FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Punwani, D Kawahara, M Yu, J Sanford, U Roy, S Patel, K Carbonaro, DA Karlen, AD Khan, S Cornetta, K Rothe, M Schambach, A Kohn, DB Malech, HL McIvor, RS Puck, JM Cowan, MJ AF Punwani, Divya Kawahara, Misako Yu, Jason Sanford, Ukina Roy, Sushmita Patel, Kiran Carbonaro, Denise A. Karlen, Andrea D. Khan, Sara Cornetta, Kenneth Rothe, Michael Schambach, Axel Kohn, Donald B. Malech, Harry L. McIvor, R. Scott Puck, Jennifer M. Cowan, Morton J. TI Lentivirus Mediated Correction of Artemis-Deficient Severe Combined Immunodeficiency SO HUMAN GENE THERAPY LA English DT Article DE severe combined immunodeficiency; Artemis; gene therapy; lentivirus; radiation sensitivity ID BONE-MARROW-TRANSPLANTATION; SPEAKING NATIVE-AMERICANS; STEM-CELL TRANSPLANTATION; ADENOSINE-DEAMINASE DEFICIENCY; COMBINED IMMUNE-DEFICIENCY; LARGE GENE LISTS; V(D)J RECOMBINATION; CHROMOSOME 10P; VECTOR; DISEASE AB During B and T lymphocyte maturation, V(D)J recombination is initiated by creation of DNA double-strand breaks. Artemis is an exonuclease essential for their subsequent repair by nonhomologous end-joining. Mutations in DCLRE1C, the gene encoding Artemis, cause T-B-NK+ severe combined immunodeficiency (ART-SCID) and also confer heightened sensitivity to ionizing radiation and alkylating chemotherapy. Although allogeneic hematopoietic cell transplantation can treat ART-SCID, conditioning regimens are poorly tolerated, leading to early mortality and/or late complications, including short stature, endocrinopathies, and dental aplasia. However, without alkylating chemotherapy as preconditioning, patients usually have graft rejection or limited T cell and no B cell recovery. Thus, addition of normal DCLRE1C cDNA to autologous hematopoietic stem cells is an attractive strategy to treat ART-SCID. We designed a self-inactivating lentivirus vector containing human Artemis cDNA under transcriptional regulation of the human endogenous Artemis promoter (AProArt). Fibroblasts from ART-SCID patients transduced with AProArt lentivirus showed correction of radiosensitivity. Mobilized peripheral blood CD34(+) cells from an ART-SCID patient as well as hematopoietic stem cells from Artemis-deficient mice demonstrated restored T and B cell development following AProArt transduction. Murine hematopoietic cells transduced with AProArt exhibited no increase in replating potential in an in vitro immortalization assay, and analysis of AProArt lentivirus insertions showed no predilection for sites that could activate oncogenes. These efficacy and safety findings support institution of a clinical trial of gene addition therapy for ART-SCID. C1 [Punwani, Divya; Kawahara, Misako; Yu, Jason; Sanford, Ukina; Roy, Sushmita; Patel, Kiran; Khan, Sara; Puck, Jennifer M.; Cowan, Morton J.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA. [Punwani, Divya; Kawahara, Misako; Yu, Jason; Sanford, Ukina; Roy, Sushmita; Patel, Kiran; Khan, Sara; Puck, Jennifer M.; Cowan, Morton J.] Univ Calif San Francisco, Benioff Childrens Hosp, San Francisco, CA 94143 USA. [Carbonaro, Denise A.; Kohn, Donald B.] Univ Calif Los Angeles, Dept Microbiol, Los Angeles, CA 90024 USA. [Carbonaro, Denise A.; Kohn, Donald B.] Univ Calif Los Angeles, Dept Immunol & Mol Genet, Los Angeles, CA 90024 USA. [Carbonaro, Denise A.; Kohn, Donald B.] Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90024 USA. [Karlen, Andrea D.; McIvor, R. Scott] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN USA. [Cornetta, Kenneth] Indiana Univ, Dept Med & Mol Genet, Indianapolis, IN 46204 USA. [Cornetta, Kenneth] Indiana Univ, Viral Prod Facil, Indianapolis, IN 46204 USA. [Rothe, Michael; Schambach, Axel] Hannover Med Sch, Inst Expt Hematol, Hannover, Germany. [Malech, Harry L.] NIAID, Lab Host Defenses, Div Intramural Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Puck, JM; Cowan, MJ (reprint author), Univ Calif San Francisco, Smith Cardiovasc Res Inst, 555 Mission Bay Blvd South,Rm SC-252K, San Francisco, CA 94158 USA. EM jennifer.puck@ucsf.edu; mort.cowan@ucsf.edu FU California Institute of Regenerative Medicine [TR3-05535]; National Institutes of Health National Institute of Allergy and Infectious Diseases, Division of Intramural Research; Warren Magnusen Clinical Center FX These studies were supported by a research grant from the California Institute of Regenerative Medicine TR3-05535 and the National Institutes of Health National Institute of Allergy and Infectious Diseases, Division of Intramural Research and Warren Magnusen Clinical Center. We thank Steve Yannone, Laurence Berkeley Laboratory, for anti-Artemis antibody and Yanning Wang for technical expertise. We also thank the ART-SCID patients who volunteered to donate cells for these studies. NR 44 TC 1 Z9 1 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1043-0342 EI 1557-7422 J9 HUM GENE THER JI Hum. Gene Ther. PD JAN PY 2017 VL 28 IS 1 BP 112 EP 124 DI 10.1089/hum.2016.064 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA EI9HF UT WOS:000392817800005 PM 27611239 ER PT J AU Dockree, T Holland, CJ Clement, M Ladell, K McLaren, JE van den Berg, HA Gostick, E Miners, KL Llewellyn-Lacey, S Bridgeman, JS Man, S Bailey, M Burrows, SR Price, DA Wooldridge, L AF Dockree, Tamsin Holland, Christopher J. Clement, Mathew Ladell, Kristin McLaren, James E. van den Berg, Hugo A. Gostick, Emma Miners, Kelly L. Llewellyn-Lacey, Sian Bridgeman, John S. Man, Stephen Bailey, Mick Burrows, Scott R. Price, David A. Wooldridge, Linda TI CD8(+) T-cell specificity is compromised at a defined MFICl/CD8 affinity threshold SO IMMUNOLOGY AND CELL BIOLOGY LA English DT Article ID MHC CLASS-I; ANTIGEN RECEPTOR; PEPTIDE-MHC; CORECEPTOR FUNCTION; CROSS-REACTIVITY; KINASE P56LCK; RECOGNITION; BINDING; LYMPHOCYTES; CD4 AB The CD8 co-receptor engages peptide-major histocompatibility complex class I (pMHCI) molecules at a largely invariant site distinct from the T-cell receptor (TCR)-binding platform and enhances the sensitivity of antigen-driven activation to promote effective CD8(+) T-cell immunity. A small increase in the strength of the pMHCl/CD8 interaction (similar to 1.5-fold) can disproportionately amplify this effect, boosting antigen sensitivity by up to two orders of magnitude. However, recognition specificity is lost altogether with more substantial increases in pMHCl/CD8 affinity (similar to 10-fold). In this study, we used a panel of MHCI mutants with altered CD8-binding properties to show that TCR-mediated antigen specificity is delimited by a pMHCl/CD8 affinity threshold. Our findings suggest that CD8 can be engineered within certain biophysical parameters to enhance the therapeutic efficacy of adoptive T-cell transfer irrespective of antigen specificity. C1 [Dockree, Tamsin; Clement, Mathew; Ladell, Kristin; McLaren, James E.; Gostick, Emma; Miners, Kelly L.; Llewellyn-Lacey, Sian; Bridgeman, John S.; Price, David A.] Cardiff Univ, Inst Infect & Immun, Sch Med, Cardiff CF14 4XN, S Glam, Wales. [Holland, Christopher J.; Bailey, Mick; Wooldridge, Linda] Univ Bristol, Fac Hlth Sci, Bristol, Avon, England. [van den Berg, Hugo A.] Univ Warwick, Math Inst, Coventry, W Midlands, England. [Man, Stephen] Cardiff Univ, Inst Canc & Genet, Sch Med, Cardiff, Wales. [Burrows, Scott R.] QIMR Berghofer Med Res Inst, Cellular Immunol Lab, Brisbane, Qld, Australia. [Price, David A.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Dockree, T (reprint author), Cardiff Univ, Inst Infect & Immun, Sch Med, Cardiff CF14 4XN, S Glam, Wales. EM WilliamsT19@cardiff.ac.uk RI Price, David/C-7876-2013; Man, Stephen/D-1391-2009 OI Price, David/0000-0001-9416-2737; FU Wellcome Trust [WT099067AIA, 100326/Z/12/Z, WT079848MA, WT096454AIA] FX We thank Dr Anya Lissina for helpful discussions. TD is supported by a Wellcome Trust Research Training Fellowship (WT099067AIA). DAP is supported by a Wellcome Trust Senior Investigator Award (100326/Z/12/Z). LW was supported by a Wellcome Trust Intermediate Clinical Fellowship (WT079848MA). Additional funding was provided by a Wellcome Trust Entry Level Fellowship awarded to TD (WT096454AIA). NR 47 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 0818-9641 EI 1440-1711 J9 IMMUNOL CELL BIOL JI Immunol. Cell Biol. PD JAN PY 2017 VL 95 IS 1 BP 68 EP 76 DI 10.1038/icb.2016.85 PG 9 WC Cell Biology; Immunology SC Cell Biology; Immunology GA EI8WG UT WOS:000392788300010 PM 27670790 ER PT J AU Diallo, MSAF Cong, XM Henderson, WA McGrath, J AF Diallo, M. S. Ana F. Cong, Xiaomei Henderson, Wendy A. McGrath, Jacqueline TI Management of childhood diarrhea by healthcare professionals in low income countries: An integrative review SO INTERNATIONAL JOURNAL OF NURSING STUDIES LA English DT Review DE Antibiotics use; Childhood diarrhea; Healthcare providers; Low income countries; Prescribing behaviors; Oral rehydration therapy; World Health Organization; Clinical management of childhood diarrhea ID PHYSICIANS PRESCRIBING BEHAVIOR; ORAL REHYDRATION THERAPY; KNOWLEDGE; GUIDELINES; CHILDREN; PRACTITIONERS; THAILAND; NIGERIA AB Background: The significant drop in child mortality due to diarrhea has been primarily attributed to the use of oral rehydration solutions, continuous feeding and zinc supplementation. Nevertheless uptake of these interventions have been slow in developing countries and many children suffering from diarrhea are not receiving adequate care according to the World Health Organization recommended guidelines for the clinical management of childhood diarrhea. Objectives: The aim of this integrative review is to appraise healthcare professionals' management of childhood diarrhea in low-income countries. Design: Whittemore and Knafl integrative review method was used, in conjunction with the Reporting of Observational Studies in Epidemiology (STROBE) checklist for reporting observational cohort, case control and cross sectional studies. Method: A comprehensive search performed from December 2014 to April 2015 used five databases and focused on observational studies of healthcare professional's management of childhood diarrhea in low-income countries. Results: A total of 21 studies were included in the review. Eight studies used a survey design while three used some type of simulated client survey referring to a fictitious case of a child with diarrhea. Retrospective chart reviews were used in one study. Only one study used direct observation of the healthcare professionals during practice and the remaining eight used a combination of research designs. Studies were completed in South East Asia (n = 13), Sub-Saharan Africa (n = 6) and South America (n = 2). Conclusion: Studies report that healthcare providers have adequate knowledge of the etiology of diarrhea and the severe signs of dehydration associated with diarrhea. More importantly, regardless of geographical settings and year of study publication, inconsistencies were noted in healthcare professionals' physical examination, prescription of oral rehydration solutions, antibiotics and other medications as well as education provided to the primary caregivers. Factors other than knowledge about diarrhea were shown to significantly influence prescriptive behaviors of healthcare professionals. This review demonstrates that "knowledge is not enough" to ensure the appropriate use of oral rehydration solutions, zinc and antibiotics by healthcare professionals in the management of childhood diarrhea. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Diallo, M. S. Ana F.; Cong, Xiaomei; McGrath, Jacqueline] Univ Connecticut, Sch Nursing, U-4026, Storrs, CT 06269 USA. [Henderson, Wendy A.] NINR, NIH, Bethesda, MD 20892 USA. [McGrath, Jacqueline] Connecticut Childrens Med Ctr, Hartford, CT USA. RP Diallo, MSAF (reprint author), Univ Connecticut, Sch Nursing, U-4026, Storrs, CT 06269 USA. EM ana.diallo@uconn.edu OI Henderson, Wendy/0000-0003-3924-7118 NR 38 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 0020-7489 EI 1873-491X J9 INT J NURS STUD JI Int. J. Nurs. Stud. PD JAN PY 2017 VL 66 BP 82 EP 92 DI 10.1016/j.ijnurstu.2016.08.014 PG 11 WC Nursing SC Nursing GA EJ5JD UT WOS:000393253300010 ER PT J AU Gilbert, MR Pugh, SL Aldape, K Sorensen, AG Mikkelsen, T Penas-Prado, M Bokstein, F Kwok, Y Lee, RJ Mehta, M AF Gilbert, Mark R. Pugh, Stephanie L. Aldape, Ken Sorensen, A. Gregory Mikkelsen, Tom Penas-Prado, Marta Bokstein, Felix Kwok, Young Lee, R. Jeffrey Mehta, Minesh TI NRG oncology RTOG 0625: a randomized phase II trial of bevacizumab with either irinotecan or dose-dense temozolomide in recurrent glioblastoma SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Glioblastoma; Anti-angiogenic treatment; Randomized trial; Combination therapy ID NEWLY-DIAGNOSED GLIOBLASTOMA; SINGLE-AGENT BEVACIZUMAB; CLINICAL-TRIALS; MALIGNANT GLIOMA; TUMORS; CRITERIA; THERAPY AB Angiogenesis, a hallmark of glioblastoma, can potentially be targeted by inhibiting the VEGF pathway using bevacizumab, a humanized monoclonal antibody against VEGF-A. This study was designed to determine the efficacy and safety of these regimens in the cooperative group setting. Eligibility included age 18, recurrent or progressive GBM after standard chemoradiation. Treatment was intravenous bevacizumab 10 mg/kg and either irinotecan (CPT) 125 mg/m(2) every 2 weeks or temozolomide (TMZ) 75-100 mg/m(2) day 1-21 of 28 day cycle. Accrual goal was 57 eligible patients per arm. Primary endpoint was 6 month progression-free survival (6-m PFS); a predetermined rate of 35 % to declare efficacy. 