, Yuchen; Carpentier, Arnaud; Cheng, Xiaoming; Block, Peter Daniel; Zhao, Yao; Zhang, Zhensheng; Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Protzer, Ulrike] Tech Univ Munich, Helmholtz Zentrum Munchen, Inst Virol, D-81675 Munich, Germany. [Protzer, Ulrike] German Ctr Infect Res DZIF, Munich Partner Site, Munich, Germany. RP Liang, TJ (reprint author), NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. EM jakel@bdg10.niddk.nih.gov OI Xia, Yuchen/0000-0001-8460-3893 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; International Liver Cancer Association (ILCA)-Fellowship FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Yuchen Xia is partly supported by The International Liver Cancer Association (ILCA)-Fellowship. NR 40 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD MAR PY 2017 VL 66 IS 3 BP 494 EP 503 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EM3MB UT WOS:000395218200007 PM 27746336 ER PT J AU Duffy, AG Ulahannan, SV Makorova-Rusher, O Rahma, O Wedemeyer, H Pratt, D Davis, JL Hughes, MS Heller, T ElGindi, M Uppala, A Korangy, F Kleiner, DE Figg, WD Venzon, D Steinberg, SM Venkatesan, AM Krishnasamy, V Abi-Jaoudeh, N Levy, E Wood, BJ Greten, TF AF Duffy, Austin G. Ulahannan, Susanna V. Makorova-Rusher, Oxana Rahma, Osama Wedemeyer, Heiner Pratt, Drew Davis, Jeremy L. Hughes, Marybeth S. Heller, Theo ElGindi, Mei Uppala, Ashish Korangy, Firouzeh Kleiner, David E. Figg, William D. Venzon, David Steinberg, Seth M. Venkatesan, Aradhana M. Krishnasamy, Venkatesh Abi-Jaoudeh, Nadine Levy, Elliot Wood, Brad J. Greten, Tim F. TI Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma SO JOURNAL OF HEPATOLOGY LA English DT Article DE Immune checkpoint; Hepatocellular carcinoma; Immune; T-Lymphocytes; Liver cirrhosis ID RANDOMIZED CONTROLLED-TRIAL; T-CELL RESPONSES; RADIOFREQUENCY ABLATION; EMBOLIZATION; CRYOABLATION; LYMPHOCYTES; ACTIVATION; THERAPY AB Background & Aims: Tremelimumab is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on the surface of activated T lymphocytes. Ablative therapies induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment in patients with advanced hepatocellular carcinoma (HCC). This study aimed to demonstrate whether tremelimumab could be combined safely and feasibly with ablation. Methods: Thirty-two patients with HCC were enrolled: male:female: 28:4; median age: 62 (range 36-76). Patients were given tremelimumab at two dose levels (3.5 and 10 mg/kg i.v.) every 4 weeks for 6 doses, followed by 3-monthly infusions until off treatment criteria were met. On day 36, patients underwent subtotal radiofrequency ablation or chemoablation. Staging was performed by contrast-enhanced CT or MRI scan every 8 weeks. Results: No dose-limiting toxicities were encountered. The most common toxicity was pruritus. Of the 19 evaluable patients, five (26.3%; 95% CI: 9.1-51.2%) achieved a confirmed partial response. Twelve of 14 patients with quantifiable HCV experienced a marked reduction in viral load. Six-week tumor biopsies showed a clear increase in CD8(+) T cells in patients showing a clinical benefit only. Six and 12-month probabilities of tumor progression free survival for this refractory HCC population were 57.1% and 33.1% respectively, with median time to tumor progression of 7.4 months (95% CI 4.7 to 19.4 months). Median overall survival was 12.3 months (95% CI 9.3 to 15.4 months). Conclusions: Tremelimumab in combination with tumor ablation is a potential new treatment for patients with advanced HCC, and leads to the accumulation of intratumoral CD8 T cells. Positive clinical activity was seen, with a possible surrogate reduction in HCV viral load. Lay summary: Studies have shown that the killing of tumors by direct methods (known as ablation) can result in the immune system being activated or switched on. The immune system could potentially also recognize and kill the cancer that is left behind. There are new drugs available known as immune checkpoint inhibitors which could enhance this effect. Here, we test one of these drugs (tremelimumab) together with ablation. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. C1 [Duffy, Austin G.; Ulahannan, Susanna V.; Makorova-Rusher, Oxana; Rahma, Osama; ElGindi, Mei; Uppala, Ashish; Korangy, Firouzeh; Greten, Tim F.] NCI, Gastrointestinal Malignancies Sect, Thorac & GI Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Wedemeyer, Heiner] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany. [Pratt, Drew; Kleiner, David E.] NCI, Lab Pathol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Davis, Jeremy L.; Hughes, Marybeth S.] NCI, Thorac & GI Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Heller, Theo] NIDDK, Translat Hepatol Unit, LDB, NIH, Bethesda, MD 20892 USA. [Figg, William D.] NCI, Clin Pharmacol Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Venzon, David; Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Venkatesan, Aradhana M.; Krishnasamy, Venkatesh; Abi-Jaoudeh, Nadine; Levy, Elliot; Wood, Brad J.] NIH, Ctr Intervent Oncol Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. [Venkatesan, Aradhana M.; Krishnasamy, Venkatesh; Abi-Jaoudeh, Nadine; Levy, Elliot; Wood, Brad J.] NIH, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. RP Greten, TF (reprint author), NCI, 9000 Rockville Pike,10-12N224, Bethesda, MD 20892 USA. EM tim.greten@nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 22 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD MAR PY 2017 VL 66 IS 3 BP 545 EP 551 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EM3MB UT WOS:000395218200013 PM 27816492 ER PT J AU Mukhopadhyay, P Horvath, B Rajesh, M Varga, ZV Gariani, K Ryu, D Cao, ZX Holovac, E Park, O Zhou, Z Xu, MJ Wang, W Godlewski, G Paloczi, J Nemeth, BT Persidsky, Y Liaudet, L Hasko, G Bai, P Boulares, AH Auwerx, J Gao, B Pacher, P AF Mukhopadhyay, Partha Horvath, Bela Rajesh, Mohanraj Varga, Zoltan V. Gariani, Karim Ryu, Dongryeol Cao, Zongxian Holovac, Eileen Park, Ogyi Zhou, Zhou Xu, Ming-Jiang Wang, Wei Godlewski, Grzegorz Paloczi, Janos Nemeth, Balazs Tamas Persidsky, Yuri Liaudet, Lucas Hasko, Gyorgy Bai, Peter Boulares, A. Hamid Auwerx, Johan Gao, Bin Pacher, Pal TI PARP inhibition protects against alcoholic and non-alcoholic steatohepatitis SO JOURNAL OF HEPATOLOGY LA English DT Article DE Mitochondria; Fatty liver; NAD(+); Reactive oxygen species; Fatty liver; NASH; Kupffer cells; Inflammation; Alcohols; Oxidative stress ID ADP-RIBOSE POLYMERASE-1; FATTY LIVER-DISEASE; MICE; RIBOSYLATION; HEPATOCYTES; CONSUMPTION; SIRT1; METABOLISM; ACTIVATION; NAD(+) AB Background & Aims: Mitochondria) dysfunction, oxidative stress, inflammation, and metabolic reprograming are crucial contributors to hepatic injury and subsequent liver fibrosis. Poly(ADP-ribose) polymerases (PARP) and their interactions with sirtuins play an important role in regulating intermediary metabolism in this process. However, there is little research into whether PARP inhibition affects alcoholic and non-alcoholic steatohepatitis (ASH/NASH). Methods: We investigated the effects of genetic deletion of PARP1 and pharmacological inhibition of PARP in models of early alcoholic steatohepatitis, as well as on Kupffer cell activation in vitro using biochemical assays, real-time PCR, and histological analyses. The effects of PARP inhibition were also evaluated in high fat or methionine and choline deficient diet-induced steatohepatitis models in mice. Results: PARP activity was increased in livers due to excessive alcohol intake, which was associated with decreased NAD content and SIRT1 activity. Pharmacological inhibition of PARP restored the hepatic NAD+ content, attenuated the decrease in SIRT1 activation and beneficially affected the metabolic-, inflammatory-, and oxidative stress-related alterations due to alcohol feeding in the liver. PARP1(-/-) animals were protected against alcoholic steatohepatitis and pharmacological inhibition of PARP or genetic deletion of PARP1 also attenuated Kupffer cell activation in vitro. Furthermore, PARP inhibition decreased hepatic triglyceride accumulation, metabolic dysregulation, or inflammation and/or fibrosis in models of NASH. Conclusion: Our results suggests that PARP inhibition is a promising therapeutic strategy in steatohepatitis with high translational potential, considering the availability of PARP inhibitors for clinical treatment of cancer. Lay summary: Poly(ADP-ribose) polymerases (PARP) are the most abundant nuclear enzymes. The PARP inhibitor olaparib (Lynparza) is a recently FDA-approved therapy for cancer. This study shows that PARP is overactivated in livers of subjects with alcoholic liver disease and that pharmacological inhibition of this enzyme with 3 different PARP inhibitors, including olaparib, attenuates high fat or alcohol induced liver injury, abnormal metabolic alteration, fat accumulation, inflammation and/or fibrosis in preclinical models of liver disease. These results suggest that PARP inhibition is a promising therapeutic strategy in the treatment of alcoholic and non-alcoholic liver diseases. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. C1 [Mukhopadhyay, Partha; Horvath, Bela; Rajesh, Mohanraj; Varga, Zoltan V.; Cao, Zongxian; Holovac, Eileen; Paloczi, Janos; Nemeth, Balazs Tamas; Pacher, Pal] NIAAA, Lab Cardiovasc Physiol & Tissue Injury, NIH, Bethesda, MD 20852 USA. [Gariani, Karim; Ryu, Dongryeol; Auwerx, Johan] Ecole Polytech Fed Lausanne, Lab Integrat & Syst Physiol, CH-1015 Lausanne, Switzerland. [Park, Ogyi; Zhou, Zhou; Xu, Ming-Jiang; Wang, Wei; Gao, Bin] NIAAA, Lab Liver Dis, Bethesda, MD 20852 USA. [Godlewski, Grzegorz] NIAAA, Lab Physiol Studies, Bethesda, MD 20852 USA. [Persidsky, Yuri] Temple Univ, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19140 USA. [Liaudet, Lucas] Univ Hosp Med Ctr, Dept Intens Care Med, BH 08-621, CH-1011 Lausanne, Switzerland. [Hasko, Gyorgy] Univ Med & Dent New Jersey, Dept Surg, Newark, NJ 07103 USA. [Hasko, Gyorgy] Univ Med & Dent New Jersey, Ctr Immun & Inflammat Surg Rutgers, Newark, NJ 07103 USA. [Bai, Peter] Univ Debrecen, Dept Med Chem, Fac Med, H-4032 Debrecen, Hungary. [Bai, Peter] MTA DE Lendulet Lab Cellular Metab, H-4032 Debrecen, Hungary. [Boulares, A. Hamid] Louisiana State Univ, Hlth Sci Ctr, Stanley Scott Canc Ctr, New Orleans, LA 70112 USA. [Boulares, A. Hamid] Louisiana State Univ, Hlth Sci Ctr, Dept Pharmacol, New Orleans, LA 70112 USA. RP Pacher, P (reprint author), Lab Cardiovasc Physiol & Tissue Injury, 5625 Fishers Lane,Room 2N-17, Bethesda, MD 20892 USA. EM mpartha@mail.nih.gov; pacher@mail.nih.gov FU Intramural Research Program of NIH/NIAAA; Rosztoczy Foundation; NKFI (Hungary) [108308, GINOP-2.3.2-15-2016-00006]; Ecole Polytechnique Federale de Lausanne, National Institute of Health [RO1AG043930]; Krebsforschung Schweiz/SwissCancerLeague [KFS-3082-02-2013, X(51RTP0151019), SNSF(31003A-124713)]; Geneva University Hospital, Switzerland; Fondation Romande pour la Recherche sur le Diabete FX This study was supported by Intramural Research Program of NIH/NIAAA (to P.P.). ZVV is supported by the Rosztoczy Foundation. P.B. is supported by the NKFI (Hungary) 108308 and GINOP-2.3.2-15-2016-00006 grants. J.A. is the Nestle Chair in Energy Metabolism. The research in the J.A. laboratory is supported by Ecole Polytechnique Federale de Lausanne, National Institute of Health(RO1AG043930), Krebsforschung Schweiz/SwissCancerLeague(KFS-3082-02-2013), Systems X(51RTP0151019), SNSF(31003A-124713). K.G. is supported by a grant from the Geneva University Hospital, Switzerland and the Fondation Romande pour la Recherche sur le Diabete. NR 32 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD MAR PY 2017 VL 66 IS 3 BP 589 EP 600 DI 10.1016/j.jhep.2016.10.023 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EM3MB UT WOS:000395218200018 ER PT J AU Ramirez, T Li, YM Yin, S Xu, MJ Feng, DC Zhou, Z Zang, MW Mukhopadhyay, P Varga, ZV Pacher, P Gao, B Wang, H AF Ramirez, Teresa Li, Yong-Mei Yin, Shi Xu, Ming-Jiang Feng, Dechun Zhou, Zhou Zang, Mengwei Mukhopadhyay, Partha Varga, Zoltan V. Pacher, Pal Gao, Bin Wang, Hua TI Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression SO JOURNAL OF HEPATOLOGY LA English DT Article DE Fatty liver; Steatohepatitis; Ethanol; PDGFR-alpha; Middle-age; Hepatic stellate cells (HSCs) ID KILLER T-CELLS; HIGH-FAT DIET; NATURAL-KILLER; MITOCHONDRIAL-FUNCTION; HEPATIC STEATOSIS; MOUSE MODEL; IN-VITRO; DISEASE; PROMOTES; INHIBITION AB Background & Aims: Aging is known to exacerbate the progression of alcoholic liver disease (ALD), but the underlying mechanisms remain obscure. The aim of this study was to use a chronic plus binge ethanol feeding model in mice to evaluate the effects of aging on alcohol-induced liver injury. Methods: C57BL/6 mice were subjected to short-term (10 days) ethanol plus one binge or long-term (8 weeks) ethanol plus multiple binges of ethanol. Liver injury and fibrosis were determined. Hepatic stellate cells (HSCs) were isolated and used in in vitro studies. Results: Middle-aged (12-14 months) and old-aged (>16 months) mice were more susceptible to liver injury, inflammation, and oxidative stress induced by short-term plus one binge or long-term plus multiple binges of ethanol feeding when compared to young (8-12 weeks) mice. Long-term plus multiple binges of ethanol feeding induced greater liver fibrosis in middle-aged mice than that in young mice. Hepatic expression of sirtuin 1 (SIRT1) protein was downregulated in the middle-aged mice compared to young mice. Restoration of SIRT1 expression via the administration of adenovirus-SIRT1 vector ameliorated short-term plus binge ethanol induced liver injury and fibrosis in middle-aged mice. HSCs isolated from middle-aged mice expressed lower levels of SIRT1 protein and were more susceptible to spontaneous activation in in vitro culture than those from young mice. Overexpression of SIRT1 reduced activation of HSCs from middle-aged mice in vitro with downregulation of PDGFR-alpha and c-Myc, while deletion of SIRT1 activated HSCs isolated from young mice in vitro. Finally, HSC-specific SIRT1 knockout mice were more susceptible to long-term chronic-plus-multiple binges of ethanol-induced liver fibrosis with upregulation of PDGFR-alpha expression. Conclusions: Aging exacerbates ALD in mice through the down regulation of SIRT1 in hepatocytes and HSCs. Activation of SIRT1 may serve as a novel target for the treatment of ALD. Lay summary: Aged mice are more susceptible to alcohol-induced liver injury and fibrosis, which is, at least in part, due to lower levels of sirtuin 1 protein in hepatocytes and hepatic stellate cells. Our findings suggest that sirtuin 1 activators may have beneficial effects for the treatment of alcoholic liver disease in aged patients. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. C1 [Ramirez, Teresa; Li, Yong-Mei; Yin, Shi; Xu, Ming-Jiang; Feng, Dechun; Zhou, Zhou; Gao, Bin; Wang, Hua] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. [Wang, Hua] Anhui Med Univ, Inst Liver Dis, Affiliated Hosp 1, Dept Oncol, 218 Jixi Rd, Hefei 230032, Peoples R China. [Yin, Shi] Anhui Med Univ, Affiliated Prov Hosp, Dept Geriatr, Hefei 230032, Peoples R China. [Zang, Mengwei] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, Dept Mol Med, San Antonio, TX 78229 USA. [Mukhopadhyay, Partha; Varga, Zoltan V.; Pacher, Pal] NIAAA, Lab Cardiovasc Physiol & Tissue Injury, NIH, Bethesda, MD 20892 USA. RP Gao, B; Wang, H (reprint author), NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA.; Gao, B; Wang, H (reprint author), Anhui Med Univ, Inst Liver Dis, Affiliated Hosp 1, Dept Oncol, 218 Jixi Rd, Hefei 230032, Peoples R China. EM bgao@mail.nih.gov; wanghua@ahmu.edu.cn RI Zhou, Zhou/R-7788-2016 FU intramural program of NIAAA, NIH, United States; National Natural Science Foundation of China [81522009/H0317, 81470879/H0318]; NIH, United States [R01 DK100603, R21AA021181] FX This work was supported by the intramural program of NIAAA, NIH, United States (BG), National Natural Science Foundation of China (No. 81522009/H0317 to HW, 81470879/H0318 to SY), the NIH, United States Grants (R01 DK100603 and R21AA021181 to MZ). No conflicts of interest exist for any of the authors. NR 41 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD MAR PY 2017 VL 66 IS 3 BP 601 EP 609 DI 10.1016/j.jhep.2016.11.004 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EM3MB UT WOS:000395218200019 PM 27871879 ER PT J AU Janelsins, MC Heckler, CE Peppone, LJ Kamen, C Mustian, KM Mohile, SG Magnuson, A Kleckner, IR Guido, JJ Young, KL Conlin, AK Weiselberg, LR Mitchell, JW Ambrosone, CA Ahles, TA Morrow, GR AF Janelsins, Michelle C. Heckler, Charles E. Peppone, Luke J. Kamen, Charles Mustian, Karen M. Mohile, Supriya G. Magnuson, Allison Kleckner, Ian R. Guido, Joseph J. Young, Kelley L. Conlin, Alison K. Weiselberg, Lora R. Mitchell, Jerry W. Ambrosone, Christine A. Ahles, Tim A. Morrow, Gary R. TI Cognitive Complaints in Survivors of Breast Cancer After Chemotherapy Compared With Age-Matched Controls: An Analysis From a Nationwide, Multicenter, Prospective Longitudinal Study SO AMERICAN JOURNAL OF PSYCHOLOGY LA English DT Article ID FUNCTIONAL ASSESSMENT; THERAPY; ANTHRACYCLINE; CARDIOTOXICITY; IMPAIRMENT; EDUCATION; TOXICITY; TRACKING; UPDATE; GENDER AB Purpose Cancer-related cognitive impairment is an important problem for patients with breast cancer, yet its trajectory is not fully understood. Some previous cancer-related cognitive impairment research is limited by heterogeneous populations, small samples, lack of prechemotherapy and longitudinal assessments, use of normative data, and lack of generalizability. We addressed these limitations in a large prospective, longitudinal, nationwide study. Patients and Methods Patients with breast cancer from community oncology clinics and age-matched noncancer controls completed the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) at prechemotherapy and postchemotherapy and at a 6-month follow-up as an a priori exploratory aim. Longitudinal models compared FACT-Cog scores between patients and controls at the three assessments and adjusted for age, education, race, menopausal status, and baseline reading ability, anxiety, and depressive symptoms. A minimal clinically important difference cutoff determined percentages of impairment over time. Results Of patients, 581 patients with breast cancer (mean age, 53 years; 48% anthracycline-based regimens) and 364 controls (mean age, 53 years) were assessed. Patients reported significantly greater cognitive difficulties on the FACT-Cog total score and four subscales from prechemotherapy to postchemotherapy compared with controls as well as from prechemotherapy to 6-month follow-up (all P<.001). Increased baseline anxiety, depression, and decreased cognitive reserve were significantly associated with lower FACT-Cog total scores. Treatment regimen, hormone, or radiation therapy was not significantly associated with FACT-Cog total scores in patients from postchemotherapy to 6-month follow-up. Patients were more likely to report a clinically significant decline in self-reported cognitive function than were controls from prechemotherapy to postchemotherapy (45.2% v 10.4%) and from prechemotherapy to 6-month follow-up (36.5% v 13.6%). Conclusion Patients with breast cancer who were treated in community oncology clinics report substantially more cognitive difficulties up to 6 months after treatment with chemotherapy than do age-matched noncancer controls. C1 [Janelsins, Michelle C.; Heckler, Charles E.; Peppone, Luke J.; Kamen, Charles; Mustian, Karen M.; Mohile, Supriya G.; Magnuson, Allison; Kleckner, Ian R.; Guido, Joseph J.; Morrow, Gary R.] Univ Rochester, Med Ctr, James P Wilmot Canc Inst, Rochester, NY 14642 USA. [Weiselberg, Lora R.] NCI, North Shore LIJ Hlth Syst, Community Clin Oncol Res Program NCORP, Lake Success, NY USA. [Ambrosone, Christine A.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Ahles, Tim A.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Young, Kelley L.] Kansas City Clin Oncol Program, Kansas City, MO USA. [Conlin, Alison K.] Pacific Canc Res Consortium NCORP, Seattle, WA USA. [Mitchell, Jerry W.] Columbus NCORP, Columbus, OH USA. RP Janelsins, MC (reprint author), Univ Rochester, Med Ctr, James P Wilmot Canc Inst, Dept Surg, 265 Crittenden Blvd,CU 420658, Rochester, NY 14642 USA.; Janelsins, MC (reprint author), Univ Rochester, Med Ctr, James P Wilmot Canc Inst, Dept Neurosci, 265 Crittenden Blvd,CU 420658, Rochester, NY 14642 USA.; Janelsins, MC (reprint author), Univ Rochester, Med Ctr, James P Wilmot Canc Inst, Dept Radiat Oncol, 265 Crittenden Blvd,CU 420658, Rochester, NY 14642 USA. EM michelle_janelsins@urmc.rochester.edu FU National Cancer Institute [U10CA037420, UG1CA189961, K07CA1688, R25CA102618] FX Supported by National Cancer Institute Grants No. U10CA037420, U10CA037420 Supplement, UG1CA189961, K07CA1688, and R25CA102618. NR 28 TC 0 Z9 0 U1 1 U2 1 PU UNIV ILLINOIS PRESS PI CHAMPAIGN PA 1325 S OAK ST, CHAMPAIGN, IL 61820-6903 USA SN 0002-9556 EI 1939-8298 J9 AM J PSYCHOL JI Am. J. Psychol. PD SPR PY 2017 VL 130 IS 1 BP 506 EP U192 DI 10.1200/JCO.2016.68.5826 PG 13 WC Psychology, Multidisciplinary SC Psychology GA EL1FI UT WOS:000394365500018 ER PT J AU Moore, AA Carney, D Moroney, E Machlin, L Towbin, KE Brotman, MA Pine, DS Leibenluft, E Roberson-Nay, R Hettema, JM AF Moore, Ashlee A. Carney, Dever Moroney, Elizabeth Machlin, Laura Towbin, Kenneth E. Brotman, Melissa A. Pine, Daniel S. Leibenluft, Ellen Roberson-Nay, Roxann Hettema, John M. TI The Inventory of Callous-Unemotional Traits (ICU) in Children: Reliability and Heritability SO BEHAVIOR GENETICS LA English DT Article DE Callous-unemotional traits; Heritability; Reliability; Measurement model; Twins ID IV CONDUCT DISORDER; PSYCHOPATHIC PERSONALITY; ANTISOCIAL-BEHAVIOR; DEVELOPMENTAL PATHWAYS; MAJOR DEPRESSION; COMMUNITY SAMPLE; TWIN; PREDICTORS; CHILDHOOD; DIAGNOSIS AB Callous-unemotional (CU) traits comprise the core symptoms of psychopathy, yet no study has estimated the heritability of CU traits in a community sample of children using an instrument designed solely to assess CU traits. The current study uses data from 339 twin pairs aged 9-14 to examine the reliability and heritability of the parent-report Inventory of Callous-unemotional Traits (ICU) at two assessments approximately 3 weeks apart. Time-specific measurement error was taken into account to obtain a more accurate estimate of the heritability reflecting the latent liability to CU traits. Test-retest reliability was 0.84 and heritability at visit 1 was 39%. The heritability of the latent liability to CU traits was 47%. This latent liability contributed 79% of the variance in ICU score at visit 1 and visit 2. This is the first study to account for measurement error while examining the heritability of CU traits, furthering our understanding of psychopathy in children. C1 [Moore, Ashlee A.; Carney, Dever; Roberson-Nay, Roxann; Hettema, John M.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, POB 980489, Richmond, VA 23298 USA. [Moore, Ashlee A.] Virginia Commonwealth Univ, Ctr Clin & Translat Res, Richmond, VA 23284 USA. [Roberson-Nay, Roxann; Hettema, John M.] Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA. [Moroney, Elizabeth; Machlin, Laura; Towbin, Kenneth E.; Brotman, Melissa A.; Pine, Daniel S.; Leibenluft, Ellen] NIMH, Dept Hlth & Human Serv, Emot & Dev Branch, NIH, Bethesda, MD 20892 USA. RP Moore, AA (reprint author), Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, POB 980489, Richmond, VA 23298 USA.; Moore, AA (reprint author), Virginia Commonwealth Univ, Ctr Clin & Translat Res, Richmond, VA 23284 USA. EM mooreaa2@vcu.edu RI Brotman, Melissa/H-7409-2013 FU National Institutes of Health [NIMH R01MH098055, NIMH IRP-ZIAMH002781]; NIMH [T32MH020030, R01MH101518]; NCATS [UL1TR000058] FX VCU-JAS was funded by the National Institutes of Health (NIMH R01MH098055 to JMH and NIMH IRP-ZIAMH002781 to DSP). AAM is supported by NIMH T32MH020030. RRN is supported by NIMH R01MH101518. The Mid-Atlantic Twin Registry is supported through NCATS UL1TR000058. NR 60 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 EI 1573-3297 J9 BEHAV GENET JI Behav. Genet. PD MAR PY 2017 VL 47 IS 2 BP 141 EP 151 DI 10.1007/s10519-016-9831-1 PG 11 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA EL0XB UT WOS:000394344000001 PM 27909830 ER PT J AU Yang, JC AF Yang, James C. TI Debugging the Black Box SO CANCER DISCOVERY LA English DT Editorial Material ID PD-1 BLOCKADE; CANCER; MELANOMA; CELLS AB A better understanding of the mechanisms by which tumor rejection succeeds and fails is needed to improve immunotherapies. Here, Anagnostou and colleagues find that mutations predicted to be the most immunogenic are preferentially lost when cancer progresses through checkpoint blockade. (C) 2017 AACR. C1 [Yang, James C.] NCI, Surg Branch, 9000 Rockville Pike,Bldg 10A-CRC,Room 3-5952, Bethesda, MD 20892 USA. RP Yang, JC (reprint author), NCI, Surg Branch, 9000 Rockville Pike,Bldg 10A-CRC,Room 3-5952, Bethesda, MD 20892 USA. EM JamesYang@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 10 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 EI 2159-8290 J9 CANCER DISCOV JI Cancer Discov. PD MAR PY 2017 VL 7 IS 3 BP 250 EP 251 DI 10.1158/2159-8290.CD-17-0070 PG 2 WC Oncology SC Oncology GA EN5AP UT WOS:000396018300019 PM 28264866 ER PT J AU Coghill, AE Strickler, HD AF Coghill, Anna E. Strickler, Howard D. TI Survival Deficit for HIV-Infected Lymphoma Patients in the National Cancer Database SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Editorial Material ID UNITED-STATES; ANTIRETROVIRAL THERAPY; TRENDS; MORTALITY; PEOPLE; ERA C1 [Coghill, Anna E.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Strickler, Howard D.] Albert Einstein Coll Med, Div Epidemiol, Bronx, NY 10467 USA. RP Coghill, AE (reprint author), NCI, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM anna.coghill@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 14 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2017 VL 26 IS 3 BP 289 EP 290 DI 10.1158/1055-9965.EPI-17-0006 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EN5BI UT WOS:000396020200001 PM 28254955 ER PT J AU Powe, CE Tobias, DK Michels, KB Chen, WY Eliassen, AH Manson, JE Rosner, B Willett, WC Hu, FB Zhang, CL Rich-Edwards, JW Rexrode, KM AF Powe, Camille E. Tobias, Deirdre K. Michels, Karin B. Chen, Wendy Y. Eliassen, A. Heather Manson, Joann E. Rosner, Bernard Willett, Walter C. Hu, Frank B. Zhang, Cuilin Rich-Edwards, Janet W. Rexrode, Kathryn M. TI History of Gestational Diabetes Mellitus and Risk of Incident Invasive Breast Cancer among Parous Women in the Nurses' Health Study II Prospective Cohort SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GLUCOSE-INTOLERANCE; PHYSICAL-ACTIVITY; MATERNAL RISK; TERM RISK; PREGNANCY; METAANALYSIS; INSULIN; BIRTH AB Background: Type II diabetes is associated with breast cancer in epidemiologic studies. Pregnancy also modifies breast cancer risk. We hypothesized that women with a history of gestational diabetes mellitus (GDM), which shares pathogenesis and risk factors with type II diabetes, would have greater invasive breast cancer risk than parous women without a history of GDM. Methods: We conducted a prospective analysis among parous women in the Nurses' Health Study II, with mean age 35 years in 1989. Multivariate Cox proportional hazards models were used to compare risks of incident invasive breast cancer in women with and without a history of GDM. Results: Among 86,972 women studied, 5,188 women reported a history of GDM and 2,377 developed invasive breast cancer (100 with history of GDM, 2,277 without GDM) over 22 years of prospective follow-up. History of GDM was inversely associated with incident invasive breast cancer [HR, 0.68; 95% confidence interval (CI), 0.55-0.84; P = 0.0004], compared with no history of GDM, after adjustment for body mass index, reproductive history, and other breast cancer risk factors. Findings were similar by menopausal status, although observed person-time was predominantly premenopausal (premenopausal: HR, 0.73; 95% CI, 0.56-0.96; P = 0.03; postmenopausal: HR, 0.63; 95% CI, 0.43-0.92; P = 0.02). Restricting to women undergoing mammography screening modestly attenuated the relationship (HR, 0.74; 95% CI, 0.57-0.96; P = 0.02). Conclusions: Among a large cohort of U.S. women, history of GDM was not associated with an elevated risk of subsequent invasive breast cancer. Impact: Our findings highlight the need to further investigate GDM's role in breast cancer development. (C)2016 AACR. C1 [Powe, Camille E.] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Tobias, Deirdre K.; Manson, Joann E.; Rexrode, Kathryn M.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Tobias, Deirdre K.; Willett, Walter C.; Hu, Frank B.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Michels, Karin B.; Chen, Wendy Y.; Eliassen, A. Heather; Rosner, Bernard; Willett, Walter C.; Hu, Frank B.; Rich-Edwards, Janet W.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Michels, Karin B.] Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Obstet & Gynecol Epidemiol Ctr, 75 Francis St, Boston, MA 02115 USA. [Michels, Karin B.; Eliassen, A. Heather; Manson, Joann E.; Willett, Walter C.; Hu, Frank B.; Rich-Edwards, Janet W.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Chen, Wendy Y.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Manson, Joann E.; Rich-Edwards, Janet W.] Brigham & Womens Hosp, Connors Ctr Womens Hlth & Gender Biol, 75 Francis St, Boston, MA 02115 USA. [Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD USA. RP Rexrode, KM (reprint author), Brigham & Womens Hosp, 900 Commonwealth Ave,3rd Floor, Boston, MA 02215 USA. EM krexrode@partners.org FU [UM1CA176726]; [CA50385]; [DK103720]; [DK007028-41]; [DK58845]; [P30DK46200]; [HHSN275201000020C] FX W.C. Willett received grants UM1CA176726 and CA50385, D.K. Tobias received grant DK103720, C.E. Powe was supported by grant DK007028-41, and F.B. Hu received grants DK58845, P30DK46200, and HHSN275201000020C. NR 36 TC 1 Z9 1 U1 2 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 2017 VL 26 IS 3 BP 321 EP 327 DI 10.1158/1055-9965.EPI-16-0601 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EN5BI UT WOS:000396020200005 PM 27729356 ER PT J AU Haraldsdottir, A Steingrimsdottir, L Valdimarsdottir, UA Aspelund, T Tryggvadottir, L Harris, TB Launer, LJ Mucci, LA Giovannucci, EL Adami, HO Gudnason, V Torfadottir, JE AF Haraldsdottir, Alfheidur Steingrimsdottir, Laufey Valdimarsdottir, Unnur A. Aspelund, Thor Tryggvadottir, Laufey Harris, Tamara B. Launer, Lenore J. Mucci, Lorelei A. Giovannucci, Edward L. Adami, Hans-Olov Gudnason, Vilmundur Torfadottir, Johanna E. TI Early Life Residence, Fish Consumption, and Risk of Breast Cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRE; POLYUNSATURATED FATTY-ACIDS; ADVANCED PROSTATE-CANCER; VITAMIN-D; GENE/ENVIRONMENT SUSCEPTIBILITY; PROSPECTIVE COHORT; OIL CONSUMPTION; RECEPTOR STATUS; REDUCED RISK; DIET AB Background: Little is known about fish intake throughout the life course and the risk of breast cancer. Methods: We used data on the first residence of 9,340 women born 1908 to 1935 in the Reykjavik Study as well as food frequency data for different periods of life from a subgroup of the cohort entering the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study (n = 2,882). Results: During a mean follow-up of 27.3 years, 744 women were diagnosed with breast cancer in the Reykjavik Study. An inverse association of breast cancer was observed among women who lived through the puberty period in coastal villages, compared with women residing in the capital area [HR, 0.78; 95% confidence interval (CI), 0.61-0.99]. In the subgroup analysis of this Icelandic population, generally characterized by high fish intake, we found an indication of lower risk of breast cancer among women with high fish consumption (more than 4 portions per week) in adolescence (HR, 0.71; 95% CI, 0.44-1.13) and midlife (HR, 0.46; 95% CI, 0.22-0.97), compared with low consumers (2 portions per week or less). No association was found for fish liver oil consumption in any time period, which could be due to lack of a reference group with low omega-3 fatty acids intake in the study group. Conclusions: Our findings suggest that very high fish consumption in early to midlife may be associated with a reduced risk of breast cancer. Impact: Very high fish consumption in early adulthood to midlife may be associated with decreased risk of breast cancer. (C)2016 AACR. C1 [Haraldsdottir, Alfheidur; Steingrimsdottir, Laufey] Univ Iceland, Fac Food Sci & Human Nutr, Reykjavik, Iceland. [Haraldsdottir, Alfheidur; Valdimarsdottir, Unnur A.; Aspelund, Thor; Torfadottir, Johanna E.] Univ Iceland, Ctr Publ Hlth Sci, Fac Med, Reykjavik, Iceland. [Steingrimsdottir, Laufey; Torfadottir, Johanna E.] Univ Iceland, Unit Nutr Res, Reykjavik, Iceland. [Steingrimsdottir, Laufey; Torfadottir, Johanna E.] Landspitali Natl Univ Hosp Reykjavik, Reykjavik, Iceland. [Valdimarsdottir, Unnur A.; Mucci, Lorelei A.; Giovannucci, Edward L.; Adami, Hans-Olov] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Valdimarsdottir, Unnur A.; Adami, Hans-Olov] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Aspelund, Thor; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Tryggvadottir, Laufey] Iceland Canc Registry, Reykjavik, Iceland. [Tryggvadottir, Laufey; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, Bethesda, MD 20892 USA. [Mucci, Lorelei A.; Giovannucci, Edward L.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Mucci, Lorelei A.; Giovannucci, Edward L.] Harvard Med Sch, Boston, MA USA. [Giovannucci, Edward L.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. RP Haraldsdottir, A (reprint author), Univ Iceland, Eiriksgata 29, IS-101 Reykjavik, Iceland. EM alh1@hi.is FU NIH [N01-AG-12100]; Intramural Research Program of the National Institute on Aging; Icelandic Heart Association; Icelandic Parliament; Icelandic Centre for Research, RANNIS [152495051]; Public Health Fund of the Icelandic Directorate of Health FX The AGES-Reykjavik Study was funded by NIH contract N01-AG-12100, the Intramural Research Program of the National Institute on Aging, the Icelandic Heart Association, and the Icelandic Parliament. This work was also supported by the Icelandic Centre for Research, RANNIS grant number: 152495051, http://en.rannis.is/ (to A. Haraldsdottir), and the Public Health Fund of the Icelandic Directorate of Health (to A. Haraldsdottir). NR 50 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2017 VL 26 IS 3 BP 346 EP 354 DI 10.1158/1055-9965.EPI-16-0473-T PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EN5BI UT WOS:000396020200008 PM 27765796 ER PT J AU Kim, S Campbell, J Yoo, W Taylor, JA Sandler, DP AF Kim, Sangmi Campbell, Jeff Yoo, Wonsuk Taylor, Jack A. Sandler, Dale P. TI Systemic Levels of Estrogens and PGE(2) Synthesis in Relation to Postmenopausal Breast Cancer Risk SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Review ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; PROSTAGLANDIN E-2 METABOLITE; CHROMATOGRAPHY-MASS SPECTROMETRY; ENDOGENOUS ESTROGENS; URINARY ESTROGENS; SERUM ESTROGENS; ADIPOSE-TISSUE; CASE-COHORT; WOMEN; AROMATASE AB Background: Prostaglandin E-2 (PGE(2)) induces aromatase expression in adipose tissue, leading to increased estrogen production that may promote the development and progression of breast cancer. However, few studies have simultaneously investigated systemic levels of PGE(2) and estrogen in relation to postmenopausal breast cancer risk. Methods: Here, we determined urinary estrogen metabolites (EM) using mass spectrometry in a case-cohort study (295 incident breast cancer cases and 294 subcohort members), and using linear regression estimated the effect of urinary levels of a major PGE(2) metabolite (PGE-M) on EMs. HRs for the risk of developing breast cancer in relation to PGE-M and EMs were compared between Cox regression models with and without mutual adjustment. Results: PGE-M was a significant predictor of estrone (E1), but not estradiol (E2) levels in multivariable analysis. Elevated E2 levels were associated with an increased risk of developing breast cancer [HRQ5vs.Q1, 1.54; 95% confidence interval (CI), 1.01-2.35], and this association remained unchanged after adjustment for PGE-M (HRQ5vs.Q1, 1.52; 95% CI, 0.99-2.33). Similarly, elevated levels of PGE-M were associated with increased risk of developing breast cancer (HRQ4vs.Q1, 2.01; 95% CI, 1.01-4.29), and this association was only nominally changed after consideration of E1 or E2 levels. Conclusions: Urinary levels of PGE-M and estrogens were independently associated with future risk of developing breast cancer among these postmenopausal women. Impact: Increased breast cancer risk associated with PGE-M might not be fully explained by the estrogens-breast cancer association alone but also by additional effects related to inflammation. (C)2016 AACR. C1 [Kim, Sangmi; Campbell, Jeff] Augusta Univ, Georgia Canc Ctr, Med Coll Georgia, Dept Med,Sect Hematol Oncol, Augusta, GA USA. [Yoo, Wonsuk] Augusta Univ, Data Coordinating Ctr, Inst Publ & Prevent Hlth, Augusta, GA USA. [Taylor, Jack A.; Sandler, Dale P.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Kim, S (reprint author), Augusta Univ, Georgia Canc Ctr, 1410 Laney Walker Blvd, Augusta, GA 30912 USA. EM sankim@augusta.edu FU Department of Defense Breast Cancer Postdoctoral Fellowship [BC0923202]; National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES044005] FX This work was supported by Department of Defense Breast Cancer Postdoctoral Fellowship BC0923202 (S. Kim) and Intramural Program of the National Institutes of Health, National Institute of Environmental Health Sciences Z01 ES044005 (S. Kim, J.A. Taylor, and D.P. Sandler). NR 41 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2017 VL 26 IS 3 BP 383 EP 388 DI 10.1158/1055-9965.EPI-16-0556 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EN5BI UT WOS:000396020200012 PM 27864342 ER PT J AU Sucheston-Campbell, LE Cannioto, R Clay, AI Etter, JL Eng, KH Liu, S Battaglia, S Hu, Q Szender, JB Minlikeeva, A Joseph, JM Mayor, P Abrams, SI Segal, BH Wallace, PK Soh, KT Zsiros, E Anton-Culver, H Bandera, EV Beckmann, MW Berchuck, A Bjorge, L Bruegl, A Campbell, IG Campbell, SP Chenevix-Trench, G Cramer, DW Dansonka-Mieszkowska, A Dao, F Diergaarde, B Doerk, T Doherty, JA du Bois, A Eccles, D Engelholm, SA Fasching, PA Gayther, SA Gentry-Maharaj, A Glasspool, RM Goodman, MT Gronwald, J Harter, P Hein, A Heitz, F Hillemmanns, P Hogdall, C Hogdall, EVS Huzarski, T Jensen, A Johnatty, SE Jung, A Karlan, BY Klapdor, R Kluz, T Konopka, B Kjaer, SK Kupryjanczyk, J Lambrechts, D Lester, J Lubinski, J Levine, DA Lundvall, L McGuire, V McNeish, IA Menon, U Modugno, F Ness, RB Orsulic, S Paul, J Pearce, CL Pejovic, T Pharoah, P Ramus, SJ Rothstein, J Rossing, MA Rubner, M Schildkraut, JM Schmalfeldt, B Schwaab, I Siddiqui, N Sieh, W Sobiczewski, P Song, HL Terry, KL Van Nieuwenhuysen, E Vanderstichele, A Vergote, I Walsh, CS Webb, PM Wentzensen, N Whittemore, AS Wu, AH Ziogas, A Odunsi, K Chang-Claude, J Goode, EL Moysich, KB AF Sucheston-Campbell, Lara E. Cannioto, Rikki Clay, Alyssa I. Etter, John Lewis Eng, Kevin H. Liu, Song Battaglia, Sebastiano Hu, Qiang Szender, J. Brian Minlikeeva, Albina Joseph, Janine M. Mayor, Paul Abrams, Scott I. Segal, Brahm H. Wallace, Paul K. Soh, Kah Teong Zsiros, Emese Anton-Culver, Hoda Bandera, Elisa V. Beckmann, Matthias W. Berchuck, Andrew Bjorge, Line Bruegl, Amanda Campbell, Ian G. Campbell, Shawn Patrice Chenevix-Trench, Georgia Cramer, Daniel W. Dansonka-Mieszkowska, Agnieszka Dao, Fanny Diergaarde, Brenda Doerk, Thilo Doherty, Jennifer A. du Bois, Andreas Eccles, Diana Engelholm, Svend Aage Fasching, Peter A. Gayther, Simon A. Gentry-Maharaj, Aleksandra Glasspool, Rosalind M. Goodman, Marc T. Gronwald, Jacek Harter, Philipp Hein, Alexander Heitz, Florian Hillemmanns, Peter Hogdall, Claus Hogdall, Estrid V. S. Huzarski, Tomasz Jensen, Allan Johnatty, Sharon E. Jung, Audrey Karlan, Beth Y. Klapdor, Reudiger Kluz, Tomasz Konopka, Bozena Kjaer, Susanne Krueger Kupryjanczyk, Jolanta Lambrechts, Diether Lester, Jenny Lubinski, Jan Levine, Douglas A. Lundvall, Lene McGuire, Valerie McNeish, Iain A. Menon, Usha Modugno, Francesmary Ness, Roberta B. Orsulic, Sandra Paul, James Pearce, Celeste Leigh Pejovic, Tanja Pharoah, Paul Ramus, Susan J. Rothstein, Joseph Rossing, Mary Anne Ruebner, Matthias Schildkraut, Joellen M. Schmalfeldt, Barbara Schwaab, Ira Siddiqui, Nadeem Sieh, Weiva Sobiczewski, Piotr Song, Honglin Terry, Kathryn L. Van Nieuwenhuysen, Els Vanderstichele, Adriaan Vergote, Ignace Walsh, Christine S. Webb, Penelope M. Wentzensen, Nicolas Whittemore, Alice S. Wu, Anna H. Ziogas, Argyrios Odunsi, Kunle Chang-Claude, Jenny Goode, Ellen L. Moysich, Kirsten B. CA Australian Ovarian Canc Study TI No Evidence That Genetic Variation in the Myeloid-Derived Suppressor Cell Pathway Influences Ovarian Cancer Survival SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ASSOCIATION AB Background: The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immunosuppressive/protumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be a prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses. Methods: We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association Study and the admixture likelihood method were used to test gene and pathway associations with survival. Results: We did not identify individual SNPs that were significantly associated with survival after correction for multiple testing (P < 3.5 x 10(-5)), nor did we identify significant associations between the MDSC pathway overall, or the 24 individual genes and EOC survival. Conclusions: In this well-powered analysis, we observed no evidence that inherited variations in MDSC-associated SNPs, individual genes, or the collective genetic pathway contributed to EOC survival outcomes. Impact: Common inherited variation in genes relevant to MDSCs was not associated with survival in women diagnosed with invasive EOC. (C)2016 AACR. C1 [Sucheston-Campbell, Lara E.] Ohio State Univ, Coll Pharm, Coll Vet Med, Columbus, OH USA. [Cannioto, Rikki; Etter, John Lewis; Minlikeeva, Albina; Joseph, Janine M.; Moysich, Kirsten B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Elm & Carlton St, Buffalo, NY 14203 USA. [Clay, Alyssa I.] Div Epidemiol, Mayo Clin, Canc Genet Epidemiol, Rochester, MN USA. [Eng, Kevin H.; Liu, Song; Hu, Qiang] Roswell Pk Canc Inst, Dept Biostat & Bioinformat, Buffalo, NY USA. [Battaglia, Sebastiano] Roswell Pk Canc Inst, Dept Canc Genet, Buffalo, NY USA. [Szender, J. Brian; Mayor, Paul; Zsiros, Emese; Odunsi, Kunle] Roswell Pk Canc Inst, Gynecol Oncol, Buffalo, NY USA. [Abrams, Scott I.; Segal, Brahm H.] Roswell Pk Canc Inst, Dept Immunol, Buffalo, NY USA. [Segal, Brahm H.] Roswell Pk Canc Inst, Dept Med, Buffalo, NY USA. [Wallace, Paul K.; Soh, Kah Teong] Roswell Pk Canc Inst, Dept Flow Image Cytometry, Buffalo, NY USA. [Anton-Culver, Hoda] Univ Calif Irvine, Genet Epidemiol Res Inst, Sch Med, Irvine, CA USA. [Bandera, Elisa V.; Walsh, Christine S.] Rutgers Canc Inst New Jersey, Canc Prevent & Control Program, New Brunswick, NJ USA. [Beckmann, Matthias W.; Fasching, Peter A.; Hein, Alexander; Ruebner, Matthias] Univ Hosp Erlangen, Friedrich Alexander Univ Erlangen Nuremberg, Comprehens Canc Ctr Erlangen EMN, Dept Gynecol & Obstet, Erlangen, Germany. [Berchuck, Andrew] Duke Univ Med Ctr, Dept Obstetr & Gynecol, Durham, NC USA. [Bjorge, Line] Haukeland Univ Horpital, Dept Gynecol & Obstet, Bergen, Norway. [Bjorge, Line] Univ Bergen, Ctr Canc Biomarkers, Dept Clin Sci, Bergen, Norway. [Bruegl, Amanda; Campbell, Shawn Patrice; Pejovic, Tanja] Oregon Hlth & Sci Univ, Dept Obstet Gynecol, Portland, OR USA. [Campbell, Ian G.] Canc Genet Lab, Melbourne, Australia. [Campbell, Ian G.] Univ Melbourne, Dept Pathol, Parkville, Vic, Australia. [Chenevix-Trench, Georgia; Johnatty, Sharon E.] QIMR Berghofer Med Res Inst, Genet & Computat Biol Dept, Herston, Qld, Australia. [Terry, Kathryn L.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, Boston, MA USA. [Terry, Kathryn L.; Australian Ovarian Canc Study] Harvard T H Chan Sch Publ Hlth, Boston, MA USA. [Cramer, Daniel W.; Konopka, Bozena; Kupryjanczyk, Jolanta] Maria Sklodowska Curie Mem Canc Ctr, Inst Oncol, Dept Pathol & Lab Diagnost, Warsaw, Poland. [Dansonka-Mieszkowska, Agnieszka; Levine, Douglas A.] Laura & Isaac Pearlmutter Canc Ctr, NYU Langone Med Ctr, Gynecol Oncol, New York, NY USA. [Dao, Fanny; Modugno, Francesmary] Univ Pittsburgh Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Diergaarde, Brenda; Doerk, Thilo; Hillemmanns, Peter; Klapdor, Reudiger] Hann Med Sch, Dept Obstet & Gynecol, Hannover, Germany. [Doherty, Jennifer A.] Geisel Sch Med, Dept Epidemiol, Dartmouth, NS, Lebanon. [du Bois, Andreas; Harter, Philipp; Heitz, Florian] Kliniken Essen Mitte Evang Huyssens Stiftung Knap, Dept Gynecol & Gynecol Oncol, Essen, Germany. [du Bois, Andreas; Heitz, Florian] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynecol & Gynecol Oncol, Wiesbaden, Germany. [Eccles, Diana] Univ Southampton, Fac Med, Southampton, England. [Eccles, Diana] Southampton Univ Hosp Trust, Wessex Clin Genet Serv, Southampton, England. [Engelholm, Svend Aage] Univ Copenhagen, Dept Oncol, Rigs Hosp, Copenhagen, Denmark. [Gayther, Simon A.] Cedars Sinai Med Ctr, Ctr Canc Prevent & Translat Genom, Los Angeles, CA USA. [Gayther, Simon A.] Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA USA. [Gentry-Maharaj, Aleksandra; Menon, Usha] UCL, Inst Womens Hlth, Womens Canc, London, England. [Glasspool, Rosalind M.; Paul, James] Beatson West Scotland Canc Ctr, Glasgow, Lanark, Scotland. [Goodman, Marc T.] Samuel Oschin Comprehens Canc Inst, Cedars Sinai Med Ctr, Canc Prevent & Control, Los Angeles, CA USA. [Goodman, Marc T.] Commun & Populat Hlth Res Inst, Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA USA. [Gronwald, Jacek; Huzarski, Tomasz; Lubinski, Jan] Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, Szczecin, Poland. [Hogdall, Claus; Kjaer, Susanne Krueger] Univ Copenhagen, Dept Gynaecol, Rigs Hosp, Herlev, Denmark. [Hogdall, Estrid V. S.; Jensen, Allan; Kjaer, Susanne Krueger] Danish Canc Soc Res Ctr, Dept Virus Lifestyle & Genes, Copenhagen, Denmark. [Hogdall, Estrid V. S.] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, Copenhagen, Denmark. [Jung, Audrey; Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Jung, Audrey; Chang-Claude, Jenny] Univ Med Ctr Hamburg Eppendorf, Univ Canc Ctr Hamburg, Heidelberg, Germany. [Karlan, Beth Y.; Lester, Jenny; Orsulic, Sandra] Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Cedars Sinai Med Ctr, Los Angeles, CA USA. [Kluz, Tomasz] Univ Rzeszow, Inst Midwifery & Emergency Med, Clin Obstet & Gynecol, Fac Med, Rzeszow, Poland. [Lambrechts, Diether] Univ Leuven, Vesalius Res Ctr, Lab Translat Genet, Dept Oncol, Leuven, Belgium. [Lundvall, Lene] Univ Copenhagen, Juliane Marie Ctr, Dept Gynecol, Copenhagen, Denmark. [McGuire, Valerie; Rothstein, Joseph; Whittemore, Alice S.] Stanford Univ Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA USA. [McNeish, Iain A.] Univ Glasgow, Beatson Inst Canc Res, Wolfson Wohl Canc Res Ctr, Inst Canc Sci, Glasgow, Lanark, Scotland. [Modugno, Francesmary] Univ Pittsburgh Sch Med, Dept Obstet, Div Gynecol Oncol, Gynecol & Reprod Sci, Pittsburgh, PA USA. [Modugno, Francesmary] Univ Pittsburgh Canc Inst, Magee Womens Res Inst, Womens Canc Res Program, Ovarian Canc Ctr Excellence, Pittsburgh, PA USA. [Ness, Roberta B.] Univ Texas Sch Publ Hlth, Houston, TX USA. [Pearce, Celeste Leigh] Univ Michigan Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI USA. [Pearce, Celeste Leigh; Wu, Anna H.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Pejovic, Tanja] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR USA. [Pharoah, Paul; Song, Honglin] Univ Cambridge, Strangeways Res Lab, Dept Oncol, Cambridge, England. [Pharoah, Paul] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge, England. [Ramus, Susan J.] Univ New South Wales, Sch Womens & Childrens Hlth, New South Wales, Australia. [Ramus, Susan J.] New South Wales, Garvan Inst Med Res, Kinghorn Canc Ctr, New South Wales, Australia. [Rossing, Mary Anne] Div Publ Hlth Sci, Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA USA. [Rossing, Mary Anne] Univ Washington, Dept Epidemiol, Seattle, WA USA. [Schildkraut, Joellen M.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Schmalfeldt, Barbara] Univ Med Ctr Hamburg Eppendorf, Dept Gynecol, Hamburg, Germany. [Schwaab, Ira] Praxis Humangenet, Wiesbaden, Germany. [Siddiqui, Nadeem] Glasgow Royal Infirm, Dept Gynaecol Oncol, Glasgow, Lanark, Scotland. [Sieh, Weiva] Icahn Sch Med, Dept Populat Hlth Sci & Policy, New York, NY USA. [Sieh, Weiva] Icahn Sch Med, Dept Genet & Genom Sci, New York, NY USA. [Sobiczewski, Piotr] Maria Sklodowska Curie Mem Canc Ctr, Inst Oncol, Dept Gynecol Oncol, Warsaw, Poland. [Van Nieuwenhuysen, Els; Vanderstichele, Adriaan; Vergote, Ignace] Univ Hosp Leuven, Dept Obstet & Gynaecol & Leuven Canc Inst, Div Gynecol Oncol, Leuven, Belgium. [Webb, Penelope M.] QIMR Berghofer Med Res Inst tute, Populat Hlth Dept, Herston, Qld, Australia. [Wentzensen, Nicolas] Div Canc Epidemiol & Genet, NCI, Bethesda, MD USA. [Ziogas, Argyrios] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Goode, Ellen L.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. RP Moysich, KB (reprint author), Roswell Pk Canc Inst, Dept Canc Prevent & Control, Elm & Carlton St, Buffalo, NY 14203 USA. EM kirsten.moysich@roswellpark.org RI Dork, Thilo/J-8620-2012 FU Ovarian Cancer Research Fund; RPCI's Cancer Center Support grant from NCI [P30CA016056]; NCI Ovarian SPORE grant [P50CA159981]; Roswell Park Alliance Foundation; Roswell Park Cancer Institute Ovarian Spore [1P50CA159981-01A1]; Interdisciplinary Training Grant in Cancer Epidemiology [R25CA113951]; U.S. Army Medical Research and Materiel Command [DAMD17-01-1-0729]; National Health & Medical Research Council of Australia [199600, 400281]; Cancer Councils of New South Wales, Victoria, Queensland, South Australia; Tasmania and Cancer Foundation of Western Australia [191, 211, 182]; ELAN Funds of the University of Erlangen-Nuremberg; Nationaal Kankerplan; NIH [R01-CA112523, R01-CA87538, R01-CA58598, N01-CN-55424, N01-PC67001, R01-CA122443, P30-CA15083, P50-CA136393, R01-CA76016, R01-CA54419, P50-CA105009, R01-CA058860]; German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research [01 GB 9401]; German Cancer Research Center (DKFZ); DOD [DAMD17-02-1-0669]; NCI [K07-CA080668, R01-CA95023, P50-CA159981, R01CA61107, NIH-K07 CA095666, NIH-K22-CA138563, P30-CA072720]; NIH/National Center for Research Resources/General Clinical Research Center [MO1-RR000056, R01-CA126841]; American Cancer Society [SIOP-06-258-01-COUN]; National Center for Advancing Translational Sciences (NCATS) [UL1TR000124]; Danish Cancer Society, Copenhagen, Denmark [94 222 52]; Mermaid I project; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; Department of Defense [DAMD17-02-1-0666, W81XWH-10-1-02802]; Cancer Institute of New Jersey; Helse Vest; Norwegian Cancer Society; Research Council of Norway; OHSU Foundation; Pomeranian Medical University; Intramural Research Program of the NCI; Herlev Hospitals Forskningsrad; Direktor Jacob Madsens og Hustru Olga Madsens fond; Arvid Nilssons fond; Gangsted fonden; Danish Cancer Society; Cancer Research UK; Royal Marsden Hospital; Cancer Research UK [C490/A10119, C490/A10124, C536/A13086, C536/A6689, C490/A6187]; UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; Imperial Experimental Cancer Research Centre [C1312/A15589]; Lon V Smith Foundation [LVS-39420]; Eve Appeal (The Oak Foundation); National Institute for Health Research University College London Hospitals Biomedical Research Centre; California Cancer Research Program [00-01389V-20170, 2II0200]; National Science Centren The Maria Sklodowska-Curie Memorial Cancer Center [N N301 5645 40]; Institute of Oncology, Warsaw, Poland; [NIH/NCIR01CA095023]; [NIH/NCIR01CA126841]; [R01CA140622]; [R01CA188900]; [5T32CA108456]; [P01CA17054]; [P30CA14089]; [R01CA61132]; [N01PC67010]; [R03CA113148]; [R03CA115195]; [N01CN025403] FX The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund.; This study used shared resources supported by RPCI's Cancer Center Support grant from the NCI (P30CA016056) and was also supported by the NCI Ovarian SPORE grant P50CA159981 and Roswell Park Alliance Foundation.; L.E. Sucheston-Campbell is supported by P50CA159981 and Roswell Park Alliance Foundation.; K.B. Moysich is supported by P50CA159981 and Roswell Park Alliance Foundation, NIH/NCIR01CA095023, and NIH/NCIR01CA126841.; S.I. Abrams was supported by R01CA140622.; B.H. Segal was supported by R01CA188900.; P.K. Wallace and this work was supported by Roswell Park Cancer Institute Ovarian Spore (1P50CA159981-01A1).; J.B. Szender was supported by 5T32CA108456.; Albina Minlikeeva was supported by Interdisciplinary Training Grant in Cancer Epidemiology (R25CA113951).; AUS (G. Chenevix-Trench and P.M. Webb): U.S. Army Medical Research and Materiel Command (DAMD17-01-1-0729), National Health & Medical Research Council of Australia (199600 and 400281), Cancer Councils of New South Wales, Victoria, Queensland, South Australia, and Tasmania and Cancer Foundation of Western Australia (under Multi-State Applications 191, 211, and 182).; BAV (P.A. Fasching): ELAN Funds of the University of Erlangen-Nuremberg. BEL (D. Lambrechts): Nationaal Kankerplan.; DOV (M.A. Rossing): NIH (R01-CA112523 and R01-CA87538).; GER (J. Chang-Claude): German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research (01 GB 9401), and the German Cancer Research Center (DKFZ).; HAW (M. Goodman): NIH (R01-CA58598, N01-CN-55424, and N01-PC67001).; HOP (F. Modugno, K. Moysich, and R. Ness): DOD (DAMD17-02-1-0669) and NCI (K07-CA080668, R01-CA95023, and P50-CA159981); NIH/National Center for Research Resources/General Clinical Research Center grant MO1-RR000056; R01-CA126841.; LAX (B.Y. Karlan): American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), grant UL1TR000124.; MAL (S.K. KjAEr): Funding for this study was provided by research grant R01CA61107 from the NCI, research grant 94 222 52 from the Danish Cancer Society, Copenhagen, Denmark, and the Mermaid I project.; MAY (E.L. Goode): NIH (R01-CA122443, P30-CA15083, and P50-CA136393), Mayo Foundation, Minnesota Ovarian Cancer Alliance, and Fred C. and Katherine B. Andersen Foundation.; NCO (J. Schildkraut and A. Berchuck): NIH (R01-CA76016) and the Department of Defense (DAMD17-02-1-0666).; NEC (D. Cramer and K. Terry): NIH (R01-CA54419 and P50-CA105009) and Department of Defense (W81XWH-10-1-02802).; NJO (E.V. Bandera): NCI (NIH-K07 CA095666, NIH-K22-CA138563, and P30-CA072720) and the Cancer Institute of New Jersey.; NOR (L. Bjorge): Helse Vest, The Norwegian Cancer Society, and The Research Council of Norway.; ORE (T. Pejovic): OHSU Foundation.; POC (J. Gronwald): Pomeranian Medical University.; POL (N. Wentzensen): Intramural Research Program of the NCI.; PVD (E. Hogdall and C. Hogdall): Herlev Hospitals Forskningsrad, Direktor Jacob Madsens og Hustru Olga Madsens fond, Arvid Nilssons fond, Gangsted fonden, Herlev Hospitals Forskningsrad, and Danish Cancer Society.; RMH (P. Pharoah): Cancer Research UK (no grant number is available) and Royal Marsden Hospital.; SEA (P. Pharoah): Cancer Research UK (C490/A10119 and C490/A10124) and UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge.; SRO (S. Banerjee, J. Paul, N. Siddiqui, R. Glasspool, and I. McNeish): Cancer Research UK (C536/A13086 and C536/A6689) and Imperial Experimental Cancer Research Centre (C1312/A15589).; STA (A.S. Whittemore and W. Sieh): NIH (U01-CA71966, R01-CA16056, K07-CA143047, and U01-CA69417) for recruitment of controls by the Cancer Prevention Institute of California.; UCI (H. Anton-Culver): NIH (R01-CA058860) and the Lon V Smith Foundation grant LVS-39420.; UKO (U Menon, A Gentry-Maharaj, and S. Gayther): 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.; UKR (P. Pharaoh): Cancer Research UK (C490/A6187) and UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge.; USC (C. L. Pearce): P01CA17054, P30CA14089, R01CA61132, N01PC67010, R03CA113148, R03CA115195, N01CN025403, and California Cancer Research Program (00-01389V-20170, 2II0200).; WOC (J. Kupryjanczyk): National Science Centren (N N301 5645 40) The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. NR 7 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2017 VL 26 IS 3 BP 420 EP 424 DI 10.1158/1055-9965.EPI-16-0631 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EN5BI UT WOS:000396020200017 PM 27677730 ER PT J AU DeClerck, YA Pienta, KJ Woodhouse, EC Singer, DS Mohla, S AF DeClerck, Yves A. Pienta, Kenneth J. Woodhouse, Elisa C. Singer, Dinah S. Mohla, Suresh TI The Tumor Microenvironment at a Turning Point Knowledge Gained Over the Last Decade, and Challenges and Opportunities Ahead: A White Paper from the NCI TME Network SO CANCER RESEARCH LA English DT Article ID PROSTATE-CANCER; FIBROBLASTS; CARCINOMAS; MECHANISMS; RESISTANCE; SURVIVAL AB Over the past 10 years, the Tumor Microenvironment Network (TMEN), supported by the NCI (Bethesda, MD), has promoted collaborative research with the explicit goal of fostering multi-institutional and transdisciplinary groups that are capable of addressing complex issues involving the tumor microenvironment. The main goal of the TMEN was to generate novel information about the dynamic complexity of tumor-host interactions in different organ systems with emphasis on using human tissues and supplemented by experimental models. As this initiative comes to a close, members of the TMEN took time to examine what has been accomplished by the Network and importantly to identify the challenges and opportunities ahead. This consensus document summarizes for the broader scientific community discussions that occurred at the two final meetings of the TMEN in 2015 and 2016. (C) 2017 AACR. C1 [DeClerck, Yves A.] Univ Southern Calif, Dept Pediat, Los Angeles, CA USA. [DeClerck, Yves A.] Childrens Hosp Los Angeles, Saban Res Inst, Los Angeles, CA 90027 USA. [DeClerck, Yves A.] Univ Southern Calif, Dept Biochem & Mol Biol, Los Angeles, CA USA. [Pienta, Kenneth J.] Johns Hopkins Univ, Sch Med, Dept Urol, Baltimore, MD 21205 USA. [Pienta, Kenneth J.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Pienta, Kenneth J.] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. [Woodhouse, Elisa C.; Singer, Dinah S.; Mohla, Suresh] NCI, Div Canc Biol, NIH, Bethesda, MD 20892 USA. RP Singer, DS (reprint author), NCI, Div Canc Biol, NIH, Bethesda, MD 20892 USA.; DeClerck, YA (reprint author), Childrens Hosp Los Angeles, 4650 Sunset Blvd,MS 54, Los Angeles, CA 90027 USA. EM declerck@usc.edu; singerd@mail.nih.gov NR 26 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD MAR 1 PY 2017 VL 77 IS 5 BP 1051 EP 1059 DI 10.1158/0008-5472.CAN-16-1336 PG 9 WC Oncology SC Oncology GA EN4XV UT WOS:000396011100001 PM 28209610 ER PT J AU Nikolich-Zugich, J Davies, JS AF Nikolich-Zugich, J. Davies, J. S. TI Homeostatic migration and distribution of innate immune cells in primary and secondary lymphoid organs with ageing SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Review DE ageing; cell trafficking; dendritic cells; immunosenescence; macrophage; natural killer cells; spleen and lymph nodes ID HETEROCHRONIC PARABIOSIS; SPHINGOSINE 1-PHOSPHATE; INFLUENZA INFECTION; COGNITIVE FUNCTION; DENDRITIC CELLS; AGE; MICE; REJUVENATION; YOUNG; RESPONSES AB Ageing of the innate and adaptive immune system, collectively termed immune senescence, is a complex process. One method to understand the components of ageing involves dissociating the effects of ageing on the cells of the immune system, on the microenvironment in lymphoid organs and tissues where immune cells reside and on the circulating factors that interact with both immune cells and their microenvironment. Heterochronic parabiosis, a surgical union of two organisms of disparate ages, is ideal for this type of study, as it has the power to dissociate the age of the cell and the age of the microenvironment into which the cell resides or is migrating. So far, however, it has been used sparingly to study immune ageing. Here we review the limited literature on homeostatic innate immune cell trafficking in ageing in the absence of chronic inflammation. We also review our own recent data on trafficking of innate immune subsets between primary and secondary lymphoid organs in heterochronic parabiosis. We found no systemic bias in retention or acceptance of neutrophils, macrophages, dendritic cells or natural killer cellswith ageing in primary and secondary lymphoid organs. We conclude that these four innate immune cell types migrate to and populate lymphoid organs (peripheral lymph nodes, spleen and bone marrow), regardless of their own age and of the age of lymphoid organs. C1 Univ Arizona, Coll Med, Dept Immunobiol, Tucson, AZ USA. Univ Arizona, Coll Med, Arizona Ctr Aging, Tucson, AZ USA. [Davies, J. S.] NCI, Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Nikolich-Zugich, J (reprint author), 1501 N Campbell Ave, Tucson, AZ 85724 USA. EM nikolich@email.arizona.edu; john.davies@nih.gov FU NIAID from the National Institutes of health. [N01-AI-000017] FX The authors wish to acknowledge Dr Vesna Pulko for help with the experiments, Drs Karuna Patil, Trenton Bryfogle and Paula Johnson from the UA Central Animal Services for helps with establishing the parabiosis model and the members of the Nikolich laboratory for helpful discussion. All animal studies were approved by the University of Arizona Animal Care and Use Committee. This study was supported by the NIAID contract N01-AI-000017 from the National Institutes of health. NR 46 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9104 EI 1365-2249 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD MAR PY 2017 VL 187 IS 3 BP 337 EP 344 DI 10.1111/cei.12920 PG 8 WC Immunology SC Immunology GA EK5OX UT WOS:000393976800002 PM 28035684 ER PT J AU George, J Saito, M Tsuta, K Iwakawa, R Shiraishi, K Scheel, AH Uchida, S Watanabe, S Nishikawa, R Noguchi, M Peifer, M Jang, SJ Petersen, I Buttner, R Harris, CC Yokota, J Thomas, RK Kohno, T AF George, Julie Saito, Motonobu Tsuta, Koji Iwakawa, Reika Shiraishi, Kouya Scheel, Andreas H. Uchida, Shinsuke Watanabe, Shun-ichi Nishikawa, Ryo Noguchi, Masayuki Peifer, Martin Jang, Se Jin Petersen, Iver Buettner, Reinhard Harris, Curtis C. Yokota, Jun Thomas, Roman K. Kohno, Takashi TI Genomic Amplification of CD274 (PD-L1) in Small-Cell Lung Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID EXPRESSION; BLOCKADE; CARCINOMA; GENE; IDENTIFICATION; NIVOLUMAB; SURVIVAL; ANTIBODY; SAFETY AB Purpose: Programmed death ligand-1 (PD-L1), encoded by the CD274 gene, is a target for immune checkpoint blockade; however, little is known about genomic CD274 alterations. A subset of small-cell lung cancer (SCLC) exhibits increased copy number of chromosome 9p24, on which CD274 resides; however, most SCLCs show low expression of PD-L1. We therefore examined whether CD274 is a target of recurrent genomic alterations. Experimental Design: We examined somatic copy number alterations in two patient cohorts by quantitative real-time PCR in 72 human SCLC cases (cohort 1) and SNP array analysis in 138 human SCLC cases (cohort 2). Whole-genome sequencing revealed the detailed genomic structure underlying focal amplification. PD-L1 expression in amplified cases from cohorts 1 and 2 was further examined by transcriptome sequencing and immunohistochemical (IHC) staining. Results: By examining somatic copy number alterations in two cohorts of primary human SCLC specimens, we observed 9p24 copy number gains (where CD274 resides) and focal, highlevel amplification of CD274. We found evidence for genomic targeting of CD274, suggesting selection during oncogenic transformation. CD274 amplification was caused by genomic rearrangements not affecting the open reading frame, thus leading to massively increased CD274 transcripts and high level expression of PD-L1. Conclusions: A subset (4/210, 1.9%) of human SCLC patient cases exhibits massive expression of PD-L1 caused by focal amplification of CD274. Such tumors may be particularly susceptible to immune checkpoint blockade. (C)2016 AACR. C1 [George, Julie; Thomas, Roman K.] Univ Cologne, Fac Med, Dept Translat Genom, Ctr Integrated Oncol Cologne Bonn, Cologne, Germany. [Saito, Motonobu; Iwakawa, Reika; Shiraishi, Kouya; Yokota, Jun; Kohno, Takashi] Natl Canc Ctr, Div Genome Biol, Res Inst, Tokyo, Japan. [Saito, Motonobu] Fukushima Med Univ, Dept Organ Regulatory Surg, Sch Med, Fukushima, Japan. [Tsuta, Koji; Uchida, Shinsuke] Natl Canc Ctr, Div Pathol & Clin Labs, Tokyo, Japan. [Scheel, Andreas H.; Buettner, Reinhard; Thomas, Roman K.] Univ Hosp Cologne, Inst Pathol, Cologne, Germany. [Watanabe, Shun-ichi] Natl Canc Ctr, Div Thorac Surg, Tokyo, Japan. [Nishikawa, Ryo] Saitama Med Univ, Dept Neurooncol Neurosurg, Int Med Ctr, Saitama, Japan. [Noguchi, Masayuki] Univ Tsukuba, Dept Pathol, Fac Med, Ibaraki, Japan. [Peifer, Martin] Univ Cologne, Ctr Mol Med Cologne, Cologne, Germany. [Jang, Se Jin] Asan Med Ctr, Asan Inst Life Sci, Ctr Canc Genome Discovery, Seoul, South Korea. [Petersen, Iver] Friedrich Schiller Univ, Jena Univ Hosp, Inst Pathol, Jena, Germany. [Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. [Yokota, Jun] Inst Predict & Personalized Med Canc, Canc Genome Biol Grp, Barcelona, Spain. [Thomas, Roman K.] German Canc Consortium DKTK, German Canc Res Ctr, Heidelberg, Germany. [Kohno, Takashi] Natl Canc Ctr, Div Translat Res Exploratory Oncol Res, Tokyo, Japan. [Kohno, Takashi] Natl Canc Ctr, Clin Trial Ctr, Tokyo, Japan. RP Kohno, T (reprint author), Natl Canc Ctr, Res Inst, Chuo Ku, 1-1 Tsukiji 5 Chome, Tokyo 1040045, Japan.; Thomas, RK (reprint author), Univ Cologne, D-50931 Cologne, Germany. EM roman.thomas@uni-koeln.de; tkkohno@ncc.go.jp FU Japan Agency for Medical Research and Development [AMED: 16ck0106012h0003]; Japanese Society for the Promotion of Science (JSPS) and Scientific Research [26293200]; National Cancer Center Research and Development Fund [26A-1]; National Cancer Institute, NIH; German Cancer Aid (Deutsche Krebshilfe) as part of the small-cell lung cancer genome sequencing consortium [109679]; German Ministry of Science and Education (BMBF) as part of the e:Med program [01ZX1303A]; Deutsche Forschungsgemeinschaft (DFG) [TH1386/3-1]; Deutsche Krebshilfe as part of the Oncology Centers of Excellence funding program; German Cancer Consortium (DKTK) Joint Funding program FX This work was supported by Grants-in-Aid from the Japan Agency for Medical Research and Development (AMED: 16ck0106012h0003) and a Grant-in-Aid from the Japanese Society for the Promotion of Science (JSPS) and Scientific Research (B: 26293200). NCC Biobank was supported by the National Cancer Center Research and Development Fund (26A-1). C C Harris was supported by intermural funding from the National Cancer Institute, NIH. This work was also supported by the German Cancer Aid (Deutsche Krebshilfe) as part of the small-cell lung cancer genome sequencing consortium (grant ID: 109679; to R.K. Thomas, R. Buttner, and M. Peifer), by the German Ministry of Science and Education (BMBF) as part of the e:Med program (grant no. 01ZX1303A; to R.K. Thomas, R. Buttner, and M. Peifer), by the Deutsche Forschungsgemeinschaft (DFG; through TH1386/3-1 to R.K. Thomas), by the Deutsche Krebshilfe as part of the Oncology Centers of Excellence funding program (to R. K. Thomas) and by the German Cancer Consortium (DKTK) Joint Funding program. NR 36 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 1 PY 2017 VL 23 IS 5 BP 1220 EP 1226 DI 10.1158/1078-0432.CCR-16-1069 PG 7 WC Oncology SC Oncology GA EN4ZO UT WOS:000396015600013 PM 27620277 ER PT J AU Xie, C Jiang, CT Shi, JM Gan, XX Sun, DX Sun, LL Wang, T Takahashi, S Anitha, M Krausz, KW Patterson, AD Gonzalez, FJ AF Xie, Cen Jiang, Changtao Shi, Jingmin Gan, Xiaoxia Sun, Dongxue Sun, Lulu Wang, Ting Takahashi, Shogo Anitha, Mallappa Krausz, Kristopher W. Patterson, Andrew D. Gonzalez, Frank J. TI An Intestinal Farnesoid X Receptor-Ceramide Signaling Axis Modulates Hepatic Gluconeogenesis in Mice SO DIABETES LA English DT Article ID ACID PHENETHYL ESTER; INSULIN-RESISTANCE; OBESITY; DYSFUNCTION; METABOLISM; ACTIVATION; LIVER; LEADS; STEATOHEPATITIS; INFLAMMATION AB Increasing evidence supports the view that intestinal farnesoid X receptor (FXR) is involved in glucose tolerance and that FXR signaling can be profoundly impacted by the gut microbiota. Selective manipulation of the gut microbiota-FXR signaling axis was reported to significantly impact glucose intolerance, but the precise molecular mechanism remains largely unknown. Here, caffeic acid phenethyl ester (CAPE), an over-the-counter dietary supplement and an inhibitor of bacterial bile salt hydrolase, increased levels of intestinal tauro-beta-muricholic acid, which selectively suppresses intestinal FXR signaling. Intestinal FXR inhibition decreased ceramide levels by suppressing expression of genes involved in ceramide synthesis specifically in the intestinal ileum epithelial cells. The lower serum ceramides mediated decreased hepatic mitochondrial acetyl-CoA levels and pyruvate carboxylase (PC) activities and attenuated hepatic gluconeogenesis, independent of body weight change and hepatic insulin signaling in vivo; this was reversed by treatment of mice with ceramides or the FXR agonist GW4064. Ceramides substantially attenuated mitochondria! citrate synthase activities primarily through the induction of endoplasmic reticulum stress, which triggers increased hepatic mitochondrial acetyl-CoA levels and PC activities. These results reveal a mechanism by which the dietary supplement CAPE and intestinal FXR regulates hepatic gluconeogenesis and suggest that inhibiting intestinal FXR is a strategy for treating hyperglycemia. C1 [Xie, Cen; Shi, Jingmin; Gan, Xiaoxia; Sun, Dongxue; Takahashi, Shogo; Krausz, Kristopher W.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Jiang, Changtao; Sun, Lulu; Wang, Ting] Peking Univ, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Beijing, Peoples R China. [Jiang, Changtao; Sun, Lulu; Wang, Ting] Minist Educ, Key Lab Mol Cardiovasc Sci, Beijing, Peoples R China. [Anitha, Mallappa; Patterson, Andrew D.