60 eligible patients were enrolled on TMZ arm and 57 patients on CPT arm. Median age was 56, median KPS was 80. For TMZ arm, the 6-m-PFS rate was 39 % (23/59); for the CPT arm, the 6-m-PFS rate was 38.6 % (22/57). Objective responses: TMZ arm had 2 (3 %) CR, 9 (16 %) PR; CPT arm had 2 (4 %) CR, 13 (24 %) PR. Overall there was moderate toxicity: TMZ arm with 33 (55 %) grade 3, 11 (18 %) grade 4, and 1 (2 %) grade 5 (fatal) toxicities; CPT arm had 22 (39 %) grade 3, 7 (12 %) grade 4, and 3 (5 %) grade 5 toxicities. The 6-m-PFS surpassed the predetermined efficacy threshold for both arms, corroborating the efficacy of bevacizumab and CPT and confirming activity for bevacizumab and protracted TMZ for recurrent/progressive GBM, even after prior temozolomide exposure. Toxicities were within anticipated frequencies with a moderately high rate of venous thrombosis, moderate hypertension and one intracranial hemorrhage. C1 [Gilbert, Mark R.] NCI, Neurooncol Branch, NIH, Bloch Bldg 82,Rm 235,9030 Old George Town Rd, Bethesda, MD 20892 USA. [Pugh, Stephanie L.] NRG Oncol Stat & Data Management Ctr, Philadelphia, PA USA. [Aldape, Ken] Univ Toronto, Toronto, ON, Canada. [Sorensen, A. Gregory] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mikkelsen, Tom] Henry Ford Hosp, Dept Neurol, Detroit, MI 48202 USA. [Penas-Prado, Marta] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Bokstein, Felix] Tel Aviv Med Ctr & Sch Med, Tel Aviv, Israel. [Kwok, Young; Mehta, Minesh] Univ Maryland, Baltimore, MD 21201 USA. [Lee, R. Jeffrey] Intermt Med Ctr, Murray, UT USA. RP Gilbert, MR (reprint author), NCI, Neurooncol Branch, NIH, Bloch Bldg 82,Rm 235,9030 Old George Town Rd, Bethesda, MD 20892 USA. EM mark.gilbert@nih.gov OI mehta, minesh/0000-0002-4812-5713 FU National Cancer Institute (NCI) [U10CA21661, U10CA180868, U10CA180822, U10CA37422, U24CA180803] FX This project was supported by grants U10CA21661, U10CA180868, U10CA180822, U10CA37422, and U24CA180803 from the National Cancer Institute (NCI). NR 24 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD JAN PY 2017 VL 131 IS 1 BP 193 EP 199 DI 10.1007/s11060-016-2288-5 PG 7 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA EJ2TX UT WOS:000393065400021 PM 27770279 ER PT J AU England, LJ Aagaard, K Bloch, M Conway, K Cosgrove, K Grana, R Gould, TJ Hatsukami, D Jensen, F Kandel, D Lanphear, B Leslie, F Pauly, JR Neiderhiser, J Rubinstein, M Slotkin, TA Spindel, E Stroud, L Wakschlag, L AF England, Lucinda J. Aagaard, Kjersti Bloch, Michele Conway, Kevin Cosgrove, Kelly Grana, Rachel Gould, Thomas J. Hatsukami, Dorothy Jensen, Frances Kandel, Denise Lanphear, Bruce Leslie, Frances Pauly, James R. Neiderhiser, Jenae Rubinstein, Mark Slotkin, Theodore A. Spindel, Eliot Stroud, Laura Wakschlag, Lauren TI Developmental toxicity of nicotine: A transdisciplinary synthesis and implications for emerging tobacco products SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Review DE Nicotine; Electronic nicotine delivery systems; Priority/special populations ID MATERNAL CIGARETTE-SMOKING; INFANT-DEATH-SYNDROME; ANXIETY-LIKE BEHAVIOR; ACETYLCHOLINE-RECEPTOR EXPRESSION; DEFICIT HYPERACTIVITY DISORDER; OBSTRUCTIVE PULMONARY-DISEASE; DEPRESSIVE-LIKE BEHAVIOR; HIGH-SCHOOL-STUDENTS; ALASKA NATIVE WOMEN; RAT-BRAIN REGIONS AB While the health risks associated with adult cigarette smoking have been well described, effects of nicotine exposure during periods of developmental vulnerability are often overlooked. Using MEDLINE and PubMed literature searches, books, reports and expert opinion, a transdisciplinary group of scientists reviewed human and animal research on the health effects of exposure to nicotine during pregnancy and adolescence. A synthesis of this research supports that nicotine contributes critically to adverse effects of gestational tobacco exposure, including reduced pulmonary function, auditory processing defects, impaired infant cardiorespiratory function, and may contribute to cognitive and behavioral deficits in later life. Nicotine exposure during adolescence is associated with deficits in working memory, attention, and auditory processing, as well as increased impulsivity and anxiety. Finally, recent animal studies suggest that nicotine has a priming effect that increases addiction liability for other drugs. The evidence that nicotine adversely affects fetal and adolescent development is sufficient to warrant public health measures to protect pregnant women, children, and adolescents from nicotine exposure. Published by Elsevier Ltd. C1 [England, Lucinda J.] Ctr Dis Control & Prevent, Off Smoking & Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. [Aagaard, Kjersti] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Bloch, Michele; Grana, Rachel] NCI, Div Canc Control & Populat Sci, NIH, Rockville, MD USA. [Conway, Kevin] NIDA, Div Epidemiol Serv & Prevent Res, NIH, Rockville, MD USA. [Cosgrove, Kelly] Yale Sch Med, Dept Psychiat, New Haven, CT USA. [Gould, Thomas J.] Penn State Univ, Dept Biobehav Hlth, University Pk, PA 16802 USA. [Hatsukami, Dorothy] Univ Minnesota Minneapolis, Masonic Canc Ctr, Minneapolis, MN USA. [Jensen, Frances] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kandel, Denise] Columbia Univ, Dept Psychiat, New York State Psychiat Inst, New York, NY USA. [Kandel, Denise] Columbia Univ, Mailman Sch Publ Hlth, New York State Psychiat Inst, New York, NY USA. [Lanphear, Bruce] Simon Frasier Univ, Burnaby, BC, Canada. [Leslie, Frances] Univ Calif Irvine, Sch Med, Dept Pharmacol, Irvine, CA 92717 USA. [Pauly, James R.] Univ Kentucky, Coll Pharm, Lexington, KY USA. [Neiderhiser, Jenae] Penn State Univ, Dept Psychol, University Pk, PA 16802 USA. [Rubinstein, Mark] Univ Calif San Francisco, Sch Med, Dept Pediat, San Francisco, CA USA. [Slotkin, Theodore A.] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC USA. [Spindel, Eliot] Oregon Hlth & Sci Univ, Div Neurosci, Oregon Natl Primate Res Ctr, Beaverton, OR USA. [Stroud, Laura] Brown Univ, Dept Psychiat & Human Behav, Alpert Med Sch, Providence, RI 02912 USA. [Wakschlag, Lauren] Northwestern Univ, Dept Med Social Sci, Feinberg Sch Med, Chicago, IL 60611 USA. RP England, LJ (reprint author), CDC, 4770 Buford Highway NE,MS F-79, Atlanta, GA 30341 USA. EM lbe9@cdc.gov FU Centers for Disease Control and Prevention; National Cancer Institute, National Institutes of Health FX All authors participated in an expert meeting, Developmental Effects of Nicotine and Implications for Emerging Tobacco Products, sponsored by the Centers for Disease Control and Prevention and the National Cancer Institute, National Institutes of Health. They are listed alphabetically. NR 323 TC 1 Z9 1 U1 8 U2 8 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 JAN PY 2017 VL 72 BP 176 EP 189 DI 10.1016/j.neubiorev.2016.11.013 PG 14 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA EI8WW UT WOS:000392789900013 PM 27890689 ER PT J AU Chen, YY Brooks, MJ Gieser, L Swaroop, A Palczewski, K AF Chen, Yuanyuan Brooks, Matthew J. Gieser, Linn Swaroop, Anand Palczewski, Krzysztof TI Transcriptome profiling of NIH3T3 cell lines expressing opsin and the P23H opsin mutant identifies candidate drugs for the treatment of retinitis pigmentosa SO PHARMACOLOGICAL RESEARCH LA English DT Article DE Rhodopsin; P23H opsin; Retinitis pigmentosa; Transcriptome; Retina; Drug discovery; Cell-based HTS; Transcriptome; RNA-seq ID VALPROIC ACID; RETINAL DEGENERATION; PHARMACOLOGICAL MANIPULATION; ACTIVATES TRANSDUCTION; GENE-THERAPY; MOUSE MODEL; RHODOPSIN; MECHANISMS; DEGRADATION; AGGREGATION AB Mammalian cells are commonly employed in screening assays to identify active compounds that could potentially affect the progression of different human diseases including retinitis pigmentosa (RP), a class of inherited diseases causing retinal degeneration with compromised vision. Using transcriptome analysis, we compared NIH3T3 cells expressing wildtype (WT) rod opsin with a retinal disease-causing single P23H mutation. Surprisingly, heterologous expression of WT opsin in NIH3T3 cells caused more than a 2-fold change in 783 out of 16,888 protein coding transcripts. The perturbed genes encoded extracellular matrix proteins, growth factors, cytoskeleton proteins, glycoproteins and metalloproteases involved in cell adhesion, morphology and migration. A different set of 347 transcripts was either up- or down regulated when the P23H mutant opsin was expressed suggesting an altered molecular perturbation compared to WT opsin. Transcriptome perturbations elicited by drug candidates aimed at mitigating the effects of the mutant protein revealed that different drugs targeted distinct molecular pathways that resulted in a similar phenotype selected by a cell-based high-throughput screen. Thus, transcriptome profiling can provide essential information about the therapeutic potential of a candidate drug to restore normal gene expression in pathological conditions. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Chen, Yuanyuan; Palczewski, Krzysztof] Case Western Reserve Univ, Cleveland Ctr Membrane & Struct Biol, Sch Med, Dept Pharmacol, Cleveland, OH 44106 USA. [Brooks, Matthew J.; Gieser, Linn; Swaroop, Anand] NIH, NEI, Neurobiol Neurodegenerat & Repair Lab N NRL, Bethesda, MD 20892 USA. RP Palczewski, K (reprint author), Case Western Reserve Univ, Sch Med, Dept Pharmacol, 10900 Euclid Ave, Cleveland, OH 44106 USA. EM kxp65@case.edu FU National Institutes of Health (NIH) [EY022326, EY R24024864, K99 EY024992]; Arnold and Mabel Beckman Foundation; Foundation Fighting Blindness; Intramural Research Program of the National Eye Institute [EY000474, EY000546] FX This research was supported in part by grants from the National Institutes of Health (NIH) (EY022326 and EY R24024864 to K.P and K99 EY024992 to Y.C.), the Arnold and Mabel Beckman Foundation, Foundation Fighting Blindness, and the Intramural Research Program of the National Eye Institute (EY000474 and EY000546 to A.S.). NR 75 TC 0 Z9 0 U1 3 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-6618 J9 PHARMACOL RES JI Pharmacol. Res. PD JAN PY 2017 VL 115 BP 1 EP 13 DI 10.1016/j.phrs.2016.10.031 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EI8XB UT WOS:000392790400001 PM 27838510 ER PT J AU Fung, S Xu, C Hamel, E Wager-Miller, JB Woodruff, G Miller, A Sanford, C Mackie, K Stella, N AF Fung, Susan Xu, Cong Hamel, Ernest Wager-Miller, James B. Woodruff, Grace Miller, Aaron Sanford, Christina Mackie, Ken Stella, Nephi TI Novel indole-based compounds that differentiate alkylindole-sensitive receptors from cannabinoid receptors and microtubules: Characterization of their activity on glioma cell migration SO PHARMACOLOGICAL RESEARCH LA English DT Article DE Alkyl-indole; Glioma; Cannabinoids; GBM; Migration ID PROTEIN-COUPLED-RECEPTOR; MACROPHAGE-LIKE CELLS; LYSOPHOSPHATIDIC ACID; GLIOBLASTOMA-MULTIFORME; DEPENDENT MECHANISM; HUMAN NEUTROPHILS; CB2 RECEPTORS; HL-60 CELLS; 2-ARACHIDONOYLGLYCEROL; PROLIFERATION AB Indole-based compounds, such as the alkyl-indole (AI) compound WIN55212-2, activate the cannabinoid receptors, CB1 and CB2, two well-characterized G protein-coupled receptors (GPCR). Reports indicate that several indole-based cannabinoid agonists, including WIN55212-2, lack selectivity and interact with at least two additional targets: AI-sensitive GPCRs and microtubules. Studying how indole-based compounds modulate the activity of these 4 targets has been difficult as selective chemical tools were not available. Here we report the pharmacological characterization of six newly-developed indole-based compounds (ST-11, ST-23, ST-25, ST-29, ST-47 and ST-48) that exhibit distinct binding affinities at AI-sensitive receptors, cannabinoid CB1 and CB2 receptors and the colchicine site of tubulin. Several compounds exhibit some level of selectivity for AI-sensitive receptors, including ST-11 that binds AI-sensitive receptors with a K-d of 52 nM and appears to have a weaker affinity for the colchicine site of tubulin (K-d = 3.2 mu M) and does not bind CB1/CB2 receptors. Leveraging these characteristics, we show that activation of AI-sensitive receptors with ST-11 inhibits both the basal and stimulated migration of the Delayed Brain Tumor (DBT) mouse glioma cell line. Our study describes a new series of indole-based compounds that enable the pharmacological and functional differentiation of alkylindole-sensitive receptors from cannabinoid receptors and microtubules. Published by Elsevier Ltd. C1 [Fung, Susan; Xu, Cong; Woodruff, Grace; Miller, Aaron; Sanford, Christina; Stella, Nephi] Univ Washington, Dept Pharmacol, 1959 NE Pacific Way, Seattle, WA 98195 USA. [Fung, Susan] Univ Washington, Grad Program Neurobiol & Behav, 1959 NE Pacific St, Seattle, WA 98195 USA. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. [Wager-Miller, James B.; Mackie, Ken] Univ Washington, Dept Psychiat & Behav Sci, 1959 NE Pacific Way, Seattle, WA 98195 USA. [Stella, Nephi] Indiana Univ, Dept Psychol & Brain Sci, 702 N Walnut Grove Ave, Bloomington, IN 47405 USA. RP Stella, N (reprint author), Univ Washington, Dept Pharmacol, 1959 NE Pacific Way, Seattle, WA 98195 USA. EM nstella@uw.edu OI Mackie, Ken/0000-0001-8501-6199 FU NIH [DA014486, DA021696, DA035068] FX This work was funded by the NIH (DA014486 to NS and DA021696 and DA035068to KM). NR 49 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 1043-6618 J9 PHARMACOL RES JI Pharmacol. Res. PD JAN PY 2017 VL 115 BP 233 EP 241 DI 10.1016/j.phrs.2016.10.025 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EI8XB UT WOS:000392790400022 PM 27832960 ER PT J AU Bonaventura, J Quiroz, C Cai, NS Rubinstein, M Tanda, G Ferre, S AF Bonaventura, Jordi Quiroz, Cesar Cai, Ning-Sheng Rubinstein, Marcelo Tanda, Gianluigi Ferre, Sergi TI Key role of the dopamine D-4 receptor in the modulation of corticostriatal glutamatergic neurotransmission SO SCIENCE ADVANCES LA English DT Article ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; NETWORK ACTIVITY; GENE; DRD4; LOCALIZATION; ADHD; POLYMORPHISM; EXPRESSION; STRIATUM AB Polymorphic variants of the dopamine D-4 receptor gene (DRD4) have been repeatedly associated with numerous neuropsychiatric disorders. Yet, the functional role of the D-4 receptor and the functional differences of the products of DRD4 polymorphic variants remained enigmatic. Immunohistochemical and optogenetic-microdialysis experiments were performed in knock-in mice expressing a D-4 receptor with the long intracellular domain of a human DRD4 polymorphic variant associated with attention deficit hyperactivity disorder (ADHD). When compared with the wild-type mouse D-4 receptor, the expanded intracellular domain of the humanized D-4 receptor conferred a gain of function, blunting methamphetamine-induced cortical activation and optogenetic and methamphetamine-induced corticostriatal glutamate release. The results demonstrate a key role of the D-4 receptor in the modulation of corticostriatal glutamatergic neurotransmission. Furthermore, these data imply that enhanced D-4 receptor-mediated dopaminergic control of corticostriatal transmission constitutes a vulnerability factor of ADHD and other neuropsychiatric disorders. C1 [Bonaventura, Jordi; Quiroz, Cesar; Cai, Ning-Sheng; Ferre, Sergi] NIDA, Integrat Neurobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Rubinstein, Marcelo] Inst Invest Genet Engn & Mol Biol, RA-1428 Buenos Aires, DF, Argentina. [Tanda, Gianluigi] NIDA, Medicat Dev Program, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Bonaventura, J; Ferre, S (reprint author), NIDA, Integrat Neurobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM jordi.bonaventura@nih.gov; sferre@intra.nida.nih.gov OI Tanda, Gianluigi/0000-0001-9526-9878 FU National Agency for Scientific and Technical Research; Argentina University of Buenos Aires [PICT2012-0893]; National Institute on Drug Abuse FX This work was supported by the National Agency for Scientific and Technical Research, Argentina University of Buenos Aires (grant no. PICT2012-0893) and intramural funds of the National Institute on Drug Abuse. NR 32 TC 0 Z9 0 U1 3 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 2375-2548 J9 SCI ADV JI Sci. Adv. PD JAN PY 2017 VL 3 IS 1 AR e1601631 DI 10.1126/sciadv.1601631 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EK2XI UT WOS:000393789900023 ER PT J AU Aredo, JV Heyrana, KJ Karp, BI Shah, JP Stratton, P AF Aredo, Jacqueline V. Heyrana, Katrina J. Karp, Barbara I. Shah, Jay P. Stratton, Pamela TI Relating Chronic Pelvic Pain and Endometriosis to Signs of Sensitization and Myofascial Pain and Dysfunction SO SEMINARS IN REPRODUCTIVE MEDICINE LA English DT Article DE endometriosis; chronic pelvic pain; sensitization; myofascial trigger points; botulinum toxin ID TOXIN TYPE-A; LEVATOR ANI MUSCLES; BOTULINUM-TOXIN; TRIGGER POINTS; DOUBLE-BLIND; NERVOUS-SYSTEM; VISCERAL PAIN; INJECTIONS; RAT; VAGINISMUS AB Chronic pelvic pain is a frustrating symptom for patients with endometriosis and is frequently refractory to hormonal and surgical management. While these therapies target ectopic endometrial lesions, they do not directly address pain due to central sensitization of the nervous system and myofascial dysfunction, which can continue to generate pain from myofascial trigger points even after traditional treatments are optimized. This article provides a background for understanding how endometriosis facilitates remodeling of neural networks, contributing to sensitization and generation of myofascial trigger points. A framework for evaluating such sensitization and myofascial trigger points in a clinical setting is presented. Treatments that specifically address myofascial pain secondary to spontaneously painful myofascial trigger points and their putative mechanisms of action are also reviewed, including physical therapy, dry needling, anesthetic injections, and botulinum toxin injections. C1 [Aredo, Jacqueline V.; Karp, Barbara I.; Stratton, Pamela] NINDS, Ctr Clin, Intramural Res Program, NIH, Bldg 31,Room B2B32,9000 Rockville Pike, Bethesda, MD 20892 USA. [Heyrana, Katrina J.] Univ Rochester, Med Ctr, Dept Obstet & Gynecol, Rochester, NY 14642 USA. [Shah, Jay P.] NIH, Dept Rehabil Med, Ctr Clin, Intramural Res Program, Bethesda, MD 20892 USA. RP Stratton, P (reprint author), NINDS, Ctr Clin, Intramural Res Program, NIH, Bldg 31,Room B2B32,9000 Rockville Pike, Bethesda, MD 20892 USA. EM strattop@mail.nih.gov FU Intramural Research Program of the National Institutes of Health; NIH Clinical Center; National Institute of Neurological Disorders and Stroke FX This work was funded by the Intramural Research Program of the National Institutes of Health, the NIH Clinical Center, and the National Institute of Neurological Disorders and Stroke. NR 71 TC 0 Z9 0 U1 4 U2 4 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1526-8004 EI 1526-4564 J9 SEMIN REPROD MED JI Semin. Reprod. Med. PD JAN PY 2017 VL 35 IS 1 BP 88 EP 97 DI 10.1055/s-0036-1597123 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA EJ2BL UT WOS:000393014800011 PM 28049214 ER PT J AU Sylvetsky, AC Bauman, V Blau, JE Garraffo, HM Walter, PJ Rother, KI AF Sylvetsky, Allison C. Bauman, Viviana Blau, Jenny E. Garraffo, H. Martin Walter, Peter J. Rother, Kristina I. TI Plasma concentrations of sucralose in children and adults SO TOXICOLOGICAL AND ENVIRONMENTAL CHEMISTRY LA English DT Article DE Non-nutritive sweeteners; diet soda; sweetener absorption; pediatric ID NONNUTRITIVE SWEETENERS; P-GLYCOPROTEIN; BREAST-MILK AB We aimed to measure concentrations of the commonly used artificial sweetener sucralose, following ingestion of doses reflecting a range of consumption and to compare concentrations in children and adults. Eleven adults consumed 355 mL water containing 0 mg (control), 68, 170, or 250 mg sucralose (equivalent to 1-4 diet sodas). A second group of adults (n = 11) consumed 355 mL Diet Rite Cola (TM) (68 mg sucralose and 41 mg acesulfame-potassium (ace-K)) or 68 mg sucralose and 41 mg ace-K in seltzer. Beverages were provided at separate visits in randomized order, prior to an oral glucose tolerance test. Eleven children consumed 0 or 68 mg sucralose in 240 mL water, in an identical study design. Blood was collected before beverage ingestion and serially for 120 min. Sucralose doses (corrected for weight) resulted in similar plasma concentrations in children and adults. Concentrations were comparable whether sucralose was administered in water, combined with ace-K, or in diet soda. Due to their lower body weight and blood volume, children have markedly higher plasma sucralose concentrations after the consumption of a typical diet soda, emphasizing the need to determine the clinical implications of sucralose use in children. C1 [Sylvetsky, Allison C.; Bauman, Viviana; Blau, Jenny E.; Rother, Kristina I.] NIDDK, Sect Pediat Diabet & Metab, NIH, Bethesda, MD 20892 USA. [Sylvetsky, Allison C.] George Washington Univ, Dept Exercise & Nutr Sci, Milken Inst Sch Publ Hlth, Washington, DC USA. [Sylvetsky, Allison C.] George Washington Univ, Sumner M Redstone Global Ctr Prevent & Wellness, Washington, DC USA. [Garraffo, H. Martin; Walter, Peter J.] NIDDK, Clin Mass Spectrometry Core, NIH, Bethesda, MD 20892 USA. RP Rother, KI (reprint author), NIDDK, Sect Pediat Diabet & Metab, NIH, Bethesda, MD 20892 USA. EM kristina.rother@nih.gov FU National Institute of Diabetes, Digestive and Kidney Diseases at the National Institutes of Health (Bethesda, MD, USA) FX This work was supported in part by the intramural research program at the National Institute of Diabetes, Digestive and Kidney Diseases at the National Institutes of Health (Bethesda, MD, USA). NR 23 TC 2 Z9 2 U1 2 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0277-2248 EI 1029-0486 J9 TOXICOL ENVIRON CHEM JI Toxicol Environ. Chem. PY 2017 VL 99 IS 3 BP 535 EP 542 DI 10.1080/02772248.2016.1234754 PG 8 WC Environmental Sciences; Toxicology SC Environmental Sciences & Ecology; Toxicology GA EI9IW UT WOS:000392822300015 ER PT J AU Geadas, C Stoszek, SK Sherman, D Andrade, BB Srinivasan, S Hamilton, CD Ellner, J AF Geadas, Carolina Stoszek, Sonia K. Sherman, David Andrade, Bruno B. Srinivasan, Sudha Hamilton, Carol D. Ellner, Jerrold TI Advances in basic and translational tuberculosis research Proceedings of the first meeting of RePORT international SO TUBERCULOSIS LA English DT Review DE RePORT; Tuberculosis; Research; Advances ID BACILLUS-CALMETTE-GUERIN; TB COMPLEX MYCOBACTERIA; TOLL-LIKE RECEPTOR; INNATE IMMUNITY; BCG VACCINATION; GUINEA-PIGS; PULMONARY TUBERCULOSIS; TRANSCRIPTION FACTOR; REGULATORY NETWORK; VITAMIN-C AB RePORT International is a collaborative research network of investigators from multiple countries and institutions with the goal of establishing a bio-repository of specimens and clinical data for the study of active TB and latent TB infection (LTBI). During the first meeting of RePORT International in Boston, Massachusetts, the results of research pertinent to TB control and eradication were presented, including advances in the research of Mycobacterium tuberculosis (MTB) persistence and drug resistance, TB diagnostics, drug and vaccine development. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Geadas, Carolina; Ellner, Jerrold] Boston Med Ctr, 801 Massachusetts Ave,2nd Floor,Room 2013, Boston, MA 02118 USA. [Geadas, Carolina; Ellner, Jerrold] Boston Univ, Sch Med, Dept Med, Infect Dis Sect, Boston, MA 02118 USA. [Stoszek, Sonia K.] Westat Corp, Hlth Studies Sect, Rockville, MD USA. [Sherman, David] Ctr Infect Dis Res, Seattle, WA USA. [Andrade, Bruno B.] Fundacao Oswaldo Cruz, Unidade Med Invest, Lab Integrado Microbiol & Imunorregulacao, Inst Goncalo Moniz, Salvador, BA, Brazil. [Srinivasan, Sudha] NIAID, Div Aids, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hamilton, Carol D.] Duke Univ, Sch Med, Dept Med,Div Infect Dis, Sci Affairs Global Hlth Populat & Nutr,FHI 360, Durham, NC 27706 USA. RP Ellner, J (reprint author), Boston Med Ctr, 801 Massachusetts Ave,2nd Floor,Room 2013, Boston, MA 02118 USA.; Ellner, J (reprint author), Boston Univ, Sch Med, Infect Dis Sect, 801 Massachusetts Ave,2nd Floor,Room 2013, Boston, MA 02118 USA. EM Jerrold.Ellner@bmc.org FU National Institute Of Allergy And Infectious Diseases of the National Institutes of Health [U19AI111276]; Lifespan/Tufts/Brown Center for AIDS Research (National Institute Of Allergy And Infectious Diseases) [P30AI042853]; Federal funds from the Government of India's (GOI) Department of Biotechnology (DBT); Indian Council of Medical Research (ICMR); United States National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID); Office of AIDS Research (OAR); Boston University School of Medicine, Department of Medicine FX Research reported in this publication was, in part, supported by the National Institute Of Allergy And Infectious Diseases of the National Institutes of Health (under Award Number U19AI111276), and by the Lifespan/Tufts/Brown Center for AIDS Research (Grant Number P30AI042853 from the National Institute Of Allergy And Infectious Diseases). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute Of Allergy And Infectious Diseases or the National Institute of Health.; Information in this manuscript was, in part, collected as part of the Regional Prospective Observational Research for Tuberculosis (RePORT) India Consortium Activities. This project has been funded in whole or in part with Federal funds from the Government of India's (GOI) Department of Biotechnology (DBT), the Indian Council of Medical Research (ICMR), the United States National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), Office of AIDS Research (OAR), and distributed in part by CRDF Global. The contents of this publication are solely the responsibility of the authors and do not represent the official views of the DBT, the ICMR, the NIH, or CRDF Global. Any mention of trade names, commercial projects, or organizations does not imply endorsement by any of the sponsoring organizations.; The First Meeting of RePORT International was made possible with support from the Boston University School of Medicine, Department of Medicine, and help from David Hom, Rachelle Joseph and Valine Valbrun, from Boston Medical Center, Section of Infectious Disease. NR 59 TC 0 Z9 0 U1 2 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1472-9792 J9 TUBERCULOSIS JI Tuberculosis PD JAN PY 2017 VL 102 BP 55 EP 67 DI 10.1016/j.tube.2016.11.006 PG 13 WC Immunology; Microbiology; Respiratory System SC Immunology; Microbiology; Respiratory System GA EI8SF UT WOS:000392777200009 PM 28061953 ER PT J AU Xu, YM Moon, AF Xu, SQ Krahn, JM Liu, J Pedersen, LC AF Xu, Yongmei Moon, Andrea F. Xu, Shuqin Krahn, Juno M. Liu, Jian Pedersen, Lars C. TI Structure Based Substrate Specificity Analysis of Heparan Sulfate 6-O-Sulfotransferases SO ACS CHEMICAL BIOLOGY LA English DT Article ID MOLECULAR-WEIGHT HEPARINS; CRYSTAL-STRUCTURE; CHEMOENZYMATIC SYNTHESIS; 3-O-SULFOTRANSFERASE; 2-O-SULFOTRANSFERASE; BIOSYNTHESIS; RECOGNITION; MECHANISM; BINDING; CELLS AB Heparan sulfate (HS) is a sulfated polysaccharide exhibiting essential physiological functions. HS 6-O-sulfotransferase (6-OST) transfers a sulfo group to the 6-OH position of glucosamine units to confer a variety of HS biological activities. There are three different isoforms of 6-OST in the human genome. Here, we report crystal structures of the ternary complex of 6-OST with the sulfo donor analog 3'-phosphoadenosine 5'-phosphate and three different oligo-saccharide substrates at 1.95 to 2.1 angstrom resolutions. Structural and mutational analyses reveal amino acid residues that contribute to catalysis and substrate recognition of 6-OST. Unexpectedly, the structures reveal 6-OST engages HS in a completely different orientation than other HS sulfotransferases and sheds light on the basic HS requirements for specificity. These findings also contribute structural information to understand mutations in human 6-OST isoform 1 associated with the human genetic disease idiopathic hypogonadotropic hypogonadisim characterized by incomplete or lack of puberty. C1 [Xu, Yongmei; Xu, Shuqin; Liu, Jian] Univ N Carolina, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. [Moon, Andrea F.; Krahn, Juno M.; Pedersen, Lars C.] NIEHS, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Xu, Shuqin] Jiangnan Univ, Sch Pharmaceut Sci, Wuxi 214122, Peoples R China. EM jian_liu@unc.edu FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [1ZIA ES102645]; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; National Institutes of Health [GM102137, HL094463]; Eshelman Institute for Innovation FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences, Grant 1ZIA ES102645 (to L.C.P.); the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences Contract W-31-109-Eng-38; grants from National Institutes of Health (GM102137 and HL094463, to J.L.); and a grant from the Eshelman Institute for Innovation (to J.L.). The authors would like to thank M. Sobhany and P. Tumbale for critical reading of the manuscript. NR 37 TC 0 Z9 0 U1 7 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 EI 1554-8937 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD JAN PY 2017 VL 12 IS 1 BP 73 EP 82 DI 10.1021/acschembio.6b00841 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EI5XK UT WOS:000392569400009 PM 28103688 ER PT J AU Muenke, M AF Muenke, Maximilian TI Standing on the Shoulders of Giants SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Editorial Material ID MORPHOLOGY STANDARD TERMINOLOGY; ELEMENTS; REGION C1 [Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM muenke@nih.gov NR 13 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JAN PY 2017 VL 173 IS 1 BP 13 EP 15 DI 10.1002/ajmg.a.38060 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA EJ3TM UT WOS:000393134900006 PM 27888637 ER PT J AU Kruszka, P Porras, AR Sobering, AK Ikolo, FA La Qua, S Shotelersuk, V Chung, BHY Mok, GTK Uwineza, A Mutesa, L Moresco, A Obregon, MG Sokunbi, OJ Kalu, N Joseph, DA Ikebudu, D Ugwu, CE Okoromah, CAN Addissie, YA Pardo, KL Brough, JJ Lee, NC Girisha, KM Patil, SJ Ng, ISL Min, BCW Jamuar, SS Tibrewal, S Wallang, B Ganesh, S Sirisena, ND Dissanayake, VHW Paththinige, CS Prabodha, LBL Richieri-Costa, A Muthukumarasamy, P Thong, MK Jones, KL Abdul-Rahman, OA Ekure, EN Adeyemo, AA Summar, M Linguraru, MG Muenke, M AF Kruszka, Paul Porras, Antonio R. Sobering, Andrew K. Ikolo, Felicia A. La Qua, Samantha Shotelersuk, Vorasuk Chung, Brian H. Y. Mok, Gary T. K. Uwineza, Annette Mutesa, Leon Moresco, Angelica Gabriela Obregon, Maria Sokunbi, Ogochukwu Jidechukwu Kalu, Nnenna Joseph, Daniel Akinsanya Ikebudu, Desmond Ugwu, Christopher Emeka Okoromah, Christy A. N. Addissie, Yonit A. Pardo, Katherine L. Brough, J. Joseph Lee, Ni-Chung Girisha, Katta M. Patil, Siddaramappa Jagdish Ng, Ivy S. L. Min, Breana Cham Wen Jamuar, Saumya S. Tibrewal, Shailja Wallang, Batriti Ganesh, Suma Sirisena, Nirmala D. Dissanayake, Vajira H. W. Paththinige, C. Sampath Prabodha, L. B. Lahiru Richieri-Costa, Antonio Muthukumarasamy, Premala Thong, Meow-Keong Jones, Kelly L. Abdul-Rahman, Omar A. Ekure, Ekanem Nsikak Adeyemo, Adebowale A. Summar, Marshall Linguraru, Marius George Muenke, Maximilian TI Down Syndrome in Diverse Populations SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE down syndrome; trisomy 21; diverse populations; facial analysis technology ID MATERNAL AGE; CLINICAL PROFILE; FACIAL DYSMORPHOLOGY; PHYSICAL FEATURES; DIAGNOSIS; CHILDREN; MONGOLISM; PREVALENCE; NEWBORN; RATES AB Down syndrome is the most common cause of cognitive impairment and presents clinically with universally recognizable signs and symptoms. In this study, we focus on exam findings and digital facial analysis technology in individuals with Down syndrome in diverse populations. Photos and clinical information were collected on 65 individuals from 13 countries, 56.9% were male and the average age was 6.6 years (range 1 month to 26 years; SD = 6.6 years). Subjective findings showed that clinical features were different across ethnicities (Africans, Asians, and Latin Americans), including brachycephaly, ear anomalies, clinodactyly, sandal gap, and abundant neck skin, which were all significantly less frequent in Africans (P < 0.001, P< 0.001, P < 0.001, P< 0.05, and P < 0.05, respectively). Evaluation using a digital facial analysis technology of a larger diverse cohort of newborns to adults (n = 129 cases; n = 132 controls) was able to diagnose Down syndrome with a sensitivity of 0.961, specificity of 0.924, and accuracy of 0.943. Only the angles at medial canthus and ala of the nose were common significant findings amongst different ethnicities (Caucasians, Africans, and Asians) when compared to ethnically matched controls. The Asian group had the least number of significant digital facial biometrics at 4, compared to Caucasians at 8 and Africans at 7. In conclusion, this study displays the wide variety of findings across different geographic populations in Down syndrome and demonstrates the accuracy and promise of digital facial analysis technology in the diagnosis of Down syndrome internationally. (C) 2016 Wiley Periodicals, Inc. C1 [Kruszka, Paul; Addissie, Yonit A.; Pardo, Katherine L.; Brough, J. Joseph; Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Porras, Antonio R.; Linguraru, Marius George] Childrens Natl Hlth Syst, Sheikh Zayed Inst Pediat Surg Innovat, Washington, DC USA. [Sobering, Andrew K.; Ikolo, Felicia A.; La Qua, Samantha] St Georges Univ, Dept Biochem, St Georges, Grenada. [Shotelersuk, Vorasuk] Chulalongkorn Univ, Ctr Excellence Med Genet, Dept Pediat, Fac Med, Bangkok, Thailand. [Chung, Brian H. Y.; Mok, Gary T. K.] Univ Hong Kong, LKS Fac Med, Dept Paediat & Adolescent Med, Hong Kong, Hong Kong, Peoples R China. [Uwineza, Annette; Mutesa, Leon] Univ Rwanda, Coll Med & Hlth Sci, Sch Med & Pharm, Ctr Human Genet, Kigali, Rwanda. [Moresco, Angelica; Gabriela Obregon, Maria] Hosp Pediat Garrahan, Serv Genet, Buenos Aires, DF, Argentina. [Sokunbi, Ogochukwu Jidechukwu; Kalu, Nnenna; Joseph, Daniel Akinsanya; Ikebudu, Desmond; Ugwu, Christopher Emeka; Okoromah, Christy A. N.; Ekure, Ekanem Nsikak] Univ Lagos, Teaching Hosp Idi Araba, Coll Med, Dept Paediat, Lagos, Nigeria. [Lee, Ni-Chung] Natl Taiwan Univ Hosp, Dept Pediat & Med Genet, Taipei, Taiwan. [Girisha, Katta M.] Manipal Univ, Kasturba Med Coll, Dept Med Genet, Manipal, India. [Patil, Siddaramappa Jagdish] Narayana Hlth City, Mazumdar Shaw Med Ctr, Bangalore, Karnataka, India. [Ng, Ivy S. L.; Min, Breana Cham Wen; Jamuar, Saumya S.] KK Womens & Childrens Hosp, Dept Paediat, Singapore, Singapore. [Tibrewal, Shailja; Wallang, Batriti; Ganesh, Suma] Dr Shroff Charity Eye Hosp, New Delhi, India. [Sirisena, Nirmala D.; Dissanayake, Vajira H. W.; Paththinige, C. Sampath; Prabodha, L. B. Lahiru] Univ Colombo, Human Genet Unit, Fac Med, Colombo, Sri Lanka. [Richieri-Costa, Antonio] Univ Sao Paulo, Hosp Rehabil Craniofacial Anomalies, BR-05508 Sao Paulo, Brazil. [Muthukumarasamy, Premala; Thong, Meow-Keong] Univ Malaya, Dept Paediat, Fac Med, Kuala Lumpur, Malaysia. [Jones, Kelly L.; Abdul-Rahman, Omar A.] Univ Mississippi, Med Ctr, Dept Pediat, Div Med Genet, Jackson, MS 39216 USA. [Adeyemo, Adebowale A.] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Summar, Marshall] Childrens Natl Hlth Syst, Div Genet & Metab, Washington, DC USA. RP Kruszka, P; Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM paul.kruszka@nih.gov; mamuenke@mail.nih.gov FU Division of Intramural Research at the National Human Genome Research Institute, NIH; Government of Abu Dhabi FX Grant sponsor: Division of Intramural Research at the National Human Genome Research Institute, NIH; Grant sponsor: Government of Abu Dhabi to the Children's National Health System. NR 47 TC 0 Z9 0 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JAN PY 2017 VL 173 IS 1 BP 42 EP 53 DI 10.1002/ajmg.a.38043 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA EJ3TM UT WOS:000393134900008 PM 27991738 ER PT J AU Christensen, ED Berger, J Alashari, MM Coon, H Robison, C Ho, HT Adams, DR Gahl, WA Smith, KR Opitz, JM Johnson, DR AF Christensen, Erik D. Berger, Justin Alashari, Mouied M. Coon, Hilary Robison, Cynthia Ho, Hsu-Tso Adams, David R. Gahl, Willian A. Smith, Ken R. Opitz, John M. Johnson, Dennis R. TI Sudden Infant Death "Syndrome"-Insights and Future Directions From a Utah Population Database Analysis SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Sudden Infant Death syndrome; SIDS; Utah population database; familial SIDS; SIDS recurrence ID SYNDROME SIDS; RISK; MUTATIONS; AUTOPSY AB "Sudden Infant Death syndrome" (SIDS) represents the commonest category of infant death after the first month of life. As genome scale sequencing greatly facilitates the identification of new candidate disease variants, the challenges of ascribing causation to these variants persists. In order to determine the extent to which SIDS occurs in related individuals and their pedigree structure we undertook an analysis of SIDS using the Utah Population Database, recording, for example, evidence of enrichment for genetic causation following the back-to-sleep recommendations of 1992 and 1994. Our evaluation of the pre- and post back-to-sleep incidence of SIDS in Utah showed a decrease in SIDS incidence on the order of eightfold following back-to-sleep. An odds ratio of 4.2 for SIDS recurrence among sibs was identified from 1968 to 2013 which was similar to the odds ratio of 4.84 for death due to other or unknown cause among sibs of SIDS cases for the same time period. Combining first through thid degree relatives yielded an odds ratio of SIDS recurrence of 9.29 in the post-back-to-sleep (1995-2013) subset of SIDS cases where similar calculations of first-third degree relatives for the entire time period of 1968-2013 showed an odds ratio of 2.95. Expanded multigenertional pedigrees showing enrichment for SIDS were also identified. Based on these findings we hypothesize that post back-to-sleep SIDS, especially recurrences within a family, are potentially enriched for genetic causes due to the impact of safe sleeping guidelines in mitigating environmental risk factors. (C) 2016 Wiley Periodicals, Inc. C1 [Christensen, Erik D.] Univ Utah, Sch Med, Dept Pathol, Salt Lake City, UT USA. [Christensen, Erik D.] Utah Dept Hlth, Off Med Examiner, Salt Lake City, UT 84116 USA. [Berger, Justin; Smith, Ken R.] Univ Utah, Huntsman Canc Inst, Populat Sci, Salt Lake City, UT USA. [Alashari, Mouied M.; Opitz, John M.; Johnson, Dennis R.] Univ Utah, Sch Med, Dept Pathol, Div Pediat Pathol, Salt Lake City, UT USA. [Coon, Hilary] Univ Utah, Sch Med, Dept Psychiat, Salt Lake City, UT 84112 USA. [Robison, Cynthia] Utah Dept Hlth, Off Vital Records & Stat, Salt Lake City, UT 84116 USA. [Ho, Hsu-Tso; Adams, David R.; Gahl, Willian A.; Johnson, Dennis R.] NIH, Natl Human Genome Res Inst, Undiagnosed Dis Program, NHGRI Bldg 50,50 South Dr, Bethesda, MD 20892 USA. [Opitz, John M.] Univ Utah, Sch Med, Dept Pediat Med Genet, Salt Lake City, UT USA. [Opitz, John M.] Univ Utah, Sch Med, Dept Obstet & Gynecol, Salt Lake City, UT 84132 USA. [Opitz, John M.] Univ Utah, Sch Med, Dept Human Genet, Salt Lake City, UT 84132 USA. RP Johnson, DR (reprint author), NIH, Natl Human Genome Res Inst, Undiagnosed Dis Program, NHGRI Bldg 50,50 South Dr, Bethesda, MD 20892 USA. EM dennis.johnson@nih.gov NR 18 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JAN PY 2017 VL 173 IS 1 BP 177 EP 182 DI 10.1002/ajmg.a.37994 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA EJ3TM UT WOS:000393134900025 PM 27792857 ER PT J AU Vallabhaneni, S Kallen, A Tsay, S Chow, N Welsh, R Kerins, J Kemble, SK Pacilli, M Black, SR Landon, E Ridgway, J Palmore, TN Zelzany, A Adams, EH Quinn, M Chaturvedi, S Greenko, J Fernandez, R Southwick, K Furuya, EY Calfee, DP Hamula, C Patel, G Barrett, P Lafaro, P Berkow, EL Moulton-Meissner, H Noble-Wang, J Fagan, RP Jackson, BR Lockhart, SR Litvintseva, AP Chiller, TM AF Vallabhaneni, S. Kallen, A. Tsay, S. Chow, N. Welsh, R. Kerins, J. Kemble, S. K. Pacilli, M. Black, S. R. Landon, E. Ridgway, J. Palmore, T. N. Zelzany, A. Adams, E. H. Quinn, M. Chaturvedi, S. Greenko, J. Fernandez, R. Southwick, K. Furuya, E. Y. Calfee, D. P. Hamula, C. Patel, G. Barrett, P. Lafaro, P. Berkow, E. L. Moulton-Meissner, H. Noble-Wang, J. Fagan, R. P. Jackson, B. R. Lockhart, S. R. Litvintseva, A. P. Chiller, T. M. TI Investigation of the First Seven Reported Cases of Candida auris, a Globally Emerging Invasive, Multidrug-Resistant FungusUnited States, May 2013-August 2016 (Reprinted from vol 65, pg 1234-1237, 2016) SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Reprint AB November 11, 2016/65(44);1234-1237. What is already known about this topic?Candida auris is an emerging pathogenic fungus that has been reported from at least a dozen countries on four continents during 2009-2015. The organism is difficult to identify using traditional biochemical methods, some isolates have been found to be resistant to all three major classes of antifungal medications, and C. auris has caused health care-associated outbreaks. What is added by this report? This is the first description of C. auris cases in the United States. C. auris appears to have emerged in the United States only in the last few years, and U.S. isolates are related to isolates from South America and South Asia. Evidence from U.S. case investigations suggests likely transmission of the organism occurred in health care settings. What are the implications for public health practice? It is important that U.S. laboratories accurately identify C. auris and for health care facilities to implement recommended infection control practices to prevent the spread of C. auris. Local and state health departments and CDC should be notified of possible cases of C. auris and of isolates of C. haemulonii and Candida spp. that cannot be identified after routine testing. This report details the first U.S. cases of a new fungal infection seen primarily in immunocompromised hosts, including stem cell transplant recipients. C1 [Vallabhaneni, S.; Tsay, S.; Chow, N.; Welsh, R.; Berkow, E. L.; Jackson, B. R.; Lockhart, S. R.; Litvintseva, A. P.; Chiller, T. M.] CDC, Mycot Dis Branch, Div Food Water & Environm Dis, Atlanta, GA 30333 USA. [Kallen, A.; Moulton-Meissner, H.; Noble-Wang, J.; Fagan, R. P.] CDC, Div Healthcare Qual Promot, Atlanta, GA 30333 USA. [Tsay, S.; Kerins, J.] CDC, Epidem Intelligence Serv, Ctr Surveillance Epidemiol & Lab Serv, Atlanta, GA 30333 USA. [Kerins, J.; Kemble, S. K.; Pacilli, M.; Black, S. R.] Chicago Dept Publ Hlth, Chicago, IL USA. [Landon, E.; Ridgway, J.] Univ Chicago, Chicago, IL 60637 USA. [Palmore, T. N.; Zelzany, A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Adams, E. H.; Quinn, M.; Chaturvedi, S.; Greenko, J.; Fernandez, R.; Southwick, K.] New York State Dept Hlth, New York, NY USA. [Furuya, E. Y.] Columbia Univ Coll Phys & Surg, 630 W 168th St, New York, NY 10032 USA. [Calfee, D. P.] Weill Cornell Med, New York, NY USA. [Hamula, C.; Patel, G.] Icahn Sch Med Mt Sinai, Mt Sinai Hlth Syst, New York, NY 10029 USA. [Barrett, P.] New Jersey Dept Hlth, Trenton, NJ USA. [Lafaro, P.] Robert Wood Johnson Univ Hosp, New Brunswick, NJ USA. EM svallabhaneni@cdc.gov NR 12 TC 1 Z9 1 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD JAN PY 2017 VL 17 IS 1 BP 296 EP 299 DI 10.1111/ajt.14121 PG 4 WC Surgery; Transplantation SC Surgery; Transplantation GA EI5BK UT WOS:000392508200036 PM 28029734 ER PT J AU Furumoto, Y Smith, CK Blanco, L Zhao, WP Brooks, SR Thacker, SG Zarzour, A Sciume, G Tsai, WXL Trier, AM Nunez, L Mast, L Hoffmann, V Remaley, AT O'Shea, JJ Kaplan, MJ Gadina, M AF Furumoto, Yasuko Smith, Carolyne K. Blanco, Luz Zhao, Wenpu Brooks, Stephen R. Thacker, Seth G. Zarzour, Abdalrahman Sciume, Giuseppe Tsai, Wanxia L. Trier, Anna M. Nunez, Leti Mast, Laurel Hoffmann, Victoria Remaley, Alan T. O'Shea, John J. Kaplan, Mariana J. Gadina, Massimo TI Tofacitinib Ameliorates Murine Lupus and Its Associated Vascular Dysfunction SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID PEPTIDYLARGININE DEIMINASE INHIBITION; RHEUMATOID-ARTHRITIS; T-CELLS; PREMATURE ATHEROSCLEROSIS; DISEASE-ACTIVITY; JAK INHIBITORS; I INTERFERON; MRL/LPR MICE; ERYTHEMATOSUS; ALPHA AB Objective. Dysregulation of innate and adaptive immune responses contributes to the pathogenesis of systemic lupus erythematosus (SLE) and its associated premature vascular damage. No drug to date targets both systemic inflammatory disease and the cardiovascular complications of SLE. Tofacitinib is a JAK inhibitor that blocks signaling downstream of multiple cytokines implicated in lupus pathogenesis. While clinical trials have shown that tofacitinib exhibits significant clinical efficacy in various autoimmune diseases, its role in SLE and the associated vascular pathology remains to be characterized. Methods. MRL/lpr lupus-prone mice were administered tofacitinib or vehicle by gavage for 6 weeks (therapeutic arm) or 8 weeks (preventive arm). Nephritis, skin inflammation, serum levels of autoantibodies and cytokines, mononuclear cell phenotype and gene expression, neutrophil extracellular traps (NETs) release, endothelium-dependent vasorelaxation, and endothelial differentiation were compared in treated and untreated mice. Results. Treatment with tofacitinib led to significant improvement in measures of disease activity, including nephritis, skin inflammation, and autoantibody production. In addition, tofacitinib treatment reduced serum levels of proinflammatory cytokines and interferon responses in splenocytes and kidney tissue. Tofacitinib also modulated the formation of NETs and significantly increased endothelium-dependent vasorelaxation and endothelial differentiation. The drug was effective in both preventive and therapeutic strategies. Conclusion. Tofacitinib modulates the innate and adaptive immune responses, ameliorates murine lupus, and improves vascular function. These results indicate that JAK inhibitors have the potential to be beneficial in SLE and its associated vascular damage. C1 [Furumoto, Yasuko; Tsai, Wanxia L.; Trier, Anna M.; Nunez, Leti; Mast, Laurel; Gadina, Massimo] NIAMS, Translat Immunol Sect, OST, NIH, Bethesda, MD USA. [Smith, Carolyne K.; Blanco, Luz; Zhao, Wenpu; Kaplan, Mariana J.] NIAMS, Syst Autoimmun Branch, NIH, Bethesda, MD USA. [Brooks, Stephen R.] NIAMS, Biodata Min & Discovery Sect, OST, NIH, Bethesda, MD USA. [Thacker, Seth G.; Zarzour, Abdalrahman; Remaley, Alan T.] NHLBI, Lipoprotein Metab Sect, NIH, Bldg 10, Bethesda, MD 20892 USA. [Sciume, Giuseppe; O'Shea, John J.] NIAMS, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD USA. [Hoffmann, Victoria] NIH, Diagnost & Res Serv Branch, Off Director, Bethesda, MD USA. EM furumoty@mail.nih.gov FU NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases [NIAMS] Intramural Research Program [AR-041181-07, ZIA-AR-041199]; Pfizer FX Supported by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases [NIAMS] Intramural Research Program grants AR-041181-07 and ZIA-AR-041199) and in part by a Cooperative Research and Development Agreement with Pfizer.; Drs. Furumoto, O'Shea, Kaplan, and Gadina have received research support based on a Cooperative Research and Development Agreement with Pfizer. NR 54 TC 1 Z9 1 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD JAN PY 2017 VL 69 IS 1 BP 148 EP 160 DI 10.1002/art.39818 PG 13 WC Rheumatology SC Rheumatology GA EI5AJ UT WOS:000392505500019 PM 27429362 ER PT J AU Gilliland, CT Sittampalam, GS Wang, PY Ryan, PE AF Gilliland, C. Taylor Sittampalam, G. Sitta Wang, Philip Y. Ryan, Philip E. TI The translational science training program at NIH: Introducing early career researchers to the science and operation of translation of basic research to medical interventions SO BIOCHEMISTRY AND MOLECULAR BIOLOGY EDUCATION LA English DT Article DE translation; translational science; education and training; preclinical development AB Translational science is an emerging field that holds great promise to accelerate the development of novel medical interventions. As the field grows, so does the demand for highly trained biomedical scientists to fill the positions that are being created. Many graduate and postdoctorate training programs do not provide their trainees with sufficient education to take advantage of this growing employment sector. To help better prepare the trainees at the National Institutes of Health for possible careers in translation, we have created the Translational Science Training Program (TSTP). The TSTP is an intensive 2- to 3-day training program that introduces NIH postdoctoral trainees and graduate students to the science and operation of turning basic research discoveries into a medical therapeutic, device or diagnostic, and also exposes them to the variety of career options in translational science. Through a combination of classroom teaching from practicing experts in the various disciplines of translation and small group interactions with pre-clinical development teams, participants in the TSTP gain knowledge that will aid them in obtaining a career in translational science and building a network to make the transition to the field. (c) 2016 by The International Union of Biochemistry and Molecular Biology, 45(1):13-24, 2017. C1 [Gilliland, C. Taylor; Sittampalam, G. Sitta] NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Wang, Philip Y.; Ryan, Philip E.] NIH, Off Intramural Training & Educ, 2 Ctr Dr MC 0234, Bethesda, MD 20814 USA. RP Ryan, PE (reprint author), NIH, Off Intramural Training & Educ, 2 Ctr Dr MC 0234, Bethesda, MD 20814 USA. EM ryanp@od.nih.gov FU NIH Office of Intramural Training and Education FX The authors would like to acknowledge the leadership, guidance and support of Dr. Sharon Milgram, OITE, and Dr. Dorit Zuk, NCATS. Special thanks is owed to previous co-organizers of the TSTP, including Dr. Rajesh Ranganathan and Ms. Neely Gal-Edd, who were instrumental in launching the program. We would also like to thank the multiple scientific and administrative staff at NCATS who volunteered their time to help implement the workshop component, in particular Dr. Nathan Coussens and Dr. Stephen Kales. Financial support for the TSTP was provided by the NIH Office of Intramural Training and Education. NR 0 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1470-8175 EI 1539-3429 J9 BIOCHEM MOL BIOL EDU JI Biochem. Mol. Biol. Educ. PD JAN-FEB PY 2017 VL 45 IS 1 BP 13 EP 24 DI 10.1002/bmb.20978 PG 12 WC Biochemistry & Molecular Biology; Education, Scientific Disciplines SC Biochemistry & Molecular Biology; Education & Educational Research GA EI8FL UT WOS:000392741100002 PM 27231204 ER PT J AU Song, JB Niu, G Chen, XY AF Song, Jibin Niu, Gang Chen, Xiaoyuan TI Amphiphilic-Polymer-Guided Plasmonic Assemblies and Their Biomedical Applications SO BIOCONJUGATE CHEMISTRY LA English DT Review ID ENHANCED RAMAN-SCATTERING; GOLD NANOPARTICLES; DRUG-DELIVERY; THERANOSTIC APPLICATIONS; PHOTOTHERMAL THERAPY; CANCER-THERAPY; SINGLE GOLD; VESICLES; NANOSTRUCTURES; SERS AB Plasmonic nanostructures with unique physical and biological properties have attracted increased attention for potential biomedical applications. Polymers grafted on metal nanoparticle surface can be used as assembly regulating molecules to guide nanoparticles organize into ordered or hierarchical structures in solution, within condensed