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.; Jiang, CT (reprint author), Peking Univ, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Beijing, Peoples R China.; Jiang, CT (reprint author), Minist Educ, Key Lab Mol Cardiovasc Sci, Beijing, Peoples R China. EM jiangchangtao@bjmu.edu.cn; gonzalef@mail.nih.gov FU Intramural Research Program, Center for Cancer Research, National Cancer Institute [ZIA BC005562 28]; National Institutes of Health; National Institutes of Environmental Health Sciences [ES022186]; National Key Research and Development Program of China [2016YFC0903100, 2016YFC09031002]; National Natural Science Foundation of China [81403007, 81522007] FX This work was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute (ZIA BC005562 28), National Institutes of Health; the National Institutes of Environmental Health Sciences (ES022186 to A.D.P.); the National Key Research and Development Program of China (2016YFC0903100 and 2016YFC09031002); and the National Natural Science Foundation of China (81403007 and 81522007). NR 37 TC 1 Z9 1 U1 6 U2 6 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 2017 VL 66 IS 3 BP 613 EP 626 DI 10.2337/db16-0663 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EL5AP UT WOS:000394634100008 PM 28223344 ER PT J AU Hummel, S Beyerlein, A Tamura, R Uusitalo, U Aronsson, CA Yang, JM Riikonen, A Lernmark, A Rewers, MJ Hagopian, WA She, JX Simell, OG Toppari, J Ziegler, AG Akolkar, B Krischer, JP Virtanen, SM Norris, JM AF Hummel, Sandra Beyerlein, Andreas Tamura, Roy Uusitalo, Ulla Aronsson, Carin Andren Yang, Jimin Riikonen, Anne Lernmark, Ake Rewers, Marian J. Hagopian, William A. She, Jin-Xiong Simell, Olli G. Toppari, Jorma Ziegler, Anette-G. Akolkar, Beena Krischer, Jeffrey P. Virtanen, Suvi M. Norris, Jill M. CA TEDDY Study Grp TI First Infant Formula Type and Risk of Islet Autoimmunity in The Environmental Determinants of Diabetes in the Young (TEDDY) Study SO DIABETES CARE LA English DT Article ID KIDNEY-DISEASE; NEPHROPATHY; PROGRESSION; PREDICTION; PROTEIN; ESRD AB OBJECTIVE Studies on the introduction of infant formulas and its effect on the risk of islet autoimmunity and type 1 diabetes (T1D) have yielded inconsistent results. We investigated whether the introduction of formula based on hydrolyzed cow'smilk as the first formula is associated with reduced islet autoimmunity risk in a large prospective cohort. RESEARCH DESIGN AND METHODS The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively monitors 8,676 children at increased genetic risk for T1D. Autoantibodies to insulin, GAD65, and IA2 were measured regularly to define islet autoimmunity. Information on formula feeding was collected by questionnaires at 3 months of age. RESULTS In survival analyses, after adjustment for family history with T1D, HLA genotype, sex, country, delivery mode, breast-feeding >= 3 months, and seasonality of birth, we observed no significant association with islet autoimmunity in infants who received extensively hydrolyzed compared with nonhydrolyzed cow'smilk-based formula as the first formula during the first 3 months (adjusted hazard ratio 1.38 [95% CI 0.95; 2.01]), and a significantly increased risk for extensively hydrolyzed formula introduced during the first 7 days (adjusted hazard ratio 1.57 [1.04; 2.38]). Using a partially hydrolyzed or other formula as the first formula, or no formula, was not associated with islet autoimmunity risk. CONCLUSIONS These results add to the existing evidence that islet autoimmunity risk is not reduced, and may be increased, by using hydrolyzed compared with nonhydrolyzed cow's milk-based infant formula as the first formula in infants at increased genetic risk for T1D. C1 [Hummel, Sandra; Beyerlein, Andreas; Ziegler, Anette-G.] Helmholtz Zentrum Munchen, Diabet Res Inst, Munich, Germany. [Hummel, Sandra; Beyerlein, Andreas; Ziegler, Anette-G.] Tech Univ Munich, Klinikum Rechts Isar, Forsch Grp Diabet eV, Forsch Grp Diabet, Neuherberg, Germany. [Tamura, Roy; Uusitalo, Ulla; Yang, Jimin; Krischer, Jeffrey P.] Univ S Florida, Morsani Coll Med, Hlth Informat Inst, Tampa, FL USA. [Aronsson, Carin Andren; Lernmark, Ake] Lund Univ, Clin Res Ctr, SUS, Dept Clin Sci, Malmo, Sweden. [Riikonen, Anne; Virtanen, Suvi M.] Natl Inst Hlth & Welf, Unit Nutr, Helsinki, Finland. [Riikonen, Anne; Virtanen, Suvi M.] Univ Tampere, Fac Social Sci, Tampere, Finland. [Rewers, Marian J.] Univ Colorado, Barbara Davis Ctr Childhood Diabet, Anschutz Med Campus, Aurora, CO USA. [Hagopian, William A.] Pacific Northwest Diabet Res Inst, Seattle, WA USA. [She, Jin-Xiong] Augusta Univ, Med Coll Georgia, Ctr Biotechnol & Genom Med, Augusta, GA USA. [Simell, Olli G.; Toppari, Jorma] Turku Univ Hosp, Dept Pediat, Turku, Finland. [Toppari, Jorma] Univ Turku, Inst Biomed, Dept Physiol, Turku, Finland. [Akolkar, Beena] NIDDK, Bethesda, MD 20892 USA. [Virtanen, Suvi M.] Univ Tampere, Ctr Child Hlth Res, Tampere, Finland. [Virtanen, Suvi M.] Tampere Univ Hosp, Tampere, Finland. [Virtanen, Suvi M.] Pirkanmaa Hosp Dist, Ctr Sci, Tampere, Finland. [Norris, Jill M.] Univ Colorado, Colorado Sch Publ Hlth, Dept Epidemiol, Anschutz Med Campus, Aurora, CO USA. RP Hummel, S (reprint author), Helmholtz Zentrum Munchen, Diabet Res Inst, Munich, Germany.; Hummel, S (reprint author), Tech Univ Munich, Klinikum Rechts Isar, Forsch Grp Diabet eV, Forsch Grp Diabet, Neuherberg, Germany. EM sandra.hummel@lrz.uni-muenchen.de FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences; JDRF; Centers for Disease Control and Prevention [U01-DK-63829, U01-DK-63861, U01-DK-63821, U01-DK-63865, U01-DK-63863, U01-DK-63836, U01-DK-63790, UC4-DK-63829, UC4-DK-63861, UC4-DK-63821, UC4-DK-63865, UC4-DK-63863, UC4 DK- 63836, UC4-DK-95300, UC4-DK-100238, HHSN267200700014C]; National Institutes of Health/National Center for Advancing Translational Sciences Clinical and Translational Science [UL1-TR-000064]; University of Colorado [UL1-TR-001082] FX This study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, National Institute of Environmental Health Sciences, JDRF, and Centers for Disease Control and Prevention grants U01-DK-63829, U01-DK-63861, U01-DK-63821, U01-DK-63865, U01-DK-63863, U01-DK-63836, U01-DK-63790, UC4-DK-63829, UC4-DK-63861, UC4-DK-63821, UC4-DK-63865, UC4-DK-63863, UC4 DK- 63836, UC4-DK-95300, and UC4-DK-100238, and Contract No. HHSN267200700014C. This work was partly supported by the National Institutes of Health/National Center for Advancing Translational Sciences Clinical and Translational Science Awards to the University of Florida (UL1-TR-000064) and the University of Colorado (UL1-TR-001082). NR 25 TC 0 Z9 0 U1 0 U2 0 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 2017 VL 40 IS 3 BP 398 EP 404 DI 10.2337/dc16-1624 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EM7UZ UT WOS:000395519100021 PM 28096222 ER PT J AU Armstrong, AC Ambale-Venkatesh, B Turkbey, E Donekal, S Chamera, E Backlund, JY Cleary, P Lachin, J Bluemke, DA Lima, JAC AF Armstrong, Anderson C. Ambale-Venkatesh, Bharath Turkbey, Evrim Donekal, Sirisha Chamera, Elzbieta Backlund, Jye-Yu Cleary, Patricia Lachin, John Bluemke, David A. Lima, Joao A. C. CA DCCT EDIC Res Grp TI Association of Cardiovascular Risk Factors and Myocardial Fibrosis With Early Cardiac Dysfunction in Type 1 Diabetes: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study SO DIABETES CARE LA English DT Article ID YOUNG-ADULTS CARDIA; HEART-FAILURE; MAGNETIC-RESONANCE; GLYCEMIC CONTROL; DIASTOLIC FUNCTION; FOLLOW-UP; CARDIOMYOPATHY; EVENTS; ATHEROSCLEROSIS; DISEASE AB OBJECTIVE We investigated the association of cardiovascular risk factors and myocardial fibrosis with early cardiac dysfunction in type 1 diabetes. RESEARCH DESIGN AND METHODS Participants with type 1 diabetes aged 13-39 years without a known history of cardiovascular disease (CVD) (n = 1,441) were recruited into the Diabetes Control and Complications Trial (1983-1993) and subsequently followed in the Epidemiology of Diabetes Interventions and Complications study (1994 to present). Seven hundred fourteen participants underwent cardiac magnetic resonance (CMR) imaging (2007-2009) with late gadolinium enhancement sequences to assess ischemic and nonischemic scars and tagging sequences to evaluate circumferential strain. CMRderived T1 mapping also was used to assess interstitial fibrosis. The influence of cardiovascular risk factors and myocardial scar on circumferential strain was assessed using linear regression. RESULTS Circumferential dysfunction was consistently associated with older age, male sex, smoking history, obesity, higher blood pressure, lower HDL cholesterol, and higher mean HbA1c. Participants with nonischemic scars (n = 16) had the worst circumferential function compared with those without scars (beta +/- SE 1.32 +/- 0.60; P = 0.03). In sex-adjusted models, the correlation between T1 times and circumferential strain was not significant. In the fully adjusted models, a trend toward circumferential dysfunction in participants with nonischemic scars was found. Left ventricular ejection fraction was not associated with risk factors but was significantly lower if a myocardial scar was present. CONCLUSIONS Traditional CVD risk factors and elevated HbA1c levels aremajor factors related to early cardiac dysfunction in type 1 diabetes. Nonischemic myocardial scar, possibly as a marker of chronic exposure to known risk factors, may predict early cardiac dysfunction mediated by diffuse myocardial fibrosis as seen in diabetic cardiomyopathy. C1 [Armstrong, Anderson C.; Ambale-Venkatesh, Bharath; Turkbey, Evrim; Donekal, Sirisha; Chamera, Elzbieta; Lima, Joao A. C.] Johns Hopkins Univ, Baltimore, MD 21218 USA. [Armstrong, Anderson C.] Univ Fed Vale Sao Francisco, Petrolina, Pernambuco, Brazil. [Turkbey, Evrim; Bluemke, David A.] NIH, Dept Radiol, Bldg 10, Bethesda, MD 20892 USA. [Backlund, Jye-Yu; Cleary, Patricia; Lachin, John] George Washington Univ, Washington, DC USA. RP Armstrong, AC; Lima, JAC (reprint author), Johns Hopkins Univ, Baltimore, MD 21218 USA. EM aarmst10@jhmi.edu; jlima@jhmi.edu FU Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases [U01-DK-094176, U01-DK-094157]; National Eye Institute; National Institute of Neurological Disorders and Stroke; General Clinical Research Centers Program; Clinical Translational Science Center Program, Bethesda, MD; Universidade Federal do Vale do Sao Francisco; Johns Hopkins University FX This work was supported by cooperative agreement grants (1982-1993, 2012-2017) and contracts (1982-2012) with the Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (current grant numbers U01-DK-094176 and U01-DK-094157) and by the National Eye Institute, the National Institute of Neurological Disorders and Stroke, the General Clinical Research Centers Program (1993-2007), and the Clinical Translational Science Center Program (2006 to present), Bethesda, MD. A.C.A. was funded by Universidade Federal do Vale do Sao Francisco and by Johns Hopkins University. NR 35 TC 1 Z9 1 U1 1 U2 1 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 2017 VL 40 IS 3 BP 405 EP 411 DI 10.2337/dc16-1889 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EM7UZ UT WOS:000395519100022 PM 27986796 ER PT J AU Solomon, SD Chew, E Duh, EJ Sobrin, L Sun, JK VanderBeek, BL Wykoff, CC Gardner, TW AF Solomon, Sharon D. Chew, Emily Duh, Elia J. Sobrin, Lucia Sun, Jennifer K. VanderBeek, Brian L. Wykoff, Charles C. Gardner, Thomas W. TI Diabetic Retinopathy: A Position Statement by the American Diabetes Association SO DIABETES CARE LA English DT Article ID MACULAR EDEMA; COST-EFFECTIVENESS; RANIBIZUMAB; PROGRESSION; RISK; PREVALENCE; DIAGNOSIS; LASER; AGE; MANAGEMENT C1 [Solomon, Sharon D.; Duh, Elia J.] Johns Hopkins Med, Wilmer Eye Inst, Baltimore, MD USA. [Chew, Emily] NEI, NIH, Bethesda, MD 20892 USA. [Sobrin, Lucia] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Sun, Jennifer K.] Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02215 USA. [VanderBeek, Brian L.] Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Wykoff, Charles C.] Retina Consultants Houston, Houston, TX USA. [Gardner, Thomas W.] Univ Michigan, Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. RP Gardner, TW (reprint author), Univ Michigan, Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. EM tomwgard@umich.edu OI VanderBeek, Brian L./0000-0003-4953-118X FU Katharine M. Graham Professorship at Wilmer Eye Institute, Johns Hopkins School of Medicine; Genentech; Optovue; Boston Micromachines; Adaptive Sensory Technology; Optos; KalVista; Roche; Allergan; Bayer; Eisai; Eleven Biotherapeutics; Kowa; Merck; Novartis; Regeneron Pharmaceuticals; National Institutes of Health [1K23EY025729-01]; Research to Prevent Blindness; Paul MacKall & Evanina MacKall Foundation Trust; Apellis Pharmaceuticals; Clearside Biomedical; Iconic Therapeutics; Diabetic Retinopathy Clinical Research Network; Ophthotech; ThromboGenics; Tyrogenex FX S.D.S. receives academic support through the Katharine M. Graham Professorship at Wilmer Eye Institute, Johns Hopkins School of Medicine. E.C. is a government employee. L.S. did the work without receiving any financial support from any third party and over the past 36 months has servedas a consultant for Santen and Genentech. J.K.S. performed the work without any financial support from any third party; her relevant financial activities outside the submitted work over the last 36 months include research support from Genentech, Optovue, Boston Micromachines, Adaptive Sensory Technology, Optos, KalVista, and Roche, and she has received fees for consulting or invited talks from Allergan, Bayer, Eisai, Eleven Biotherapeutics, Kowa, Merck, Novartis, and Regeneron Pharmaceuticals. B.L.V. receives financial support from National Institutes of Health K23 Award (1K23EY025729-01). Additional funding was provided by Research to Prevent Blindness and the Paul MacKall & Evanina MacKall Foundation Trust as block grants to the Scheie Eye Institute. C. C. W. is a consultant for Alimera Sciences, Allergan, Alnylam, Bayer, Clearside Biomedical, DORC, Genentech, ONL Therapeutics, Regeneron Pharmaceuticals, Thrombogenics, and Valeant; has minor equity in ONL Therapeutics; receives research support from Allergan, Apellis Pharmaceuticals, Clearside Biomedical, Iconic Therapeutics, Genentech, Regeneron Pharmaceuticals, Diabetic Retinopathy Clinical Research Network, Ophthotech, ThromboGenics, and Tyrogenex; and has been a speaker for Allergan and Regeneron Pharmaceuticals. T. W. G. is a consultant for Novo Nordisk, KalVista, Janssen Research, PureTech Health, Johnson & Johnson, and BetaStem, which have no relationship to this manuscript. No other potential conflicts of interest relevant to this article were reported. NR 49 TC 0 Z9 0 U1 2 U2 2 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 2017 VL 40 IS 3 BP 412 EP 418 DI 10.2337/dc16-2641 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EM7UZ UT WOS:000395519100023 PM 28223445 ER PT J AU Manservisi, F Marquillas, CB Buscaroli, A Huff, J Lauriola, M Mandrioli, D Manservigi, M Panzacchi, S Silbergeld, EK Belpoggi, F AF Manservisi, Fabiana Marquillas, Clara Babot Buscaroli, Annalisa Huff, James Lauriola, Michelina Mandrioli, Daniele Manservigi, Marco Panzacchi, Simona Silbergeld, Ellen K. Belpoggi, Fiorella TI An Integrated Experimental Design for the Assessment of Multiple Toxicological End Points in Rat Bioassays SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID ENDOCRINE-DISRUPTING CHEMICALS; MAMMARY-GLAND DEVELOPMENT; BISPHENOL-A; CARCINOGENESIS BIOASSAYS; RODENT CARCINOGENICITY; GENOTOXIC CHEMICALS; MICRONUCLEUS ASSAY; BOLOGNA INSTITUTE; PREDICTIVE-VALUE; SPRAGUE-DAWLEY AB Background: For nearly five decades long-term studies in rodents have been the accepted benchmark for assessing chronic long-termtoxic effects, particularly carcinogenicity, of chemicals. The European Food Safety Authority (EFSA) and the World Health Organization (WHO) have pointed out that the current set of internationally utilized test methods capture only some of the potential adverse effects associated with exposures to these agents over the lifetime. Objectives: In this paper, we propose the adaption of the carcinogenicity bioassay to integrate additional protocols for comprehensive long-term toxicity assessment that includes developmental exposures and long-term outcomes, capable of generating information on a broad spectrum of different end points. Discussion: An integrated study design based on a stepwise process is described that includes the priority end points of the Economic Co-operation and Development and the National Toxicology Program guidelines on carcinogenicity and chronic toxicity and developmental and reproductive toxicity. Integrating a comprehensive set of relevant toxicological end points in a single protocol represents an opportunity to optimize animal use in accordance with the 3Rs (replacement, reduction and refinement). This strategy has the potential to provide sufficient data on multiple windows of susceptibility of specific interest for risk assessments and public health decision-making by including prenatal, lactational, neonatal exposures and evaluating outcomes over the lifespan. Conclusion: This integrated study design is efficient in that the same generational cohort of rats used for evaluating long-term outcomes can be monitored in satellite parallel experiments to measure biomarkers and other parameters related to system-specific responses including metabolic alterations and endocrine disturbances. Citation: Manservisi F, Babot Marquillas C, Buscaroli A, Huff J, Lauriola M, Mandrioli D, Manservigi M, Panzacchi S, Silbergeld EK, Belpoggi F. 2017. An integrated experimental design for the assessment of multiple toxicological end points in rat bioassays. Environ Health Perspect 125:289-295; http://dx.doi.org/10.1289/EHP419 C1 [Manservisi, Fabiana; Buscaroli, Annalisa; Lauriola, Michelina; Mandrioli, Daniele; Manservigi, Marco; Panzacchi, Simona; Belpoggi, Fiorella] Ramazzini Inst, Cesare Maltoni Canc Res Ctr, Via Saliceto 3, I-40010 Bologna, Italy. [Marquillas, Clara Babot; Silbergeld, Ellen K.] Ramazzini Inst, Cesare Maltoni Canc Res Ctr, Leonardo da Vinci Programme, Bologna, Italy. [Huff, James] NIEHS, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. [Mandrioli, Daniele] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Belpoggi, F (reprint author), Ramazzini Inst, Cesare Maltoni Canc Res Ctr, Via Saliceto 3, I-40010 Bologna, Italy. EM belpoggif@ramazzini.it NR 73 TC 0 Z9 0 U1 2 U2 2 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 2017 VL 125 IS 3 BP 289 EP 295 DI 10.1289/EHP419 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA EN0QL UT WOS:000395714400008 PM 27448388 ER PT J AU Deziel, NC Freeman, LEB Graubard, BI Jones, RR Hoppin, JA Thomas, K Hines, CJ Blair, A Sandler, DP Chen, HL Lubin, JH Andreotti, G Alavanja, MCR Friesen, MC AF Deziel, Nicole C. Freeman, Laura E. Beane Graubard, Barry I. Jones, Rena R. Hoppin, Jane A. Thomas, Kent Hines, Cynthia J. Blair, Aaron Sandler, Dale P. Chen, Honglei Lubin, Jay H. Andreotti, Gabriella Alavanja, Michael C. R. Friesen, Melissa C. TI Relative Contributions of Agricultural Drift, Para-Occupational, and Residential Use Exposure Pathways to House Dust Pesticide Concentrations: Meta-Regression of Published Data SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review ID CHILDRENS EXPOSURE; CARPET DUST; HOME; CONTAMINATION; PROXIMITY; COMMUNITY; FAMILIES; FARM; IOWA; VARIABILITY AB Background: Increased pesticide concentrations in house dust in agricultural areas have been attributed to several exposure pathways, including agricultural drift, para-occupational, and residential use. Objective: To guide future exposure assessment efforts, we quantified relative contributions of these pathways using meta-regression models of published data on dust pesticide concentrations. Methods: From studies in North American agricultural areas published from 1995 to 2015, we abstracted dust pesticide concentrations reported as summary statistics [e.g., geometric means (GM)]. We analyzed these data using mixed-effects meta-regression models that weighted each summary statistic by its inverse variance. Dependent variables were either the log-transformed GM (drift) or the log-transformed ratio of GMs from two groups (para-occupational, residential use). Results: For the drift pathway, predicted GMs decreased sharply and nonlinearly, with GMs 64% lower in homes 250 m versus 23 m from fields (interquartile range of published data) based on 52 statistics from seven studies. For the para-occupational pathway, GMs were 2.3 times higher [95% confidence interval (CI): 1.5, 3.3; 15 statistics, five studies] in homes of farmers who applied pesticides more recently or frequently versus less recently or frequently. For the residential use pathway, GMs were 1.3 (95% CI: 1.1, 1.4) and 1.5 (95% CI: 1.2, 1.9) times higher in treated versus untreated homes, when the probability that a pesticide was used for the pest treatment was 1-19% and >= 20%, respectively (88 statistics, five studies). Conclusion: Our quantification of the relative contributions of pesticide exposure pathways in agricultural populations could improve exposure assessments in epidemiologic studies. The meta-regression models can be updated when additional data become available. Citation: Deziel NC, Beane Freeman LE, Graubard BI, Jones RR, Hoppin JA, Thomas K, Hines CJ, Blair A, Sandler DP, Chen H, Lubin JH, Andreotti G, Alavanja MC, Friesen MC. 2017. Relative contributions of agricultural drift, para-occupational, and residential use exposure pathways to house dust pesticide concentrations: meta-regression of published data. Environ Health Perspect 125:296-305; http://dx.doi.org/10.1289/EHP426 C1 [Deziel, Nicole C.; Freeman, Laura E. Beane; Graubard, Barry I.; Jones, Rena R.; Blair, Aaron; Lubin, Jay H.; Andreotti, Gabriella; Alavanja, Michael C. R.; Friesen, Melissa C.] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Deziel, Nicole C.] Yale Univ, Yale Sch Publ Hlth, Dept Environm Hlth Sci, New Haven, CT USA. [Hoppin, Jane A.] North Carolina State Univ, Ctr Human Hlth & Environm, Dept Biol Sci, Raleigh, NC USA. [Thomas, Kent] US EPA, Natl Exposure Res Lab, Res Triangle Pk, NC 27711 USA. [Hines, Cynthia J.] NIOSH, Div Surveillance Hazard Evaluat & Field Studi, Cincinnati, OH 45226 USA. [Sandler, Dale P.; Chen, Honglei] NIEHS, Epidemiol Branch, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Deziel, NC (reprint author), Yale Sch Publ Hlth, 60 Coll St, New Haven, CT 06510 USA. EM nicole.deziel@yale.edu RI Friesen, Melissa/A-5362-2009; Beane Freeman, Laura/C-4468-2015; OI Beane Freeman, Laura/0000-0003-1294-4124; Chen, Honglei/0000-0003-3446-7779 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics [Z01CP010119]; National Institute of Environmental Health Sciences [Z01-ES049030]; NCI [HHSN261201400231P] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics (Z01CP010119), and the National Institute of Environmental Health Sciences (Z01-ES049030). N.C.D. was supported, in part, through NCI (HHSN261201400231P). The U.S. Environmental Protection Agency through its Office of Research and Development collaborated in the research described here. It has been subjected to agency review and approved for publication. NR 40 TC 0 Z9 0 U1 5 U2 5 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 2017 VL 125 IS 3 BP 296 EP 305 DI 10.1289/EHP426 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA EN0QL UT WOS:000395714400009 PM 27458779 ER PT J AU Harlid, S Adgent, M Jefferson, WN Panduri, V Umbach, DM Xu, ZL Stallings, VA Williams, CJ Rogan, WJ Taylor, JA AF Harlid, Sophia Adgent, Margaret Jefferson, Wendy N. Panduri, Vijayalakshmi Umbach, David M. Xu, Zongli Stallings, Virginia A. Williams, Carmen J. Rogan, Walter J. Taylor, Jack A. TI Soy Formula and Epigenetic Modifications: Analysis of Vaginal Epithelial Cells from Infant Girls in the IFED Study SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID ESTROGENIC ACTIVITY; CANCER PREVENTION; FETAL EPIGENOME; MILK FORMULA; BREAST-MILK; IN-UTERO; GENISTEIN; EXPOSURE; LIFE; TRISTETRAPROLIN AB BACKGROUND: Early-life exposure to estrogenic compounds affects the development of the reproductive system in rodent models and humans. Soy products, which contain phytoestrogens such as genistein, are one source of exposure in infants fed soy formula, and they result in high serum concentrations. OBJECTIVES: Our goal was to determine whether soy exposure is associated with differential DNA methylation in vaginal cells from soy-fed infant girls. METHODS: Using the Illumina HumanMethylation450 BeadChip, we evaluated epigenome-wide DNA methylation in vaginal cells from four soy formula-fed and six cow formula-fed girls from the Infant Feeding and Early Development (IFED) study. Using pyrosequencing we followed up the two most differentially methylated sites in 214 vaginal cell samples serially collected between birth and 9 months of age from 50 girls (28 soy formula-fed and 22 cow formula-fed). With a mouse model, we examined the effect of neonatal exposure to genistein on gene specific mRNA levels in vaginal tissue. RESULTS: The epigenome-wide scan suggested differences in methylation between soy formula-fed and cow formula-fed infants at three CpGs in the gene proline rich 5 like (PRR5L) (p < 10(4)). Pyrosequencing of the two feeding groups found that methylation levels progressively diverged with age, with pointwise differences becoming statistically significant after 126 days. Genistein-exposed mice showed a 50% decrease in vaginal Prr5l mRNA levels compared to controls. CONCLUSIONS: Girls fed soy formula have altered DNA methylation in vaginal cell DNA which may be associated with decreased expression of an estrogen-responsive gene. C1 [Harlid, Sophia; Panduri, Vijayalakshmi; Taylor, Jack A.] NIEHS, Epigenet & Stem Cell Biol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. [Harlid, Sophia; Adgent, Margaret; Xu, Zongli; Rogan, Walter J.; Taylor, Jack A.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Jefferson, Wendy N.; Williams, Carmen J.] NIEHS, Reprod & Dev Biol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Umbach, David M.] NIEHS, Biostat & Computat Biol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Stallings, Virginia A.] Univ Penn, Div Gastroenterol Hepatol & Nutr, Childrens Hosp Philadelphia, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Taylor, JA (reprint author), NIEHS, MD A3-05,111 TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM taylor@niehs.nih.gov FU Intramural Research Program of the NIH/NIEHS; National Center for Research Resources [UL1RR024134]; National Center for Advancing Translational Sciences [UL1TR000003] FX This research was supported by the Intramural Research Program of the NIH/NIEHS. Additional support was provided by the National Center for Research Resources (grant UL1RR024134) and by the National Center for Advancing Translational Sciences (grant UL1TR000003). NR 51 TC 1 Z9 1 U1 1 U2 1 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 2017 VL 125 IS 3 BP 447 EP 452 DI 10.1289/EHP428 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA EN0QL UT WOS:000395714400027 PM 27539829 ER PT J AU Ha, SD Liu, DP Zhu, YY Kim, SS Sherman, S Mendola, P AF Ha, Sandie Liu, Danping Zhu, Yeyi Kim, Sung Soo Sherman, Seth Mendola, Pauline TI Ambient Temperature and Early Delivery of Singleton Pregnancies SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID PRETERM BIRTH; ENVIRONMENTAL EXPOSURES; EXTREME HEAT; RISK; OUTCOMES; MORTALITY; ASSOCIATION; STRESS; CHINA AB BACKGROUND: Extreme temperature is associated with adverse birth outcomes but it is unclear whether it increases early delivery risk. OBJECTIVES: We aimed to determine the association between ambient temperature and early delivery. METHODS: Medical records from 223,375 singleton deliveries from 12 U.S. sites were linked to local ambient temperature. Exposure to hot (> 90th percentile) or cold (< 10th percentile) using site-specific and window-specific temperature distributions were defined for 3-months preconception, 7-week periods during the first two trimesters, 1 week preceding delivery, and whole pregnancy. Poisson regression with generalized estimating equations calculated the relative risk (RR) and 95% confidence interval for early deliveries associated with hot/cold exposures, adjusting for conception month, humidity, site, sex, maternal demographics, parity, insurance, prepregnancy body mass index, pregnancy complications, and smoking or drinking during pregnancy. Acute temperature associations were estimated separately for warm (May-September) and cold season (October-April) in a case-crossover analysis using conditional logistic regression. RESULTS: Compared with mild temperature (10-90th percentile), exposure to hot or cold during weeks 1-7 increased risk for early preterm (< 34 weeks) [RRhot: 1.11 (95% CI: 1.01, 1.21); RRcold: 1.20 (95% CI: 1.11, 1.30)], late preterm (34-36 weeks) [RRcold: 1.09 (95% CI: 1.04, 1.15)], and early term (37-38 weeks) [RRhot: 1.04 (95% CI: 1.02, 1.07); RRcold: 1.03 (95% CI: 1.00, 1.05)] delivery. Findings were similar for hot exposures during weeks 15-21. Examining deliveries at each week from 23 through 38, whole-pregnancy hot exposures increased delivery risk by 6-21% at weeks 34 and 36-38. In the case-crossover analysis, a 5 degrees F increase during the week preceding delivery was associated with 12-16% higher and 4-5% lower early delivery risk during warm and cold season, respectively. CONCLUSIONS: Both acute and chronic ambient temperature extremes may affect early delivery risk. C1 [Ha, Sandie; Zhu, Yeyi; Kim, Sung Soo; Mendola, Pauline] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Rockville, MD USA. [Liu, Danping] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, Rockville, MD USA. [Sherman, Seth] Emmes Corp, Rockville, MD USA. RP Mendola, P (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, 6710B Rockledge Dr,Room 3119,MSC 7004, Bethesda, MD 20892 USA. EM pauline.mendola@nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health; Consortium on Safe Labor [HHSN267200603425C]; Air Quality and Reproductive Health [HHSN27500008]; [HHSN275200800002I] FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; including contract no. HHSN267200603425C (Consortium on Safe Labor), contract no. HHSN275200800002I, and task order no. HHSN27500008 (Air Quality and Reproductive Health). NR 34 TC 0 Z9 0 U1 0 U2 0 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 2017 VL 125 IS 3 BP 453 EP 459 DI 10.1289/EHP97 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA EN0QL UT WOS:000395714400028 PM 27580125 ER PT J AU Diaz, KM Booth, JN Seals, SR Abdalla, M Dubbert, PM Sims, M Ladapo, JA Redmond, N Muntner, P Shimbo, D AF Diaz, Keith M. Booth, John N., III Seals, Samantha R. Abdalla, Marwah Dubbert, Patricia M. Sims, Mario Ladapo, Joseph A. Redmond, Nicole Muntner, Paul Shimbo, Daichi TI Physical Activity and Incident Hypertension in African Americans The Jackson Heart Study SO HYPERTENSION LA English DT Article DE African Americans; blood pressure; exercise; hypertension; physical activity ID BLOOD-PRESSURE; ATHEROSCLEROSIS RISK; METAANALYSIS; MORTALITY; COHORT; ADULTS; ASSOCIATIONS; COMMUNITIES; DISPARITIES; PREVENTION AB There is limited empirical evidence to support the protective effects of physical activity in the prevention of hypertension among African Americans. The purpose of this study was to examine the association of physical activity with incident hypertension among African Americans. We studied 1311 participants without hypertension at baseline enrolled in the Jackson Heart Study, a community-based study of African Americans residing in Jackson, Mississippi. Overall physical activity, moderate-vigorous physical activity, and domain-specific physical activity (work, active living, household, and sport/exercise) were assessed by self-report during the baseline examination (2000-2004). Incident hypertension, assessed at examination 2 (2005-2008) and examination 3 (2009-2013), was defined as the first visit with systolic/diastolic blood pressure >= 140/90 mm Hg or self-reported antihypertensive medication use. Over a median follow-up of 8.0 years, there were 650 (49.6%) incident hypertension cases. The multivariable-adjusted hazard ratios (95% confidence interval) for incident hypertension comparing participants with intermediate and ideal versus poor levels of moderate-vigorous physical activity were 0.84 (0.67-1.05) and 0.76 (0.58-0.99), respectively (P trend = 0.038). A graded, dose-response association was also present for sport/exercise-related physical activity (Quartiles 2, 3, and 4 versus Quartile 1: 0.92 [0.68-1.25], 0.87 [0.67-1.13], 0.75 [0.58-0.97], respectively; P trend = 0.032). There were no statistically significant associations observed for overall physical activity, or work, active living, and household-related physical activities. In conclusion, the results of the current study suggest that regular moderate-vigorous physical activity or sport/exercise-related physical activity may reduce the risk of developing hypertension in African Americans. C1 [Diaz, Keith M.; Abdalla, Marwah; Shimbo, Daichi] Columbia Univ, Dept Med, Med Ctr, New York, NY USA. [Booth, John N., III; Muntner, Paul] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Seals, Samantha R.] Univ Mississippi, Ctr Biostat & Bioinformat, Med Ctr, Jackson, MS 39216 USA. [Sims, Mario] Univ Mississippi, Dept Med, Med Ctr, Jackson, MS 39216 USA. [Dubbert, Patricia M.] South Cent Mental Illness, Res & Clin Ctr, N Little Rock, AR USA. [Dubbert, Patricia M.] Little Rock Geriatr Res Educ & Clin Ctr, Little Rock, AR USA. [Ladapo, Joseph A.] Univ Calif Los Angeles, David Geffen Sch Med, Div Gen Internal Med, Los Angeles, CA 90095 USA. [Ladapo, Joseph A.] Univ Calif Los Angeles, David Geffen Sch Med, Hlth Serv Res, Los Angeles, CA 90095 USA. [Redmond, Nicole] NHLBI, Clin Applicat & Prevent Branch, Bldg 10, Bethesda, MD 20892 USA. RP Diaz, KM (reprint author), Columbia Univ, Med Ctr, 622 West 168th St,PH9-301, New York, NY 10032 USA. EM kd2442@columbia.edu FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]; National Institute on Minority Health and Health Disparities; NHLBI/National Institutes of Health (NIH) [R01-HL117323, K24-HL125704]; NHLBI/NIH Diversity Supplements [R01-HL116470-02S1, R01-HL117323-02S2] FX The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, and HHSN268201300050C from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute on Minority Health and Health Disparities. This work was also supported by R01-HL117323 and K24-HL125704 from NHLBI/National Institutes of Health (NIH) and NHLBI/NIH Diversity Supplements awarded to K.M. Diaz (R01-HL116470-02S1) and M. Abdalla (R01-HL117323-02S2). NR 37 TC 1 Z9 1 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD MAR PY 2017 VL 69 IS 3 BP 421 EP + DI 10.1161/HYPERTENSIONAHA.116.08398 PG 18 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EL0PA UT WOS:000394323100010 PM 28137988 ER PT J AU Strickland, J Zang, QD Paris, M Lehmann, DM Allen, D Choksi, N Matheson, J Jacobs, A Casey, W Kleinstreuer, N AF Strickland, Judy Zang, Qingda Paris, Michael Lehmann, David M. Allen, David Choksi, Neepa Matheson, Joanna Jacobs, Abigail Casey, Warren Kleinstreuer, Nicole TI Multivariate models for prediction of human skin sensitization hazard SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Article DE Skin sensitization; allergic contact dermatitis (ACD); integrated decision strategy; machine learning; LLNA; DPRA; KeratinoSens; h-CLAT ID LYMPH-NODE ASSAY; LINE ACTIVATION TEST; TEST H-CLAT; IN-VITRO METHODS; SCREENING CONTACT ALLERGENS; INTEGRATED TESTING STRATEGY; PEPTIDE REACTIVITY ASSAY; RISK-ASSESSMENT MODEL; ICCVAM EVALUATION; RANDOM FOREST AB One of the Interagency Coordinating Committee on the Validation of Alternative Method's (ICCVAM) top priorities is the development and evaluation of non-animal approaches to identify potential skin sensitizers. The complexity of biological events necessary to produce skin sensitization suggests that no single alternative method will replace the currently accepted animal tests. ICCVAM is evaluating an integrated approach to testing and assessment based on the adverse outcome pathway for skin sensitization that uses machine learning approaches to predict human skin sensitization hazard. We combined data from three in chemico or in vitro assays - the direct peptide reactivity assay (DPRA), human cell line activation test (h-CLAT) and KeratinoSens assay - six physicochemical properties and an in silico read-across prediction of skin sensitization hazard into 12 variable groups. The variable groups were evaluated using two machine learning approaches, logistic regression and support vector machine, to predict human skin sensitization hazard. Models were trained on 72 substances and tested on an external set of 24 substances. The six models (three logistic regression and three support vector machine) with the highest accuracy (92%) used: (1) DPRA, h-CLAT and read-across; (2) DPRA, h-CLAT, read-across and KeratinoSens; or (3) DPRA, h-CLAT, read-across, KeratinoSens and log P. The models performed better at predicting human skin sensitization hazard than the murine local lymph node assay (accuracy 88%), any of the alternative methods alone (accuracy 63-79%) or test batteries combining data from the individual methods (accuracy 75%). These results suggest that computational methods are promising tools to identify effectively the potential human skin sensitizers without animal testing. Published 2016. This article has been contributed to by US Government employees and their work is in the public domain in the USA. The Interagency Coordinating Committee on the Validation of Alternative Methods evaluated a non-animal decision strategy using machine learning approaches to integrate in vitro, in chemico and in silico data and physicochemical properties to predict human skin sensitization hazard for 96 substances. The six most accurate models used different combinations of variables and outperformed the local lymph node assay and individual non-animal methods. Results of this evaluation suggest that computational approaches are promising tools to integrate data effectively to identify potential sensitizers without animal testing. C1 [Strickland, Judy; Zang, Qingda; Paris, Michael; Allen, David; Choksi, Neepa] ILS, POB 13501, Res Triangle Pk, NC 27709 USA. [Lehmann, David M.] US FDA, Res Triangle Pk, NC 27709 USA. [Casey, Warren; Kleinstreuer, Nicole] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. [Matheson, Joanna] US Consumer Prod Safety Commiss, Rockville, MD 20850 USA. [Jacobs, Abigail] US FDA, Silver Spring, MD USA. RP Strickland, J (reprint author), ILS, POB 13501, Res Triangle Pk, NC 27709 USA. EM strickl2@niehs.nih.gov OI Kleinstreuer, Nicole/0000-0002-7914-3682 FU NIEHS, NIH of the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods [HHSN273201500010C] FX The authors thank Drs. R. Luebke, M. Ward, D. Germolec and B.A. Merrick for their thoughtful critical review of this manuscript. This project was funded in whole or in part with federal funds from the NIEHS, NIH under contract HHSN273201500010C to ILS in support of the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods. NR 69 TC 2 Z9 2 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0260-437X EI 1099-1263 J9 J APPL TOXICOL JI J. Appl. Toxicol. PD MAR PY 2017 VL 37 IS 3 BP 347 EP 360 DI 10.1002/jat.3366 PG 14 WC Toxicology SC Toxicology GA EL2BR UT WOS:000394425600011 PM 27480324 ER PT J AU Korczak, JF Chung, DW Rosemond, E Von Hoff, DD Haspel, RL Waterbor, JW Chang, S Ramirez, AG Perkins, S Wiest, J Lei, M AF Korczak, Jeannette F. Chung, Davyd W. Rosemond, Erica Von Hoff, Daniel D. Haspel, Richard L. Waterbor, John W. Chang, Shine Ramirez, Amelie G. Perkins, Susan Wiest, Jonathan Lei, Ming TI The National Cancer Institute R25 Cancer Education Grants Program: A Workshop Report SO JOURNAL OF CANCER EDUCATION LA English DT Review DE Cancer education; R25; NCI ID RESEARCH TRAINING-PROGRAMS AB Through the R25 Cancer Education Grants Program (CEGP), the National Cancer Institute (NCI) has been supporting the broad educational needs of the cancer research and cancer healthcare communities since 1974. NCI sponsored a workshop on September 13, 2016 in Bethesda, Maryland, with the objectives of sharing best practices in cancer education, communicating R25 CEGP programmatic information, and gathering ideas to strengthen the R25 CEGP to better meet the emerging needs in cancer education in the face of a rapidly changing landscape in cancer research and cancer care. With 53 leaders in cancer education in attendance, the workshop featured an overview of the R25 CEGP by NCI Program Staff, a showcase of several types of CEGP programs by current R25 grantees, and in-depth discussions on a broad range of questions critical for the continued success of the R25 CEGP. The workshop afforded an opportunity, for the first time, for cancer researchers and clinicians conducting different forms of cancer education activities to gather in one place as leaders of a community of increasing importance. The discussion resulted in a set of suggestions that will benefit the R25 CEGP and cancer education in general. There was a general consensus among the participants that bringing the cancer education community together is a significant achievement of the workshop that will have a long-lasting impact on cancer education. C1 [Korczak, Jeannette F.; Chung, Davyd W.; Perkins, Susan; Wiest, Jonathan; Lei, Ming] NCI, 9609 Med Ctr Dr,Room 2W110, Rockville, MD 20852 USA. [Rosemond, Erica] Natl Ctr Adv Translat Sci, Bethesda, MD USA. [Von Hoff, Daniel D.] Amer Assoc Canc Res, Philadelphia, PA USA. [Haspel, Richard L.