phases, or at interfaces. In this Topical Review, we will highlight recent efforts on self-assembly of gold nanoparticles coated with polymer brushes. How and what kind of polymer graft can be used to adjust nanoparticle interactions, to dictate interparticle orientation, and to determine assembled nanostructures will be discussed. Furthermore, the Topical Review will shed light on the physicochemical properties, including self-assembly behavior and kinetics, tunable localized surface plasmon resonance effect, enhanced surface enhanced Raman scattering, and other optical and thermal properties. The potential of self-assembled nanostructures for applications in different fields, especially in biomedicine, will also be elaborated. C1 [Song, Jibin; Niu, Gang; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov FU Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) FX This work was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH). NR 66 TC 0 Z9 0 U1 16 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD JAN PY 2017 VL 28 IS 1 BP 105 EP 114 DI 10.1021/acs.bioconjchem.6b00521 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA EI4JG UT WOS:000392459200014 PM 28095685 ER PT J AU Wald, I Bitton, S Levi, O Zusmanovich, S Fruchter, E Ginat, K Charney, DS Pine, DS Bar-Haim, Y AF Wald, Ilan Bitton, Shani Levi, Ofir Zusmanovich, Sergei Fruchter, Eyal Ginat, Keren Charney, Dennis S. Pine, Daniel S. Bar-Haim, Yair TI Acute delivery of attention bias modification training (ABMT) moderates the association between combat exposure and posttraumatic symptoms: A feasibility study SO BIOLOGICAL PSYCHOLOGY LA English DT Article DE Stress; Combat; Army; PTSD; Prevention; Attention bias modification training (ABMT); Anxiety ID ACUTE STRESS DISORDER; COGNITIVE-BEHAVIORAL THERAPY; PERITRAUMATIC DISSOCIATION; PTSD; PREVENTION; METAANALYSIS; DEPRESSION; ANXIETY; IRAQ; INTERVENTIONS AB Combat deployment enhances risk for posttraumatic stress symptoms. We assessed whether attention bias modification training (ABMT), delivered immediately prior to combat, attenuates the association between combat exposure and stress-related symptoms. 99 male soldiers preparing for combat were randomized to receive either an ABMT condition designed to enhance vigilance toward threat or an attention control training (ACT) designed to balance attention deployment between neutral and threat words. Frequency of combat events, and symptoms of PTSD and depression were measured prior to deployment and at a two-month follow-up. Regression analysis revealed that combat exposure uniquely accounted for 4.6% of the variance in stress-related symptoms change from baseline to follow-up and that the interaction between ABMT and combat exposure accounted for additional 5.4% of the variance. Follow-up analyses demonstrate that ABMT moderated the association between combat exposure and symptoms. ABMT appear to have potential as a preventative intervention to reduce risk for stress-related symptoms associated with combat exposure. (C) 2016 Elsevier B.V. All rights reserved. C1 [Wald, Ilan; Bitton, Shani; Bar-Haim, Yair] Tel Aviv Univ, Sch Psychol Sci, Tel Aviv, Israel. [Levi, Ofir; Zusmanovich, Sergei; Fruchter, Eyal; Ginat, Keren] Israel Def Forces, Div Mental Hlth, Med Corps, Ramat Gan, Israel. [Charney, Dennis S.] Icahn Sch Med Mt Sinai, 1428 Madison Ave, New York, NY 10029 USA. [Pine, Daniel S.] NIMH, 6001 Execut Blvd, Rockville, MD 20852 USA. [Bar-Haim, Yair] Tel Aviv Univ, Sagol Sch Neurosci, Tel Aviv, Israel. EM ilanwald@013net.net FU Iranian American Jewish Federation (IAJF) of New York, USA FX This work was supported by the Iranian American Jewish Federation (IAJF) of New York, USA. The IAJF 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 45 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 EI 1873-6246 J9 BIOL PSYCHOL JI Biol. Psychol. PD JAN PY 2017 VL 122 SI SI BP 93 EP 97 DI 10.1016/j.biopsycho.2016.01.005 PG 5 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA EI7JS UT WOS:000392674600011 PM 26780267 ER PT J AU Shechner, T Jarcho, JM Wong, S Leibenluft, E Pine, DS Nelson, EE AF Shechner, Tomer Jarcho, Johanna M. Wong, Stuart Leibenluft, Ellen Pine, Daniel S. Nelson, Eric E. TI Threats, rewards, and attention deployment in anxious youth and adults: An eye tracking study SO BIOLOGICAL PSYCHOLOGY LA English DT Article DE Anxiety; Development; Attention allocation; Eye tracking; Pupil dilation; Social and non-social stimuli ID ADOLESCENT DEVELOPMENT; EMOTIONAL INFORMATION; PUPILLARY RESPONSES; TIME-COURSE; BIAS; ANXIETY; CHILDREN; DEPRESSION; BRAIN; NEUROSCIENCE AB The current study examines anxiety and age associations with attention allocation and physiological response to threats and rewards. Twenty-two healthy-adults, 20 anxious-adults, 26 healthy-youth, and 19 anxious-youth completed two eye-tracking tasks. In the Visual Scene Task (VST), participants' fixations were recorded while they viewed a central neutral image flanked by two threatening or two rewarding stimuli. In the Negative Words Task (NWT), physiological response was measured by means of pupil diameter change while negative and neutral words were presented. For both tasks, no interaction was found between anxiety and age-group. In the VST, anxious participants avoided the threatening images when groups were collapsed across age. Similarly, adults but not adolescents avoided the threatening images when collapsed across anxiety. No differences were found for rewarding images. In NWT, all subjects demonstrated increase in pupil dilation after word presentation. Only main effect of age emerged with stronger pupil dilation in adults than children. Finally, maximum pupil change was correlated with threat avoidance bias in the scene task. Gaze patterns and pupil dilation show that anxiety and age are associated with attention allocation to threats. The relations between attention and autonomic arousal point to a complex interaction between bottom-up and top-down processes as they relate to attention allocation. (C) 2015 Elsevier B.V. All rights reserved. C1 [Shechner, Tomer] Univ Haifa, Dept Psychol, Abu Hussi 234, Har Hakarmel, Israel. [Jarcho, Johanna M.; Wong, Stuart; Pine, Daniel S.; Nelson, Eric E.] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. [Leibenluft, Ellen] NIMH, Sect Bipolar Disorder, Bethesda, MD 20892 USA. EM tshechner@psy.haifa.ac.il FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health; Marie Curie Career Integration Grant [PCIG13-GA-2013-618534]; Israel Science Foundation [1377/14] FX This research was supported in part by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health. The first author (TS) is supported by the Marie Curie Career Integration Grant (PCIG13-GA-2013-618534) and the Israel Science Foundation grant (1377/14). NR 39 TC 1 Z9 1 U1 6 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 EI 1873-6246 J9 BIOL PSYCHOL JI Biol. Psychol. PD JAN PY 2017 VL 122 SI SI BP 121 EP 129 DI 10.1016/j.biopsycho.2015.10.004 PG 9 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA EI7JS UT WOS:000392674600014 PM 26493339 ER PT J AU Hamdi, Y Soucy, P Kuchenbaeker, KB Pastinen, T Droit, A Lemacon, A Adlard, J Aittomaki, K Andrulis, IL Arason, A Arnold, N Arun, BK Azzollini, J Bane, A Barjhoux, L Barrowdale, D Benitez, J Berthet, P Blok, MJ Bobolis, K Bonadona, V Bonanni, B Bradbury, AR Brewer, C Buecher, B Buys, SS Caligo, MA Chiquette, J Chung, WK Claes, KBM Daly, MB Damiola, F Davidson, R De la Hoya, M De Leeneer, K Diez, O Ding, YC Dolcetti, R Domchek, SM Dorfling, CM Eccles, D Eeles, R Einbeigi, Z Ejlertsen, B Engel, C Evans, DG Feliubadalo, L Foretova, L Fostira, F Foulkes, WD Fountzilas, G Friedman, E Frost, D Ganschow, P Ganz, PA Garber, J Gayther, SA Gerdes, AM Glendon, G Godwin, AK Goldgar, DE Greene, MH Gronwald, J Hahnen, E Hamann, U Hansen, TVO Hart, S Hays, JL Hogervorst, FBL Hulick, PJ Imyanitov, EN Isaacs, C Izatt, L Jakubowska, A James, P Janavicius, R Jensen, UB John, EM Joseph, V Just, W Kaczmarek, K Karlan, BY Kets, CM Kirk, J Kriege, M Laitman, Y Laurent, M Lazaro, C Leslie, G Lester, J Lesueur, F Liljegren, A Loman, N Loud, JT Manoukian, S Mariani, M Mazoyer, S McGuffog, L Meijers-Heijboer, HEJ Meindl, A Miller, A Montagna, M Mulligan, AM Nathanson, KL Neuhausen, SL Nevanlinna, H Nussbaum, RL Olah, E Olopade, OI Ong, KR Oosterwijk, JC Osorio, A Papi, L Park, SK Pedersen, IS Peissel, B Segura, PP Peterlongo, P Phelan, CM Radice, P Rantala, J Rappaport-Fuerhauser, C Rennert, G Richardson, A Robson, M Rodriguez, GC Rookus, MA Schmutzler, RK Sevenet, N Shah, PD Singer, CF Slavin, TP Snape, K Sokolowska, J Sonderstrup, IMH Southey, M Spurdle, AB Stadler, Z Stoppa-Lyonnet, D Sukiennicki, G Sutter, C Tan, Y Tea, MK Teixeira, MR Teule, A Teo, SH Terry, MB Thomassen, M Tihomirova, L Tischkowitz, M Tognazzo, S Toland, AE Tung, N van den Ouweland, AMW van der Luijt, RB van Engelen, K van Rensburg, EJ Varon-Mateeva, R Wappenschmidt, B Wijnen, JT Rebbeck, T Chenevix-Trench, G Offit, K Couch, FJ Nord, S Easton, DF Antoniou, AC Simard, J AF Hamdi, Yosr Soucy, Penny Kuchenbaeker, Karoline B. Pastinen, Tomi Droit, Arnaud Lemacon, Audrey Adlard, Julian Aittomaki, Kristiina Andrulis, Irene L. Arason, Adalgeir Arnold, Norbert Arun, Banu K. Azzollini, Jacopo Bane, Anita Barjhoux, Laure Barrowdale, Daniel Benitez, Javier Berthet, Pascaline Blok, Marinus J. Bobolis, Kristie Bonadona, Valerie Bonanni, Bernardo Bradbury, Angela R. Brewer, Carole Buecher, Bruno Buys, Saundra S. Caligo, Maria A. Chiquette, Jocelyne Chung, Wendy K. Claes, Kathleen B. M. Daly, Mary B. Damiola, Francesca Davidson, Rosemarie De la Hoya, Miguel De Leeneer, Kim Diez, Orland Ding, Yuan Chun Dolcetti, Riccardo Domchek, Susan M. Dorfling, Cecilia M. Eccles, Diana Eeles, Ros Einbeigi, Zakaria Ejlertsen, Bent Engel, Christoph Evans, D. Gareth Feliubadalo, Lidia Foretova, Lenka Fostira, Florentia Foulkes, William D. Fountzilas, George Friedman, Eitan Frost, Debra Ganschow, Pamela Ganz, Patricia A. Garber, Judy Gayther, Simon A. Gerdes, Anne-Marie Glendon, Gord Godwin, Andrew K. Goldgar, David E. Greene, Mark H. Gronwald, Jacek Hahnen, Eric Hamann, Ute Hansen, Thomas V. O. Hart, Steven Hays, John L. Hogervorst, Frans B. L. Hulick, Peter J. Imyanitov, Evgeny N. Isaacs, Claudine Izatt, Louise Jakubowska, Anna James, Paul Janavicius, Ramunas Jensen, Uffe Birk John, Esther M. Joseph, Vijai Just, Walter Kaczmarek, Katarzyna Karlan, Beth Y. Kets, Carolien M. Kirk, Judy Kriege, Mieke Laitman, Yael Laurent, Maite Lazaro, Conxi Leslie, Goska Lester, Jenny Lesueur, Fabienne Liljegren, Annelie Loman, Niklas Loud, Jennifer T. Manoukian, Siranoush Mariani, Milena Mazoyer, Sylvie McGuffog, Lesley Meijers-Heijboer, Hanne E. J. Meindl, Alfons Miller, Austin Montagna, Marco Mulligan, Anna Marie Nathanson, Katherine L. Neuhausen, Susan L. Nevanlinna, Heli Nussbaum, Robert L. Olah, Edith Olopade, Olufunmilayo I. Ong, Kai-ren Oosterwijk, Jan C. Osorio, Ana Papi, Laura Park, Sue Kyung Pedersen, Inge Sokilde Peissel, Bernard Segura, Pedro Perez Peterlongo, Paolo Phelan, Catherine M. Radice, Paolo Rantala, Johanna Rappaport-Fuerhauser, Christine Rennert, Gad Richardson, Andrea Robson, Mark Rodriguez, Gustavo C. Rookus, Matti A. Schmutzler, Rita Katharina Sevenet, Nicolas Shah, Payal D. Singer, Christian F. Slavin, Thomas P. Snape, Katie Sokolowska, Johanna Sonderstrup, Ida Marie Heeholm Southey, Melissa Spurdle, Amanda B. Stadler, Zsofia Stoppa-Lyonnet, Dominique Sukiennicki, Grzegorz Sutter, Christian Tan, Yen Tea, Muy-Kheng Teixeira, Manuel R. Teule, Alex Teo, Soo-Hwang Terry, Mary Beth Thomassen, Mads Tihomirova, Laima Tischkowitz, Marc Tognazzo, Silvia Toland, Amanda Ewart Tung, Nadine van den Ouweland, Ans M. W. van der Luijt, Rob B. van Engelen, Klaartje van Rensburg, Elizabeth J. Varon-Mateeva, Raymonda Wappenschmidt, Barbara Wijnen, Juul T. Rebbeck, Timothy Chenevix-Trench, Georgia Offit, Kenneth Couch, Fergus J. Nord, Silje Easton, Douglas F. Antoniou, Antonis C. Simard, Jacques CA EMBRACE GEMO Study Collaborators HEBON KConFab Investigators TI Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3 SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer; Genetic modifiers; Differential allelic expression; Genetic susceptibility; Cis-regulatory variants; BRCA1 and BRCA2 mutation carriers ID OVARIAN-CANCER; CYCLIN E-CDK2; HUMAN-CELLS; DISEASE; NPAT; INVESTIGATORS; CONSORTIUM; DNA AB Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of similar to 320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 x 10(-6)). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk. C1 [Hamdi, Yosr; Soucy, Penny; Droit, Arnaud; Lemacon, Audrey; Simard, Jacques] Ctr Hosp Univ Quebec, Res Ctr, Genom Ctr, 2705 Laurier Blvd, Quebec City, PQ G1V 4G2, Canada. [Kuchenbaeker, Karoline B.; Barrowdale, Daniel; Frost, Debra; Leslie, Goska; McGuffog, Lesley; Easton, Douglas F.; Antoniou, Antonis C.] Univ Cambridge, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Ctr Canc Genet Epidemiol, Worts Causeway, Cambridge, England. [Kuchenbaeker, Karoline B.] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus Hinxton, Cambridge CB10 1HH, England. [Pastinen, Tomi] McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada. [Pastinen, Tomi] McGill Univ, Montreal, PQ H3A 0G1, Canada. [Adlard, Julian] Chapel Allerton Hosp, Yorkshire Reg Genet Serv, Leeds LS7 4SA, W Yorkshire, England. [Aittomaki, Kristiina] Helsinki Univ Hosp, Dept Clin Genet, Meilahdentie 2,POB 160, Helsinki 00029, Finland. [Andrulis, Irene L.; Glendon, Gord] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G IX5, Canada. [Andrulis, Irene L.; Mulligan, Anna Marie] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Arason, Adalgeir] Landspitali LSH V Hringbraut, Dept Pathol Hus 9, IS-101 Reykjavik, Iceland. [Arason, Adalgeir] Univ Iceland, Fac Med, BMC Biomed Ctr, Vatnsmyrarvegi 16, IS-101 Reykjavik, Iceland. [Arnold, Norbert; Meindl, Alfons] Christian Albrechts Univ Kiel, Univ Hosp Schleswig Holstein, Dept Obstet & Gynaecol, Campus Kiel, D-24105 Kiel, Germany. [Arun, Banu K.] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, 1515 Pressler St CBP 5, Houston, TX 77030 USA. [Azzollini, Jacopo; Manoukian, Siranoush; Mariani, Milena; Peissel, Bernard] Fdn IRCCS Ist Ric Cura & Carattere Sci, Dept Prevent & Predict Med, Unit Med Genet, INT, Via Giacomo Venezian 1, I-20133 Milan, Italy. [Bane, Anita] McMaster Univ, Juravinski Hosp & Canc Ctr, Dept Pathol Mol Med, 711 Concess St, Hamilton, ON L8V 1C3, Canada. [Barjhoux, Laure; Damiola, Francesca] Ctr Leon Berard, Bat Cheney D,28 Rue Laennec, F-69373 Lyon, France. [Benitez, Javier; Osorio, Ana] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Madrid, Spain. [Benitez, Javier; Osorio, Ana] Biomed Network Rare Dis CIBERER, Madrid 28029, Spain. [Benitez, Javier] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genotyping CEGEN Unit, Madrid, Spain. [Berthet, Pascaline] Ctr Francois Baclesse, 3 Ave Gen Harris, F-14076 Caen, France. [Blok, Marinus J.] Maastricht Univ, Dept Clin Genet, Med Ctr, POB 5800, NL-6202 AZ Maastricht, Netherlands. [Bobolis, Kristie] City Hope Natl Med Ctr, Clin Canc Genom Community Res Network, 1500 East Duarte Rd, Duarte, CA 91010 USA. [Bonadona, Valerie] Ctr Leon Berard, Unite Prevent & Epidemiol Genet, 28 Rue Laennec, F-69373 Lyon, France. [Bonanni, Bernardo] IEO, Div Canc Prevent & Genet, Via Ripamonti 435, I-20141 Milan, Italy. [Bradbury, Angela R.; Domchek, Susan M.; Nathanson, Katherine L.; Shah, Payal D.; Rebbeck, Timothy] Univ Penn, Dept Med, Abramson Canc Ctr, Perelman Sch Med, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. [Brewer, Carole] Royal Devon & Exeter Hosp, Dept Clin Genet, Exeter EX1 2ED, Devon, England. [Buecher, Bruno; Laurent, Maite; Stoppa-Lyonnet, Dominique] Inst Curie, Serv Genet Oncol, 26 Rue Ulm, F-75248 Paris 05, France. [Buys, Saundra S.] Huntsman Canc Inst, Dept Med, 2000 Circle Hope, Salt Lake City, UT 84112 USA. [Caligo, Maria A.] Univ & Univ Hosp Pisa, Sect Genet Oncol, Dept Lab Med, Pisa, Italy. [Chiquette, Jocelyne] Hop St Sacrement, Ctr Malad Sein Deschenes Fabia, Unite Rech Sante Populat, 1050 Chemin Sainte Foy, Quebec City, PQ G1S 4L8, Canada. [Chung, Wendy K.] Columbia Univ, Dept Pediat, 1150 St Nicholas Ave, New York, NY 10032 USA. [Claes, Kathleen B. M.; De Leeneer, Kim] Univ Ghent, Ctr Med Genet, De Pintelaan 185, Ghent, Belgium. [Daly, Mary B.] Fox Chase Canc Ctr, Div Populat Sci, 333 Cottman Ave, Philadelphia, PA 19111 USA. [Davidson, Rosemarie] South Glasgow Univ Hosp, Dept Clin Genet, Glasgow G51 4TF, Lanark, Scotland. [De la Hoya, Miguel] IdISSC Inst Invest Sanitaria Hosp Clin San Carlos, Hosp Clinico San Carlos, Mol Oncol Lab, Martin Lagos S-N, Madrid, Spain. [Diez, Orland] Vall dHebron Univ Hosp, Clin & Mol Genet Area, Oncogenet Grp, Vall dHebron Inst Oncol VHIO, Passeig Vall dHebron 119-129, Barcelona 08035, Spain. [Ding, Yuan Chun; Neuhausen, Susan L.] City Hope Natl Med Ctr, Dept Populat Sci, Beckman Res Inst, Duarte, CA USA. [Dolcetti, Riccardo] IRCCS Ist Ric & Cura Carattere Sci, Dept Med Oncol, Canc Bioimmunotherapy Unit, Ctr Riferimento Oncol,Natl Canc Inst, Via Franco Gallini 2, I-33081 Aviano, PN, Italy. [Dolcetti, Riccardo] Univ Queensland, Translat Res Inst, Diamantina Inst, Brisbane, Qld, Australia. [Dorfling, Cecilia M.; van Rensburg, Elizabeth J.] Univ Pretoria, Dept Genet, Canc Genet Lab, Private Bag X323, ZA-0007 Arcadia, South Africa. [Eccles, Diana] Univ Southampton, Southampton Univ Hosp NHS Trust, Fac Med, Southampton, Hants, England. [Eeles, Ros] Inst Canc Res, Oncogenet Team, Sutton SM2 5NG, Surrey, England. [Einbeigi, Zakaria] Sahlgrens Univ Hosp, Dept Oncol, S-41345 Gothenburg, Sweden. [Ejlertsen, Bent] Copenhagen Univ Hosp, Dept Oncol, Rigshosp, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. [Engel, Christoph] Univ Leipzig, Inst Med Informat Stat & Epidemiol, D-04107 Leipzig, Germany. [Engel, Christoph] Univ Leipzig, Leipzig Res Ctr Civilizat Dis, LIFE, Leipzig, Germany. [Evans, D. Gareth] Univ Manchester, Manchester Acad Hlth Sci Ctr, Inst Human Dev, NHS Fdn Trust,Cent Manchester Univ Hosp,Genom Med, Manchester M13 9WL, Lancs, England. [Feliubadalo, Lidia; Lazaro, Conxi] IDIBELL Bellvitge Biomed Res Inst, Catalan Inst Oncol, Hereditary Canc Program, Mol Diagnost Unit, Gran Via Hosp 199-203, Barcelona 08908, Spain. [Foretova, Lenka] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Zluty Kopec 7, Brno 65653, Czech Republic. [Fostira, Florentia] INRASTES Inst Nucl & Radiol Sci & Technol, Natl Ctr Sci Res Demokritos, Mol Diagnost Lab, Patriarchou Gregoriou & Neapoleos Str, Athens, Greece. [Foulkes, William D.; Tischkowitz, Marc] McGill Univ, Dept Human Genet, Program Canc Genet, Montreal, PQ, Canada. [Fountzilas, George] Aristotle Univ Thessaloniki, Papageorgiou Hosp, Dept Med Oncol, Sch Med, Thessaloniki, Greece. [Friedman, Eitan; Laitman, Yael] Chaim Sheba Med Ctr, Inst Human Genet, Susanne Levy Gertner Oncogenet Unit, IL-52621 Ramat Gan, Israel. [Friedman, Eitan] Tel Aviv Univ, Sackler Fac Med, IL-69978 Ramat Aviv, Israel. [Ganschow, Pamela; Slavin, Thomas P.] City Hope Natl Med Ctr, Clin Canc Genet, 1500 East Duarte Rd, Duarte, CA 91010 USA. [Ganz, Patricia A.] UCLA, Div Canc Prevent Control Res, Jonsson Comprehens Canc Ctr, Sch Med, 650 Charles Young Dr South,Room A2-125 HS, Los Angeles, CA 90095 USA. [Garber, Judy] Dana Farber Canc Inst, Canc Risk & Prevent Clin, 450 Brookline Ave, Boston, MA 02115 USA. [Gayther, Simon A.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. Inst Curie, Dept Tumour Biol, Paris, France. Inst Curie, INSERM, U830, Paris, France. Univ Paris 05, Sorbonne Paris Cite, Paris, France. [Gerdes, Anne-Marie] Rigshosp, Dept Clincial Genet, Blegdamsvej 9, DK-4062 Copenhagen, Denmark. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, 3901 Rainbow Blvd,4019 Wahl Hall East,MS 3040, Kansas City, KS 66103 USA. [Goldgar, David E.] Univ Utah, Sch Med, Dept Dermatol, 30 North 1900 East,SOM 4B454, Salt Lake City, UT 84132 USA. [Greene, Mark H.; Loud, Jennifer T.] NCI, Clin Genet Branch, DCEG, NIH, 9609 Med Ctr Dr,Room 6E-454, Bethesda, MD 20892 USA. [Gronwald, Jacek; Jakubowska, Anna; Kaczmarek, Katarzyna; Sukiennicki, Grzegorz] Pomeranian Med Univ, Dept Genet & Pathol, Polabska 4, PL-70115 Szczecin, Poland. [Hahnen, Eric; Wappenschmidt, Barbara] Univ Hosp Cologne, Dept Gynaecol & Obstet, Ctr Familial Breast & Ovarian Canc, Ctr Mol Med Cologne CMMC, D-50931 Cologne, Germany. [Hamann, Ute] German Canc Res Ctr, Mol Genet Breast Canc, Neuenheimer Feld 580, D-69120 Heidelberg, Germany. [Hansen, Thomas V. O.] Copenhagen Univ Hosp, Ctr Genom Med, Rigshosp, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. [Hart, Steven; Couch, Fergus J.] Mayo Clin, Dept Hlth Sci Res, 200 First St SW, Rochester, MN 55905 USA. [Hays, John L.] Ohio State Univ, Div Med Oncol, Dept Internal Med, Columbus, OH 43210 USA. [Hays, John L.] Ohio State Univ, Div Gynecol Oncol, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Hays, John L.] Ctr Comprehens Canc, Arthur C James Canc Hosp & Richard J Solove Res I, Columbus, OH 43210 USA. Netherlands Canc Inst, Hereditary Breast & Ovarian Canc Res Grp Netherla, Coordinating Ctr, Amsterdam, Netherlands. [Hogervorst, Frans B. L.] Netherlands Canc Inst, Family Canc Clin, POB 90203, NL-1006 BE Amsterdam, Netherlands. [Hulick, Peter J.] Univ Chicago, Pritzker Sch Med, NorthShore Univ HealthSyst, Ctr Med Genet, 1000 Cent St,Suite 620, Evanston, IL 60201 USA. [Imyanitov, Evgeny N.] NN Petrov Inst Oncol, St Petersburg 197758, Russia. [Isaacs, Claudine] Georgetown Univ, Lombardi Comprehens Canc Ctr, 3800 Reservoir Rd NW, Washington, DC 20007 USA. [Izatt, Louise] Guys & St Thomas NHS Fdn Trust, Clin Genet, London SE1 9RT, England. [James, Paul] Peter MacCallum Canc Ctr, Familial Canc Ctr, Melbourne, Vic 3000, Australia. [James, Paul] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic 3010, Australia. [Janavicius, Ramunas] Vilnius Univ Hosp, Santariskiu Clin, Dept Mol & Regenerat Med, Hematol Oncol & Transfus Med Ctr, Santariskiu St 2, LT-08661 Vilnius, Lithuania. [Janavicius, Ramunas] State Res Inst Ctr Innovat Med, Zygymantu St 9, Vilnius, Lithuania. [Jensen, Uffe Birk] Aarhus Univ Hosp, Dept Clin Genet, Brendstrupgaardsvej 21C, Aarhus N, Denmark. [John, Esther M.] Canc Prevent Inst Calif, Dept Epidemiol, 2201 Walnut Ave Suite 300, Fremont, CA 94538 USA. [John, Esther M.] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA. [Joseph, Vijai; Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Res Lab, 1275 York Ave, New York, NY 10044 USA. [Just, Walter] Univ Ulm, Inst Human Genet, D-89091 Ulm, Germany. [Karlan, Beth Y.; Lester, Jenny] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, 8700 Beverly Blvd,Suite 290W, Los Angeles, CA 90048 USA. Peter MacCallum Canc Ctr, Res Dept, Melbourne, Vic 8006, Australia. [Kets, Carolien M.] Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, POB 9101, NL-6500 HB Nijmegen, Netherlands. [Kirk, Judy] Westmead Hosp, Familial Canc Serv, Hawkebury Rd,POB 533, Westmead, NSW 2145, Australia. [Kriege, Mieke] Erasmus Univ, Med Ctr, Family Canc Clin, Dept Med Oncol, POB 5201, NL-3008 AE Rotterdam, Netherlands. [Lesueur, Fabienne] PSL Univ, Inst Curie Mines ParisTech, Genet Epidemiol Canc Team, INSERM,U900, 26 Rue Ulm, F-75248 Paris 05, France. [Liljegren, Annelie] Karolinska Univ Hosp, Dept Oncol, S-17176 Stockholm, Sweden. [Loman, Niklas] Univ Lund Hosp, Dept Oncol, S-22185 Lund, Sweden. [Mazoyer, Sylvie] Univ Lyon, Lyon Neurosci Res Ctr CRNL, INSERM, CNRS,UMR5292,U1028, Lyon, France. [Meijers-Heijboer, Hanne E. J.] Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, POB 7057, NL-1007 MB Amsterdam, Netherlands. [Miller, Austin] Roswell Pk Canc Inst, NRG Oncol Stat & Data Management Ctr, Elm St & Carlton St, Buffalo, NY 14263 USA. [Montagna, Marco; Tognazzo, Silvia] Veneto Inst Oncol IOV IRCCS, Immunol & Mol Oncol Unit, Via Gattamelata 64, I-35128 Padua, Italy. [Mulligan, Anna Marie] St Michaels Hosp, Dept Lab Med, Toronto, ON, Canada. [Nevanlinna, Heli] Univ Helsinki, Dept Obstet & Gynecol, Haartmaninkatu 8,POB 700, Helsinki 00029, Finland. [Nussbaum, Robert L.] Univ Calif San Francisco, Dept Med & Genet, 513 Parnassus Ave,HSE 901E, San Francisco, CA 94143 USA. [Olah, Edith] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary. [Olopade, Olufunmilayo I.] Univ Chicago, Dept Med, 5841 South Maryland Ave,MC 2115, Chicago, IL 60637 USA. [Ong, Kai-ren] Birmingham Womens Hosp Healthcare NHS Trust, West Midlands Reg Genet Serv, Birmingham, W Midlands, England. [Oosterwijk, Jan C.] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands. [Papi, Laura] Univ Florence, Dept Biomed Expt & Clin Sci, Unit Med Genet, Viale Morgagni 50, I-50134 Florence, Italy. [Park, Sue Kyung] Seoul Natl Univ, Dept Prevent Med, Coll Med, 103 Daehak Ro, Seoul 110799, South Korea. [Pedersen, Inge Sokilde] Aalborg Univ Hosp, Sect Mol Diagnost, Dept Biochem, Reberbansgade 15, Aalborg, Denmark. [Segura, Pedro Perez] IdISSC Inst Investigacin Sanitaria Hosp Clin, Hosp Clinico San Carlos, Dept Oncol, Martin Lagos S-N, Madrid, Spain. [Peterlongo, Paolo] IFOM, IFOM IEO Campus,Via Adamello 16, I-20139 Milan, Italy. [Phelan, Catherine M.