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Waterbor, John W.] Univ Alabama Birmingham, Sch Publ Hlth, Birmingham, AL 35294 USA. [Chang, Shine] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Ramirez, Amelie G.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. RP Lei, M (reprint author), NCI, 9609 Med Ctr Dr,Room 2W110, Rockville, MD 20852 USA. EM leim@mail.nih.gov NR 21 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 EI 1543-0154 J9 J CANCER EDUC JI J. Cancer Educ. PD MAR PY 2017 VL 32 IS 1 BP 3 EP 10 DI 10.1007/s13187-016-1161-8 PG 8 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA EK7ZZ UT WOS:000394145000002 PM 28064401 ER PT J AU Atkinson, TM Hay, JL Shoushtari, A Li, YL Paucar, DJ Smith, SC Kudchadkar, RR Doyle, A Sosman, JA Quevedo, JF Milhem, MM Joshua, AM Linette, GP Gajewski, TF Lutzky, J Lawson, DH Lao, CD Flynn, PJ Albertini, MR Sato, T Lewis, K Marr, B Abramson, DH Dickson, MA Schwartz, GK Carvajal, RD AF Atkinson, Thomas M. Hay, Jennifer L. Shoushtari, Alexander Li, Yuelin Paucar, Daniel J. Smith, Sloane C. Kudchadkar, Ragini R. Doyle, Austin Sosman, Jeffrey A. Quevedo, Jorge Fernando Milhem, Mohammed M. Joshua, Anthony M. Linette, Gerald P. Gajewski, Thomas F. Lutzky, Jose Lawson, David H. Lao, Christopher D. Flynn, Patrick J. Albertini, Mark R. Sato, Takami Lewis, Karl Marr, Brian Abramson, David H. Dickson, Mark Andrew Schwartz, Gary K. Carvajal, Richard D. TI Relationship between physician-adjudicated adverse events and patient-reported health-related quality of life in a phase II clinical trial (NCT01143402) of patients with metastatic uveal melanoma SO JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY LA English DT Article DE Patient-reported outcomes; Quality of life; Selumetinib; Neoplasms; Uveal melanoma; Adverse events; Clinical trials ID COMMON TERMINOLOGY CRITERIA; FUNCTIONAL ASSESSMENT; CANCER-TREATMENT; OUTCOMES; THERAPY; CTCAE; PRO; CHEMOTHERAPY; ONCOLOGY; VERSION AB Clinical trials commonly use physician-adjudicated adverse event (AE) assessment via the common terminology criteria for adverse events (CTCAE) for decision-making. Patient-reported health-related quality of life (HRQoL) data are becoming more frequent in oncology; however, the relationship between physician-adjudicated AE assessment and HRQoL is understudied. Data from a phase II trial (clinicaltrials.gov identifier: NCT01143402) where patients with metastatic uveal melanoma were randomized to receive selumetinib, an oral MEK inhibitor, or chemotherapy were analyzed. Patients reported HRQoL at baseline, after 1 month, and end of treatment (n = 118), whereas physicians adjudicated AEs via CTCAE. Mean HRQoL scores were compared between patient randomization arms, as well as between those patients who did/did not receive dose modifications. Ninety-four percent had a CTCAE grade >= 1 for at least one treatment-associated AE, with 18% undergoing dose modification due to toxicity. Mean HRQoL scores did not significantly differ at each of the three time points. Patient and physician-adjudicated reports of nausea were significantly correlated at the start (r = 0.31, p < 0.01) and end of treatment (r = 0.42, p < 0.05). There were no significant correlations between need for dose modification and HRQoL scores. Despite the high rate of physician-adjudicated AEs and need for dose modifications with selumetinib, patient-reported HRQoL was not impacted by treatment. Since HRQoL did not differ in the subgroup of patients who received dosage reductions due to AEs, patients may be willing to tolerate select AEs without dose modification (if medically appropriate). More research is needed to determine how to best integrate HRQoL data into clinical trial conduct. C1 [Atkinson, Thomas M.; Hay, Jennifer L.; Shoushtari, Alexander; Li, Yuelin; Smith, Sloane C.; Marr, Brian; Abramson, David H.; Dickson, Mark Andrew] Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, New York, NY 10022 USA. [Paucar, Daniel J.] Montefiore Med Ctr, Albert Einstein Canc Ctr, Bronx, NY 10467 USA. [Kudchadkar, Ragini R.; Lawson, David H.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Doyle, Austin] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Sosman, Jeffrey A.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Quevedo, Jorge Fernando] Mayo Clin, Rochester, MN USA. [Milhem, Mohammed M.] Univ Iowa, Carver Coll Med, Iowa City, IA USA. [Joshua, Anthony M.] Princess Margaret Hosp, Univ Hlth Network, Toronto, ON, Canada. [Linette, Gerald P.] Penn Med, Philadelphia, PA USA. [Gajewski, Thomas F.] Univ Chicago, Chicago, IL 60637 USA. [Lutzky, Jose] Mt Sinai Med Ctr, Miami Beach, FL 33140 USA. [Lao, Christopher D.] Univ Michigan, Ann Arbor, MI 48109 USA. [Flynn, Patrick J.] Minnesota Oncol, Woodbury, MN USA. [Albertini, Mark R.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Sato, Takami] Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA. [Lewis, Karl] Univ Colorado, Denver, CO 80202 USA. [Schwartz, Gary K.; Carvajal, Richard D.] Columbia Univ, Med Ctr, New York, NY USA. RP Atkinson, TM (reprint author), Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, 641 Lexington Ave,7th Floor, New York, NY 10022 USA. EM atkinsot@mskcc.org OI Atkinson, Thomas/0000-0002-4965-3913 FU Cancer Therapy Evaluation Program; National Cancer Institute; Conquer Cancer Foundation; Cycle for Survival; Fund for Opthalmic Knowledge; National Institutes of Health [P30CA08748] FX This project was sponsored by the Cancer Therapy Evaluation Program. Financial support was provided by the National Cancer Institute, the Conquer Cancer Foundation, Cycle for Survival, and the Fund for Opthalmic Knowledge, as well as a National Institutes of Health Support Grant (P30CA08748), which provides partial support for the Behavioral Research Methods Core Facility used in conducting this investigation. NR 27 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0171-5216 EI 1432-1335 J9 J CANCER RES CLIN JI J. Cancer Res. Clin. Oncol. PD MAR PY 2017 VL 143 IS 3 BP 439 EP 445 DI 10.1007/s00432-016-2318-x PG 7 WC Oncology SC Oncology GA EL1KE UT WOS:000394378500007 PM 27921276 ER PT J AU Rummo, PE Guilkey, DK Shikany, JM Reis, JP Gordon-Larsen, P AF Rummo, Pasquale E. Guilkey, David K. Shikany, James M. Reis, Jared P. Gordon-Larsen, Penny TI How do individual-level sociodemographics and neighbourhood-level characteristics influence residential location behaviour in the context of the food and built environment? Findings from 25 years of follow-up in the CARDIA Study SO JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH LA English DT Article ID MODE CHOICE DECISIONS; SELF-SELECTION; COMPACT DEVELOPMENT; AUTO OWNERSHIP; ADULTS AB Background Little is known about how diet-related and activity-related amenities relate to residential location behaviour. Understanding these relationships is essential for addressing residential self-selection bias. Methods Using 25 years (6 examinations) of data from the Coronary Artery Risk Development in Young Adults (CARDIA) study (n=11 013 observations) and linked neighbourhood-level data from the 4 CARDIA baseline cities (Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota; Oakland, California, USA), we characterised participants' neighbourhoods as having low, average or high road connectivity and amenities using non-hierarchical cluster analysis. We then used repeated measures multinomial logistic regression with random effects to examine the associations between individual-level sociodemographics and neighbourhood-level characteristics with residential neighbourhood types over the 25-year period, and whether these associations differed by individual-level income. Results Being female was positively associated with living in neighbourhoods with low (vs high) road connectivity and activity-related and diet-related amenities among high-income individuals only. At all income levels, a higher percentage of neighbourhood white population and neighbourhood population <18 years were associated with living in neighbourhoods with low (vs high) connectivity and amenities. Individual-level race; age; and educational attainment, neighbourhood socioeconomic status and housing prices did not influence residential location behaviour related to neighbourhood connectivity and amenities at any income level. Conclusions Neighbourhood-level factors appeared to play a comparatively greater role in shaping residential location behaviour than individual-level sociodemographics. Our study is an important step in understanding how residential locational behaviour relates to amenities and physical activity opportunities, and may help mitigate residential self-selection bias in built environment studies. C1 [Rummo, Pasquale E.; Gordon-Larsen, Penny] Univ North Carolina Chapel Hill, Carolina Populat Ctr, Gillings Sch Global Publ Hlth, Dept Nutr, Chapel Hill, NC USA. [Guilkey, David K.] Univ North Carolina Chapel Hill, Carolina Populat Ctr, Dept Econ, Chapel Hill, NC USA. [Shikany, James M.] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL USA. [Reis, Jared P.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. RP Gordon-Larsen, P (reprint author), Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Nutr, Chapel Hill, NC 27514 USA. EM pglarsen@unc.edu FU National Heart, Lung, and Blood Institute (NHLBI) [R01HL104580]; NHLBI [HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, HHSN268200900041C, AG0005]; Intramural Research Program of the National Institute on Aging (NIA); NIA [AG0005]; Carolina Population Center, University of North Carolina at Chapel Hill from Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [P2C HD050924]; Nutrition Obesity Research Center (NORC), University of North Carolina from National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) [P30DK56350]; Center for Environmental Health Sciences (CEHS), University of North Carolina from National Institute for Environmental Health Sciences (NIEHS) [P30ES010126] FX This work was funded by the National Heart, Lung, and Blood Institute (NHLBI) R01HL104580. The Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C and HHSN268200900041C from the NHLBI, the Intramural Research Program of the National Institute on Aging (NIA), and an intra-agency agreement between NIA and NHLBI (AG0005). The authors are grateful to the Carolina Population Center, University of North Carolina at Chapel Hill, for general support (grant P2C HD050924 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)), the Nutrition Obesity Research Center (NORC), University of North Carolina (grant P30DK56350 from the National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK)), and to the Center for Environmental Health Sciences (CEHS), University of North Carolina (grant P30ES010126 from the National Institute for Environmental Health Sciences (NIEHS)). NR 28 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 0143-005X EI 1470-2738 J9 J EPIDEMIOL COMMUN H JI J. Epidemiol. Community Health PD MAR PY 2017 VL 71 IS 3 BP 261 EP 268 DI 10.1136/jech-2016-207249 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EK9VE UT WOS:000394271200009 PM 27660400 ER PT J AU Lepow, L Luckenbaugh, DA Park, L Henter, ID Zarate, CA AF Lepow, Lauren Luckenbaugh, David A. Park, Lawrence Henter, Ioline D. Zarate, Carlos A., Jr. TI Case series: Antidepressant effects of low-affinity and low-trapping NMDA receptor antagonists did not predict response to ketamine in seven subjects SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Letter DE Antidepressant; Depression; Glutamate; NMDA receptor antagonist; Ketamine; Memantine ID MAJOR DEPRESSION; DOUBLE-BLIND; INFUSION C1 [Lepow, Lauren; Luckenbaugh, David A.; Park, Lawrence; Henter, Ioline D.; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. RP Zarate, CA (reprint author), 10 Ctr Dr,Bldg 10 CRC,Unit 7 Southeast, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov FU Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) [ZIA MH002857]; NARSAD Independent Investigator Award; Brain and Behavior Mood Disorders Research Award FX Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIA MH002857), by a NARSAD Independent Investigator Award to Dr. Zarate, and by a Brain and Behavior Mood Disorders Research Award to Dr. Zarate. The NIMH, NARSAD, and the Brain and Behavior Research Foundation had no further role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. NR 9 TC 0 Z9 0 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD MAR PY 2017 VL 86 BP 55 EP 57 DI 10.1016/j.jpsychires.2016.10.023 PG 3 WC Psychiatry SC Psychiatry GA EK6YR UT WOS:000394072700008 PM 27914292 ER PT J AU Kramer, HJ Stilp, AM Laurie, CC Reiner, AP Lash, J Daviglus, ML Rosas, SE Ricardo, AC Tayo, BO Flessner, MF Kerr, KF Peralta, C Durazo-Arvizu, R Conomos, M Thornton, T Rotter, J Taylor, KD Cai, J Eckfeldt, J Chen, H Papanicolau, G Franceschini, N AF Kramer, Holly J. Stilp, Adrienne M. Laurie, Cathy C. Reiner, Alex P. Lash, James Daviglus, Martha L. Rosas, Sylvia E. Ricardo, Ana C. Tayo, Bamidele O. Flessner, Michael F. Kerr, Kathleen F. Peralta, Carmen Durazo-Arvizu, Ramon Conomos, Matt Thornton, Timothy Rotter, Jerome Taylor, Kent D. Cai, Jainwen Eckfeldt, John Chen, Han Papanicolau, George Franceschini, Nora TI African Ancestry-Specific Alleles and Kidney Disease Risk in Hispanics/Latinos SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; COUNTRY-OF-ORIGIN; POPULATION-STRUCTURE; HISPANIC AMERICANS; GENETIC ANCESTRY; APOL1 VARIANTS; RENAL-DISEASE; UNITED-STATES; ASSOCIATION AB African ancestry alleles may contribute to CKD among Hispanics/Latinos, but whether associations differ by Hispanic/Latino background remains unknown. We examined the association of CKD measures with African ancestry-specific APOL1 alleles that were directly genotyped and sickle cell trait (hemoglobin subunit beta gene [HBB] variant) on the basis of imputation in 12,226 adult Hispanics/Latinos grouped according to Caribbean or Mainland background. We also performed an unbiased genome-wide association scan of urine albumin-to-creatinine ratios. Overall, 41.4% of participants were male, 44.6% of participants had a Caribbean background, and the mean age of all participants was 46.1 years. The Caribbean background group, compared with the Mainland background group, had a higher frequency of two APOL1 alleles (1.0% versus 0.1%) and the HBB variant (2.0% versus 0.7%). In the Caribbean background group, presence of APOL1 alleles (2 versus 0/1 copies) or the HBB variant (1 versus 0 copies) were significantly associated with albuminuria (odds ratio [OR], 3.2; 95% confidence interval [95% CI], 1.7 to 6.1; and OR, 2.6; 95% CI, 1.8 to 3.8, respectively) and albuminuria and/or eGFR<60 ml/min per 1.73 m(2) (OR, 2.9; 95% CI, 1.5 to 5.4; and OR, 2.4; 95% CI, 1.7 to 3.5, respectively). The urine albumin-to-creatinine ratio genome-wide association scan identified associations with the HBB variant among all participants, with the strongest association in the Caribbean background group (P=3.1 x 10(-10) versus P=9.3x 10(-3) for the Mainland background group). In conclusion, African-specific alleles associate with CKD in Hispanics/Latinos, but allele frequency varies by Hispanic/Latino background/ancestry. C1 [Kramer, Holly J.; Tayo, Bamidele O.; Durazo-Arvizu, Ramon] Loyola Univ Chicago, Dept Publ Hlth Sci & Med, Maywood, IL USA. [Kramer, Holly J.] Loyola Univ Chicago, Div Nephrol & Hypertens, Maywood, IL USA. [Stilp, Adrienne M.; Laurie, Cathy C.; Kerr, Kathleen F.; Conomos, Matt; Thornton, Timothy; Chen, Han] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Reiner, Alex P.] Univ Washington, Sch Publ Hlth, Div Publ Hlth Sci, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Lash, James; Ricardo, Ana C.] Univ Illinois, Dept Med, Div Nephrol, Chicago, IL USA. [Lash, James; Daviglus, Martha L.; Ricardo, Ana C.] Univ Illinois, Dept Med, Inst Minor Hlth Res, Chicago, IL USA. [Rosas, Sylvia E.] Beth Israel Deaconess Med Ctr, Dept Med, Div Nephrol, Boston, MA 02215 USA. [Flessner, Michael F.] NIDDK, Bethesda, MD USA. [Peralta, Carmen] Univ Calif San Francisco, Dept Med, Div Nephrol, San Francisco, CA USA. [Rotter, Jerome; Taylor, Kent D.] Harbor Univ Calif Los Angeles Med Ctr, Biomed Res Inst, Inst Translat Genom & Populat Sci Los Angeles, Torrance, CA 90509 USA. [Rotter, Jerome; Taylor, Kent D.] Harbor Univ Calif Los Angeles Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Cai, Jainwen] Univ North Carolina Chapel Hill, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. [Franceschini, Nora] Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC USA. [Eckfeldt, John] Univ Minnesota, Dept Lab Med & Pathol, Adv Res & Diagnost Labs, Minneapolis, MN 55455 USA. [Papanicolau, George] NHLBI, Epidemiol Branch, Bldg 10, Bethesda, MD 20892 USA. RP Franceschini, N (reprint author), Univ N Carolina, Gillings Sch Publ Hlth, 137 E Franklin St 306, Chapel Hill, NC 27599 USA. EM noraf@unc.edu FU National Heart, Lung, and Blood Institute (NHLBI) [N01-HC65233, N01-HC65234, N01-HC65235, N01-HC65236, N01-HC65237]; NIDCR [HHSN268201300005C AM03, HHSN268201300005C MOD03]; NHLBI [HSN 26220/20054C, HL123677-01]; National Center for Advancing Translational Sciences Clinical and Translational Science Institute grant [UL1TR000124]; NIDDK Diabetes Research Center grant [DK063491]; NHLBI: National Institute on Minority Health and Health Disparities; National Institute on Deafness and Other Communication Disorders; National Institute of Dental and Craniofacial Research (NIDCR); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institute of Neurological Disorders and Stroke; National Institutes of Health Institution Office of Dietary Supplements FX The baseline examination of HCHS/SOL was carried out as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), and San Diego State University (N01-HC65237). The following Institutes/Centers/Offices contributed to the first phase of HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research (NIDCR), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Neurological Disorders and Stroke, National Institutes of Health Institution Office of Dietary Supplements. The Genetic Analysis Center at Washington University was supported by NHLBI and NIDCR contracts (HHSN268201300005C AM03 and MOD03). Additional analysis support was provided by the NHLBI grant HL123677-01 (N.F.). Genotyping efforts were supported by NHLBI HSN 26220/20054C, National Center for Advancing Translational Sciences Clinical and Translational Science Institute grant UL1TR000124, and NIDDK Diabetes Research Center grant DK063491. NR 39 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD MAR PY 2017 VL 28 IS 3 BP 915 EP 922 DI 10.1681/ASN.2016030357 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA EM1AG UT WOS:000395049000021 PM 27650483 ER PT J AU Parsa, A Kanetsky, PA Xiao, R Gupta, J Mitra, N Limou, S Xie, DW Xu, HC Anderson, AH Ojo, A Kusek, JW Lora, CM Hamm, LL He, J Sandholm, N Jeff, J Raj, DE Boger, CA Bottinger, E Salimi, S Parekh, RS Adler, SG Langefeld, CD Bowden, DW Forsblom, C Freedman, BI Lipkowitz, M Fox, CS Winkler, CA Feldman, HI AF Parsa, Afshin Kanetsky, Peter A. Xiao, Rui Gupta, Jayanta Mitra, Nandita Limou, Sophie Xie, Dawei Xu, Huichun Anderson, Amanda Hyre Ojo, Akinlolu Kusek, John W. Lora, Claudia M. Hamm, L. Lee He, Jiang Sandholm, Niina Jeff, Janina Raj, Dominic E. Boeger, Carsten A. Bottinger, Erwin Salimi, Shabnam Parekh, Rulan S. Adler, Sharon G. Langefeld, Carl D. Bowden, Donald W. Forsblom, Carol Freedman, Barry I. Lipkowitz, Michael Fox, Caroline S. Winkler, Cheryl A. Feldman, Harold I. CA FIND Consortium Per-Henrik Grp Chronic Renal Insufficiency Cohort TI Genome-Wide Association of CKD Progression: The Chronic Renal Insufficiency Cohort Study SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; DIABETIC-NEPHROPATHY; DESIGN; GENES; HCARG; SET; PROTEINURIA; COMPONENTS; AMERICANS; VARIANTS AB The rate of decline of renal function varies significantly among individuals with CKD. To understand better the contribution of genetics to CKD progression, we performed a genome-wide association study among participants in the Chronic Renal Insufficiency Cohort Study. Our outcome of interest was CKD progression measured as change in eGFR over time among 1331 blacks and 1476 whites with CKD. We stratified all analyses by race and subsequently, diabetes status. Single-nucleotide polymorphisms (SNPs) that surpassed a significance threshold of P<1 x10(-6) for association with eGFR slope were selected as candidates for follow-up and secondarily tested for association with proteinuria and time to ESRD. We identified 12 such SNPs among black patients and six such SNPs among white patients. We were able to conduct follow-up analyses of three candidate SNPs in similar (replication) cohorts and eight candidate SNPs in phenotype-related (validation) cohorts. Among blacks without diabetes, rs653747 in LINC00923 replicated in the African American Study of Kidney Disease and Hypertension cohort (discovery P=5.42 x10(-7); replication P=0.039; combined P=7.42x 10(-9)). This SNP also associated with ESRD (hazard ratio, 2.0 (95% confidence interval, 1.5 to 2.7); P=4.90x10(-6)). Similarly, rs931891 in LINC00923 associated with eGFR decline (P=1.44 X 10(-4)) in white patients without diabetes. In summary, SNPs in LINC00923, an RNA gene expressed in the kidney, significantly associated with CKD progression in individuals with nondiabetic CKD. However, the lack of equivalent cohorts hampered replication for most discovery loci. Further replication of our findings in comparable study populations is warranted. C1 [Parsa, Afshin] Univ Maryland, Sch Med, Div Nephrol, Baltimore, MD 21201 USA. [Xu, Huichun] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Salimi, Shabnam] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Parsa, Afshin] Baltimore Vet Affairs Med Ctr, Dept Med, Baltimore, MD USA. [Kanetsky, Peter A.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA. [Xiao, Rui; Mitra, Nandita; Xie, Dawei; Winkler, Cheryl A.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Anderson, Amanda Hyre; Feldman, Harold I.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Gupta, Jayanta] Florida Gulf Coast Univ, Dept Hlth Sci, Coll Hlth Profess & Social Work, Ft Myers, FL USA. [Limou, Sophie] NCI, Mol Genet Epidemiol Sect, Basic Res Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Limou, Sophie] Leidos Biomed Res Inc, Frederick Natl Lab, Basic Sci Program, Frederick, MD USA. [Ojo, Akinlolu] Univ Michigan, Div Nephrol, Ann Arbor, MI USA. [Kusek, John W.] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD USA. [Lora, Claudia M.] Univ Illinois, Div Nephrol, Dept Med, Chicago, IL USA. [Hamm, L. Lee; He, Jiang] Tulane Univ, Nephrol Sect, Med, New Orleans, LA USA. [Sandholm, Niina; Forsblom, Carol] Folkhalsan Res Ctr, Folkhalsan Inst Genet, Helsinki, Finland. [Sandholm, Niina; Forsblom, Carol] Univ Helsinki, Abdominal Ctr Nephrol, Helsinki, Finland. [Sandholm, Niina; Forsblom, Carol] Helsinki Univ Hosp, Helsinki, Finland. [Sandholm, Niina; Forsblom, Carol; Per-Henrik Grp] Univ Helsinki, Res Programs Unit, Diabet & Obes, Helsinki, Finland. [Jeff, Janina; Bottinger, Erwin] Icahn Sch Med Mt Sinai, Dept Med, Charles Bronfman Inst Personalized Med, New York, NY USA. [Raj, Dominic E.] George Washington Univ, Sch Med, Dept Med, Washington, DC USA. [Boeger, Carsten A.] Univ Hosp Regensburg, Dept Nephrol, Regensburg, Germany. [Parekh, Rulan S.] Hosp Sick Children, Univ Hlth Network, Dept Pediat & Med, Div Nephrol, Toronto, ON, Canada. [Parekh, Rulan S.] Univ Toronto, Toronto, ON, Canada. [Adler, Sharon G.] Harbor Univ Calif, Los Angeles Med Ctr, Div Nephrol & Hypertens, Dept Med, Los Angeles, CA USA. [Langefeld, Carl D.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Bowden, Donald W.] Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA. [Freedman, Barry I.] Wake Forest Sch Med, Nephrol Sect, Dept Internal Med, Winston Salem, NC USA. [Lipkowitz, Michael] Georgetown Univ, Med Ctr, Dept Med, Washington, DC 20007 USA. [Fox, Caroline S.] NHLBI, Natl Heart Lung & Blood Inst Framingham Heart Stu, Div Intramural Res, Framingham, MA USA. RP Parsa, A (reprint author), Univ Maryland, Sch Med, 685 West Baltimore St,MSTF 357, Baltimore, MD 21201 USA. EM aparsa@medicine.umaryland.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902]; National Cancer Institute, National Institutes of Health (NIH) [HHSN26120080001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science awards NIH/National Center for Advancing Translational Sciences (NCATS) [UL1TR000003, K01DK092353]; Johns Hopkins University grant [UL1 TR-00042]; University of Maryland grant [GCRC MO1 RR-16500]; Clinical and Translational Science Collaborative of Cleveland; NCATS component of the NIH and NIH Roadmap for Medical Research [UL1TR000439]; Michigan Institute for Clinical and Health Research grant [UL1TR000433]; University of Illinois at Chicago grant [CTSA UL1RR029879]; NIH grant [T32 AG00262]; Passano Foundation; Tulane University Translational Research in Hypertension and Renal Biology grant [P30GM103337]; Kaiser Permanente grant [NIH/NCRR UCSF-CTSI UL1 RR-024131] FX Support for the Chronic Renal Insufficiency Cohort (CRIC) Study was obtained under a cooperative agreement from National Institute of Diabetes and Digestive and Kidney Diseases (grants U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902). This project has been funded in whole or in part with federal funds from National Cancer Institute, National Institutes of Health (NIH) contract HHSN26120080001E. This research was supported, in part, by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. In addition, this work was supported, in part, by Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science awards NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR000003 and K01DK092353, Johns Hopkins University grant UL1 TR-000424, University of Maryland grant GCRC MO1 RR-16500, the Clinical and Translational Science Collaborative of Cleveland, grant UL1TR000439 from the NCATS component of the NIH and NIH Roadmap for Medical Research, Michigan Institute for Clinical and Health Research grant UL1TR000433, University of Illinois at Chicago grant CTSA UL1RR029879, NIH grant T32 AG00262, the Passano Foundation, Tulane University Translational Research in Hypertension and Renal Biology grant P30GM103337, and Kaiser Permanente grant NIH/NCRR UCSF-CTSI UL1 RR-024131. NR 47 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD MAR PY 2017 VL 28 IS 3 BP 923 EP 934 DI 10.1681/ASN.2015101152 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA EM1AG UT WOS:000395049000022 PM 27729571 ER PT J AU Li, M Li, Y Weeks, O Mijatovic, V Teumer, A Huffman, JE Tromp, G Fuchsberger, C Gorski, M Lyytikainen, LP Nutile, T Sedaghat, S Sorice, R Tin, A Yang, Q Ahluwalia, TS Arking, DE Bihlmeyer, NA Boger, CA Carroll, RJ Chasman, DI Comelis, MC Dehghan, A Faul, JD Feitosa, MF Gambaro, G Gasparini, P Giulianini, F Heid, I Huang, JY Imboden, M Jackson, AU Jeff, J Jhun, MA Katz, R Kifley, A Kilpelainen, T Kumar, A Laakso, M Li-Gao, RF Lohman, K Lu, YC Magi, R Malerba, G Mihailov, E Mohlke, KL Mook-Kanamori, DO Robino, A Ruderfer, D Salvi, E Schick, UM Schulz, CA Smith, AV Smith, JA Traglia, M Yerges-Armstrong, LM Zhao, W Goodarzi, MO Kraja, AT Liu, CY Wessel, J Boerwinkle, E Borecki, IB Bork-Jensen, J Bottinger, EP Braga, D Brandslund, I Brody, JA Campbell, A Carey, DJ Christensen, C Coresh, J Crook, E Curhan, GC Cusi, D de Boer, IH de Vries, APJ Denny, JC Devuyst, O Dreisbach, AW Endlich, K Esko, T Franco, OH Fulop, T Gerhard, GS Glumer, C Gottesman, O Grarup, N Gudnason, V Hansen, T Harris, TB Hayward, C Hocking, L Hofman, A Hu, FB Husemoen, LLN Jackson, RD Jorgensen, T Jorgensen, ME Kahonen, M Kardia, SLR Konig, W Kooperberg, C Kriebel, J Launer, LJ Lauritzen, T Lehtimaki, T Levy, D Linksted, P Linneberg, A Liu, YM Loos, RJF Lupo, A Meisinger, C Melander, O Metspalu, A Mitchell, P Nauck, M Nurnberg, P Orho-Melander, M Parsa, A Pedersen, O Peters, A Peters, U Polasek, O Porteous, D Probst-Hensch, NM Psaty, BM Qi, L Raitakari, OT Reiner, AP Rettig, R Ridker, PM Rivadeneira, F Rossouw, JE Schmidt, F Siscovick, D Soranzo, N Strauch, K Toniolo, D Turner, ST Uitterlinden, AG Ulivi, S Velayutham, D Volker, U Volzke, H Waldenberger, M Wang, JJ Weir, DR Witte, D Kuivaniemi, H Fox, CS Franceschini, N Goessling, W Kottgen, A Chu, AY AF Li, Man Li, Yong Weeks, Olivia Mijatovic, Vladan Teumer, Alexander Huffman, Jennifer E. Tromp, Gerard Fuchsberger, Christian Gorski, Mathias Lyytikainen, Leo-Pekka Nutile, Teresa Sedaghat, Sanaz Sorice, Rossella Tin, Adrienne Yang, Qiong Ahluwalia, Tarunveer S. Arking, Dan E. Bihlmeyer, Nathan A. Boeger, Carsten A. Carroll, Robert J. Chasman, Daniel I. Comelis, Marilyn C. Dehghan, Abbas Faul, Jessica D. Feitosa, Mary F. Gambaro, Giovanni Gasparini, Paolo Giulianini, Franco Heid, Iris Huang, Jinyan Imboden, Medea Jackson, Anne U. Jeff, Janina Jhun, Min A. Katz, Ronit Kifley, Annette Kilpelainen, Tuomas Kumar, Ashish Laakso, Markku Li-Gao, Ruifang Lohman, Kurt Lu, Yingchang Maegi, Reedik Malerba, Giovanni Mihailov, Evelin Mohlke, Karen L. Mook-Kanamori, Dennis O. Robino, Antonietta Ruderfer, Douglas Salvi, Erika Schick, Ursula M. Schulz, Christina-Alexandra Smith, Albert V. Smith, Jennifer A. Traglia, Michela Yerges-Armstrong, Laura M. Zhao, Wei Goodarzi, Mark O. Kraja, Aldi T. Liu, Chunyu Wessel, Jennifer Boerwinkle, Eric Borecki, Ingrid B. Bork-Jensen, Jette Bottinger, Erwin P. Braga, Daniele Brandslund, Ivan Brody, Jennifer A. Campbell, Archie Carey, David J. Christensen, Cramer Coresh, Josef Crook, Errol Curhan, Gary C. Cusi, Daniele de Boer, Ian H. de Vries, Aiko P. J. Denny, Joshua C. Devuyst, Olivier Dreisbach, Albert W. Endlich, Karlhans Esko, Tonu Franco, Oscar H. Fulop, Tibor Gerhard, Glenn S. Gluemer, Charlotte Gottesman, Omri Grarup, Niels Gudnason, Vilmundur Hansen, Torben Harris, Tamara B. Hayward, Caroline Hocking, Lynne Hofman, Albert Hu, Frank B. Husemoen, Lise Lotte N. Jackson, Rebecca D. Jorgensen, Torben Jorgensen, Marit E. Kaehoenen, Mika Kardia, Sharon L. R. Koenig, Wolfgang Kooperberg, Charles Kriebel, Jennifer Launer, Lenore J. Lauritzen, Torsten Lehtimaki, Terho Levy, Daniel Linksted, Pamela Linneberg, Allan Liu, Yongmei Loos, Ruth J. F. Lupo, Antonio Meisinger, Christine Melander, Olle Metspalu, Andres Mitchell, Paul Nauck, Matthias Nuernberg, Peter Orho-Melander, Marju Parsa, Afshin Pedersen, Oluf Peters, Annette Peters, Ulrike Polasek, Ozren Porteous, David Probst-Hensch, Nicole M. Psaty, Bruce M. Qi, Lu Raitakari, Olli T. Reiner, Alex P. Rettig, Rainer Ridker, Paul M. Rivadeneira, Fernando Rossouw, Jacques E. Schmidt, Frank Siscovick, David Soranzo, Nicole Strauch, Konstantin Toniolo, Daniela Turner, Stephen T. Uitterlinden, Andre G. Ulivi, Sheila Velayutham, Dinesh Voelker, Uwe Volzke, Henry Waldenberger, Melanie Wang, Jie Jin Weir, David R. Witte, Daniel Kuivaniemi, Helena Fox, Caroline S. Franceschini, Nora Goessling, Wolfram Koettgen, Anna Chu, Audrey Y. CA CKDGen Consortium CHARGE Glycemic-T2D Working Grp CHARGE Blood Pressure Working Grp TI SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID LOW-FREQUENCY; NOONAN SYNDROME; RARE VARIANTS; SEQUENCE VARIANTS; DISEASE; ASSOCIATION; METAANALYSIS; COMMON; TRAITS AB Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (n(stage1);111,666;n(stage2): 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; P-stage1<3.7 x10(-7)), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4x 10(-8) by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation. C1 [Li, Man; Tin, Adrienne; Coresh, Josef; Koettgen, Anna] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Li, Man] Univ Utah, Div Nephrol, Salt Lake City, UT USA. [Li, Man] Univ Utah, Dept Human Genet, Salt Lake City, UT USA. [Li, Yong; Koettgen, Anna] Univ Freiburg, Div Genet Epidemiol, Med Ctr, Freiburg, Germany. [Weeks, Olivia; Goessling, Wolfram] Harvard Med Sch, Brigham & Womens Hosp, Div Genet, Boston, MA USA. [Ridker, Paul M.] Harvard Med Sch, Brigham & Womens Hosp, Div Prevent Med, Boston, MA USA. [Ridker, Paul M.] Harvard Med Sch, Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA USA. [Goessling, Wolfram] Harvard Med Sch, Brigham & Womens Hosp, Div Gastroenterol, Boston, MA USA. [Mijatovic, Vladan] Univ Verona, Dept Life & Reprod Sci, Verona, Italy. [Malerba, Giovanni; Soranzo, Nicole] Univ Verona, Sect Biol & Genet, Verona, Italy. [Teumer, Alexander; Volzke, Henry] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Endlich, Karlhans] Univ Med Greifswald, Dept Anat & Cell Biol, Greifswald, Germany. [Nauck, Matthias] Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany. [Rettig, Rainer] Univ Med Greifswald, Inst Physiol, Greifswald, Germany. [Schmidt, Frank; Voelker, Uwe] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Huffman, Jennifer E.; Liu, Chunyu; Levy, Daniel; Rossouw, Jacques E.; Fox, Caroline S.; Chu, Audrey Y.] NHLBI, Framingham Heart Study, 73 Mt Wayte Ave Suite 2, Framingham, MA 01702 USA. [Huffman, Jennifer E.; Liu, Chunyu; Levy, Daniel; Rossouw, Jacques E.; Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [Huffman, Jennifer E.; Campbell, Archie; Hayward, Caroline; Linksted, Pamela; Porteous, David] Univ Edinburgh, Ctr Genom & Expt Med, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Hayward, Caroline] Univ Edinburgh, Inst Genet & Mol Med, Med Res Council Human Genet, Edinburgh, Midlothian, Scotland. [Polasek, Ozren] Univ Edinburgh, Ctr Populat Hlth, Edinburgh, Midlothian, Scotland. [Tromp, Gerard; Carey, David J.; Kuivaniemi, Helena] Geisinger Hlth Syst, Sigfried & Janet Weis Ctr Res, Danville, PA USA. [Tromp, Gerard; Kuivaniemi, Helena] Univ Stellenbosch, Div Mol Biol & Human Genet, Dept Biomed Sci, Fac Med & Hlth Sci, Tygerberg, South Africa. [Fuchsberger, Christian] Univ Lubeck, Ctr Biomed, European Acad Bolzano Bozen, Bolzano, Italy. [Fuchsberger, Christian; Jackson, Anne U.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Faul, Jessica D.; Weir, David R.] Univ Michigan, Sch Publ Hlth, Survey Res Ctr, Inst Social Res, Ann Arbor, MI 48109 USA. [Jhun, Min A.; Smith, Jennifer A.; Zhao, Wei; Kardia, Sharon L. R.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Gorski, Mathias; Heid, Iris] Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, Regensburg, Germany. [Gorski, Mathias; Boeger, Carsten A.; Kaehoenen, Mika] Univ Hosp Regensburg, Dept Nephrol, Regensburg, Germany. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Fimlab Labs, Dept Clin Chem, Tampere, Finland. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Univ Tampere, Sch Med, Tampere, Finland. [Nutile, Teresa; Sorice, Rossella] Inst Genet & Biophys Adriano Buzzati Traverso, Naples, Italy. [Dehghan, Abbas] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Ahluwalia, Tarunveer S.; Kilpelainen, Tuomas; Bork-Jensen, Jette; Grarup, Niels; Hansen, Torben; Pedersen, Oluf] Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark. [Hansen, Torben; Linneberg, Allan] Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark. [Ahluwalia, Tarunveer S.; Jorgensen, Marit E.; Goessling, Wolfram] Steno Diabet Ctr, Gentofte, Denmark. [Arking, Dan E.; Bihlmeyer, Nathan A.; Esko, Tonu] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Carroll, Robert J.; Chasman, Daniel I.; Denny, Joshua C.] Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Nashville, TN USA. [Chasman, Daniel I.] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA. [Comelis, Marilyn C.] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Feitosa, Mary F.; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Gambaro, Giovanni] Catholic Univ, Gemelli Fdn Univ Hosp, Div Nephrol, Rome, Italy. [Gasparini, Paolo; Robino, Antonietta; Ulivi, Sheila] Univ Trieste, Inst Maternal & Child Hlth, IRCCS Burlo Garofolo, Trieste, Italy. [Heid, Iris] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Kriebel, Jennifer; Meisinger, Christine; Peters, Annette; Strauch, Konstantin; Waldenberger, Melanie] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany. [Huang, Jinyan] Shanghai Jiao Tong Univ, Sch Med, Inst Hematol, Rui Jin Hosp, Shanghai, Peoples R China. [Huang, Jinyan] State Key Lab Med Genom, Shanghai, Peoples R China. [Imboden, Medea; Kumar, Ashish; Probst-Hensch, Nicole M.] Swiss Trop & Publ Hlth Inst, Basel, Switzerland. [Jeff, Janina; Lu, Yingchang; Bottinger, Erwin P.; Gottesman, Omri; Loos, Ruth J. F.] Charles Bronfman Inst Personalized Med, New York, NY USA. [Ruderfer, Douglas] Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY 10029 USA. [Katz, Ronit; de Boer, Ian H.] Univ Washington, Kidney Res Inst, Seattle, WA 98195 USA. [Brody, Jennifer A.; Siscovick, David] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Kifley, Annette; Mitchell, Paul; Wang, Jie Jin] Univ Sydney, Ctr Vis Res, Dept Ophthalmol, Westmead, NSW, Australia. [Kifley, Annette; Mitchell, Paul; Wang, Jie Jin] Univ Sydney, Westmead Millennium Inst Med Res, Westmead, NSW, Australia. [Laakso, Markku] Univ Eastern Finland, Dept Med, Kuopio, Finland. [Laakso, Markku] Kuopio Univ Hosp, Kuopio, Finland. [Mook-Kanamori, Dennis O.; Franco, Oscar H.] Leiden Univ, Med Ctr, Dept Epidemiol, Leiden, Netherlands. [Lohman, Kurt] Wake Forest Univ, Div Publ Hlth Sci, Sch Med, Biostat Sci, Winston Salem, NC 27109 USA. [Liu, Yongmei] Wake Forest Univ, Div Publ Hlth Sci, Sch Med, Epidemiol & Prevent, Winston Salem, NC 27109 USA. [Maegi, Reedik; Mihailov, Evelin; Esko, Tonu; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, Tartu, Estonia. [Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Franco, Oscar H.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Mook-Kanamori, Dennis O.] King Faisal Specialist Hosp & Res Ctr, Epidemiol Sect, Dept Biostat Epidemiol & Sci Comp, Riyadh, Saudi Arabia. [Robino, Antonietta; Ulivi, Sheila] IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy. [Salvi, Erika; Braga, Daniele; Cusi, Daniele; Velayutham, Dinesh] Univ Milan, Dept Hlth Sci, Milan, Italy. [Schick, Ursula M.; Kooperberg, Charles; Peters, Ulrike; Reiner, Alex P.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Schulz, Christina-Alexandra; Melander, Olle; Orho-Melander, Marju] Lund Univ, Dept Clin Sci, Malmo, Sweden. [Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Traglia, Michela; Toniolo, Daniela] Ist Sci San Raffaele, Milan, Italy. [Yerges-Armstrong, Laura M.] Univ Maryland, Sch Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA. [Yerges-Armstrong, Laura M.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Goodarzi, Mark O.] Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA. [Goodarzi, Mark O.] Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA. [Goodarzi, Mark O.] Cedars Sinai Med Ctr, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA. [Kraja, Aldi T.] Washington Univ, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA. [Kraja, Aldi T.] Washington Univ, Ctr Genome Sci & Syst Biol, St Louis, MO USA. [Wessel, Jennifer] Fairbanks Sch Publ Hlth, Dept Epidemiol, Indianapolis, IN USA. [Wessel, Jennifer] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Brandslund, Ivan] Vejle Hosp, Dept Clin Biochem, Vejle, Denmark. [Christensen, Cramer] Vejle Hosp, Dept Internal Med & Endocrinol, Vejle, Denmark. [Crook, Errol] Univ S Alabama, Coll Med, Dept Med, Mobile, AL USA. [Curhan, Gary C.] Brigham & Womens Hosp, Div Renal, Boston, MA 02115 USA. [Curhan, Gary C.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Cusi, Daniele] San Paolo Hosp, Div Nephrol, Milan, Italy. [de Vries, Aiko P. J.] Leiden Univ, Med Ctr, Div Nephrol, Dept Med, NL-2300 RA Leiden, Netherlands. [de Vries, Aiko P. J.] Leiden Univ, NL-2300 RA Leiden, Netherlands. [Devuyst, Olivier] Univ Zurich, Zurich Ctr Integrat Human Physiol, Inst Physiol, Mech Inherited Kidney Disorders Grp, Zurich, Switzerland. [Dreisbach, Albert W.] Univ Mississippi, Dept Med, Jackson, MS 39216 USA. [Esko, Tonu] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Esko, Tonu] Harvard Med Sch, Dept Genet, Boston, MA USA. [Gerhard, Glenn S.] Temple Univ, Dept Med Genet & Mol Biochem, Sch Med, Philadelphia, PA 19122 USA. [Gluemer, Charlotte] Glostrup Univ Hosp, Res Ctr Prevent & Hlth, Capital Reg Denmark, Glostrup, Denmark. [Harris, Tamara B.; Launer, Lenore J.] NIA, Bethesda, MD 20892 USA. [Hocking, Lynne] Univ Aberdeen, Div Appl Hlth Sci, Aberdeen, Scotland. [Hu, Frank B.; Qi, Lu] Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Jackson, Rebecca D.] Ohio State Univ, Dept Internal Med, Columbia, OH USA. [Koenig, Wolfgang] Univ Ulm, Med Ctr, Dept Internal Med 2, Cardiol, Ulm, Germany. [Koenig, Wolfgang] Tech Univ Munich, German Heart Ctr Munich, Munich, Germany. [Koenig, Wolfgang] German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany. [Lauritzen, Torsten] Aarhus Univ, Dept Gen Practice, Aarhus, Denmark. [Linneberg, Allan] Rigshosp, Dept Clin Expt Res, Copenhagen, Denmark. [Lupo, Antonio] Univ Hosp Verona, Dept Med, Renal Unit, Verona, Italy. [Nauck, Matthias; Voelker, Uwe; Volzke, Henry] German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany. [Nuernberg, Peter] Univ Cologne, Cologne Ctr Genom, Cologne, Germany. [Parsa, Afshin] Univ Maryland, Sch Med, Dept Med, Div Nephrol, Baltimore, MD 21201 USA. [Peters, Annette] German Ctr Cardiovasc Dis Res, Munich, Germany. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Raitakari, Olli T.] Univ Turku, Dept Clin Physiol & Nucl Med, Turku Univ Hosp, Turku, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Rossouw, Jacques E.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Strauch, Konstantin] Ludwig Maximilians Univ Munchen, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Turner, Stephen T.] Mayo Clin, Div Nephrol & Hypertens, Rochester, MN USA. [Volzke, Henry] German Ctr Diabet Res, Partner Site Greifswald, Greifswald, Germany. [Witte, Daniel] Aarhus Univ, Dept Publ Hlth, Aarhus, Denmark. [Goessling, Wolfram] Harvard Stem Cell Inst, Cambridge, MA USA. [Goessling, Wolfram] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Kottgen, A (reprint author), Univ Med Ctr Freiburg, Berliner Allee 29, D-79110 Freiburg, Germany.; Chu, AY (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave Suite 2, Framingham, MA 01702 USA. EM anna.koettgen@uniklinik-freiburg.de; audrey.chu@nih.gov RI Grarup, Niels/K-2807-2015; Polasek, Ozren/B-6002-2011; Feitosa, Mary/K-8044-2012; OI Grarup, Niels/0000-0001-5526-1070; Polasek, Ozren/0000-0002-5765-1862; Feitosa, Mary/0000-0002-0933-2410; Peters, Annette/0000-0001-6645-0985 FU Chief Scientist Office [CZD/16/6/4]; Medical Research Council [MC_PC_U127561128]; NIH HHS [S10 OD020069] NR 33 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD MAR PY 2017 VL 28 IS 3 BP 981 EP 994 DI 10.1681/ASN.2016020131 PG 14 WC Urology & Nephrology SC Urology & Nephrology GA EM1AG UT WOS:000395049000028 PM 27920155 ER PT J AU Gehlert, S Hall, KL Palinkas, LA AF Gehlert, Sarah Hall, Kara L. Palinkas, Lawrence A. TI Preparing Our Next-Generation Scientific Workforce to Address the Grand Challenges for Social Work SO JOURNAL OF THE SOCIETY FOR SOCIAL WORK AND RESEARCH LA English DT Article DE social work; training; transdisciplinary; team science; translation ID PUBLIC-HEALTH; IMPLEMENTATION; INTERVENTIONS; INNOVATIONS; DISPARITIES; STRATEGIES; SCIENCE; MODEL AB The 12 Grand Challenges for Social Work make clear the need for a broad new approach for social work to solve complex contemporary social problems. The grand challenges likewise highlight the importance of developing and coordinating a plan to prepare the next generations of social work scholars for high-impact careers that contribute to the identification and implementation of solutions. This paper provides an overview of contemporary trends affecting the scientific enterprise in which our current and emerging scholars operate and within which strong practice, policy, and community-engaged research partnerships must be forged and sustained. We discuss modes of successful transdisciplinary team and translational science and how we expect these new scientific approaches to advance the Grand Challenges for Social Work. We identify the major challenges entailed in this ambitious agenda and highlight strategies for successfully conducting coordinated team science that spans disciplines and extends across the entire translational continuum. We outline a series of skills and competencies needed to conduct transdisciplinary team science across the translational continuum, and we offer potential education and training strategies to enhance the transdisciplinary team science and translational capacity of social work research. We conclude with perspectives on how to unite social work visions and organizational capacities to support our transdisciplinary team and translational science efforts. C1 [Gehlert, Sarah] Washington Univ, St Louis, MO 63130 USA. [Hall, Kara L.] NCI, Bethesda, MD 20892 USA. [Palinkas, Lawrence A.] Univ Southern Calif, Los Angeles, CA 90089 USA. RP Gehlert, S (reprint author), Washington Univ, George Warren Brown Sch Social Work, Box 1196,One Brookings Dr, St Louis, MO 63130 USA. EM sgehlert@wustl.edu FU NCI/NIH [5U54CA155496-05] FX This research was supported in part by NCI/NIH 5U54CA155496-05. NR 43 TC 0 Z9 0 U1 1 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 2334-2315 EI 1948-822X J9 J SOC SOC WORK RES JI J. Soc. Soc. Work Res. PD SPR PY 2017 VL 8 IS 1 BP 119 EP 136 DI 10.1086/690659 PG 18 WC Social Work SC Social Work GA EM6TH UT WOS:000395444600008 ER PT J AU Im, A Hakim, FT Pavletic, SZ AF Im, A. Hakim, F. T. Pavletic, S. Z. TI Novel targets in the treatment of chronic graft-versus-host disease SO LEUKEMIA LA English DT Review ID CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; HEMATOPOIETIC-CELL TRANSPLANTATION; BRONCHIOLITIS OBLITERANS SYNDROME; UNRELATED DONOR TRANSPLANTATION; NEUTROPHIL ELASTASE INHIBITOR; REGULATORY T-CELLS; LABEL PHASE 1B/2; CHRONIC GVHD; STEM-CELL AB Despite advances that have improved survival after allogeneic hematopoietic stem cell transplantation (HCT), chronic graft-versushost disease (GVHD) remains a leading cause of late morbidity and mortality after transplant. Current treatment options show limited efficacy in steroid- refractory disease, and there exists a paucity of robust data to guide management decisions. Lack of United States Food and Drug Administration (FDA)- or European Medicines Agency (EMA)-approved agents in GVHD underscore the importance of developing novel therapies. Better understanding of the biology of chronic GVHD has provided novel targets for treatment, and structured guidelines in diagnosis and in clinical trial design have provided a common language and pathways for research in this area. These, combined with the surge of drug development in Oncology and Immunology, are factors that have contributed to the accelerating field of drug development and clinical research in chronic GVHD. In these exciting times, it is possible to foresee long awaited advances in the treatment of this devastating complication of HCT. This review will summarize the ongoing clinical development for novel therapies in chronic GVHD. C1 [Im, A.] Univ Pittsburgh, Inst Canc, Dept Med, Div Hematol Oncol, Pittsburgh, PA USA. [Im, A.] UPMC, Canc Ctr, Pittsburgh, PA USA. [Im, A.; Hakim, F. T.; Pavletic, S. Z.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD USA. RP Pavletic, SZ (reprint author), NCI, NIH, 10 Ctr Dr,Bldg 10,Room CRC 3-3330, Bethesda, MD 20792 USA. EM pavletis@mail.nih.gov FU National Institutes of Health's (NIH) National Cancer Institute (NCI), Center for Cancer Research, Intramural Research Program FX This work was supported by the National Institutes of Health's (NIH) National Cancer Institute (NCI), Center for Cancer Research, Intramural Research Program. The opinions expressed here are those of the authors and do not represent the official position of the NIH, NCI or the United States Government. NR 101 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD MAR PY 2017 VL 31 IS 3 BP 543 EP 554 DI 10.1038/leu.2016.367 PG 12 WC Oncology; Hematology SC Oncology; Hematology GA EN3CW UT WOS:000395887600004 PM 27899803 ER PT J AU Tran, E Robbins, PF Rosenberg, SA AF Tran, Eric Robbins, Paul F. Rosenberg, Steven A. TI 'Final common pathway' of human cancer immunotherapy: targeting random somatic mutations SO NATURE IMMUNOLOGY LA English DT Review ID CYTOLYTIC T-LYMPHOCYTES; TUMOR-INFILTRATING LYMPHOCYTES; EXOME ANALYSIS REVEALS; CELL TRANSFER THERAPY; METASTATIC MELANOMA; POINT MUTATION; ANTIGENIC PEPTIDE; LUNG-CARCINOMA; PD-1 BLOCKADE; GENE-THERAPY AB Effective clinical cancer immunotherapies, such as administration of the cytokine IL-2, adoptive cell transfer (ACT) and the recent success of blockade of the checkpoint modulators CTLA-4 and PD-1, have been developed without clear identification. of the immunogenic targets expressed by human cancers in vivo. Immunotherapy of patients with cancer through the use of ACT with autologous lymphocytes has provided an opportunity to directly investigate the antigen recognition of lymphocytes that mediate cancer regression in humans. High-throughput immunological testing of such lymphocytes in combination with improvements in deep sequencing of the autologous cancer have provided new insight into the molecular characterization and incidence of anti-tumor lymphocytes present in patients with cancer. Here we highlight evidence suggesting that T cells that target tumor neoantigens arising from cancer mutations are the main mediators of many effective cancer immunotherapies in humans. C1 [Tran, Eric; Robbins, Paul F.; Rosenberg, Steven A.] NCI, Surg Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM sar@mail.nih.gov NR 77 TC 0 Z9 0 U1 8 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD MAR PY 2017 VL 18 IS 3 BP 255 EP 262 DI 10.1038/ni.3682 PG 8 WC Immunology SC Immunology GA EL1WZ UT WOS:000394413400005 PM 28198830 ER PT J AU Jellusova, J Cato, MH Apgar, JR Ramezani-Rad, P Leung, CR Chen, CD Richardson, AD Conner, EM Benschop, RJ Woodgett, JR Rickert, RC AF Jellusova, Julia Cato, Matthew H. Apgar, John R. Ramezani-Rad, Parham Leung, Charlotte R. Chen, Cindi Richardson, Adam D. Conner, Elaine M. Benschop, Robert J. Woodgett, James R. Rickert, Robert C. TI Gsk3 is a metabolic checkpoint regulator in B cells SO NATURE IMMUNOLOGY LA English DT Article ID GLYCOGEN-SYNTHASE KINASE-3; GERMINAL CENTER; C-MYC; PHOSPHORYLATION; GROWTH; HYPOXIA; INACTIVATION; LYMPHOCYTES; PATHWAY; INSULIN AB B cells predominate in a quiescent state until an antigen is encountered, which results in rapid growth, proliferation and differentiation of the B cells. These distinct cell states are probably accompanied by differing metabolic needs, yet little is known about the metabolic control of B cell fate. Here we show that glycogen synthase kinase 3 (Gsk3) is a metabolic sensor that promotes the survival of naive recirculating B cells by restricting cell mass accumulation. In antigen-driven responses, Gsk3 was selectively required for regulation of B cell size, mitochondrial biogenesis, glycolysis and production of reactive oxygen species (ROS), in a manner mediated by the co-stimulatory receptor CD40. Gsk3 was required to prevent metabolic collapse and ROS-induced apoptosis after glucose became limiting, functioning in part by repressing growth dependent on the myelocytomatosis oncoprotein c-Myc. Notably, we found that Gsk3 was required for the generation and maintenance of germinal center B cells, which require high glycolytic activity to support growth and proliferation in a hypoxic microenvironment. C1 [Jellusova, Julia; Cato, Matthew H.; Apgar, John R.; Ramezani-Rad, Parham; Leung, Charlotte R.; Chen, Cindi; Rickert, Robert C.] Sanford Burnham Prebys Med Discovery Inst SBP, Tumor Microenvironm & Canc Immunol Program, La Jolla, CA 92037 USA. [Jellusova, Julia; Cato, Matthew H.; Apgar, John R.; Ramezani-Rad, Parham; Leung, Charlotte R.; Chen, Cindi; Richardson, Adam D.; Rickert, Robert C.] NCI, Sanford Burnham Prebys Med Discovery Inst, Designated Canc Ctr, La Jolla, CA 92037 USA. [Conner, Elaine M.; Benschop, Robert J.] Eli Lilly & Co, La Jolla, CA USA. [Woodgett, James R.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [Woodgett, James R.] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. RP Rickert, RC (reprint author), Sanford Burnham Prebys Med Discovery Inst SBP, Tumor Microenvironm & Canc Immunol Program, La Jolla, CA 92037 USA.; Rickert, RC (reprint author), NCI, Sanford Burnham Prebys Med Discovery Inst, Designated Canc Ctr, La Jolla, CA 92037 USA. EM robert@sbpdiscovery.org FU US National Institutes of Health [R01AI41649]; Lilly Research Award Program; Deutsche Forschungsgemeinschaft; Cancer Centers Council (C3); Arthritis National Research Foundation; Canadian Institutes of Health Research; NCI award [5P30CA030199] FX We thank the SBP vivarium staff for animal care, M. Shlomchik (University of Pittsburgh) for providing the hCD20-TamCre mice, D. Kitamura (Tokyo University of Science) for providing the CD40LB cell line and C. Lyssiotis (University of Michigan) for discussions. Supported by US National Institutes of Health grant R01AI41649 (R.C.R.), the Lilly Research Award Program (R.C.R.), fellowships from the Deutsche Forschungsgemeinschaft (J.J.) and the Cancer Centers Council (C3) (P.R.-R.) and grants from the Arthritis National Research Foundation (J.J.) and the Canadian Institutes of Health Research (J.W.). The Animal Resources and Cancer Metabolism Cores at SBP are supported by NCI award 5P30CA030199. NR 37 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD MAR PY 2017 VL 18 IS 3 BP 303 EP 312 DI 10.1038/ni.3664 PG 10 WC Immunology SC Immunology GA EL1WZ UT WOS:000394413400010 PM 28114292 ER PT J AU Wu, C Chen, ZJ Dardalhon, V Xiao, S Thalhamer, T Liao, MY Madi, A Franca, RF Han, T Oukka, M Kuchroo, V AF Wu, Chuan Chen, Zuojia Dardalhon, Valerie Xiao, Sheng Thalhamer, Theresa Liao, Mengyang Madi, Asaf Franca, Rafael F. Han, Timothy Oukka, Mohammed Kuchroo, Vijay TI The transcription factor musculin promotes the unidirectional development of peripheral T-reg cells by suppressing the T(H)2 transcriptional program SO NATURE IMMUNOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; TGF-BETA; FOXP3 GENE; EXPRESSION; DIFFERENTIATION; BINDING; INFLAMMATION; PLASTICITY; INDUCTION; INFECTION AB Although master transcription factors (TFs) are key to the development of specific T cell subsets, whether additional transcriptional regulators are induced by the same stimuli that dominantly repress the development of other, non-specific T cell lineages has not been fully elucidated. Through the use of regulatory T cells (T-reg cells) induced by transforming growth factor-beta (TGF-(3), we identified the TF musculin (MSC) as being critical for the development of induced Treg cells (iT(reg) cells) by repression of the T helper type 2 (T(H)2) transcriptional program. Loss of MSC reduced expression of the Treg cell master TF Foxp3 and induced TH2 differentiation even under iT(reg)-cell-differentiation conditions. MSC interrupted binding of the TF GATA-3 to the locus encoding T(H)2-cell-related cytokines and diminished intrachromosomal interactions within that locus. MSC-deficient (Msc(-/-)) iTreg cells were unable to suppress T(H)2 responses, and Msc(-/-) mice spontaneously developed gut and lung inflammation with age. MSC therefore enforced Foxp3 expression and promoted the unidirectional induction of iT(reg) cells by repressing the T(H)2 developmental program. C1 [Wu, Chuan; Chen, Zuojia; Dardalhon, Valerie; Xiao, Sheng; Thalhamer, Theresa; Madi, Asaf; Franca, Rafael F.; Han, Timothy; Kuchroo, Vijay] Harvard Med Sch, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA. [Wu, Chuan; Chen, Zuojia; Dardalhon, Valerie; Xiao, Sheng; Thalhamer, Theresa; Madi, Asaf; Franca, Rafael F.; Han, Timothy; Kuchroo, Vijay] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Liao, Mengyang] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA USA. [Oukka, Mohammed] Seattle Childrens Res Inst, Ctr Immun & Immunotherapies, Seattle, WA USA. [Wu, Chuan] NCI, Expt Immunol Branch, US NIH, Bldg 10, Bethesda, MD 20892 USA. [Dardalhon, Valerie] CNRS, UMR5535, GMM, Montpellier, France. [Franca, Rafael F.] Univ Sao Paulo, Dept Pharmacol, Ribeirao Preto, SP, Brazil. RP Wu, C; Kuchroo, V (reprint author), Harvard Med Sch, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA.; Wu, C; Kuchroo, V (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA.; Wu, C (reprint author), NCI, Expt Immunol Branch, US NIH, Bldg 10, Bethesda, MD 20892 USA. EM cwu11@rics.bwh.harvard.edu; vkuchroo@evergrande.hms.harvard.edu FU National Multiple Sclerosis Society [TA 3059-A-2]; US National Institutes of Health [KAI110649A, K01DK09105, P01AI073748, P01AI056299, P01AI039671, R01NS045937, R01 NS030843] FX We thank D. Kozoriz for cell sorting; T. Chatila for advice; M. Collins for advice and editing the manuscript; E.N. Olson (University of Texas Southwestern Medical Center at Dallas) for Msc-/- mice; L. Maggio-Price (University of Washington) for Smad3-/- mice; and A. Yoshimura (Keio University School of Medicine) for the plasmid pCMV5-Smad3. Supported by the National Multiple Sclerosis Society (Career Transition Award TA 3059-A-2 to C.W.) and the US National Institutes of Health (K99 NIH Pathway to Independence Award KAI110649A to C.W.; K01DK09105 to S.X.; and P01AI073748, P01AI056299, P01AI039671, R01NS045937 and R01 NS030843 to V.K.). NR 48 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD MAR PY 2017 VL 18 IS 3 BP 344 EP 353 DI 10.1038/ni.3667 PG 10 WC Immunology SC Immunology GA EL1WZ UT WOS:000394413400014 PM 28114290 ER PT J AU Simmonds, P Adams, MJ Benko, M Breitbart, M Brister, JR Carstens, EB Davison, AJ Delwart, E Gorbalenya, AE Harrach, B Hull, R King, AMQ Koonin, EV Krupovic, M Kuhn, JH Lefkowitz, EJ Nibert, ML Orton, R Roossinck, MJ Sabanadzovic, S Sullivan, MB Suttle, CA Tesh, RB van der Vlugt, RA Varsani, A Zerbini, M AF Simmonds, Peter Adams, Mike J. Benko, Maria Breitbart, Mya Brister, J. Rodney Carstens, Eric B. Davison, Andrew J. Delwart, Eric Gorbalenya, Alexander E. Harrach, Balazs Hull, Roger King, Andrew M. Q. Koonin, Eugene V. Krupovic, Mart Kuhn, Jens H. Lefkowitz, Elliot J. Nibert, Max L. Orton, Richard Roossinck, Marilyn J. Sabanadzovic, Sead Sullivan, Matthew B. Suttle, Curtis A. Tesh, Robert B. van der Vlugt, Rene A. Varsani, Arvind Zerbini, Murilo TI Virus taxonomy in the age of metagenomics SO NATURE REVIEWS MICROBIOLOGY LA English DT Review ID STRANDED-DNA VIRUSES; NON-A; DIVERSITY; EVOLUTION; PROTEIN; BIODIVERSITY; GENOMES; FAMILY; LIFE; TREE AB The number and diversity of viral sequences that are identified in metagenomic data far exceeds that of experimentally characterized virus isolates. In a recent workshop, a panel of experts discussed the proposal that, with appropriate quality control, viruses that are known only from metagenomic data can, and should be, incorporated into the official classification scheme of the International Committee on Taxonomy of Viruses (ICTV). Although a taxonomy that is based on metagenomic sequence data alone represents a substantial departure from the traditional reliance on phenotypic properties, the development of a robust framework for sequence-based virus taxonomy is indispensable for the comprehensive characterization of the global virome. In this Consensus Statement article, we consider the rationale for why metagenomic sequence data should, and how it can, be incorporated into the ICTV taxonomy, and present proposals that have been endorsed by the Executive Committee of the ICTV. C1 [Hull, Roger] John Innes Ctr, Norwich, Norfolk, England. [Simmonds, Peter] Univ Oxford, Nuffield Dept Med, South Parks Rd, Oxford OX1 3SY, England. [Adams, Mike J.] 24 Woodland Way, Stevenage SG2 8BT, Herts, England. [Benko, Maria; Harrach, Balazs] Hungarian Acad Sci, Agr Res Ctr, Inst Vet Med Res, 21 Hungaria Krt, H-1143 Budapest, Hungary. [Breitbart, Mya] Univ S Florida, Coll Marine Sci, 140 7th Ave South, St Petersburg, FL 33701 USA. [Brister, J. Rodney; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Carstens, Eric B.] Queens Univ, Dept Biomed & Mol Sci, 18 Stuart St, Kingston, ON K7L 3N6, Canada. [Davison, Andrew J.; Orton, Richard] Univ Glasgow, Ctr Virus Res, UK Med Res Council MRC, Sir Michael Stoker Bldg,464 Bearsden Rd, Glasgow G61 1QH, Lanark, Scotland. [Delwart, Eric] Blood Syst Res Inst, 270 Mason Ave, San Francisco, CA 94118 USA. [Delwart, Eric] Univ Calif San Francisco, Dept Lab Med, 521 Parnassus Ave, San Francisco, CA 94118 USA. [Gorbalenya, Alexander E.] Leiden Univ, Dept Med Microbiol, Med Ctr, POB 9600,E4-P,Room E4-72, NL-2300 RC Leiden, Netherlands. [Gorbalenya, Alexander E.] Lomonosov Moscow State Univ, Fac Bioengn & Bioinformat, Moscow 119899, Russia. [Hull, Roger] 3 Portman Dr, Blandford Forum DT11 8HU, Dorset, England. [King, Andrew M. Q.] Pirbright Inst, Ash Rd, Woking GU24 0NF, Surrey, England. [Krupovic, Mart] Inst Pasteur, Dept Microbiol, 25 Rue Dr Roux, F-75015 Paris, France. [Kuhn, Jens H.] NIAID, Integrated Res Facil Ft Detrick IRF Frederick, B-8200 Res Plaza, Frederick, MD 21702 USA. [Lefkowitz, Elliot J.] Univ Alabama Birmingham, Dept Microbiol, Bevill Biomed Res Bldg BBRB Suite 276, Birmingham, AL 35294 USA. [Nibert, Max L.] Harvard Med Sch, Dept Microbiol & Immunobiol, 77 Ave Louis Pasteur, Boston, MA 02115 USA. [Roossinck, Marilyn J.] Penn State Univ, Ctr Infect Dis Dynam, Dept Plant Pathol & Environm Microbiol, University Pk, PA 16802 USA. [Sabanadzovic, Sead] Mississippi State Univ, Dept Biochem Mol Biol Entomol & Plant Pathol, 100 Old Highway 12 Mail Stop 9775, Mississippi State, MS 39762 USA. [Sullivan, Matthew B.] Ohio State Univ, Dept Microbiol, Columbus, OH 43210 USA. [Sullivan, Matthew B.] Ohio State Univ, Dept Civil Environm & Geodet Engn, Columbus, OH 43210 USA. [Suttle, Curtis A.] Univ British Columbia, Dept Earth Ocean & Atmospher Sci, Vancouver, BC V6T 1Z4, Canada. [Suttle, Curtis A.] Univ British Columbia, Dept Microbiol & Immunol, Vancouver, BC V6T 1Z4, Canada. [Suttle, Curtis A.] Univ British Columbia, Dept Bot, Vancouver, BC V6T 1Z4, Canada. [Suttle, Curtis A.] CIFAR, 180 Dundas St West, Toronto, ON M5G 1Z8, Canada. [Tesh, Robert B.] Univ Texas Med Branch, Dept Pathol, 301 Univ Blvd, Galveston, TX 77555 USA. [Tesh, Robert B.] Univ Texas Med Branch, Ctr Biodef & Emerging Infect Dis, 301 Univ Blvd, Galveston, TX 77555 USA. [van der Vlugt, Rene A.] Wageningen Univ & Res Ctr WUR PRI, Wageningen Plant Res, Droevendaalsesteeg 1, NL-6708 PB Wageningen, Netherlands. [Varsani, Arvind] Arizona State Univ, Biodesign Inst, Ctr Fundamental & Appl Microbiom, 1001 South McAllister Ave, Tempe, AZ 85281 USA. [Varsani, Arvind] Arizona State Univ, Sch Life Sci, 1001 South McAllister Ave, Tempe, AZ 85281 USA. [Zerbini, Murilo] Univ Fed Vicosa, Dept Fitopatol BIOAGRO, BR-36570900 Vicosa, MG, Brazil. RP Simmonds, P (reprint author), Univ Oxford, Nuffield Dept Med, South Parks Rd, Oxford OX1 3SY, England. EM Peter.Simmonds@ndm.ox.ac.uk FU Wellcome Trust [WT108418AIA]; Hungarian Scientific Research Fund (OTKA) [NN107632, K100163]; European Union [653316]; EU [FA1407]; Mississippi State University (MSU)-Mississippi Agricultural and Forestry Experiment Station (MAFES) Strategic Research Initiative grants; US National Heart, Lung, and Blood Institute (NHLBI) [R01 HL105770]; Intramural Research Program of the US National Institutes of Health (NIH), US National Library of Medicine; Assembling the Tree of Life Programme of the US National Science Foundation [DEB-1239976]; Gordon and Betty Moore Foundation [3790]; Battelle Memorial Institute; US National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272200700016I] FX The workshop and discussions were funded by the Wellcome Trust (grant WT108418AIA). The authors thank the members of the International Committee on Taxonomy of Viruses (ICTV) Executive Committee who did not attend (A. Kropinski, R. Harrison, H. Sanfacon, A. Mushegian, N. Knowles and S. Siddell) for thoughtful comments and discussion, and S. Roux from the Department of Microbiology at Ohio State University, USA, for the preparation of figure 1. B.H. and M. Benko were supported by the Hungarian Scientific Research Fund (OTKA; grants NN107632 and K100163, respectively). The work of A. E. G. was partially supported by the European Union's Horizon 2020 research and innovation programme (under grant agreement number 653316; the European Virus Archive goes Global, EVAg). R. A. v. d. V. was partly supported by the EU Cooperation in Science and Technology (COST) programme (action FA1407). S. S. acknowledges partial financial support from Mississippi State University (MSU)-Mississippi Agricultural and Forestry Experiment Station (MAFES) Strategic Research Initiative grants. The work of E. D. was supported by the US National Heart, Lung, and Blood Institute (NHLBI; grant R01 HL105770). Research by J. R. B. and E. V. K. was supported, in part, by the Intramural Research Program of the US National Institutes of Health (NIH), US National Library of Medicine. M. Breitbart was supported through the Assembling the Tree of Life Programme of the US National Science Foundation (grant DEB-1239976). M. B. S. was supported by an award from the Gordon and Betty Moore Foundation (number 3790). The involvement of J. H. K. was supported, in part, through the prime contract of the Battelle Memorial Institute with the US National Institute of Allergy and Infectious Diseases (NIAID) under contract number HHSN272200700016I. A subcontractor to the Battelle Memorial Institute who carried out this work is J. H. K., who is an employee of Tunnell Government Services, Inc. The views and conclusions that are contained in this document are those of the authors and should not be interpreted as necessarily representing the official policies, either expressed or implied, of the US Department of Health and Human Services or of the institutions and companies that are affiliated with the authors. NR 71 TC 1 Z9 1 U1 10 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1740-1526 EI 1740-1534 J9 NAT REV MICROBIOL JI Nat. Rev. Microbiol. PD MAR PY 2017 VL 15 IS 3 BP 161 EP 168 DI 10.1038/nrmicro.2016.177 PG 8 WC Microbiology SC Microbiology GA EK9ZD UT WOS:000394281600010 PM 28134265 ER PT J AU Shmakov, S Smargon, A Scott, D Cox, D Pyzocha, N Yan, W Abudayyeh, OO Gootenberg, JS Makarova, KS Wolf, YI Severinov, K Zhang, F Koonin, EV AF Shmakov, Sergey Smargon, Aaron Scott, David Cox, David Pyzocha, Neena Yan, Winston Abudayyeh, Omar O. Gootenberg, Jonathan S. Makarova, Kira S. Wolf, Yuri I. Severinov, Konstantin Zhang, Feng Koonin, Eugene V. TI Diversity and evolution of class 2 CRISPR-Cas systems SO NATURE REVIEWS MICROBIOLOGY LA English DT Review ID CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; DEFENSE SYSTEMS; HUMAN-CELLS; PROKARYOTIC DIVERSITY; ADAPTIVE IMMUNITY; STRUCTURAL BASIS; DNA RECOGNITION; RNA; COMPLEX AB Class 2 CRISPR-Cas systems are characterized by effector modules that consist of a single multidomain protein, such as Cas9 or Cpf1. We designed a computational pipeline for the discovery of novel class 2 variants and used it to identify six new CRISPR-Cas subtypes. The diverse properties of these new systems provide potential for the development of versatile tools for genome editing and regulation. In this Analysis article, we present a comprehensive census of class 2 types and class 2 subtypes in complete and draft bacterial and archaeal genomes, outline evolutionary scenarios for the independent origin of different class 2 CRISPR-Cas systems from mobile genetic elements, and propose an amended classification and nomenclature of CRISPR-Cas. C1 [Shmakov, Sergey] Skolkovo Innovat Ctr, Skolkovo Inst Sci & Technol, Skolkovo 143025, Russia. [Shmakov, Sergey; Makarova, Kira S.; Wolf, Yuri I.; Koonin, Eugene V.] NIH, NCBI, Natl Lib Med, Bethesda, MD 20894 USA. [Smargon, Aaron; Scott, David; Cox, David; Pyzocha, Neena; Yan, Winston; Abudayyeh, Omar O.; Gootenberg, Jonathan S.; Zhang, Feng] Broad Inst Massachusetts Inst Technol MIT & Harva, Cambridge, MA 02142 USA. [Smargon, Aaron] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Pyzocha, Neena] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Pyzocha, Neena; Abudayyeh, Omar O.; Zhang, Feng] MIT, Dept Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Gootenberg, Jonathan S.; Zhang, Feng] MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Severinov, Konstantin] Rutgers State Univ, Waksman Inst Microbiol, Piscataway, NJ 08854 USA. [Severinov, Konstantin] Russian Acad Sci, Inst Mol Genet, Moscow 123182, Russia. [Zhang, Feng] MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. [Zhang, Feng] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Koonin, EV (reprint author), NIH, NCBI, Natl Lib Med, Bethesda, MD 20894 USA.; Zhang, F (reprint author), Broad Inst Massachusetts Inst Technol MIT & Harva, Cambridge, MA 02142 USA. EM zhang@broadinstitute.org; koonin@ncbi.nlm.nih.gov FU intramural funds of the US Department of Health and Human Services; US National Institutes of Health (NIH) [GM10407]; Russian Science Foundation [14-14-00988]; Skolkovo Institute of Science and Technology (Skoltech); NIH through the US National Institute of Mental Health (NIMH) [5DP1-MH100706, 1R01-MH110049]; US National Science Foundation (NSF); New York Stem Cell Foundation; Allen Distinguished Investigator Program; Paul G. Allen Frontiers Group; Simons Foundation; Vallee Foundation; Howard Hughes Medical Institute; Skoltech-MIT Next Generation Program; Poitras Center for Affective Disorders FX S.S., K.S.M., Y.I.W. and E.V.K. are supported by intramural funds of the US Department of Health and Human Services (to the US National Library of Medicine). K.S. is supported by a US National Institutes of Health (NIH) grant (GM10407), a Russian Science Foundation grant (14-14-00988), and by the Skolkovo Institute of Science and Technology (Skoltech). F.Z. is supported by the NIH through the US National Institute of Mental Health (NIMH; grants 5DP1-MH100706 and 1R01-MH110049); the US National Science Foundation (NSF); the New York Stem Cell Foundation; the Allen Distinguished Investigator Program; through The Paul G. Allen Frontiers Group; the Simons and Vallee Foundations; the Howard Hughes Medical Institute; the Skoltech-MIT Next Generation Program; James and Patricia Poitras and the Poitras Center for Affective Disorders; R. Metcalfe; and D. Cheng. F.Z. is a New York Stem Cell Foundation-Robertson Investigator. NR 80 TC 0 Z9 0 U1 20 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1740-1526 EI 1740-1534 J9 NAT REV MICROBIOL JI Nat. Rev. Microbiol. PD MAR PY 2017 VL 15 IS 3 BP 169 EP 182 DI 10.1038/nrmicro.2016.184 PG 14 WC Microbiology SC Microbiology GA EK9ZD UT WOS:000394281600011 PM 28111461 ER PT J AU Tian, Q Chastan, N Bair, WN Resnick, SM Ferrucci, L Studenski, SA AF Tian, Qu Chastan, Nathalie Bair, Woei-Nan Resnick, Susan M. Ferrucci, Luigi Studenski, Stephanie A. TI The brain map of gait variability in aging, cognitive impairment and dementia A systematic review SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Review DE Gait variability; Neuroimaging; Older adults; Aging; Cognitive impairment; Dementia ID FUNCTIONING OLDER-ADULTS; GRAY-MATTER INTEGRITY; PARKINSONS-DISEASE; INTRAINDIVIDUAL VARIABILITY; TESTING PROTOCOL; WALKING; STIMULATION; ASSOCIATION; DECLINE; SPEED AB While gait variability may reflect subtle changes due to aging or cognitive impairment (CI), associated brain characteristics remain unclear. We summarize structural and functional neuroimaging findings associated with gait variability in older adults with and without CI and dementia. We identified 17 eligible studies; all were cross-sectional; few examined multiple brain areas. In older adults, temporal gait variability was associated with structural differences in medial areas important for lower limb coordination and balance. Both temporal and spatial gait variability were associated with structural and functional differences in hippocampus and primary sensorimotor cortex and structural differences in anterior cingulate cortex, basal ganglia, association tracts, and posterior thalamic radiation. In CI or dementia, some associations were found in primary motor cortex, hippocampus, prefrontal cortex and basal ganglia. In older adults, gait variability may be associated with areas important for sensorimotor integration and coordination. To comprehend the neural basis of gait variability with aging and Cl, longitudinal studies of multiple brain areas are needed. Published by Elsevier Ltd. C1 [Tian, Qu; Chastan, Nathalie; Bair, Woei-Nan; Ferrucci, Luigi; Studenski, Stephanie A.] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. [Chastan, Nathalie] Rouen Univ Hosp, Dept Neurophysiol, 1 Rue Germont, F-76000 Rouen, France. [Chastan, Nathalie] Normandy Univ, COMETE, INSERM U1075, F-14032 Caen, France. [Resnick, Susan M.] NIA, Lab Behav Neurosci, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. RP Tian, Q (reprint author), 251 Bayview Blvd,Suite 100,Rm04B316, Baltimore, MD 21224 USA. EM qu.tian@nih.gov FU Intramural Research Program of the National Institute on Aging, National Institutes of Health [03-AG-0325] FX This research was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (grant number: 03-AG-0325). NR 61 TC 0 Z9 0 U1 4 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7634 EI 1873-7528 J9 NEUROSCI BIOBEHAV R JI Neurosci. Biobehav. Rev. PD MAR PY 2017 VL 74 BP 149 EP 162 DI 10.1016/j.neubiorev.2017.01.020 PN A PG 14 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA EM9BF UT WOS:000395605200010 PM 28115194 ER PT J AU McDonough, CM Ni, PS Peterik, K Marfeo, EE Marino, ME Meterko, M Rasch, EK Brandt, DE Jette, AM Chan, L AF McDonough, Christine M. Ni, Pengsheng Peterik, Kara Marfeo, Elizabeth E. Marino, Molly E. Meterko, Mark Rasch, Elizabeth K. Brandt, Diane E. Jette, Alan M. Chan, Leighton TI Improving measures of work-related physical functioning SO QUALITY OF LIFE RESEARCH LA English DT Article DE Disability evaluation; Work disability; Questionnaires ID BEHAVIORAL HEALTH FUNCTION; FUNCTION INSTRUMENT; DISABILITY; INDEX; DIF; IRT AB To expand content of the physical function domain of the Work Disability Functional Assessment Battery (WD-FAB), developed for the US Social Security Administration's (SSA) disability determination process. Newly developed questions were administered to 3532 recent SSA applicants for work disability benefits and 2025 US adults. Factor analyses and item response theory (IRT) methods were used to calibrate and link the new items to the existing WD-FAB, and computer-adaptive test simulations were conducted. Factor and IRT analyses supported integration of 44 new items into three existing WD-FAB scales and the addition of a new 11-item scale (Community Mobility). The final physical function domain consisting of: Basic Mobility (56 items), Upper Body Function (34 items), Fine Motor Function (45 items), and Community Mobility (11 items) demonstrated acceptable psychometric properties. The WD-FAB offers an important tool for enhancement of work disability determination. The FAB could provide relevant information about work-related functioning for initial assessment of claimants; identifying denied applicants who may benefit from interventions to improve work and health outcomes; enhancing periodic review of work disability beneficiaries; and assessing outcomes for policies, programs and services targeting people with work disability. C1 [McDonough, Christine M.; Ni, Pengsheng; Peterik, Kara; Marfeo, Elizabeth E.; Marino, Molly E.; Meterko, Mark; Jette, Alan M.] Boston Univ, Sch Publ Hlth, Hlth & Disabil Res Inst, 715 Albany St,T5W, Boston, MA 02118 USA. [McDonough, Christine M.] Geisel Sch Med Dartmouth, Dept Orthopaed Surg, Hanover, NH 03755 USA. [Marfeo, Elizabeth E.] Tufts Univ, Medford, MA 02155 USA. [Meterko, Mark] US Dept Vet Affairs, Ctr Healthcare Org & Implementat Res, Boston, MA USA. [Rasch, Elizabeth K.; Brandt, Diane E.; Chan, Leighton] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. RP McDonough, CM (reprint author), Boston Univ, Sch Publ Hlth, Hlth & Disabil Res Inst, 715 Albany St,T5W, Boston, MA 02118 USA.; McDonough, CM (reprint author), Geisel Sch Med Dartmouth, Dept Orthopaed Surg, Hanover, NH 03755 USA. EM cmm@bu.edu FU Social Security Administration-National Institutes of Health Interagency Agreements under the National Institutes of Health [HHSN269200900004C, HHSN269201000011C, HHSN269201100009I, HHSN269201200005C]; National Institutes of Health Intramural Research Program FX This study was supported by Social Security Administration-National Institutes of Health Interagency Agreements under the National Institutes of Health (Contract Nos. HHSN269200900004C, HHSN269201000011C, HHSN269201100009I, HHSN269201200005C), and by the National Institutes of Health Intramural Research Program. NR 24 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD MAR PY 2017 VL 26 IS 3 BP 789 EP 798 DI 10.1007/s11136-016-1477-1 PG 10 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA EL1DX UT WOS:000394361800025 PM 28005243 ER PT J AU Li, N Katz, S Dutta, B Benet, ZL Sun, J Fraser, IDC AF Li, Ning Katz, Samuel Dutta, Bhaskar Benet, Zachary L. Sun, Jing Fraser, Iain D. C. TI Data Descriptor: Genome-wide siRNA screen of genes regulating the LPS-induced NF-kappa B and TNF-alpha responses in mouse macrophages SO SCIENTIFIC DATA LA English DT Article ID SINGLE-STRANDED RNA; PATHOGEN RESPONSES; RECOGNITION; INTERFERENCE; ACTIVATION; MECHANISMS; IMMUNITY; CELLS AB The mammalian innate immune system senses many bacterial stimuli through the toll-like receptor (TLR) family. Activation of the TLR4 receptor by bacterial lipopolysaccharide (LPS) is the most widely studied TLR pathway due to its central role in host responses to gram-negative bacterial infection and its contribution to endotoxemia and sepsis. Here we describe a genome-wide siRNA screen to identify genes regulating the mouse macrophage TNF-alpha and NF-kappa B responses to LPS. We include a secondary validation screen conducted with six independent siRNAs per gene to facilitate removal of off-target screen hits. We also provide microarray data from the same LPS-treated macrophage cells to facilitate downstream data analysis. These data provide a resource for analyzing gene function in the predominant pathway driving inflammatory signaling and cytokine expression in mouse macrophages. C1 [Li, Ning; Katz, Samuel; Benet, Zachary L.; Sun, Jing; Fraser, Iain D. C.] Lab Syst Biol, Signaling Syst Unit, Bethesda, MD 20892 USA. [Katz, Samuel] Univ Cambridge, Dept Vet Med, Madingley Rd, Cambridge CB3 0ES, England. [Dutta, Bhaskar] NIAID, Bioinformat Team, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Dutta, Bhaskar] AstraZeneca, Adv Analyt Ctr, Gaithersburg, MD 20878 USA. RP Fraser, IDC (reprint author), Lab Syst Biol, Signaling Syst Unit, Bethesda, MD 20892 USA. EM fraseri@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases; El-Hibri Biomedical Research Scholarship FX We thank colleagues in the Laboratory of Systems Biology for helpful discussions and critical reading of the manuscript, Tim Myers for assistance with Microarray data analysis and GEO data deposition, and Yanli Wang and Ben Shoemaker for assistance with PubChem data curation and upload. This work was generously supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. S.K. is also supported by the El-Hibri Biomedical Research Scholarship. NR 23 TC 1 Z9 1 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2052-4463 J9 SCI DATA JI Sci. Data PD MAR 1 PY 2017 VL 4 AR 170008 DI 10.1038/sdata.2017.8 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EM1HF UT WOS:000395068000002 PM 28248925 ER PT J AU Sun, J Katz, S Dutta, B Wang, Z Fraser, IDC AF Sun, Jing Katz, Samuel Dutta, Bhaskar Wang, Ze Fraser, Iain D. C. TI Data Descriptor: Genome-wide siRNA screen of genes regulating the LPS-induced TNF-alpha response in human macrophages SO SCIENTIFIC DATA LA English DT Article ID PATHOGEN RESPONSES; IMMUNITY AB The mammalian innate immune system senses many bacterial stimuli through the toll-like receptor (TLR) family. Activation of the TLR4 receptor by bacterial lipopolysaccharide (LPS) is the most widely studied TLR pathway due to its central role in host responses to gram-negative bacterial infection and its contribution to endotoxemia and sepsis. Here we describe a genome-wide siRNA screen to identify genes regulating the human macrophage TNF-alpha response to LPS. We include a secondary validation screen conducted with six independent siRNAs per gene to facilitate removal of off-target screen hits. We also provide microarray data from the same LPS-treated macrophage cells to facilitate downstream data analysis. Tertiary screening with multiple TLR ligands and a microbial extract demonstrate that novel screen hits have broad effects on the innate inflammatory response to microbial stimuli. These data provide a resource for analyzing gene function in the predominant pathway driving inflammatory cytokine expression in human macrophages. C1 [Sun, Jing; Katz, Samuel; Fraser, Iain D. C.] NIAID, Signaling Syst Unit, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Katz, Samuel] Univ Cambridge, Dept Vet Med, Madingley Rd, Cambridge CB3 0ES, England. [Dutta, Bhaskar] NIAID, Bioinformat Team, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Wang, Ze] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Dutta, Bhaskar] AstraZeneca, Adv Analyt Ctr, Gaithersburg, MD 20878 USA. RP Fraser, IDC (reprint author), NIAID, Signaling Syst Unit, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. EM fraseri@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases; El-Hibri Biomedical Research Scholarship FX We thank colleagues in the Laboratory of Systems Biology for helpful discussions and critical reading of the manuscript, Tim Myers for assistance with Microarray data analysis and GEO data deposition, Yanli Wang and Ben Shoemaker for assistance with PubChem data curation and upload and Carl Feng for provision of the extract from BCG-attenuated M. Tuberculosis. This work was generously supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. S.K. is also supported by the El-Hibri Biomedical Research Scholarship. NR 16 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2052-4463 J9 SCI DATA JI Sci. Data PD MAR 1 PY 2017 VL 4 AR 170007 DI 10.1038/sdata.2017.7 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EM1HF UT WOS:000395068000001 PM 28248930 ER PT J AU Minter, DJ Mejia, R Salas, I Thrasher, J Perez-Stable, EJ AF Minter, Daniel J. Mejia, Raul Salas, Ignacio Thrasher, James Perez-Stable, Eliseo J. TI Tobacco point-of-sale advertising in downtown Buenos Aires, Argentina and compliance with the new tobacco advertising restrictions SO TOBACCO CONTROL LA English DT Editorial Material C1 [Minter, Daniel J.; Salas, Ignacio] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Mejia, Raul] Ctr Estudios Estado & Soc CEDES, Buenos Aires, DF, Argentina. [Mejia, Raul] Univ Buenos Aires, Buenos Aires, DF, Argentina. [Thrasher, James] Univ South Carolina, Dept Hlth Promot Educ & Behav, Columbia, SC USA. [Thrasher, James] Inst Nacl Salud Publ, Ctr Invest Salud Poblac, Dept Invest Tabaco, Cuernavaca, Morelos, Mexico. [Perez-Stable, Eliseo J.] Natl Inst Minor Hlth & Hlth Dispar NIMHD, NIH, Bethesda, MD USA. RP Minter, DJ (reprint author), Univ Calif San Francisco, San Francisco, CA 94143 USA. EM daniel.minter@ucsf.edu FU University of California San Francisco FX This work was supported by the University of California San Francisco 'Resource Allocation Program for Trainees'. This research received did not receive any additional support from any funding agency in the public, commercial or not-for-profit sectors. NR 5 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 0964-4563 EI 1468-3318 J9 TOB CONTROL JI Tob. Control PD MAR PY 2017 VL 26 IS 2 DI 10.1136/tobaccocontrol-2015-052870 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EL3QH UT WOS:000394533400029 PM 27030591 ER PT J AU Vogtmann, E Graubard, B Loftfield, E Chaturvedi, A Dye, BA Abnet, CC Freedman, ND AF Vogtmann, Emily Graubard, Barry Loftfield, Erikka Chaturvedi, Anil Dye, Bruce A. Abnet, Christian C. Freedman, Neal D. TI Contemporary impact of tobacco use on periodontal disease in the USA SO TOBACCO CONTROL LA English DT Editorial Material ID UNITED-STATES; SMOKING; UPDATE C1 [Vogtmann, Emily; Graubard, Barry; Loftfield, Erikka; Chaturvedi, Anil; Abnet, Christian C.; Freedman, Neal D.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Vogtmann, Emily] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Dye, Bruce A.] Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. RP Vogtmann, E (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr MSC 9768, Bethesda, MD 20892 USA. EM emily.vogtmann@nih.gov FU NCI; NIH; FDA FX This study was supported by funds from the Intramural Research Program of the NCI and the Tobacco Regulatory Science Program through the NIH and FDA. NR 6 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 0964-4563 EI 1468-3318 J9 TOB CONTROL JI Tob. Control PD MAR PY 2017 VL 26 IS 2 DI 10.1136/tobaccocontrol-2015-052750 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EL3QH UT WOS:000394533400028 PM 26880744 ER PT J AU Zhang, KN Xu, XY Pasha, MA Siebel, CW Costello, A Haczku, A MacNamara, K Liang, TB Zhu, JF Bhandoola, A Maillard, I Yang, Q AF Zhang, Kangning Xu, Xingyuan Pasha, Muhammad Asghar Siebel, Christian W. Costello, Angelica Haczku, Angela MacNamara, Katherine Liang, Tingbo Zhu, Jinfang Bhandoola, Avinash Maillard, Ivan Yang, Qi TI Cutting Edge: Notch Signaling Promotes the Plasticity of Group-2 Innate Lymphoid Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FUNCTIONAL PLASTICITY; LYMPHOCYTES; EXPRESSION AB The mechanisms underlying lymphocyte lineage stabil-ity and plasticity remain elusive. Recent work indicates that innate lymphoid cells (ILC) possess substantial plasticity. Whereas natural ILC2 (nILC2) produce type-2 cytokines, plastic inflammatory ILC2 (iILC2) can coproduce both type-2 cytokines and the ILC3-characteristic cytokine, IL-17. Mechanisms that elicit this lineage plasticity, and the importance in health and disease, remain unclear. In this study we show that iILC2 are potent inducers of airway inflammation in response to acute house dust mite challenge. We find that Notch signaling induces lineage plasticity of ma-ture ILC2 and drives the conversion of nILC2 into iILC2. Acute blockade of Notch signaling abolished functional iILC2, but not nILC2, in vivo. Exposure of isolated nILC2 to Notch ligands induced Rorc ex-pression and elicited dual IL-13/ IL-17 production, con-verting nILC2 into iILC2. Together these results reveal a novel role for Notch signaling in eliciting ILC2 plasticity and driving the emergence of highly proinflammatory innate lymphocytes. C1 [Zhang, Kangning; Xu, Xingyuan; Costello, Angelica; MacNamara, Katherine; Yang, Qi] Albany Med Coll, Dept Immunol & Microbial Dis, 47 New Scotland Ave,MC-151, Albany, NY 12208 USA. [Xu, Xingyuan; Liang, Tingbo] Zhejiang Univ, Dept Hepatobiliary & Pancreat Surg, Affiliated Hosp 2, Hangzhou 310009, Zhejiang, Peoples R China. [Pasha, Muhammad Asghar] Albany Med Coll, Dept Med, Div Allergy & Immunol, Albany, NY 12203 USA. [Siebel, Christian W.] Genentech Inc, Dept Discovery Oncol, San Francisco, CA 94080 USA. [Haczku, Angela] Univ Calif Davis, Div Pulm Crit Care & Sleep Med, Dept Internal Med, Translat Lung Biol Ctr, Davis, CA 95616 USA. [Zhu, Jinfang] NIAID, Mol & Cellular Immunoregulat Unit, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Bhandoola, Avinash] NCI, T Cell Biol & Dev Unit, Lab Genome Integr, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Maillard, Ivan] Univ Michigan, Inst Life Sci, Div Hematol Oncol, Dept Internal Med, Ann Arbor, MI 48109 USA. [Maillard, Ivan] Univ Michigan, Dept Cell & Dev Biol, Ann Arbor, MI 48109 USA. RP Yang, Q (reprint author), Albany Med Coll, Dept Immunol & Microbial Dis, 47 New Scotland Ave,MC-151, Albany, NY 12208 USA. EM yangq@mail.amc.edu FU National Institutes of Health (NIH) [K22-AI116728, R01-GM105949, R01-AI091627]; Leukemia and Lymphoma Society [CDP 1227-14, TRP 6462-15]; NIH Intramural Research Programs of the National Institute of Allergy and Infectious Diseases; NIH Intramural Research Programs of the National Cancer Institute; NIH Intramural Research Programs of Center for Cancer Research; Natural Science Foundation of China FX This work was supported by National Institutes of Health (NIH) Grants K22-AI116728 (to Q.Y.), R01-GM105949 (to K.M.), and R01-AI091627 (to I.M.), Leukemia and Lymphoma Society Grants CDP 1227-14 and TRP 6462-15 (to I.M.), the NIH Intramural Research Programs of the National Institute of Allergy and Infectious Diseases (to J.Z.), the NIH Intramural Research Programs of the National Cancer Institute and the Center for Cancer Research (to A.B.), and the Natural Science Foundation of China (to T.L.). NR 18 TC 0 Z9 0 U1 3 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAR 1 PY 2017 VL 198 IS 5 BP 1798 EP 1803 DI 10.4049/jimmunol.1601421 PG 6 WC Immunology SC Immunology GA EN3JE UT WOS:000395904000006 PM 28115527 ER PT J AU Robinson, MJ Prout, M Mearns, H Kyle, R Camberis, M Forbes-Blom, EE Paul, WE Allen, CDC Le Gros, G AF Robinson, Marcus J. Prout, Melanie Mearns, Helen Kyle, Ryan Camberis, Mali Forbes-Blom, Elizabeth E. Paul, William E. Allen, Christopher D. C. Le Gros, Graham TI IL-4 Haploinsufficiency Specifically Impairs IgE Responses against Allergens in Mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD4(+) T-CELLS; IN-VIVO; FOOD ALLERGY; GENETIC-VARIANTS; INDUCED DIARRHEA; MURINE MODEL; ASTHMA RISK; MAST-CELLS; EXPRESSION; ANAPHYLAXIS AB Polymorphisms in genes involved in IL-4 responses segregate with allergic disease risk and correlate with IgE levels in humans, and IL-4 promotes IgE and IgG1 Ab production against allergens in mice. We report that mice with only one intact Il4 gene copy are significantly impaired in their ability to make specific IgE responses against allergens, whereas IgG1 responses to allergens remain unaffected. Il4-hemizygosity also resulted in a modest but detectable drop in IL-4 production by CD4(+) T cells isolated from lymph nodes and prevented IgE-dependent oral allergen-induced diarrhea. We conclude that a state of haploinsufficiency for the Il4 gene locus is specifically relevant for IL-4-dependent IgE responses to allergens with the amount of IL-4 produced in the hemizygous condition falling close to the threshold required for switching to IgE production. These results may be relevant for how poly-morphisms in genes affecting IL-4 responses influence the risk of IgE-mediated allergic disease in humans. C1 [Robinson, Marcus J.; Prout, Melanie; Mearns, Helen; Kyle, Ryan; Camberis, Mali; Forbes-Blom, Elizabeth E.; Le Gros, Graham] Malaghan Inst Med Res, POB 7060, Wellington 6242, New Zealand. [Robinson, Marcus J.; Allen, Christopher D. C.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. [Robinson, Marcus J.; Allen, Christopher D. C.] Univ Calif San Francisco, Sandler Asthma Basic Res Ctr, San Francisco, CA 94143 USA. [Paul, William E.] NIAID, Labs Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Allen, Christopher D. C.] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. [Mearns, Helen] Univ Cape Town, South African TB Vaccine Initiat, Inst Infect Dis & Mol Med, Cape Town, South Africa. RP Le Gros, G (reprint author), Malaghan Inst Med Res, POB 7060, Wellington 6242, New Zealand. EM glegros@malaghan.org.nz OI Le Gros, Graham/0000-0002-5721-0442; Robinson, Marcus/0000-0001-5677-3078 FU Health Research Council of New Zealand; Marjorie Barclay Trust; Sandler Asthma Basic Research Center at the University of California, San Francisco; Weston Havens Foundation; National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R01AI103146] FX This work was supported by the Health Research Council of New Zealand, the Marjorie Barclay Trust, and in part by the Sandler Asthma Basic Research Center at the University of California, San Francisco, the Weston Havens Foundation, and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number R01AI103146. NR 54 TC 0 Z9 0 U1 0 U2 0 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 2017 VL 198 IS 5 BP 1815 EP 1822 DI 10.4049/jimmunol.1601434 PG 8 WC Immunology SC Immunology GA EN3JE UT WOS:000395904000008 PM 28115531 ER PT J AU Knode, LMR Naradikian, MS Myles, A Scholz, JL Hao, Y Liu, DY Ford, ML Tobias, JW Cancro, MP Gearhart, PJ AF Knode, Lisa M. Russell Naradikian, Martin S. Myles, Arpita Scholz, Jean L. Hao, Yi Liu, Danya Ford, Mandy L. Tobias, John W. Cancro, Michael P. Gearhart, Patricia J. TI Age-Associated B Cells Express a Diverse Repertoire of V-H and V kappa Genes with Somatic Hypermutation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MEMORY B; AFFINITY MATURATION; T-BET; MICE REFLECTS; OLD MICE; PRECURSORS; PHOSPHORYLCHOLINE; INDIVIDUALS; GENERATION; EXPANSIONS AB The origin and nature of age-associated B cells (ABCs) in mice are poorly understood. In this article, we show that their emergence required MHC class II and CD40/CD40L interactions. Young donor B cells were adoptively transferred into congenic recipients and allowed to remain for 1 mo in the absence of external Ag. B cells expressing the T-bet transcription factor, a marker for ABCs, were generated after multiple cell divisions from C57BL/6 donors but not from MHC class II- or CD40-deficient donors. Furthermore, old CD154 (CD40L)-deficient mice did not accrue ABCs, confirming that they arise primarily through T-dependent interactions. To determine what Igs ABCs express, we sequenced V-H and V kappa rearranged genes from unimmunized 22-mo-old C57BL/6 mice and showed that they had a heterogeneous repertoire, which was comparable to that seen in old follicular and marginal zone B cell subsets. However, in contrast to the follicular and marginal zone cells, ABCs displayed significant somatic hypermutation. The mutation frequency was lower than found in germinal center cells after deliberate immunization, suggesting that ABCs have undergone mild stimulation from endogenous Ags over time. These observations show that quiescent ABCs are Ag-experienced cells that accumulate during T cell-dependent responses to diverse Ags during the life of an individual. C1 [Knode, Lisa M. Russell; Cancro, Michael P.; Gearhart, Patricia J.] NIA, NIH, Lab Mol Biol & Immunol, 251 Bayview Blvd, Baltimore, MD 21224 USA. [Naradikian, Martin S.; Myles, Arpita; Scholz, Jean L.; Hao, Yi; Cancro, Michael P.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Liu, Danya; Ford, Mandy L.] Emory Univ, Emory Transplant Ctr, Atlanta, GA 30322 USA. [Liu, Danya; Ford, Mandy L.] Emory Univ, Dept Surg, Atlanta, GA 30322 USA. [Tobias, John W.] Univ Penn, Penn Mol Profiling Facil, Perelman Sch Med, Philadelphia, PA 19104 USA. [Hao, Yi] Tongji Med Coll, Wuhan, Peoples R China. RP Gearhart, PJ (reprint author), NIA, NIH, Lab Mol Biol & Immunol, 251 Bayview Blvd, Baltimore, MD 21224 USA.; Cancro, MP (reprint author), Univ Penn, Dept Pathol & Lab Med, 284 John Morgan Bldg,3620 Hamilton Walk, Philadelphia, PA 19104 USA. EM cancro@mail.med.upenn.edu; gearhartp@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute on Aging; National Institute of Allergy and Infectious Diseases [T32 AI055428]; Department of the Army [PR130769]; National Institute on Aging [R01 AG030227] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging (to L.M.R.K. and P.J.G.) and by Grants PR130769 (Department of the Army) and R01 AG030227 (National Institute on Aging) (to M.P.C.). M.S.N. was supported in part by National Institute of Allergy and Infectious Diseases Grant T32 AI055428. NR 39 TC 0 Z9 0 U1 2 U2 2 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 2017 VL 198 IS 5 BP 1921 EP 1927 DI 10.4049/jimmunol.1601106 PG 7 WC Immunology SC Immunology GA EN3JE UT WOS:000395904000018 ER PT J AU Plank, MW Kaiko, GE Maltby, S Weaver, J Tay, HL Shen, W Wilson, MS Durum, SK Foster, PS AF Plank, Maximilian W. Kaiko, Gerard E. Maltby, Steven Weaver, Jessica Tay, Hock L. Shen, Wei Wilson, Mark S. Durum, Scott K. Foster, Paul S. TI Th22 Cells Form a Distinct Th Lineage from Th17 Cells In Vitro with Unique Transcriptional Properties and Tbet-Dependent Th1 Plasticity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IL-22 PRODUCTION; INTERLEUKIN 22; T(H)17 CELLS; INFLAMMATION; CYTOKINE; DISEASE; EXPRESSION; PROTECTION; PSORIASIS; MEMORY AB Th22 cells are a major source of IL-22 and have been found at sites of infection and in a range of inflammatory diseases. However, their molecular characteristics and functional roles remain largely unknown because of our inability to generate and isolate pure populations. We developed a novel Th22 differentiation assay and generated dual IL-22/ IL-17A reporter mice to isolate and compare pure populations of cultured Th22 and Th17 cells. Il17a fate-mapping and transcriptional profiling provide evidence that these Th22 cells have never expressed IL-17A, suggesting that they are potentially a distinct cell lineage from Th17 cells under in vitro culture conditions. Interestingly, Th22 cells also expressed granzymes, IL-13, and increased levels of Tbet. Using transcription factor-deficient cells, we demonstrate that RORgt and Tbet act as positive and negative regulators of Th22 differentiation, respectively. Furthermore, under Th1 culture conditions in vitro, as well as in an IFN-gamma-rich inflammatory environment in vivo, Th22 cells displayed marked plasticity toward IFN-g production. Th22 cells also displayed plasticity under Th2 conditions in vitro by upregulating IL-13 expression. Our work has identified conditions to generate and characterize Th22 cells in vitro. Further, it provides evidence that Th22 cells develop independently of the Th17 lineage, while demonstrating plasticity toward both Th1-and Th2-type cells. C1 [Plank, Maximilian W.; Kaiko, Gerard E.; Maltby, Steven; Weaver, Jessica; Tay, Hock L.; Foster, Paul S.] Univ Newcastle, Sch Pharm & Biomed Sci, Fac Hlth & Hunter Med Res Inst, Dept Microbiol & munol, Newcastle, NSW, Australia. [Shen, Wei; Durum, Scott K.] Natl Canc Inst, Natl Inst Hlth, Ctr Canc Res, Immunoregulat Lab, Frederick, MD 21702 USA. [Wilson, Mark S.] Francis Crick Inst, Div Mol Immunol, London NW1 1AT, England. RP Foster, PS (reprint author), Hunter Med Res Inst, Ctr Healthy Lungs, Lot 1 Kooka burra Circuit, Newcastle, NSW 2305, Australia. EM paul.foster@newcastle.edu.au FU National Health and Medical Research Council of Australia [APP1061413]; Australian Respiratory Council under Harry Windsor Research Grants; European Respiratory Society Fellowship (STRTF) FX This work was supported by the National Health and Medical Research Council of Australia under project Grant APP1061413 and the Australian Respiratory Council under the Harry Windsor Research Grants Scheme. M.W.P. is the recipient of a European Respiratory Society Fellowship (STRTF 2015). NR 31 TC 0 Z9 0 U1 0 U2 0 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 2017 VL 198 IS 5 BP 2182 EP 2190 DI 10.4049/jimmunol.1601480 PG 9 WC Immunology SC Immunology GA EN3JE UT WOS:000395904000043 PM 28100680 ER PT J AU Zhang, JH Paksarian, D Lamers, F Hickie, IB He, JP Merikangas, KR AF Zhang, Jihui Paksarian, Diana Lamers, Femke Hickie, Ian B. He, Jianping Merikangas, Kathleen Ries TI Sleep Patterns and Mental Health Correlates in US Adolescents SO JOURNAL OF PEDIATRICS LA English DT Article ID SUPPLEMENT NCS-A; SCHOOL START TIME; BIPOLAR DISORDER; DURATION; METAANALYSIS; DEPRESSION; INSOMNIA; ADULTS; CHILDREN; MOOD AB Objective To investigate systematically the associations of sleep patterns with a range of mental disorders and other outcomes among a nationally representative sample of US adolescents. Study design Using the National Comorbidity Survey Adolescent Supplement, a nationally representative cross-sectional survey of 10 123 US adolescents 13-18 years of age, we assessed associations between adolescent-reported sleep patterns (tertiles of weeknight bedtime, weeknight sleep duration, weekend bedtime delay, and weekend oversleep) and past-year mental disorders based on the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, smoking, injury, suicidality, and perceived mental and physical health, assessed via direct diagnostic interview. Results The average weeknight bedtime was at 22: 37 and sleep duration was 7.72 hours. Average weekend bedtime delay was 1.81 hours and average weekend oversleep was 1.17 hours. Later weeknight bedtime, shorter weeknight sleep duration, greater weekend bedtime delay, and both short and long periods of weekend oversleep were associated with increased odds of mood, anxiety, substance use, and behavioral disorders, as well as suicidality, tobacco smoking, and poor perceived mental and physical health. ORs ranged from 1.27 to 2.15. The only outcomes not associated with any sleep patterns were past-year injury and eating disorder. Conclusions Suboptimal sleep patterns were associated with an array of mental disorders and other health-related outcomes among adolescents. Abnormal sleep patterns may serve as markers of prodromal or untreated mental disorders among adolescents, and may provide opportunities for prevention and intervention in mental disorders. C1 [Zhang, Jihui] Chinese Univ Hong Kong, Dept Psychiat, Fac Med, Shatin, Hong Kong, Peoples R China. [Paksarian, Diana; Lamers, Femke; He, Jianping; Merikangas, Kathleen Ries] Natl Inst Mental Hlth, Genet Epidemiol Res Branch, Intramural Res Program, Amsterdam, Netherlands. [Lamers, Femke] Vrije Univ Amsterdam Med Ctr, Dept Psychiat, GGZ Geest, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Lamers, Femke] Vrije Univ Amsterdam Med Ctr, GGZ Geest, Neurosci Campus, Amsterdam, Netherlands. [Hickie, Ian B.] Univ Sydney, Brain & Mind Res Inst, Camperdown, NSW 2050, Australia. RP Merikangas, KR (reprint author), NIMH, Intramural Res Program, Genet Epidemiol Res Branch, 35 Convent Dr,MSC 3720, Bethesda, MD 20892 USA. EM Kathleen.merikangas@nih.gov FU National Institute of Mental Health [U01-MH60220, ZIAMH002808]; National Institute on Drug Abuse [R01DA016558] FX The National Comorbidity Survey-Adolescent Supplement is supported by the National Institute of Mental Health (U01-MH60220), the National Institute on Drug Abuse (R01DA016558), and the Intramural Research Program of the National Institute of Mental Health (ZIAMH002808). The views and opinions expressed in this article are those of the authors and should not be construed to represent the views of any of the sponsoring organizations, agencies, or the US government. The authors declare no conflicts of interest. NR 53 TC 0 Z9 0 U1 6 U2 6 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 2017 VL 182 BP 137 EP 143 DI 10.1016/j.jpeds.2016.11.007 PG 7 WC Pediatrics SC Pediatrics GA EN8LR UT WOS:000396252400024 PM 27939122 ER PT J AU Frye, TP George, AK Kilchevsky, A Maruf, M Siddiqui, MM Kongnyuy, M Muthigi, A Han, H Parnes, HL Merino, M Choyke, PL Turkbey, B Wood, B Pinto, PA AF Frye, Thomas P. George, Arvin K. Kilchevsky, Amichai Maruf, Mahir Siddiqui, M. Minhaj Kongnyuy, Michael Muthigi, Akhil Han, Hui Parnes, Howard L. Merino, Maria Choyke, Peter L. Turkbey, Baris Wood, Brad Pinto, Peter A. TI Magnetic Resonance Imaging-Transrectal Ultrasound Guided Fusion Biopsy to Detect Progression in Patients with Existing Lesions on Active Surveillance for Low and Intermediate Risk Prostate Cancer SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; watchful waiting; ultrasonography; magnetic resonance imaging; biopsy ID TARGETED BIOPSY; JOHNS-HOPKINS; FOLLOW-UP; MEN; EXPERIENCE; DIAGNOSIS; ACCURACY; CRITERIA; OUTCOMES; PROGRAM AB Purpose: Active surveillance is an established option for men with low risk prostate cancer. Multiparametric magnetic resonance imaging with magnetic resonance imaging-transrectal ultrasound fusion guided biopsy may better identify patients for active surveillance compared to systematic 12-core biopsy due to improved risk stratification. To our knowledge the performance of multiparametric magnetic resonance imaging in following men on active surveillance with visible lesions is unknown. We evaluated multiparametric magnetic resonance imaging and magnetic resonance imaging-transrectal ultrasound fusion guided biopsy to monitor men on active surveillance. Materials and Methods: This retrospective review included men from 2007 to 2015 with prostate cancer on active surveillance in whom magnetic resonance imaging visible lesions were monitored by multiparametric magnetic resonance imaging and fusion guided biopsy. Progression was defined by ISUP ( International Society of Urological Pathology) grade group 1 to 2 and ISUP grade group 2 to 3. Significance was considered at p <= 0.05. Results: A total of 166 patients on active surveillance with 2 or more fusion guided biopsies were included in analysis. Mean followup was 25.5 months. Of the patients 29.5% had pathological progression. Targeted biopsy alone identified 44.9% of patients who progressed compared to 30.6% identified by systematic 12core biopsy alone ( p = 0.03). Fusion guided biopsy detected 26% more cases of pathological progression on surveillance biopsy compared to systematic 12-core biopsy. Progression on multiparametric magnetic resonance imaging was the sole predictor of pathological progression at surveillance biopsy ( p = 0.013). Multiparametric magnetic resonance imaging progression in the entire cohort had 81% negative predictive value, 35% positive predictive value, 77.6% sensitivity and 40.5% specificity in detecting pathological progression. Conclusions: Multiparametric magnetic resonance imaging progression predicts the risk of pathological progression. Patients with stable multiparametric magnetic resonance imaging findings have a low rate of progression. Incorporating fusion guided biopsy in active surveillance nearly doubled our detection of pathological progression compared to systematic 12-core biopsy. C1 [Frye, Thomas P.] Univ Rochester, Dept Urol, Rochester, NY USA. [George, Arvin K.] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA. [Frye, Thomas P.; George, Arvin K.; Kilchevsky, Amichai; Maruf, Mahir; Kongnyuy, Michael; Muthigi, Akhil; Han, Hui; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Merino, Maria] NCI, Surg Pathol, NIH, Bethesda, MD 20892 USA. [Choyke, Peter L.; Turkbey, Baris] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Wood, Brad; Pinto, Peter A.] NCI, Intervent Oncol, NIH, Bethesda, MD 20892 USA. [Parnes, Howard L.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. Univ Maryland, Div Urol, Baltimore, MD 21201 USA. RP Pinto, PA (reprint author), NCI, Prostate Canc Sect, Urol Oncol Branch, Hatfield CRC, Bldg 10,Room 2W-5940, Bethesda, MD 20892 USA. EM pintop@mail.nh.gov FU National Institutes of Health and Philips Cooperative Research and Development Agreement FX Financial interest and/or other relationship with National Institutes of Health and Philips Cooperative Research and Development Agreement. NR 30 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD MAR PY 2017 VL 197 IS 3 BP 640 EP 646 DI 10.1016/j.juro.2016.08.109 PN 1 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA EN2VY UT WOS:000395869600037 PM 27613356 ER PT J AU Turkbey, B AF Turkbey, Baris TI Editorial Comment SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 [Turkbey, Baris] NCI, NIH, Bethesda, MD 20892 USA. RP Turkbey, B (reprint author), NCI, 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 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD MAR PY 2017 VL 197 IS 3 BP 683 EP 683 PN 1 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA EN2VY UT WOS:000395869600045 PM 27886779 ER PT J AU O'Connor, JPB Aboagye, EO Adams, JE Aerts, HJWL Barrington, SF Beer, AJ Boellaard, R Bohndiek, SE Brady, M Brown, G Buckley, DL Chenevert, TL Clarke, LP Collette, S Cook, GJ Desouza, NM Dickson, JC Dive, C Evelhoch, JL Faivre-Finn, C Gallagher, FA Gilbert, FJ Gillies, RJ Goh, V Griffiths, JR Groves, AM Halligan, S Harris, AL Hawkes, DJ Hoekstra, OS Huang, EP Hutton, BF Jackson, EF Jayson, GC Jones, A Koh, DM Lacombe, D Lambin, P Lassau, N Leach, MO Lee, TY Leen, EL Lewis, JS Liu, Y Lythgoe, MF Manoharan, P Maxwell, RJ Miles, KA Morgan, B Morris, S Ng, T Padhani, AR Parker, GJM Partridge, M Pathak, AP Peet, AC Punwani, S Reynolds, AR Robinson, SP Shankar, LK Sharma, RA Soloviev, D Stroobants, S Sullivan, DC Taylor, SA Tofts, PS Tozer, GM van Herk, M Walker-Samuel, S Wason, J Williams, KJ Workman, P Yankeelov, TE Brindle, KM McShane, LM Jackson, A Waterton, JC AF O'Connor, James P. B. Aboagye, Eric O. Adams, Judith E. Aerts, Hugo J. W. L. Barrington, Sally F. Beer, Ambros J. Boellaard, Ronald Bohndiek, Sarah E. Brady, Michael Brown, Gina Buckley, David L. Chenevert, Thomas L. Clarke, Laurence P. Collette, Sandra Cook, Gary J. Desouza, Nandita M. Dickson, John C. Dive, Caroline Evelhoch, Jeffrey L. Faivre-Finn, Corinne Gallagher, Ferdia A. Gilbert, Fiona J. Gillies, Robert J. Goh, Vicky Griffiths, John R. Groves, Ashley M. Halligan, Steve Harris, Adrian L. Hawkes, David J. Hoekstra, Otto S. Huang, Erich P. Hutton, Brian F. Jackson, Edward F. Jayson, Gordon C. Jones, Andrew Koh, Dow-Mu Lacombe, Denis Lambin, Philippe Lassau, Nathalie Leach, Martin O. Lee, Ting-Yim Leen, Edward L. Lewis, Jason S. Liu, Yan Lythgoe, Mark F. Manoharan, Prakash Maxwell, Ross J. Miles, Kenneth A. Morgan, Bruno Morris, Steve Ng, Tony Padhani, Anwar R. Parker, Geoff J. M. Partridge, Mike Pathak, Arvind P. Peet, Andrew C. Punwani, Shonit Reynolds, Andrew R. Robinson, Simon P. Shankar, Lalitha K. Sharma, Ricky A. Soloviev, Dmitry Stroobants, Sigrid Sullivan, Daniel C. Taylor, Stuart A. Tofts, Paul S. Tozer, Gillian M. van Herk, Marcel Walker-Samuel, Simon Wason, James Williams, Kaye J. Workman, Paul Yankeelov, Thomas E. Brindle, Kevin M. McShane, Lisa M. Jackson, Alan Waterton, John C. TI Imaging biomarker roadmap for cancer studies SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Article ID CONTRAST-ENHANCED MRI; POSITRON-EMISSION-TOMOGRAPHY; CELL LUNG-CANCER; GROUP DEVELOPMENTAL PATHWAY; ADVANCED SOLID TUMORS; SURROGATE END-POINTS; HIGH FAMILIAL RISK; DRUG DEVELOPMENT; CLINICAL-TRIALS; BREAST-CANCER AB Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use. C1 [O'Connor, James P. B.; Manoharan, Prakash; Parker, Geoff J. M.; Williams, Kaye J.; Jackson, Alan; Waterton, John C.] Univ Manchester, CRUK & EPSRC Canc Imaging Ctr Cambridge & Manches, Manchester, Lancs, England. [Aboagye, Eric O.; Leen, Edward L.] Imperial Coll, Dept Surg & Canc, London, England. [Adams, Judith E.] Cent Manchester Univ Hosp NHS Fdn Trust, Dept Clin Radiol, Manchester, Lancs, England. [Aerts, Hugo J. W. L.] Harvard Med Sch, Dept Radiat Oncol, Boston, MA USA. [Barrington, Sally F.; Cook, Gary J.; Goh, Vicky; Ng, Tony] Kings Coll London, CRUK & EPSRC Comprehens Imaging Ctr KCL & UCL, London, England. [Beer, Ambros J.] Univ Hosp Ulm, Dept Nucl Med, Ulm, Germany. [Boellaard, Ronald] Univ Med Ctr Groningen, Dept Nucl Med & Mol Imaging, Groningen, Netherlands. [Bohndiek, Sarah E.; Gallagher, Ferdia A.; Gilbert, Fiona J.; Griffiths, John R.; Soloviev, Dmitry; Brindle, Kevin M.] Univ Cambridge, CRUK & EPSRC Canc Imaging Ctr Cambridge & Manches, Cambridge, England. [Brady, Michael; Harris, Adrian L.; Partridge, Mike] Univ Oxford, CRUK & EPSRC Canc Imaging Ctr, Oxford, England. [Brown, Gina] Royal Marsden Hosp, Dept Radiol, London, England. [Buckley, David L.] Univ Leeds, Div Biomed Imaging, Leeds, W Yorkshire, England. [Chenevert, Thomas L.] Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. [Clarke, Laurence P.; Shankar, Lalitha K.] NCI, Canc Imaging Program, Bethesda, MD 20892 USA. [Collette, Sandra] EORTC, Biostat, Brussels, Belgium. [Desouza, Nandita M.; Koh, Dow-Mu; Leach, Martin O.; Robinson, Simon P.] Inst Canc Res, CRUK Canc Imaging Ctr, London, England. [Dickson, John C.; Groves, Ashley M.; Halligan, Steve; Hawkes, David J.; Hutton, Brian F.; Miles, Kenneth A.; Punwani, Shonit; Sharma, Ricky A.; Taylor, Stuart A.] UCL, CRUK & EPSRC Canc Imaging Ctr KCL & UCL, London, England. [Dive, Caroline] CRUK Manchester Inst, Clin & Expt Pharmacol, Manchester, Lancs, England. [Evelhoch, Jeffrey L.] Merck & Co Inc, Translat Biomarkers, West Point, PA USA. [Faivre-Finn, Corinne; van Herk, Marcel] Univ Manchester, Radiotherapy Related Res Grp, Manchester, Lancs, England. [Gillies, Robert J.] H Lee Moffitt Canc Ctr & Res Inst, Canc Imaging & Metab, Tampa, FL USA. [Hoekstra, Otto S.] Vrije Univ Amsterdam, Med Ctr, Dept Radiol & Nucl Med, Amsterdam, Netherlands. [Huang, Erich P.; McShane, Lisa M.] NCI, Biometr Res Program, Bethesda, MD 20892 USA. [Jackson, Edward F.] Univ Wisconsin, Dept Med Phys, 1530 Med Sci Ctr, Madison, WI 53706 USA. [Jayson, Gordon C.] Univ Manchester, Inst Canc Sci, Manchester, Lancs, England. [Jones, Andrew] Christie Hosp NHS Fdn Trust, Med Phys, Manchester, Lancs, England. [Lacombe, Denis; Liu, Yan] EORTC, EORTC Headquarters, Brussels, Belgium. [Lambin, Philippe] Maastricht Univ, Dept Radiat Oncol, Maastricht, Netherlands. [Lassau, Nathalie] Gustave Roussy Canc Campus, Dept Imaging, Villejuif, France. [Lee, Ting-Yim] Robarts Res Inst, Imaging Res Labs, London, ON, Canada. [Lewis, Jason S.] Mem Sloan Kettering Canc Ctr, Dept Radiol, 1275 York Ave, New York, NY 10021 USA. [Lythgoe, Mark F.; Walker-Samuel, Simon] UCL, Ctr Adv Biomed Imaging, London, England. [Maxwell, Ross J.] Newcastle Univ, Northern Inst Canc Res, Newcastle Upon Tyne, Tyne & Wear, England. [Morgan, Bruno] Univ Leicester, Canc Studies & Mol Med, Leicester, Leics, England. [Morris, Steve] UCL, Inst Epidemiol & Hlth, London, England. [Padhani, Anwar R.] Mt Vernon Hosp, Paul Strickland Scanner Ctr, London, England. [Pathak, Arvind P.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [Peet, Andrew C.] Univ Birmingham, Inst Canc & Genom, Birmingham, W Midlands, England. [Reynolds, Andrew R.] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London, England. [Stroobants, Sigrid] Univ Antwerp, Mol Imaging Ctr Antwerp, Antwerp, Belgium. [Sullivan, Daniel C.] Duke Univ, Sch Med, Dept Radiol, Durham, NC USA. [Tofts, Paul S.] Univ Sussex, Brighton & Sussex Med Sch, Brighton, E Sussex, England. [Tozer, Gillian M.] Univ Sheffield, Dept Oncol & Metab, Sheffield, S Yorkshire, England. [Wason, James] MRC Biostat Unit, Cambridge, England. [Workman, Paul] Inst Canc Res, CRUK Canc Therapeut Unit, London, England. [Yankeelov, Thomas E.] Univ Texas Austin, Inst Computat Engn & Sci, Austin, TX 78712 USA. RP O'Connor, JPB (reprint author), Univ Manchester, Manchester Inst, Canc Res UK, Wilmslow Rd, Manchester M20 4BX, Lancs, England. EM james.o'connor@manchester.ac.uk RI van Herk, Marcel/P-6307-2015; Aerts, Hugo/P-6350-2015; OI van Herk, Marcel/0000-0001-6448-898X; Aerts, Hugo/0000-0002-2122-2003; O'Connor, James/0000-0002-4044-8497; Bohndiek, Sarah/0000-0003-0371-8635; Parker, Geoffrey/0000-0003-2934-2234 FU Engineering and Physical Sciences Research Council [A/15267, A/16463, A/16464, A/16465, A/16466, A/18097]; Innovative Medicines Initiative Joint Undertaking [115151]; European Union FX Development of this roadmap received support from Cancer Research UK and the Engineering and Physical Sciences Research Council (grant references A/15267, A/16463, A/16464, A/16465, A/16466 and A/18097), the EORTC Cancer Research Fund, and the Innovative Medicines Initiative Joint Undertaking (grant agreement number 115151), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies' in kind contribution. NR 150 TC 1 Z9 1 U1 8 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 EI 1759-4782 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD MAR PY 2017 VL 14 IS 3 BP 169 EP 186 DI 10.1038/nrclinonc.2016.162 PG 18 WC Oncology SC Oncology GA EO6XP UT WOS:000396836100006 PM 27725679 ER PT J AU Brasky, TM Felix, AS Cohn, DE McMeekin, DS Mutch, DG Creasman, WT Thaker, PH Walker, JL Moore, RG Lele, SB Guntupalli, SR Downs, LS Nagel, CI Boggess, JF Pearl, ML Ioffe, OB Park, KJ Ali, S Brinton, LA AF Brasky, Theodore M. Felix, Ashley S. Cohn, David E. McMeekin, D. Scott Mutch, David G. Creasman, William T. Thaker, Premal H. Walker, Joan L. Moore, Richard G. Lele, Shashikant B. Guntupalli, Saketh R. Downs, Levi S. Nagel, Christa I. Boggess, John F. Pearl, Michael L. Ioffe, Olga B. Park, Kay J. Ali, Shamshad Brinton, Louise A. TI Nonsteroidal Anti-inflammatory Drugs and Endometrial Carcinoma Mortality and Recurrence SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID COLORECTAL-CANCER SURVIVAL; LOW-DOSE ASPIRIN; RANDOMIZED CONTROLLED-TRIALS; MIXED MULLERIAN TUMORS; WOMENS HEALTH; CYCLOOXYGENASE-2 COX-2; POSTMENOPAUSAL WOMEN; RISK FACTORS; FOLLOW-UP; EXPRESSION AB Background: Recent data suggest that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with reductions in endometrial cancer risk, yet very few have examined whether their use is related to prognosis among endometrial cancer patients. Methods: Study subjects comprised 4374 participants of the NRG Oncology/Gynecology Oncology Group 210 Study with endometrial carcinoma who completed a presurgical questionnaire that assessed history of regular prediagnostic NSAID use and endometrial cancer risk factors. Recurrences, vital status, and causes of death were obtained from medical records and cancer registries. Fine-Gray semiproportional hazards regression estimated adjusted subhazard ratios (HRs) and 95% confidence intervals (CIs) for associations of NSAID use with endometrial carcinoma-specific mortality and recurrence. Models were stratified by endometrial carcinoma type (ie, type I [endometrioid] vs type II [serous, clear cell, or carcinosarcoma]) and histology. Results: Five hundred fifty endometrial carcinoma-specific deaths and 737 recurrences occurred during a median of five years of follow-up. NSAID use was associated with 66% (HR = 1.66, 95% CI = 1.21 to 2.30) increased endometrial carcinoma-specific mortality among women with type I cancers. Associations were statistically significant for former and current users, and strongest among former users who used NSAIDs for 10 years or longer (HR = 2.23, 95% CI = 1.19 to 4.18, two-sided P-trend =.01). NSAID use was not associated with recurrence or endometrial carcinoma-specific mortality among women with type II tumors. Conclusions: In this study, use of NSAIDs was associated with increased endometrial carcinoma-specific mortality, especially in patients with type I tumors. Barring a clear biologic mechanism by which NSAIDs would increase the risk of cause-specific mortality, cautious interpretation is warranted. C1 [Brasky, Theodore M.] Ohio State Univ, Coll Med, Div Canc Prevent & Control, Columbus, OH 43210 USA. [Cohn, David E.] Ohio State Univ, Coll Med, Div Gynecol Oncol, Columbus, OH 43210 USA. [Felix, Ashley S.] Ohio State Univ, Coll Publ Hlth, Div Epidemiol, Columbus, OH 43210 USA. [Felix, Ashley S.; Brinton, Louise A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Felix, Ashley S.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [McMeekin, D. Scott; Walker, Joan L.] Univ Oklahoma, Dept Obstet & Gynecol, Oklahoma City, OK USA. [Mutch, David G.; Thaker, Premal H.] Washington Univ, Sch Med, St Louis, MO USA. [Creasman, William T.] Med Univ South Carolina, Dept Obstet & Gynecol, Charleston, SC USA. [Moore, Richard G.] Brown Univ, Women & Infants Hosp, Dept Obstet & Gynecol, Program Womens Oncol, Providence, RI USA. [Lele, Shashikant B.] Roswell Pk Canc Inst, Gynecol Oncol, Buffalo, NY 14263 USA. [Ali, Shamshad] Roswell Pk Canc Inst, NRG Stat & Data Management Ctr, Buffalo, NY 14263 USA. [Guntupalli, Saketh R.] Univ Colorado, Ctr Canc, Gynecol Oncol, Aurora, CO USA. [Downs, Levi S.] Univ Minnesota, Gynecol Oncol, Minneapolis, MN USA. [Nagel, Christa I.] Case Western Reserve Univ, Div Gynecol Oncol, Cleveland, OH 44106 USA. [Boggess, John F.] Univ N Carolina, Gynecol Oncol Program, Chapel Hill, NC USA. [Pearl, Michael L.] SUNY Stony Brook, Gynecol Oncol, Stony Brook, NY 11794 USA. [Ioffe, Olga B.] Univ Maryland, Anat Pathol, College Pk, MD 20742 USA. [Park, Kay J.] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA. RP Brasky, TM (reprint author), 1590 N High St,Suite 525, Columbus, OH 43201 USA. EM theodore.brasky@osumc.edu FU National Cancer Institute [CA 27469]; Gynecologic Oncology Group Statistical and Data Center [CA 37517]; NRG Oncology Grant [1 U10 CA180822, U10 CA180868]; National Cancer Institute, National Institutes of Health FX This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469), the Gynecologic Oncology Group Statistical and Data Center (CA 37517), and the NRG Oncology Grant (numbers 1 U10 CA180822 and U10 CA180868). In addition, this research was supported in part by funds provided by the intramural research program of the National Cancer Institute, National Institutes of Health. NR 54 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD MAR PY 2017 VL 109 IS 3 AR djw251 DI 10.1093/jnci/djw251 PG 10 WC Oncology SC Oncology GA EO6AK UT WOS:000396773900015 ER PT J AU Kelly, SP Graubard, BI Andreotti, G Younes, N Cleary, SD Cook, MB AF Kelly, Scott P. Graubard, Barry I. Andreotti, Gabriella Younes, Naji Cleary, Sean D. Cook, Michael B. TI Prediagnostic Body Mass Index Trajectories in Relation to Prostate Cancer Incidence and Mortality in the PLCO Cancer Screening Trial SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID DOSE-RESPONSE METAANALYSIS; FOLLOW-UP; HEALTH-PROFESSIONALS; INSULIN-RESISTANCE; INITIAL-VALUE; WEIGHT CHANGE; LIFE-COURSE; TIME-SCALE; RISK; OBESITY AB Background: Evidence suggests that obesity in adulthood is associated with increased risk of "clinically significant" prostate cancer. However, studies of body mass index (BMI) across the adult life course and prostate cancer risks remain limited. Methods: In a prospective cohort of 69 873 men in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, we examined associations of prediagnostic BMI across the adult life course with risk of incident prostate cancer and fatal prostate cancer (prostate cancer-specific mortality). At 13 years of follow-up, we identified 7822 incident prostate cancer cases, of which 3078 were aggressive and 255 fatal. BMI trajectories were determined using latent-class trajectory modeling. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: BMI at age 20 years, 50 years, and baseline questionnaire (mean age = 63 years) were associated with increased risks of fatal prostate cancer (HRs = 1.27-1.32 per five-unit increase). In five BMI trajectories identified, fatal prostate cancer risk was increased in men who had a normal BMI (HR = 1.95, 95% CI = 1.21 to 3.12) or who were overweight (HR = 2.65, 95% CI = 1.35 to 5.18) at age 20 years and developed obesity by baseline compared with men who maintained a normal BMI. Aggressive and nonaggressive prostate cancer were not associated with BMI, and modest inverse associations were seen for total prostate cancer. Conclusions: Our results suggest that BMI trajectories during adulthood that result in obesity lead to an elevated risk of fatal prostate cancer. C1 [Kelly, Scott P.; Graubard, Barry I.; Andreotti, Gabriella; Cook, Michael B.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, 9609 Med Ctr Dr,Rm 7E-106,MSC 9774, Bethesda, MD 20892 USA. [Kelly, Scott P.; Younes, Naji; Cleary, Sean D.] George Washington Univ, Sch Publ Hlth, Milken Inst, Dept Epidemiol & Biostat, Washington, DC USA. RP Cook, MB (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, 9609 Med Ctr Dr,Rm 7E-106,MSC 9774, Bethesda, MD 20892 USA. EM michael.cook@nih.gov OI Kelly, Scott/0000-0002-0375-1040 FU Intramural Program of the National Cancer Institute at the National Institutes of Health; Department of Health and Human Services FX This work was supported by the Intramural Program of the National Cancer Institute at the National Institutes of Health and Department of Health and Human Services. NR 59 TC 0 Z9 0 U1 2 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 2017 VL 109 IS 3 AR djw225 DI 10.1093/jnci/djw225 PG 9 WC Oncology SC Oncology GA EO6AK UT WOS:000396773900005 ER PT J AU Maddocks, K Barr, PM Cheson, BD Little, RF Baizer, L Kahl, BS Leonard, JP Fowler, N Gordon, LI Link, BK Friedberg, JW Ansell, SM AF Maddocks, Kami Barr, Paul M. Cheson, Bruce D. Little, Richard F. Baizer, Lawrence Kahl, Brad S. Leonard, John P. Fowler, Nathan Gordon, Leo I. Link, Brian K. Friedberg, Jonathan W. Ansell, Stephen M. TI Recommendations for Clinical Trial Development in Follicular Lymphoma SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID TERM-FOLLOW-UP; BONE-MARROW-TRANSPLANTATION; RANDOMIZED CONTROLLED-TRIAL; NON-HODGKINS-LYMPHOMA; CHOP PLUS RITUXIMAB; 1ST-LINE TREATMENT; PHASE-III; DES LYMPHOMES; GRADE 3B; CHEMOTHERAPY AB Follicular lymphoma (FL) is the second most common lymphoid malignancy, representing 20% to 25% of all cases of nonHodgkin's lymphoma (NHL), and the most common of the indolent NHLs. FL is considered incurable in the majority of patients with the current standard therapeutic approaches, although outcomes have improved in the last few decades with our current therapies, with a median overall survival that now exceeds 18 years. While the majority of patients with FL have improved outcomes with our current therapeutic approaches, there are patients with high-risk disease features that have inferior outcomes to these therapies. There is an urgent need to integrate novel therapeutic agents into the treatment regimens for these patients to improve outcomes with continued evaluation of biomarkers indicative of prognosis and effects of these regimens on quality of life. C1 [Maddocks, Kami] Ohio State Univ, Columbus, OH 43210 USA. [Barr, Paul M.] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Cheson, Bruce D.] Georgetown Univ Hosp, Washington, DC 20007 USA. [Little, Richard F.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Baizer, Lawrence] NCI, Coordinating Ctr Clin Trials, Bethesda, MD 20892 USA. [Kahl, Brad S.] Washington Univ, Dept Med, Div Oncol, St Louis, MO USA. [Leonard, John P.] Weil Cornell Univ, Dept Med, New York, NY USA. [Fowler, Nathan] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Gordon, Leo I.] Northwestern Univ, Chicago, IL 60611 USA. [Link, Brian K.] Univ Iowa, Iowa City, IA USA. [Friedberg, Jonathan W.] Univ Rochester, Wilmot Canc Ctr, Rochester, NY USA. [Friedberg, Jonathan W.] Univ Rochester, Div Hematol Oncol, Rochester, NY USA. [Ansell, Stephen M.] Mayo Clin, Rochester, MN USA. RP Maddocks, K (reprint author), A350C Starling Loving Hall,320 W 10th Ave, Columbus, OH 43210 USA. EM kami.maddocks@osumc.edu FU Coordinating Center for Clinical Trials, National Cancer Institute/National Institutes of Health FX Partial support was from the Office of the Director, Coordinating Center for Clinical Trials, National Cancer Institute/National Institutes of Health. NR 48 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 2017 VL 109 IS 3 AR djw255 DI 10.1093/jnci/djw255 PG 8 WC Oncology SC Oncology GA EO6AK UT WOS:000396773900016 ER PT J AU Xu, WP Neckers, L AF Xu, Wanping Neckers, Len TI A USE1ful Biomarker and Molecular Target in Lung Cancer? SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID ACTIVATION C1 [Xu, Wanping; Neckers, Len] NCI, Urol Oncol Branch, Ctr Canc Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Neckers, L (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM neckers@nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 10 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 2017 VL 109 IS 3 AR djw227 DI 10.1093/jnci/djw227 PG 3 WC Oncology SC Oncology GA EO6AK UT WOS:000396773900007 ER PT J AU Manson, AL Cohen, KA Abeel, T Desjardins, CA Armstrong, DT Barry, CE Brand, J Chapman, SB Cho, SN Gabrielian, A Gomez, J Jodals, AM Joloba, M Jureen, P Lee, JS Malinga, L Maiga, M Nordenberg, D Noroc, E Romancenco, E Salazar, A Ssengooba, W Velayati, AA Winglee, K Zalutskaya, A Via, LE Cassell, GH Dorman, SE Ellner, J Farnia, P Galagan, JE Rosenthal, A Crudu, V Homorodean, D Hsueh, PR Narayanan, S Pym, AS Skrahina, A Swaminathan, S Van der Walt, M Alland, D Bishai, WR Cohen, T Hoffner, S Birren, BW Earl, AM AF Manson, Abigail L. Cohen, Keira A. Abeel, Thomas Desjardins, Christopher A. Armstrong, Derek T. Barry, Clifton E., III Brand, Jeannette Chapman, Sinead B. Cho, Sang-Nae Gabrielian, Andrei Gomez, James Jodals, Andreea M. Joloba, Moses Jureen, Pontus Lee, Jong Seok Malinga, Lesibana Maiga, Mamoudou Nordenberg, Dale Noroc, Ecaterina Romancenco, Elena Salazar, Alex Ssengooba, Willy Velayati, A. A. Winglee, Kathryn Zalutskaya, Aksana Via, Laura E. Cassell, Gail H. Dorman, Susan E. Ellner, Jerrold Farnia, Parissa Galagan, James E. Rosenthal, Alex Crudu, Valeriu Homorodean, Daniela Hsueh, Po-Ren Narayanan, Sujatha Pym, Alexander S. Skrahina, Alena Swaminathan, Soumya Van der Walt, Martie Alland, David Bishai, William R. Cohen, Ted Hoffner, Sven Birren, Bruce W. Earl, Ashlee M. CA TBresist Global Genome Consortium TI Genomic analysis of globally diverse Mycobacterium tuberculosis strains provides insights into the emergence and spread of multidrug resistance SO NATURE GENETICS LA English DT Article ID PULMONARY TUBERCULOSIS; TREATMENT OUTCOMES; MONORESISTANT TUBERCULOSIS; ISONIAZID RESISTANCE; MUTATION-RATE; RIFAMPIN; TRANSMISSION; TARGET; INHA; EPIDEMIOLOGY AB Multidrug-resistant tuberculosis (MDR-TB), caused by drug-resistant strains of Mycobacterium tuberculosis, is an increasingly serious problem worldwide. Here we examined a data set of whole-genome sequences from 5,310 M. tuberculosis isolates from five continents. Despite the great diversity of these isolates with respect to geographical point of isolation, genetic background and drug resistance, the patterns for the emergence of drug resistance were conserved globally. We have identified harbinger mutations that often precede multidrug resistance. In particular, the katG mutation encoding p.Ser315Thr, which confers resistance to isoniazid, overwhelmingly arose before mutations that conferred rifampicin resistance across all of the lineages, geographical regions and time periods. Therefore, molecular diagnostics that include markers for rifampicin resistance alone will be insufficient to identify pre-MDR strains. Incorporating knowledge of polymorphisms that occur before the emergence of multidrug resistance, particularly katG p.Ser315Thr, into molecular diagnostics should enable targeted treatment of patients with pre-MDR-TB to prevent further development of MDR-TB. C1 [Manson, Abigail L.; Cohen, Keira A.; Abeel, Thomas; Desjardins, Christopher A.; Chapman, Sinead B.; Gomez, James; Salazar, Alex; Galagan, James E.; Birren, Bruce W.; Earl, Ashlee M.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Manson, Abigail L.; Cohen, Keira A.; Pym, Alexander S.; Bishai, William R.] KwaZulu Natal Res Inst TB & HIV K RITH, Durban, South Africa. [Cohen, Keira A.] Harvard Med Sch, Brigham & Womens Hosp, Div Pulm & Crit Care Med, Boston, MA USA. [Abeel, Thomas; Salazar, Alex] Delft Univ Technol, Delft Bioinformat Lab, Delft, Netherlands. [Armstrong, Derek T.; Winglee, Kathryn; Dorman, Susan E.; Bishai, William R.] Johns Hopkins Univ, Ctr TB Res, Baltimore, MD USA. [Barry, Clifton E., III; Via, Laura E.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Brand, Jeannette; Malinga, Lesibana; Van der Walt, Martie] MRC, TB Platform, Pretoria, South Africa. [Cho, Sang-Nae; Lee, Jong Seok] Int TB Res Ctr, Chang Won, South Korea. [Cho, Sang-Nae; Lee, Jong Seok] Yonsei Univ, Coll Med, Dept Microbiol, Seoul, South Korea. [Gabrielian, Andrei; Rosenthal, Alex] NIH, Off Cyber Infrastruct & Computat Biol, Rockville, MD USA. [Jodals, Andreea M.; Homorodean, Daniela] Clin Hosp Pneumol Leon Daniello, Cluj Napoca, Romania. [Joloba, Moses; Ssengooba, Willy] Makerere Univ, Dept Med Microbiol, Mycobacteriol Lab, Kampala, Uganda. [Jureen, Pontus; Hoffner, Sven] Publ Hlth Agcy Sweden, Solna, Sweden. [Maiga, Mamoudou] USTTB, Bamako, Mali. [Nordenberg, Dale] Novasano Hlth & Sci, New York, NY USA. [Noroc, Ecaterina; Romancenco, Elena; Crudu, Valeriu] Phthisiopneumol Inst, Microbiol & Morphol Lab, Kishinev, Moldova. [Velayati, A. A.; Farnia, Parissa] Shahid Beheshti Univ Med Sci, NRITLD, Mycobacteriol Res Ctr, Tehran, Iran. [Zalutskaya, Aksana; Skrahina, Alena] Republican Res & Pract Ctr Pulmonol & TB, Minsk, Byelarus. [Cassell, Gail H.] Harvard Med Sch, Brigham & Womens Hosp, Div Global Hlth Equ, Dept Global Hlth & Social Med, Boston, MA USA. [Ellner, Jerrold] Boston Med Ctr, Sect Infect Dis, Boston, MA USA. [Galagan, James E.] Boston Univ, Dept Biomed Engn & Microbiol, Boston, MA 02215 USA. [Hsueh, Po-Ren] Natl Taiwan Univ, Coll Med, Natl Taiwan Univ Hosp, Taipei, Taiwan. [Narayanan, Sujatha; Swaminathan, Soumya] Natl Inst Res TB, Madras, Tamil Nadu, India. [Alland, David] Rutgers New Jersey Med Sch, Newark, NJ USA. [Cohen, Ted] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Cohen, Ted] Yale Sch Publ Hlth, Dept Epidemiol Microbial Dis, New Haven, CT USA. RP Earl, AM (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. EM aearl@broadinstitute.org FU National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Department of Health and Human Services [HHSN272200900018C, HHSN2722000900050C]; Korean CDC, Korean Ministry of Health and Welfare; NIAID, NIH; NIH [5U01AI069924-07, R01 AI110386]; Howard Hughes Medical Institute FX We would like to thank the Broad Institute's Genome Sequencing Platform and Assembly and Annotation teams, including S.K. Young, M.E. Priest, T.P. Shea, B.J. Walker, L. Alvarado, M.G. Fitzgerald, S. Gujja, S. Hamilton, C. Howarth, J.D. Larimer, M.D. Pearson, Q. Zeng and J. Wortman. We would like to thank J. Romano and A. Keo for help with lineage detection, and M. Zambrano, B. Ferro and J.C. Rozo for isolation and phenotypic characterization of strains. We are also grateful to members of the TBResist Consortium for contribution of their strains, phenotypic data and expertise, and their help in forging collaborations, and to V. Dartois, D. Thomas, D. Hung and D. Plachetzki for helpful conversations. We also thank three anonymous reviewers of our manuscript for their insights and helpful suggestions. This project has been funded in whole or in part with federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Department of Health and Human Services (grant U19AI110818 to the Broad Institute (B.W.B. and A.M.E.)), contract HHSN272200900018C to the Broad Institute (B.W.B.) and contract HHSN2722000900050C to the TB Clinical Diagnostics Research Consortium, the Intramural Research Program of NIAID (C.E.B and L.E.V.) and the Korean CDC, Korean Ministry of Health and Welfare. This work was also funded (in part) by the intramural research program of the NIAID, NIH (C.E.B.). Funding was also provided by NIH grant 5U01AI069924-07 for IeDEA (A.S.P.), the Howard Hughes Medical Institute (W.R.B.) and NIH grant R01 AI110386 for 'Host-pathogen interactions in a failing global lineage of MTBC: M. africanum' (W.R.B.). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. NR 64 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD MAR PY 2017 VL 49 IS 3 BP 395 EP 402 DI 10.1038/ng.3767 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA EL9CU UT WOS:000394917800013 PM 28092681 ER PT J AU Warren, HR Evangelou, E Cabrera, CP Gao, H Ren, MX Mifsud, B Ntalla, I Surendran, P Liu, CY Cook, JP Kraja, AT Drenos, F Loh, M Verweij, N Marten, J Karaman, I Lepe, MPS O'Reilly, PF Knight, J Snieder, H Kato, N He, J Tai, ES Said, MA Porteous, D Alver, M Poulter, N Farrall, M Gansevoort, RT Padmanabhan, S Magi, R Stanton, A Connell, J Bakker, SJL Metspalu, A Shields, DC Thom, S Brown, M Sever, P Esko, T Hayward, C van der Harst, P Saleheen, D Chowdhury, R Chambers, JC Chasman, DI Chakravarti, A Newton-Cheh, C Lindgren, CM Levy, D Kooner, JS Keavney, B Tomaszewski, M Samani, NJ Howson, JMM Tobin, MD Munroe, PB Ehret, GB Wain, LV Barnes, MR Tzoulaki, J Caulfield, MJ Elliott, P Wain, LV Vaez, A Jansen, R Joehanes, R van der Most, PJ Erzurumluoglu, AM O'Reilly, P Cabrera, CP Warren, HR Rose, LM Verwoert, GC Hottenga, JJ Strawbridge, RJ Esko, T Arking, DE Hwang, SJ Guo, XQ Kutalik, Z Trompet, S Shrine, N Teumer, A Ried, JS Bis, JC Smith, AV Amin, N Nolte, IM Lyytikainen, LP Mahajan, A Wareham, NJ Hofer, E Joshi, PK Kristiansson, K Traglia, M Havulinna, AS Goel, A Nalls, MA Sober, S Vuckovic, D Luan, JA Del Greco, F Ayers, KL Marrugat, J Ruggiero, D Lopez, LM Niiranen, T Enroth, S Jackson, AU Nelson, CP Huffman, JE Zhang, WH Marten, J Gandin, I Harris, SE Zemonik, T Lu, YC Evangelou, E Shah, N de Borst, MH Mangino, M Prins, BP Campbell, A Li-Gao, RF Chauhan, G Oldmeadow, C Abecasis, G Abedi, M Barbieri, CM Barnes, MR Batini, C Blake, T Boehnke, M Bottinger, EP Braund, PS Brown, M Brumat, M Campbell, H Chambers, JC Cocca, M Collins, F Connell, J Cordell, HJ Damman, JJ Davies, G de Geus, EJ de Mutsert, R Deelen, J Demirkale, Y Doney, ASF Dorr, M Farrall, M Ferreira, T Franberg, M Gao, H Giedraitis, V Gieger, C Giulianini, F Gow, AJ Hamsten, A Harris, TB Hofman, A Holliday, EG Jarvelin, MR Johansson, A Johnson, AD Jousilahti, P Jula, A Kahonen, M Kathiresan, S Khaw, KT Kolcic, I Koskinen, S Langenberg, C Larson, M Launer, LJ Lehne, B Liewald, DCM Lin, L Lind, L Mach, F Mamasoula, C Menni, C Mifsud, B Milaneschi, Y Morgan, A Morris, AD Morrison, AC Munson, PJ Nandakumar, P Nguyen, QT Nutile, T Oldehinkel, AJ Oostra, BA Org, E Padmanabhan, S Palotie, A Pare, G Pattie, A Penninx, BWJH Poulter, N Pramstaller, PP Raitakari, OT Ren, MX Rice, K Ridker, PM Riese, H Ripatti, S Robino, A Rotter, JI Rudan, I Saba, Y Saint Pierre, A Sala, CF Sarin, AP Schmidt, R Scott, R Seelen, MA Shields, DC Siscovick, D Sorice, R Stanton, A Stott, DJ Sundstrom, J Swertz, M Taylor, KD Thom, S Tzoulaki, I Tzourio, C Uitterlinden, AG Volker, U Vollenweider, P Wild, S Willemsen, G Wright, AF Yao, J Theriault, S Conen, D John, A Sever, P Debette, S Mook-Kanamori, DO Zeggini, E Spector, TD van der Harst, P Palmer, CNA Vergnaud, AC Loos, RJF Polasek, O Starr, JM Girotto, G Hayward, C Kooner, JS Lindgren, CM Vitart, V Samani, NJ Tuomilehto, J Gyllensten, U Knekt, P Deary, IJ Ciullo, M Elosua, R Keavney, BD Hicks, AA Scott, RA Gasparini, P Laan, M Liu, YM Watkins, H Hartman, CA Salomaa, V Toniolo, D Perola, M Wilson, JF Schmidt, H Zhao, JH Lehtimaki, T van Duijn, CM Gudnason, V Psaty, BM Peters, A Rettig, R James, A Jukema, JW Strachan, DP Palmas, W Metspalu, A Ingelsson, E Boomsma, DI Franco, OH Bochud, M Newton-Cheh, C Munroe, PB Elliott, P Chasman, DI Chakravarti, A Knight, J Morris, AP Levy, D Tobin, MD Snieder, H Caulfield, MJ Ehret, GB AF Warren, Helen R. Evangelou, Evangelos Cabrera, Claudia P. Gao, He Ren, Meixia Mifsud, Borbala Ntalla, Ioanna Surendran, Praveen Liu, Chunyu Cook, James P. Kraja, Aldi T. Drenos, Fotios Loh, Marie Verweij, Niek Marten, Jonathan Karaman, Ibrahim Lepe, Marcelo P. Segura O'Reilly, Paul F. Knight, Joanne Snieder, Harold Kato, Norihiro He, Jiang Tai, E. Shyong Said, M. Abdullah Porteous, David Alver, Maris Poulter, Neil Farrall, Martin Gansevoort, Ron T. Padmanabhan, Sandosh Magi, Reedik Stanton, Alice Connell, John Bakker, Stephan J. L. Metspalu, Andres Shields, Denis C. Thom, Simon Brown, Morris Sever, Peter Esko, Tonu Hayward, Caroline van der Harst, Pim Saleheen, Danish Chowdhury, Rajiv Chambers, John C. Chasman, Daniel I. Chakravarti, Aravinda Newton-Cheh, Christopher Lindgren, Cecilia M. Levy, Daniel Kooner, Jaspal S. Keavney, Bernard Tomaszewski, Maciej Samani, Nilesh J. Howson, Joanna M. M. Tobin, Martin D. Munroe, Patricia B. Ehret, Georg B. Wain, Louise V. Barnes, Michael R. Tzoulaki, Joanna Caulfield, Mark J. Elliott, Paul Wain, Louise V. Vaez, Ahmad Jansen, Rick Joehanes, Roby van der Most, Peter J. Erzurumluoglu, A. Mesut O'Reilly, Paul Cabrera, Claudia P. Warren, Helen R. Rose, Lynda M. Verwoert, Germaine C. Hottenga, Jouke-Jan Strawbridge, Rona J. Esko, Tonu Arking, Dan E. Hwang, Shih-Jen Guo, Xiuqing Kutalik, Zoltan Trompet, Stella Shrine, Nick Teumer, Alexander Ried, Janina S. Bis, Joshua C. Smith, Albert V. Amin, Najaf Nolte, Ilja M. Lyytikainen, Leo-Pekka Mahajan, Anubha Wareham, Nicholas J. Hofer, Edith Joshi, Peter K. Kristiansson, Kati Traglia, Michela Havulinna, Aki S. Goel, Anuj Nalls, Mike A. Sober, Siim Vuckovic, Dragana Luan, Jian'an Del Greco M, Fabiola Ayers, Kristin L. Marrugat, Jaume Ruggiero, Daniela Lopez, Lorna M. Niiranen, Teemu Enroth, Stefan Jackson, Anne U. Nelson, Christopher P. Huffman, Jennifer E. Zhang, Weihua Marten, Jonathan Gandin, Ilaria Harris, Sarah E. Zemonik, Tatijana Lu, Yingchang Evangelou, Evangelos Shah, Nabi de Borst, Martin H. Mangino, Massimo Prins, Bram P. Campbell, Archie Li-Gao, Ruifang Chauhan, Ganesh Oldmeadow, Christopher Abecasis, Goncalo Abedi, Maryam Barbieri, Caterina M. Barnes, Michael R. Batini, Chiara Blake, Tineka Boehnke, Michael Bottinger, Erwin P. Braund, Peter S. Brown, Morris Brumat, Marco Campbell, Harry Chambers, John C. Cocca, Massimiliano Collins, Francis Connell, John Cordell, Heather J. Damman, Jeffrey J. Davies, Gail de Geus, Eco J. de Mutsert, Renee Deelen, Joris Demirkale, Yusuf Doney, Alex S. F. Dorr, Marcus Farrall, Martin Ferreira, Teresa Franberg, Mattias Gao, He Giedraitis, Vilmantas Gieger, Christian Giulianini, Franco Gow, Alan J. Hamsten, Anders Harris, Tamara B. Hofman, Albert Holliday, Elizabeth G. Jarvelin, Marjo-Riitta Johansson, Asa Johnson, Andrew D. Jousilahti, Pekka Jula, Antti Kahonen, Mika Kathiresan, Sekar Khaw, Kay-Tee Kolcic, Ivana Koskinen, Seppo Langenberg, Claudia Larson, Marty Launer, Lenore J. Lehne, Benjamin Liewald, David C. M. Lin, Li Lind, Lars Mach, Francois Mamasoula, Chrysovalanto Menni, Cristina Mifsud, Borbala Milaneschi, Yuri Morgan, Anna Morris, Andrew D. Morrison, Alanna C. Munson, Peter J. Nandakumar, Priyanka Quang Tri Nguyen Nutile, Teresa Oldehinkel, Albertine J. Oostra, Ben A. Org, Elin Padmanabhan, Sandosh Palotie, Aarno Pare, Guillaume Pattie, Alison Penninx, Brenda W. J. H. Poulter, Neil Pramstaller, Peter P. Raitakari, Olli T. Ren, Meixia Rice, Kenneth Ridker, Paul M. Riese, Harriette Ripatti, Samuli Robino, Antonietta Rotter, Jerome I. Rudan, Igor Saba, Yasaman Saint Pierre, Aude Sala, Cinzia F. Sarin, Antti-Pekka Schmidt, Reinhold Scott, Rodney Seelen, Marc A. Shields, Denis C. Siscovick, David Sorice, Rossella Stanton, Alice Stott, David J. Sundstrom, Johan Swertz, Morris Taylor, Kent D. Thom, Simon Tzoulaki, Ioanna Tzourio, Christophe Uitterlinden, Andre G. Volker, Uwe Vollenweider, Peter Wild, Sarah Willemsen, Gonneke Wright, Alan F. Yao, Jie Theriault, Sebastien Conen, David John, Attia Sever, Peter Debette, Stephanie Mook-Kanamori, Dennis O. Zeggini, Eleftheria Spector, Tim D. van der Harst, Pim Palmer, Colin N. A. Vergnaud, Anne-Claire Loos, Ruth J. F. Polasek, Ozren Starr, John M. Girotto, Giorgia Hayward, Caroline Kooner, Jaspal S. Lindgren, Cecila M. Vitart, Veronique Samani, Nilesh J. Tuomilehto, Jaakko Gyllensten, Ulf Knekt, Paul Deary, Ian J. Ciullo, Marina Elosua, Roberto Keavney, Bernard D. Hicks, Andrew A. Scott, Robert A. Gasparini, Paolo Laan, Maris Liu, YongMei Watkins, Hugh Hartman, Catharina A. Salomaa, Veikko Toniolo, Daniela Perola, Markus Wilson, James F. Schmidt, Helena Zhao, Jing Hua Lehtimaki, Terho van Duijn, Cornelia M. Gudnason, Vilmundur Psaty, Bruce M. Peters, Annette Rettig, Rainer James, Alan Jukema, J. Wouter Strachan, David P. Palmas, Walter Metspalu, Andres Ingelsson, Erik Boomsma, Dorret I. Franco, Oscar H. Bochud, Murielle Newton-Cheh, Christopher Munroe, Patricia B. Elliott, Paul Chasman, Daniel I. Chakravarti, Aravinda Knight, Joanne Morris, Andrew P. Levy, Daniel Tobin, Martin D. Snieder, Harold Caulfield, Mark J. Ehret, Georg B. CA Int Consortium Blood Pressure ICBP CHD Exome Consortium ExomeBP Consortium T2D-GENES Consortium GoT2D Genes Consortium CHARGE BP Exome Consortium iGEN-BP Consortium UK Biobank CardioMetab Consortium BIOS Consortium Lifelines Cohort Study Understanding Soc Sci Grp TI Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk SO NATURE GENETICS LA English DT Article ID CORONARY-ARTERY-DISEASE; ENDOTHELIAL-CELL; MYOCARDIAL-INFARCTION; NEUROTROPHIC FACTOR; NADPH OXIDASE; UK BIOBANK; KEY ROLE; IN-VIVO; HYPERTENSION; COMMON AB Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk. C1 [Warren, Helen R.; Cabrera, Claudia P.; Ren, Meixia; Mifsud, Borbala; Ntalla, Ioanna; Barnes, Michael R.; Caulfield, Mark J.; Cabrera, Claudia P.; Warren, Helen R.; Barnes, Michael R.; Mifsud, Borbala; Ren, Meixia; Caulfield, Mark J.] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England. [Warren, Helen R.; Cabrera, Claudia P.; Ren, Meixia; Barnes, Michael R.; Caulfield, Mark J.; Cabrera, Claudia P.; Warren, Helen R.; Barnes, Michael R.; Caulfield, Mark J.] Queen Mary Univ London, Barts Cardiovasc Biomed Res Unit, Natl Inst Hlth Res, London, England. [Evangelou, Evangelos; Gao, He; Loh, Marie; Karaman, Ibrahim; Lepe, Marcelo P. Segura; Chambers, John C.; Tzoulaki, Joanna; Elliott, Paul; Zhang, Weihua; Evangelou, Evangelos; Chambers, John C.; Gao, He; Lehne, Benjamin; Tzoulaki, Ioanna; Vergnaud, Anne-Claire] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Evangelou, Evangelos; Tzoulaki, Joanna; Evangelou, Evangelos] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, Ioannina, Greece. [Gao, He; Tzoulaki, Joanna; Elliott, Paul; Jarvelin, Marjo-Riitta; Elliott, Paul] Imperial Coll London, MRC PHE Ctr Environm & Hlth, London, England. [Surendran, Praveen; Chowdhury, Rajiv; Howson, Joanna M. M.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cardiovasc Epidemiol Unit, Cambridge, England. [Liu, Chunyu; Levy, Daniel; Levy, Daniel] NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Liu, Chunyu] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Liu, Chunyu; Levy, Daniel; Joehanes, Roby; Johnson, Andrew D.; Larson, Marty] NHLBI, Framingham Heart Study, Framingham, MA USA. [Cook, James P.; Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England. [Kraja, Aldi T.] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA. [Kraja, Aldi T.] Washington Univ, Sch Med, Ctr Genome Sci & Syst Biol, St Louis, MO 63110 USA. [Drenos, Fotios] Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol, Avon, England. [Drenos, Fotios] UCL, Inst Cardiovasc Sci, Ctr Cardiovasc Genet, London, England. [Loh, Marie] ASTAR, Translat Lab Genet Med, Singapore, Singapore. [Verweij, Niek; Said, M. Abdullah; van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Verweij, Niek; Esko, Tonu; Newton-Cheh, Christopher; Lindgren, Cecilia M.; Kathiresan, Sekar; Newton-Cheh, Christopher] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Verweij, Niek; Newton-Cheh, Christopher; Kathiresan, Sekar; Newton-Cheh, Christopher] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Verweij, Niek; Newton-Cheh, Christopher; Kathiresan, Sekar; Newton-Cheh, Christopher] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Marten, Jonathan; Hayward, Caroline; Huffman, Jennifer E.; Wright, Alan F.; Hayward, Caroline; Vitart, Veronique; Wilson, James F.] Univ Edinburgh, MRC Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland. [Lepe, Marcelo P. Segura] Bayer Pharma, Berlin, Germany. [O'Reilly, Paul F.; O'Reilly, Paul] Kings Coll London, Inst Psychiat Psychol & Neurosci, London, England. [Knight, Joanne] Univ Lancaster, Data Sci Inst, Lancaster, England. [Snieder, Harold; Vaez, Ahmad; van der Most, Peter J.; Nolte, Ilja M.; Damman, Jeffrey J.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. [Kato, Norihiro] Natl Ctr Global Hlth & Med, Res Inst, Dept Gene Diagnost & Therapeut, Tokyo, Japan. [He, Jiang] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA. [Tai, E. Shyong] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. [Tai, E. Shyong] Natl Univ Hlth Syst, Singapore, Singapore. [Tai, E. Shyong] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore, Singapore. [Porteous, David; Harris, Sarah E.; Campbell, Archie] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland. [Alver, Maris; Magi, Reedik; Metspalu, Andres; Esko, Tonu; Esko, Tonu; Org, Elin] Univ Tartu, Estonian Genome Ctr, Tartu, Estonia. Imperial Coll London, Sch Publ Hlth, Imperial Clin Trials Unit, London, England. [Farrall, Martin] Univ Oxford, Radcliffe Dept Med, Wellcome Trust Ctr Human Genet, Div Cardiovasc Med, Oxford, England. [Gansevoort, Ron T.] Univ Groningen, Univ Med Ctr Groningen, Dept Nephrol, Groningen, Netherlands. [Padmanabhan, Sandosh; Stott, David J.] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Stanton, Alice] Royal Coll Surgeons Ireland, Mol & Cellular Therapeut, Dublin, Ireland. [Connell, John] Univ Dundee, Ninewells Hosp & Med Sch, Dundee, Scotland. [Bakker, Stephan J. L.; de Borst, Martin H.; Seelen, Marc A.] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Groningen, Netherlands. [Shields, Denis C.] Univ Coll Dublin, Conway Inst, Sch Med, Dublin, Ireland. [Thom, Simon; Sever, Peter; Kooner, Jaspal S.] Imperial Coll London, Natl Heart & Lung Inst, London, England. [Saleheen, Danish] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Saleheen, Danish] Ctr Noncommun Dis, Karachi, Pakistan. [Saleheen, Danish; Khaw, Kay-Tee] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Chambers, John C.] Ealing Hosp Natl Hlth Serv NHS Trust, Southall, Middx, England. [Chambers, John C.; Kooner, Jaspal S.; Chambers, John C.; Kooner, Jaspal S.] Imperial Coll Healthcare NHS Trust, London, England. [Chambers, John C.] Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore, Singapore. [Rose, Lynda M.; Giulianini, Franco; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Ridker, Paul M.] Harvard Med Sch, Boston, MA USA. [Chakravarti, Aravinda; Arking, Dan E.; Nandakumar, Priyanka] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD USA. [Lindgren, Cecilia M.; Mahajan, Anubha; Goel, Anuj; Farrall, Martin; Ferreira, Teresa; Lindgren, Cecila M.; Watkins, Hugh; Morris, Andrew P.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Lindgren, Cecilia M.] Univ Oxford, Big Data Inst, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford, England. [Kooner, Jaspal S.; Zhang, Weihua; Chambers, John C.; Kooner, Jaspal S.] Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England. [Kooner, Jaspal S.] Imperial Coll London, Cardiovasc Sci, Natl Heart & Lung Inst, Hammersmith Campus, London, England. [Keavney, Bernard; Tomaszewski, Maciej; Keavney, Bernard D.] Univ Manchester, Fac Biol Med & Hlth, Div Cardiovasc Sci, Manchester, Lancs, England. [Keavney, Bernard; Tomaszewski, Maciej] Cent Manchester NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Div Med, Manchester, Lancs, England. [Nelson, Christopher P.; Braund, Peter S.] Univ Leicester, Glenfield Hosp, BHF Cardiovasc Res Ctr, Dept Cardiovasc Sci, Leicester, Leics, England. [Nelson, Christopher P.; Braund, Peter S.] Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England. [Tobin, Martin D.; Wain, Louise V.; Erzurumluoglu, A. Mesut; Shrine, Nick; Batini, Chiara; Blake, Tineka] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. [Lin, Li; Mach, Francois] Univ Hosp Geneva, Dept Med, Cardiol, Geneva, Switzerland. [Vaez, Ahmad] Isfahan Univ Med Sci, Res Inst Primordial Prevent Noncommun Dis, Esfahan, Iran. [Jansen, Rick] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Neurosci Campus Amsterdam, Amsterdam, Netherlands. [Joehanes, Roby] Harvard Med Sch, Hebrew SeniorLife, Boston, MA USA. [Verwoert, Germaine C.; Hofman, Albert; Uitterlinden, Andre G.; Franco, Oscar H.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Hottenga, Jouke-Jan; de Geus, Eco J.; Willemsen, Gonneke; Boomsma, Dorret I.] Vrije Univ, Dept Biol Psychol, Amsterdam, Netherlands. [Hottenga, Jouke-Jan; de Geus, Eco J.; Willemsen, Gonneke; Boomsma, Dorret I.] Vrije Univ Amsterdam, Med Ctr, EMGO Inst, Amsterdam, Netherlands. [Strawbridge, Rona J.; Franberg, Mattias; Hamsten, Anders] Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden. [Strawbridge, Rona J.; Franberg, Mattias; Hamsten, Anders] Karolinska Univ Sjukhuset, Ctr Mol Med, Solna, Sweden. [Esko, Tonu] Childrens Hosp, Div Endocrinol, 300 Longwood Ave, Boston, MA 02115 USA. [Esko, Tonu; Lindgren, Cecila M.; Newton-Cheh, Christopher] Broad Inst Harvard & MIT, Cambridge, England. [Hwang, Shih-Jen] NHLBI, Populat Sci Branch, US NIH, Bldg 10, Bethesda, MD 20892 USA. [Hwang, Shih-Jen; Levy, Daniel] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Guo, Xiuqing; Rotter, Jerome I.; Yao, Jie] Harbor UCLA Med Ctr, LABioMed, Dept Pediat, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Kutalik, Zoltan; Bochud, Murielle] Univ Lausanne Hosp, Inst Social & Prevent Med, Lausanne, Switzerland. [Kutalik, Zoltan] Swiss Inst Bioinformat, Lausanne, Switzerland. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands. [Trompet, Stella] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands. [Teumer, Alexander] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Teumer, Alexander; Dorr, Marcus; Volker, Uwe] DZHK German Ctr Cardiovasc Res, Greifswald, Germany. [Ried, Janina S.; Peters, Annette] Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Bis, Joshua C.; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Amin, Najaf; Oostra, Ben A.; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Fimlab Labs, Dept Clin Chem, Tampere, Finland. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Univ Tampere, Sch Med, Dept Clin Chem, Tampere, Finland. [Wareham, Nicholas J.; Luan, Jian'an; Langenberg, Claudia; Scott, Robert A.; Zhao, Jing Hua] Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Inst Metab Sci, Cambridge Biomed Campus, Cambridge, England. [Hofer, Edith; Schmidt, Reinhold; Loos, Ruth J. F.] Med Univ Graz, Dept Neurol, Clin Div Neurogeriatr, Graz, Austria. [Hofer, Edith] Med Univ Graz, Inst Med Informat Stat & Documentat, Graz, Austria. [Joshi, Peter K.; Campbell, Harry; Rudan, Igor; Wild, Sarah; Perola, Markus; Wilson, James F.] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland. [Kristiansson, Kati; Havulinna, Aki S.; Niiranen, Teemu; Jousilahti, Pekka; Jula, Antti; Koskinen, Seppo; Knekt, Paul; Salomaa, Veikko] Natl Inst Hlth & Welf THL, Dept Hlth, Helsinki, Finland. [Traglia, Michela; Barbieri, Caterina M.; Sala, Cinzia F.; Toniolo, Daniela] Ist Sci San Raffaele, Div Genet & Cell Biol, Milan, Italy. [Goel, Anuj; Farrall, Martin; Watkins, Hugh] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford, England. [Nalls, Mike A.] NIA, Neurogenet Lab, US NIH, Bethesda, MD 20892 USA. [Nalls, Mike A.] Kelly Serv, Rockville, MD USA. [Sober, Siim; Laan, Maris] Univ Tartu, Inst Mol & Cell Biol, Human Mol Genet Res Grp, Tartu, Estonia. [Vuckovic, Dragana; Girotto, Giorgia; Gasparini, Paolo] Sidra Med & Res Ctr, Expt Genet Div, Doha, Qatar. [Vuckovic, Dragana; Gandin, Ilaria; Brumat, Marco; Cocca, Massimiliano; Morgan, Anna; Girotto, Giorgia; Gasparini, Paolo] Univ Trieste, Dept Med Surg & Hlth Sci, Trieste, Italy. [Del Greco M, Fabiola; Pramstaller, Peter P.; Saint Pierre, Aude; Hicks, Andrew A.] European Acad Bozen Bolzano EURAC, Ctr Biomed, Bolzano, Italy. [Del Greco M, Fabiola; Pramstaller, Peter P.; Saint Pierre, Aude; Hicks, Andrew A.] Univ Lubeck, Lubeck, Germany. [Ayers, Kristin L.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Marrugat, Jaume; Elosua, Roberto; Int Consortium Blood Pressure ICBP] IMIM, Cardiovasc Epidemiol & Genet, Barcelona, Spain. [Ruggiero, Daniela; Nutile, Teresa; Sorice, Rossella; Ciullo, Marina] CNR, Inst Genet & Biophys Buzzati Traverso, Naples, Italy. [Lopez, Lorna M.; Harris, Sarah E.; Davies, Gail; Gow, Alan J.; Liewald, David C. M.; Starr, John M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. 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[Gieger, Christian] Helmholtz Zentrum Munchen, Deutsch Forsch Zentrum Gesundheit & Umwelt, Neuherberg, Germany. [Gow, Alan J.] Heriot Watt Univ, Sch Life Sci, Dept Psychol, Edinburgh, Midlothian, Scotland. [Harris, Tamara B.; Launer, Lenore J.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Hofman, Albert] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Jarvelin, Marjo-Riitta] Univ Oulu, Ctr Life Course Hlth Res, Oulu, Finland. [Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Jarvelin, Marjo-Riitta] Oulu Univ Hosp, Unit Primary Care, Oulu, Finland. [Johnson, Andrew D.] NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Bldg 10, Bethesda, MD 20892 USA. [Kahonen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland. [Kahonen, Mika] Univ Tampere, Sch Med, Dept Clin Physiol, Tampere, Finland. [Kolcic, Ivana; Polasek, Ozren] Univ Split, Fac Med, Dept Publ Hlth, Split, Croatia. [Lind, Lars; Sundstrom, Johan] Uppsala Univ, Cardiovasc Epidemiol, Dept Med Sci, Uppsala, Sweden. [Mamasoula, Chrysovalanto] Newcastle Univ, Inst Hlth & Soc, Newcastle Upon Tyne, Tyne & Wear, England. [Milaneschi, Yuri; Penninx, Brenda W. J. H.] Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, Dept Psychiat, Amsterdam, Netherlands. [Morris, Andrew D.] Univ Edinburgh, Sch Med, Sch Mol Genet & Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Morrison, Alanna C.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA. [Oldehinkel, Albertine J.; Riese, Harriette; Hartman, Catharina A.] Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Groningen, Netherlands. [Padmanabhan, Sandosh] Univ Glasgow, Coll Med Vet & Life Sci, Inst Cardiovasc & Med Sci, British Heart Fdn Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. [Palotie, Aarno; Ripatti, Samuli; Sarin, Antti-Pekka; Perola, Markus] Univ Helsinki, FIMM, Helsinki, Finland. [Pare, Guillaume; Theriault, Sebastien] McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada. [Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, Bolzano, Italy. [Pramstaller, Peter P.] Univ Lubeck, Dept Neurol, Lubeck, Germany. [Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Ren, Meixia] Fujian Med Univ, Fujian Prov Hosp, Dept Cardiol, Fuzhou, Peoples R China. [Rice, Kenneth] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Robino, Antonietta] IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy. [Rotter, Jerome I.] Harbor UCLA Med Ctr, LABioMed, Dept Med, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Saba, Yasaman; Schmidt, Helena] Med Univ Graz, Ctr Mol Med, Inst Mol Biol & Biochem, Graz, Austria. [Saint Pierre, Aude] Etab Francais Sang, INSERM, U1078, Brest, France. [Scott, Rodney; John, Attia] Univ Newcastle, Fac Hlth, Callaghan, NSW, Australia. [Scott, Rodney; John, Attia] John Hunter Hosp, Sch Biomed Sci & Pharm, New Lambton, NSW, Australia. [Siscovick, David] New York Acad Med, New York, NY USA. [Sorice, Rossella; Ciullo, Marina] IRCCS Neuromed, Pozzilli, Italy. [Swertz, Morris] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Taylor, Kent D.] Harbor UCLA Med Ctr, Los Angeles BioMed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Taylor, Kent D.] Harbor UCLA Med Ctr, Dept Pediat, Div Genet Outcomes, Torrance, CA 90509 USA. [Thom, Simon] Imperial Coll London, Int Ctr Circulatory Hlth, London, England. [Tzourio, Christophe] Bordeaux Univ Hosp, Dept Publ Hlth, Bordeaux, France. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Volker, Uwe] Univ Med Greifswald, Interfac Inst Genet & Funct Gen, Greifswald, Germany. [Vollenweider, Peter] CHU Vaudois, Univ Lausanne Hosp, Dept Internal Med, Lausanne, Switzerland. [Conen, David] McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada. [Debette, Stephanie] Bordeaux Univ Hosp, Dept Neurol, Bordeaux, France. [Mook-Kanamori, Dennis O.] Leiden Univ, Med Ctr, Dept Publ Hlth & Primary Care, Leiden, Netherlands. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth Dev Inst, New York, NY 10029 USA. [Starr, John M.] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland. [Tuomilehto, Jaakko] Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland. [Tuomilehto, Jaakko] South Ostrobothnia Cent Hosp, Seinajoki, Finland. [Tuomilehto, Jaakko] Hosp Univ La Paz, Red RECAVA Grp RD06 0014 0015, Madrid, Spain. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria. [Laan, Maris] Univ Tartu, Inst Biomed & Translat Med, Tartu, Estonia. [Liu, YongMei] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. [Perola, Markus] Univ Tartu, Estonian Genome Ctr, Tartu, Estonia. [Schmidt, Helena] Med Univ Graz, Dept Neurol, Graz, Austria. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth, Grp Hlth Res Inst, Seattle, WA USA. [Rettig, Rainer] Univ Med Greifswald, Inst Physiol, Karlsburg, Germany. [James, Alan] Sir Charles Gairdner Hosp, Dept Pulm Physiol & Sleep, Nedlands, WA, Australia. [James, Alan] Univ Western Australia, Sch Med & Pharmacol, Crawley, WA, Australia. [Strachan, David P.] St Georges Univ London, Populat Hlth Res Inst, London, England. [Palmas, Walter] Columbia Univ, Med Ctr, Dept Med, New York, NY USA. [Ingelsson, Erik] Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden. [Ingelsson, Erik] Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA. RP Caulfield, MJ (reprint author), Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.; Caulfield, MJ (reprint author), Queen Mary Univ London, Barts Cardiovasc Biomed Res Unit, Natl Inst Hlth Res, London, England.; Elliott, P (reprint author), Imperial Coll London, MRC PHE Ctr Environm & Hlth, London, England. EM p.elliott@imperial.ac.uk; m.j.caulfield@qmul.ac.uk RI Polasek, Ozren/B-6002-2011; Hicks, Andrew/E-9518-2017; OI Polasek, Ozren/0000-0002-5765-1862; Hicks, Andrew/0000-0001-6320-0411; Evangelou, Evangelos/0000-0002-5488-2999; Knight, Joanne/0000-0002-7148-1660; Tai, E Shyong/0000-0003-2929-8966; Erzurumluoglu, A. Mesut/0000-0003-1322-8138; Peters, Annette/0000-0001-6645-0985; Mifsud, Borbala/0000-0003-3429-3094; Wain, Louise/0000-0003-4951-1867 FU National Institute for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Biomedical Research Unit at Barts and The London School of Medicine and Dentistry; NIHR Imperial College Health Care NHS Trust and Imperial College London Biomedical Research Centre; China Scholarship Council [2011632047]; UK Medical Research Council [G0800270, MR/N015746/1]; British Heart Foundation [SP/09/002, SP/13/2/30111]; UK National Institute for Health Research Cambridge Biomedical Research Centre; European Research Council [268834]; European Commission Framework Programme 7 [HEALTH-F2-2012-279233]; MRC Unit at the University of Bristol [MC_UU_12013/1-9]; NHLBI; National Institutes of Health [HL113933, HL124262, HL128782, HL086694]; ZonMw [90.700.441]; Marie Sklodowska-Curie GF [H2020-MSCA-IF-2014, 661395]; Marie Sklodowska-Curie GF grant [661395]; ICIN-NHI; UK National Institute for Health Research Biomedical Research Centre at Imperial College Healthcare NHS Trust; NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London; Wellcome Trust [109863/Z/15/Z]; EU PhenoMeNal project (Horizon) [654241]; Wellcome Trust core award [090532/Z/09/Z]; BHF Centre of Research Excellence, Oxford [RE/13/1/30181]; MRC core grant for QTL in Health and Disease programme; NIHR Health Protection Research Unit in Health Impact of Environmental Hazards [HPRU-2012-10141]; Public Health England [MR/L01341X/1]; Medical Research Council [MR/L01632X/1]; [MR/L016311/1] FX H.R.W., C.P.C., M.R., M.R.B., P.B.M., M.B. and M.J.C. were funded by the National Institute for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Biomedical Research Unit at Barts and The London School of Medicine and Dentistry. H.G. was funded by the NIHR Imperial College Health Care NHS Trust and Imperial College London Biomedical Research Centre. M.R. was a recipient of a grant from the China Scholarship Council (2011632047). B.M. holds an MRC eMedLab Medical Bioinformatics Career Development Fellowship, funded from award MR/L016311/1. J.M.M.H. was funded by the UK Medical Research Council (G0800270), British Heart Foundation (SP/09/002), UK National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council (268834) and European Commission Framework Programme 7 (HEALTH-F2-2012-279233). B.K. holds a British Heart Foundation Personal Chair (CH/13/2/30154). N.J.S. holds a chair funded by the British Heart Foundation and is an NIHR Senior Investigator. F.D. was funded by the MRC Unit at the University of Bristol (MC_UU_12013/1-9). P. Surendran was funded by the UK Medical Research Council (G0800270). C.L. and A.K. were funded by NHLBI intramural funding. C.N.-C. was funded by the National Institutes of Health (HL113933, HL124262). P.v.d.H. was funded by ZonMw grant 90.700.441, Marie Sklodowska-Curie GF (call, H2020-MSCA-IF-2014; project ID, 661395). N.V. was supported by a Marie Sklodowska-Curie GF grant (661395) and ICIN-NHI. N.P. received funding from the UK National Institute for Health Research Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London and also from his Senior Investigator Award. P. Sever was supported by the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London. S.T. was supported by the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London. P.F.O'R. received funding from the UK Medical Research Council (MR/N015746/1) and the Wellcome Trust (109863/Z/15/Z). I.K. was supported by the EU PhenoMeNal project (Horizon 2020, 654241). A.C. was funded by the National Institutes of Health (HL128782, HL086694). M.F. was supported by a Wellcome Trust core award (090532/Z/09/Z) and the BHF Centre of Research Excellence, Oxford (RE/13/1/30181). C.H. was funded by an MRC core grant for QTL in Health and Disease programme. Some of this work used the ALICE and SPECTRE High-Performance Computing Facilities at the University of Leicester. M.J.C. is a National Institute for Health Research (NIHR) senior investigator. P.E. is a National Institute for Health Research (NIHR) senior investigator and acknowledges support from the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London, and the NIHR Health Protection Research Unit in Health Impact of Environmental Hazards (HPRU-2012-10141). As director of the MRC-PHE Centre for Environment and Health, P.E. acknowledges support from the Medical Research Council and Public Health England (MR/L01341X/1). This work used the computing resources of the UK Medical Bioinformatics partnership-aggregation, integration, visualisation and analysis of large, complex data (UK MED-BIO), which is supported by the Medical Research Council (MR/L01632X/1). This research was supported by the British Heart Foundation (grant SP/13/2/30111).; Project title: Large-Scale Comprehensive Genotyping of UK Biobank for Cardiometabolic Traits and Diseases: UK CardioMetabolic Consortium (UKCMC). This research has been conducted using the UK Biobank Resource under application number 236. NR 62 TC 1 Z9 1 U1 7 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD MAR PY 2017 VL 49 IS 3 BP 403 EP 415 DI 10.1038/ng.3768 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA EL9CU UT WOS:000394917800014 PM 28135244 ER PT J AU Hobbs, BD de Jong, K Lamontagne, M Bosse, Y Shrine, N Artigas, MS Wain, LV Hall, IP Jackson, VE Wyss, AB London, SJ North, KE Franceschini, N Strachan, DP Beaty, TH Hokanson, JE Crapo, JD Castaldi, PJ Chase, RP Bartz, TM Heckbert, SR Psaty, BM Gharib, SA Zanen, P Lammers, JW Oudkerk, M Groen, HJ Locantore, N Tal-Singer, R Rennard, SI Vestbo, J Timens, W Pare, PD Latourelle, JC Dupuis, J O'Connor, GT Wilk, JB Kim, WJ Lee, MK Oh, YM Vonk, JM de Koning, HJ Leng, SG Belinsky, SA Tesfaigzi, Y Manichaikul, A Wang, XQ Rich, SS Barr, RG Sparrow, D Litonjua, AA Bakke, P Gulsvik, A Lahousse, L Brusselle, GG Stricker, BH Uitterlinden, AG Ampleford, EJ Bleecker, ER Woodruff, PG Meyers, DA Qiao, DD Lomas, DA Yim, JJ Kim, DK Hawrylkiewicz, I Sliwinski, P Hardin, M Fingerlin, TE Schwartz, DA Postma, DS MacNee, W Tobin, MD Silverman, EK Boezen, HM Cho, MH AF Hobbs, Brian D. de Jong, Kim Lamontagne, Maxime Bosse, Yohan Shrine, Nick Artigas, Maria Soler Wain, Louise V. Hall, Ian P. Jackson, Victoria E. Wyss, Annah B. London, Stephanie J. North, Kari E. Franceschini, Nora Strachan, David P. Beaty, Terri H. Hokanson, John E. Crapo, James D. Castaldi, Peter J. Chase, Robert P. Bartz, Traci M. Heckbert, Susan R. Psaty, Bruce M. Gharib, Sina A. Zanen, Pieter Lammers, Jan W. Oudkerk, Matthijs Groen, H. J. Locantore, Nicholas Tal-Singer, Ruth Rennard, Stephen I. Vestbo, Jurgen Timens, Wim Pare, Peter D. Latourelle, Jeanne C. Dupuis, Josee O'Connor, George T. Wilk, Jemma B. Kim, Woo Jin Lee, Mi Kyeong Oh, Yeon-Mok Vonk, Judith M. de Koning, Harry J. Leng, Shuguang Belinsky, Steven A. Tesfaigzi, Yohannes Manichaikul, Ani Wang, Xin-Qun Rich, Stephen S. Barr, R. Graham Sparrow, David Litonjua, Augusto A. Bakke, Per Gulsvik, Amund Lahousse, Lies Brusselle, Guy G. Stricker, Bruno H. Uitterlinden, Andre G. Ampleford, Elizabeth J. Bleecker, Eugene R. Woodruff, Prescott G. Meyers, Deborah A. Qiao, Dandi Lomas, David A. Yim, Jae-Joon Kim, Deog Kyeom Hawrylkiewicz, Iwona Sliwinski, Pawel Hardin, Megan Fingerlin, Tasha E. Schwartz, David A. Postma, Dirkje S. MacNee, William Tobin, Martin D. Silverman, Edwin K. Boezen, H. Marike Cho, Michael H. CA COPDGene Investigators ECLIPSE Investigators LifeLines Investigators SPIROMICS Res Grp Int COPD Genetics Network UK BiLEVE Investigators Int COPD Genetics Consortium TI Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; SURFACTANT PROTEIN-D; AIR-FLOW OBSTRUCTION; SMOKING-BEHAVIOR; COMPLEX TRAITS; I INTERFERON; VARIANTS; COPD; SUSCEPTIBILITY; EMPHYSEMA AB Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide(1). We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 x 10(-6)) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples(2-7), while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis(8,9) (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity(10). We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases. C1 [Hobbs, Brian D.; Castaldi, Peter J.; Chase, Robert P.; Litonjua, Augusto A.; Qiao, Dandi; Hardin, Megan; Silverman, Edwin K.; Cho, Michael H.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Hobbs, Brian D.; Litonjua, Augusto A.; Hardin, Megan; Silverman, Edwin K.; Cho, Michael H.] Brigham & Womens Hosp, Div Pulm & Crit Care Med, 75 Francis St, Boston, MA 02115 USA. [de Jong, Kim; Vonk, Judith M.; Boezen, H. Marike] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. [de Jong, Kim; Vonk, Judith M.; Postma, Dirkje S.; Boezen, H. Marike] Univ Groningen, Univ Med Ctr Groningen, GRIAC, Groningen, Netherlands. [Lamontagne, Maxime; Bosse, Yohan] Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ, Canada. [Bosse, Yohan] Univ Laval, Dept Mol Med, Quebec City, PQ, Canada. [Shrine, Nick; Artigas, Maria Soler; Wain, Louise V.; Jackson, Victoria E.; Tobin, Martin D.] Univ Leicester, Dept Hlth Sci, Genet Epidemiol Grp, Leicester, Leics, England. [Hall, Ian P.] Univ Nottingham, Queens Med Ctr, Div Resp Med, Nottingham, England. [Wyss, Annah B.; London, Stephanie J.] US Dept Hlth & Human Serv, Epidemiol Branch, NIEHS, US Natl Inst Hlth, Res Triangle Pk, NC USA. [North, Kari E.; Franceschini, Nora] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Strachan, David P.] St Georges Univ London, Populat Hlth Res Inst, London, England. [Beaty, Terri H.] Johns Hopkins Univ Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Hokanson, John E.] Univ Colorado, Dept Epidemiol, Anschutz Med Campus, Aurora, CO USA. [Crapo, James D.] Natl Jewish Hlth, Dept Med, Div Pulm & Crit Care Med, Denver, CO USA. [Castaldi, Peter J.] Brigham & Womens Hosp, Div Gen Internal Med, 75 Francis St, Boston, MA 02115 USA. [Bartz, Traci M.; Heckbert, Susan R.; Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Bartz, Traci M.; Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Bartz, Traci M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Heckbert, Susan R.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Heckbert, Susan R.; Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Gharib, Sina A.] Univ Washington, Dept Med, UW Med Sleep Ctr, Computat Med Core,Ctr Lung Biol, Seattle, WA USA. [Zanen, Pieter; Lammers, Jan W.] Univ Utrecht, Univ Med Ctr Utrecht, Dept Pulmonol, Utrecht, Netherlands. [Oudkerk, Matthijs] Univ Groningen, Univ Med Ctr Groningen, Ctr Med Imaging, Groningen, Netherlands. [Groen, H. J.; Postma, Dirkje S.] Univ Groningen, Univ Med Ctr Groningen, Dept Pulmonol, Groningen, Netherlands. [Locantore, Nicholas; Tal-Singer, Ruth] GlaxoSmithKline Res & Dev Ltd, King Of Prussia, PA USA. [Rennard, Stephen I.] Univ Nebraska Med Ctr, Dept Internal Med, Pulm Crit Care Sleep & Allergy Div, Omaha, NE USA. [Rennard, Stephen I.; Hardin, Megan] AstraZeneca, Clin Discovery Unit, Cambridge, England. [Vestbo, Jurgen] Univ Manchester, Sch Biol Sci, Manchester, Lancs, England. [Timens, Wim] Univ Groningen, Univ Med Ctr Groningen, GRIAC Res Inst, Dept Pathol & Med Biol, Groningen, Netherlands. [Pare, Peter D.] Univ British Columbia, Ctr Heart Lung Innovat, Vancouver, BC, Canada. [Pare, Peter D.] St Pauls Hosp, Inst Heart & Lung Hlth, Vancouver, BC, Canada. [Latourelle, Jeanne C.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Dupuis, Josee; O'Connor, George T.; Wilk, Jemma B.] NHLBI, Framingham Heart Study, Framingham, MA USA. [O'Connor, George T.] Boston Univ, Sch Med, Dept Med, Pulm Ctr, Boston, MA 02118 USA. [Kim, Woo Jin; Lee, Mi Kyeong] Kangwon Natl Univ, Sch Med, Dept Internal Med, Chunchon, South Korea. [Kim, Woo Jin; Lee, Mi Kyeong] Kangwon Natl Univ, Sch Med, Ctr Environm Hlth, Chunchon, South Korea. [Oh, Yeon-Mok] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pulm & Crit Care Med, Seoul, South Korea. [Oh, Yeon-Mok] Univ Ulsan, Coll Med, Asan Med Ctr, Clin Res Ctr Chron Obstruct Airway Dis, Seoul, South Korea. [de Koning, Harry J.] Erasmus MC, Dept Publ Hlth, Rotterdam, Netherlands. [Leng, Shuguang; Belinsky, Steven A.; Tesfaigzi, Yohannes] Lovelace Resp Res Inst, Albuquerque, NM USA. [Manichaikul, Ani; Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Manichaikul, Ani; Wang, Xin-Qun; Rich, Stephen S.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Barr, R. Graham] Columbia Univ Coll Phys & Surg, Dept Med, New York, NY USA. [Barr, R. Graham] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Sparrow, David] Boston Univ, Sch Med, VA Boston Healthcare Syst, Boston, MA 02118 USA. [Sparrow, David] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Bakke, Per; Gulsvik, Amund] Univ Bergen, Dept Clin Sci, Bergen, Norway. [Lahousse, Lies; Brusselle, Guy G.; Stricker, Bruno H.; Uitterlinden, Andre G.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Lahousse, Lies; Brusselle, Guy G.] Ghent Univ Hosp, Dept Resp Med, Ghent, Belgium. [Brusselle, Guy G.] Erasmus MC, Dept Resp Med, Rotterdam, Netherlands. [Stricker, Bruno H.] Netherlands Hlth Care Inspectorate, The Hague, Netherlands. [Stricker, Bruno H.; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Stricker, Bruno H.; Uitterlinden, Andre G.] NCHA, NGI, Leiden, Netherlands. [Ampleford, Elizabeth J.; Bleecker, Eugene R.; Meyers, Deborah A.] Wake Forest Univ, Bowman Gray Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA. [Woodruff, Prescott G.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA USA. [Woodruff, Prescott G.] Univ Calif San Francisco, Dept Med, Div Pulm Crit Care Sleep & Allergy, San Francisco, CA USA. [Lomas, David A.] UCL, London, England. [Yim, Jae-Joon] Seoul Natl Univ, Coll Med, Dept Internal Med, Div Pulm & Crit Care Med, Seoul, South Korea. [Hawrylkiewicz, Iwona; Sliwinski, Pawel] Seoul Natl Univ, Coll Med, SMG SNU Boramae Med Ctr, Seoul, South Korea. [Hawrylkiewicz, Iwona; Sliwinski, Pawel] Inst TB & Lung Dis, Dept Resp Med 2, Warsaw, Poland. [Fingerlin, Tasha E.; Schwartz, David A.] Natl Jewish Hlth, Ctr Genes Environm & Hlth, Denver, CO USA. [Fingerlin, Tasha E.] Univ Colorado Denver, Dept Biostat & Informat, Aurora, CO USA. [Schwartz, David A.] Univ Colorado Denver, Sch Med, Dept Med, Aurora, CO USA. [Schwartz, David A.] Univ Colorado Denver, Sch Med, Dept Immunol, Aurora, CO USA. [MacNee, William] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Tobin, Martin D.] Glenfield Hosp, NIHR, Leicester Resp Biomed Res Unit, Leicester, Leics, England. RP Cho, MH (reprint author), Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.; Cho, MH (reprint author), Brigham & Womens Hosp, Div Pulm & Crit Care Med, 75 Francis St, Boston, MA 02115 USA. EM remhc@channing.harvard.edu OI Hobbs, Brian/0000-0001-9564-0745; Wain, Louise/0000-0003-4951-1867 FU Medical Research Council [G0902313]; NHLBI NIH HHS [R01 HL126596, K01 HL129039, K08 HL097029, P01 HL105339, P01 HL114501, R01 HL075478, R01 HL084323, R01 HL089856, R01 HL089897, R01 HL113264, R01 HL124233, T32 HL007427] NR 53 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD MAR PY 2017 VL 49 IS 3 BP 426 EP 432 DI 10.1038/ng.3752 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA EL9CU UT WOS:000394917800016 PM 28166215 ER PT J AU Takeuchi, M Mizuki, N Meguro, A Ombrello, MJ Kirino, Y Satorius, C Le, J Blake, M Erer, B Kawagoe, T Ustek, D Tugal-Tutkun, I Seyahi, E Ozyazgan, Y Sousa, I Davatchi, F Francisco, V Shahram, F Abdollahi, BS Nadji, A Shafiee, NM Ghaderibarmi, F Ohno, S Ueda, A Ishigatsubo, Y Gadina, M Oliveira, SA Gul, A Kastner, DL Remmers, EF AF Takeuchi, Masaki Mizuki, Nobuhisa Meguro, Akira Ombrello, Michael J. Kirino, Yohei Satorius, Colleen Le, Julie Blake, Mary Erer, Burak Kawagoe, Tatsukata Ustek, Duran Tugal-Tutkun, Ilknur Seyahi, Emire Ozyazgan, Yilmaz Sousa, Ines Davatchi, Fereydoun Francisco, Vania Shahram, Farhad Abdollahi, Bahar Sadeghi Nadji, Abdolhadi Shafiee, Niloofar Mojarad Ghaderibarmi, Fahmida Ohno, Shigeaki Ueda, Atsuhisa Ishigatsubo, Yoshiaki Gadina, Massimo Oliveira, Sofia A. Gul, Ahmet Kastner, Daniel L. Remmers, Elaine F. TI Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behcet's disease susceptibility SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; INFLAMMATORY-BOWEL-DISEASE; MHC CLASS-I; CROHNS-DISEASE; GENE POLYMORPHISMS; FUT2; RISK; LEPROSY; HLA-B-ASTERISK-51; IL23R-IL12RB2 AB We analyzed 1,900 Turkish Behcet's disease cases and 1,779 controls genotyped with the Immunochip. The most significantly associated SNP was rs1050502, a tag SNP for HLA-B*51. In the Turkish discovery set, we identified three new risk loci, IL1A-IL18, IRF8, and CEBPB-PTPN1, with genomewide significance (P < 5 x 10(-8)) by direct genotyping and ADO-EGR2 by imputation. We replicated the ADO-EGR2, IRF8, and CEBPB-PTPN1 loci by genotyping 969 Iranian cases and 826 controls. Imputed data in 608 Japanese cases and 737 controls further replicated ADO-EGR2 and IRF8, and meta analysis additionally identified R1PK2 and LACC1. The disease associated allele of rs4402765, the lead marker at 11.1A-ILIB, was associated with both decreased IL-1 alpha and increased IL-1 beta production. ABO non-secretor genotypes for two ancestry specific FUT2 SNPs showed strong disease association (P = 5.89 x 10(-15)). Our findings extend the list of susceptibility genes shared with Crohn's disease and leprosy and implicate mucosal factors and the innate immune response to microbial exposure in Behcet's disease susceptibility. C1 [Takeuchi, Masaki; Satorius, Colleen; Le, Julie; Erer, Burak; Kastner, Daniel L.; Remmers, Elaine F.] NHGRI, Inflammatory Dis Sect, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Takeuchi, Masaki; Mizuki, Nobuhisa; Meguro, Akira; Kawagoe, Tatsukata] Yokohama City Univ, Grad Sch Med, Dept Ophthalmol & Visual Sci, Yokohama, Kanagawa, Japan. [Ombrello, Michael J.] NIAMSD, Translat Genet & Genom Unit, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Kirino, Yohei; Ueda, Atsuhisa; Ishigatsubo, Yoshiaki] Yokohama City Univ, Grad Sch Med, Dept Stem Cell & Immune Regulat, Yokohama, Kanagawa, Japan. [Blake, Mary; Gadina, Massimo] NIAMSD, Translat Immunol Sect, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Ustek, Duran] Istanbul Univ, Inst Expt Med, Dept Genet, Istanbul, Turkey. [Tugal-Tutkun, Ilknur] Istanbul Univ, Istanbul Fac Med, Dept Ophthalmol, Istanbul, Turkey. [Seyahi, Emire] Istanbul Univ, Cerrahpasa Fac Med, Dept Internal Med, Div Rheumatol, Istanbul, Turkey. [Ozyazgan, Yilmaz] Istanbul Univ, Cerrahpasa Fac Med, Dept Ophthalmol, Istanbul, Turkey. [Sousa, Ines; Francisco, Vania; Oliveira, Sofia A.] Univ Lisbon, Fac Med, Inst Med Mol, Lisbon, Portugal. [Sousa, Ines; Francisco, Vania; Oliveira, Sofia A.] Inst Gulbenkian Ciencias, Oeiras, Portugal. [Davatchi, Fereydoun; Shahram, Farhad; Abdollahi, Bahar Sadeghi; Nadji, Abdolhadi; Shafiee, Niloofar Mojarad; Ghaderibarmi, Fahmida] Univ Tehran Med Sci, Rheumatol Res Ctr, Tehran, Iran. [Ohno, Shigeaki] Hokkaido Univ, Grad Sch Med, Dept Ophthalmol, Sapporo, Hokkaido, Japan. [Gul, Ahmet] Istanbul Univ, Istanbul Fac Med, Div Rheumatol, Dept Internal Med, Istanbul, Turkey. RP Kastner, DL; Remmers, EF (reprint author), NHGRI, Inflammatory Dis Sect, US Natl Inst Hlth, Bethesda, MD 20892 USA. EM kastnerd@mail.nih.gov; elaine.remmers@nih.gov FU Intramural Research Programs of the National Human Genome Research Institute; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Fellowship for Japanese Biomedical and Behavioral Researchers at the NIH from the Japan Society for the Promotion of Science Research; Japan Foundation for Applied Enzymology; Japan Society for the Promotion of Science [26713036]; Kanae Foundation for the Promotion of Medical Science; Takeda Science Foundation; SENSHIN Medical Research Foundation; Yokohama Foundation for Advancement of Medical Science; Portuguese Fundacao para a Ciencia e a Tecnologia (Investigator-FCT) [CMUP-ERI/TPE/0028/2013, SFRH/BPD/70008/2010]; Research Committee of the Tehran University of Medical Sciences [132/714] FX This research was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. We thank all the patients, the healthy controls, and medical staff for their enthusiastic support during this research study. M.T. is supported by a Fellowship for Japanese Biomedical and Behavioral Researchers at the NIH from the Japan Society for the Promotion of Science Research and a grant from the Japan Foundation for Applied Enzymology. Y.K. is supported by grants from the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (grant 26713036), the Kanae Foundation for the Promotion of Medical Science, the Takeda Science Foundation, the SENSHIN Medical Research Foundation, and the Yokohama Foundation for Advancement of Medical Science. This research was also supported by the Portuguese Fundacao para a Ciencia e a Tecnologia (grant CMUP-ERI/TPE/0028/2013, fellowship SFRH/BPD/70008/2010 to I.S., and an Investigator-FCT contract to S.A.O.) and the Research Committee of the Tehran University of Medical Sciences (grant 132/714). We thank A.F. Wilson for insightful comments on this manuscript. NR 42 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD MAR PY 2017 VL 49 IS 3 BP 438 EP 443 DI 10.1038/ng.3786 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA EL9CU UT WOS:000394917800018 PM 28166214 ER EF