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL 33612 USA. [Radice, Paolo] Fdn IRCCS Ist Ric & Cura Carattere Sci, Dept Prevent & Predicted Med, Unit Mol Bases Genet Risk & Genet Testing, Ist Nazl Tumori, Amaedeolab Via GA Amadeo 42, I-20133 Milan, Italy. [Rantala, Johanna] Karolinska Univ Hosp, Dept Clin Genet, Hosp L5 03, S-17176 Stockholm, Sweden. [Rappaport-Fuerhauser, Christine; Singer, Christian F.; Tan, Yen; Tea, Muy-Kheng] Med Univ Vienna, Dept OB GYN, Waehringer Guertel 18-20, A-1090 Vienna, Austria. [Rennert, Gad] Carmel Hosp, Clalit Natl Israeli Canc Control Ctr, 7 Michal St, IL-34362 Haifa, Israel. [Richardson, Andrea] Johns Hopkins Univ, Dept Pathol, Sch Med, Baltimore, MD 21205 USA. [Robson, Mark] Mem Sloan Kettering Canc Ctr, Serv Dept Med, Clin Genet, 1275 York Ave, New York, NY USA. [Rodriguez, Gustavo C.] Univ Chicago, NorthShore Univ HealthSyst, Div Gynecol Oncol, 2650 Ridge Ave,Suite 1507, Evanston, IL 60201 USA. [Rookus, Matti A.] Netherlands Canc Inst, Dept Epidemiol, POB 90203, NL-1006 BE Amsterdam, Netherlands. [Schmutzler, Rita Katharina] Univ Hosp Cologne, Fac Med, Ctr Hereditary Breast & Ovarian Canc, D-50931 Cologne, Germany. [Schmutzler, Rita Katharina] Univ Hosp Cologne, Fac Med, Ctr Integrated Oncol CIO, Cologne, Germany. [Sevenet, Nicolas] Inst Bergonie, Oncogenet, 229 Cours Argonne, F-33076 Bordeaux, France. [Snape, Katie] St Georges Univ London, Med Genet Unit, London SW17 0RE, England. [Sokolowska, Johanna] Nancy Univ, Lab Genet Med, Ctr Hosp Reg & Univ, Rue Morvan, F-54511 Vandoeuvre Les Nancy 1, France. [Sonderstrup, Ida Marie Heeholm] Slagelse Hosp, Dept Pathol Reg Zealand Sect Slagelse, Ingemannsvej 18, Slagelse, Cpoenhagen, Denmark. [Southey, Melissa] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Parkville, Vic 3010, Australia. [Spurdle, Amanda B.; Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Genet & Computat Biol Dept, Herston Rd, Herston, Qld 4006, Australia. [Stadler, Zsofia] Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, 1275 York Ave, New York, NY 10021 USA. [Sutter, Christian] Univ Heidelberg Hosp, Inst Human Genet, Dept Human Genet, Heidelberg, Germany. [Teixeira, Manuel R.] Portuguese Oncol Inst, Dept Genet, Rua Dr Antonio Bernardino Almeida, P-4200072 Oporto, Portugal. [Teixeira, Manuel R.] Univ Porto, Biomed Sci Inst ICBAS, Oporto, Portugal. [Teule, Alex] IDIBELL Bellvitge Biomed Res Inst, Catalan Inst Oncol, Hereditary Canc Program, Genet Counseling Unit, Gran Via Hosp 199-203, Barcelona 08908, Spain. [Teo, Soo-Hwang] Canc Res Initiat Fdn, Sime Darby Med Ctr, 1 Jalan SS12-1A, Subang Jaya 47500, Malaysia. [Teo, Soo-Hwang] Univ Malaya, Univ Malaya Canc Res Inst, 1 Jalan SS12-1A, Kuala Lumpur 50603, Malaysia. [Terry, Mary Beth] Columbia Univ, Dept Epidemiol, New York, NY USA. [Thomassen, Mads] Odense Univ Hosp, Dept Clin Genet, Sonder Blvd 29, Odense C, Denmark. [Tihomirova, Laima] Latvian Biomed Res & Study Ctr, Ratsupites Str 1, Riga, Latvia. [Tischkowitz, Marc] Addenbrookes Hosp, Dept Med Genet, Addenbrookes Treatment Ctr, Level 6,Hills Rd,Box 134, Cambridge CB2 0QQ, England. [Toland, Amanda Ewart] Ohio State Univ, Div Human Genet, Dept Internal Med, 998 Biomedical Res Tower, Columbus, OH 43210 USA. [Tung, Nadine] Beth Israel Deaconess Med Ctr, Dept Med Oncol, 330 Brookline Ave, Boston, MA 02215 USA. [van den Ouweland, Ans M. W.] Erasmus Univ, Med Ctr, Family Canc Clin, Dept Clin Genet, 330 Brookline Ave,POB 2040, NL-3000 CA Rotterdam, Netherlands. [van der Luijt, Rob B.] Univ Med Ctr Utrecht, Dept Med Genet, NL-3584 EA Utrecht, Netherlands. [van Engelen, Klaartje] Acad Med Ctr, Dept Clin Genet, POB 22700, NL-1100 DE Amsterdam, Netherlands. [Varon-Mateeva, Raymonda] Charite, Inst Human Genet, Campus Virchov Klinikum, D-13353 Berlin, Germany. [Wijnen, Juul T.] Leiden Univ, Med Ctr, Dept Human Genet, NL-2300 RC Leiden, Netherlands. [Rebbeck, Timothy] Univ Penn, Ctr Clin Epidemiol & Biostat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, 200 First St SW, Rochester, MN 55905 USA. [Nord, Silje] Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Radiumhosp, N-0372 Oslo, Norway. [Hamdi, Yosr; Soucy, Penny; Droit, Arnaud; Lemacon, Audrey; Simard, Jacques] Univ Laval, 2705 Laurier Blvd, Quebec City, PQ G1V 4G2, Canada. [Pastinen, Tomi] Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada. [Andrulis, Irene L.; Mulligan, Anna Marie] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Arun, Banu K.] Univ Texas MD Anderson Canc Ctr, Clin Canc Genet Program, 1515 Pressler St CBP 5, Houston, TX 77030 USA. [Chung, Wendy K.] Columbia Univ, Dept Med, 1150 St Nicholas Ave, New York, NY 10032 USA. [Eeles, Ros] Royal Marsden NHS Fdn Trust, Sutton SM2 5NG, Surrey, England. [Foulkes, William D.; Tischkowitz, Marc] McGill Univ, Dept Oncol, Program Canc Genet, Montreal, PQ, Canada. [Ganz, Patricia A.] UCLA, Div Canc Prevent Control Res, Jonsson Comprehens Canc Ctr, Sch Publ Hlth, 650 Charles Young Dr South,Room A2-125 HS, Los Angeles, CA 90095 USA. [Hahnen, Eric; Schmutzler, Rita Katharina; Wappenschmidt, Barbara] Univ Hosp Cologne, Ctr Mol Med Cologne CMMC, Ctr Integrated Oncol CIO, D-50931 Cologne, Germany. [John, Esther M.] Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA. [Mulligan, Anna Marie] St Michaels Hosp, Li Ka Shing Knowledge Inst, Keenan Res Ctr, Toronto, ON, Canada. [Nevanlinna, Heli] Helsinki Univ Hosp, Biomedicum Helsinki, Haartmaninkatu 8,POB 700, Helsinki 00029, Finland. [Rennert, Gad] Carmel Hosp, Dept Community Med & Epidemiol, 7 Michal St, IL-34362 Haifa, Israel. [Rennert, Gad] B Rappaport Fac Med, 7 Michal St, IL-34362 Haifa, Israel. [Toland, Amanda Ewart] Ohio State Univ, Div Human Genet, Dept Canc Biol, 998 Biomedical Res Tower, Columbus, OH 43210 USA. [Toland, Amanda Ewart] Ohio State Univ, Genet Comprehens Canc Ctr, 998 Biomedical Res Tower, Columbus, OH 43210 USA. [Wijnen, Juul T.] Leiden Univ, Med Ctr, Dept Clin Genet, NL-2300 RC Leiden, Netherlands. EM Jacques.Simard@crchudequebec.ulaval.ca RI Gronwald, Jacek/A-4576-2017; Arnold, Norbert/E-3012-2010; Jansen van Rensburg, Elizabeth (Lizette)/B-9104-2011; Osorio, Ana/I-4324-2014; Azzollini, Jacopo/E-7134-2017; manoukian, siranoush/E-7132-2017; Peissel, Bernard/E-8187-2017; montagna, marco/E-2225-2012; OI Gronwald, Jacek/0000-0002-3643-2871; Arnold, Norbert/0000-0003-4523-8808; Osorio, Ana/0000-0001-8124-3984; Azzollini, Jacopo/0000-0002-9364-9778; manoukian, siranoush/0000-0002-6034-7562; Peissel, Bernard/0000-0001-9233-3571; montagna, marco/0000-0002-4929-2150; Dunning, Alison Margaret/0000-0001-6651-7166 FU European Community's Seventh Framework Programme [223175 (HEALTH-F2-2009-223175)]; Cancer Research UK [C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565, C1287/A11990, C5047/A8385]; National Institutes of Health [CA128978]; Post-cancer GWAS Initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR); Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; National Cancer Institute [UM1 CA164920, RC4CA153828]; Lithuania (BFBOCC-LT): Research Council of Lithuania [SEN-18/2015]; Cancer Association of South Africa (CANSA); Morris and Horowitz Families Endowed Professorship; Spanish Association Against Cancer [AECC08]; RTICC [06/0020/1060, FISPI08/1120]; Mutua Madrilena Foundation (FMMA); Office of the Director, National Institutes of Health; Fondazione IRCCS Istituto Nazionale Tumori; Cancer Research: UK [C12292/A11174, C12292/A20861]; Fondation ARC (FONDATION ARC) [SAE20131200623]; Canadian Institutes of Health Research [CRN-87521]; Ministry of Economic Development, Innovation and Export Trade [PSR-SIIRI-701]; Government of Canada through Genome Canada; Canadian Institutes of Health Research; Ministere de l'Economie, Innovation et Exportation du Quebec through Genome Quebec; Quebec Breast Cancer Foundation; Ministere de l'Economie, Innovation et Exportation du Quebec [PSR-SIIRI-701]; European Union (European Social Fund: ESF); Greek National Funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF): Research Funding Program of the General Secretariat for Research and Technology [SYN11_10_19 NBCA]; DKFZ; NIHR; University of Kansas Cancer Center [P30 CA168524]; Kansas Bioscience Authority Eminent Scholar Program; Chancellors Distinguished Chair in Biomedical Sciences Professorship; German Cancer Aid [110837]; European Regional Development Fund; Free State of Saxony, Germany (LIFE: Leipzig Research Centre for Civilization Diseases) [713-241202, 14505/2470]; Ligue Nationale Contre le Cancer; Association "Le cancer du sein, parlons-en!" Award; French National Institute of Cancer (INCa); Non-therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI) [P30-CA051008]; Fisher Center for Hereditary Cancer and Clinical GenomicsResearch; Swing Fore the Cure; IWT; ISCIII (Spain) [RD12/0036/0006, 15/00059]; European Regional Development FEDER Funds; Helsinki University Hospital Research Fund; Academy of Finland [266528]; Finnish Cancer Society; Sigrid Juselius Foundation; Dutch Cancer Society [NKI1998-1854, NKI2004-3088, NKI2007-3756]; Netherlands Organization of Scientific Research [NWO 91109024]; Pink Ribbon Grants [110005, 2014-187.WO76]; BBMRI [NWO 184.021.007/CP46]; Transcan Grant JTC Cancer [12-054]; Hong Kong Sanatorium and Hospital; Dr. Ellen Li Charitable Foundation; Kerry Group Kuok Foundation; National Institute of Health [1R 03CA130065]; North California Cancer Center; Hungarian Research Grants [KTIA-OTKA CK-80745, OTKA K-112228]; Asociacion Espanola Contra el Cancer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute; Autonomous Government of Catalonia [ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, PIE13/00022, 2009SGR290, 2014SGR364]; Icelandic Association; Landspitali University Hospital Research Fund; Ministere de l'Economie, Science et Innovation du Quebec through Genome Quebec; Ministero della Salute and "5x1000" Istituto Oncologico Veneto Grant; Liga Portuguesa Contra o Cancro; National Breast Cancer Foundation; National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea [1020350]; NIH [CA116167, CA192393, CA176785]; NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; MH CZ: DRO (MMCI) [00209805]; State Budget of the Czech Republic (RECAMO) [CZ.1.05/2.1.00/03.0101]; Charles University in Prague [UNCE204024]; Robert and Kate Niehaus Clinical Cancer Genetics Initiative; Andrew Sabin Research Fund; Intramural Research Program of the US National Cancer Institute, NIH; Westat, Inc., Rockville, MD [NO2-CP-11019-50, N02-CP-65504]; Clalit Health Services in Israel; Israel Cancer Association; Breast Cancer Research Foundation (BCRF), NY; Russian Federation for Basic Research [15-04-01744, 16-54-00055]; NRG Oncology Operations Grant [U10 CA180868]; NRG SDMC Grant [U10 CA180822]; Gynecologic Oncology Group (GOG) Administrative Office; GOG Tissue Bank [CA 27469]; GOG Statistical and Data Center [CA 37517]; Intramural Research Program, NCI; Ohio State University Comprehensive Cancer Center; Italian Association of Cancer Research (AIRC) [IG 2013 N.14477]; Tuscany Institute for Tumors (ITT); Israeli Cancer Association; Swedish Cancer Society; NCI [CA125183, R01 CA142996, 1U01CA161032]; Ralph and Marion Falk Medical Research Trust; Entertainment Industry Fund National Women's Cancer Research Alliance; CRUK; [SAF2010-20493]; [5U01CA113916]; [R01CA140323]; [PBZ_KBN_122/P05/2004] FX Funding for the iCOGS infrastructure came from the European Community's Seventh Framework Programme under Grant Agreement No. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-cancer GWAS Initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112: the GAME-ON Initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. BCFR: this work was supported by Grant UM1 CA164920 from the National Cancer Institute. BFBOCC was supported by Lithuania (BFBOCC-LT): Research Council of Lithuania Grant SEN-18/2015. BIDMC was supported by the Breast Cancer Research Foundation. BRCA-gene mutations and breast cancer in South African women (BMBSA) was supported by Grants from the Cancer Association of South Africa (CANSA) to Elizabeth J. van Rensburg. BRICOH: SLN was partially supported by the Morris and Horowitz Families Endowed Professorship. CNIO: this work was partially supported by Spanish Association Against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrilena Foundation (FMMA), and SAF2010-20493. COH-CCGCRN: patients were recruited for this study from the City of Hope Clinical Cancer Genomics Community Research Network, supported in part by Award Number RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. CONSIT Team: Associazione Italiana Ricerca sul Cancro (AIRC) to P. Peterlongo (IG 2012 Id. 12821) and P. Radice (IG 2014 Id. 15547). Funds from Italian citizens who allocated the 5 9 1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional Strategic Projects '5x1000') to S. Manoukian. FiorGen Foundation for Pharmacogenomics to L. Papi. CORE: the CIMBA Data Management and Data Analysis were supported by Cancer Research: UK Grants C12292/A20861, C12292/A11174. ACA is a Cancer Research-UK Senior Cancer Research Fellow. GCT is an NHMRC Senior Principal Research Fellow. J. Lecarpentier has been financially supported by the Fondation ARC (FONDATION ARC, 9 rue Guy Moquet 94803 Villejuif: France), Grant Number SAE20131200623. This work was supported by the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" Program: Grant No. CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade: Grant No. PSR-SIIRI-701. The PERSPECTIVE Project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministere de l'Economie, Innovation et Exportation du Quebec through Genome Quebec, and The Quebec Breast Cancer Foundation. This work was also supported by the Ministere de l'Economie, Innovation et Exportation du Quebec: Grant No. PSR-SIIRI-701. DEMOKRITOS: this research has been co-financed by the European Union (European Social Fund: ESF) and Greek National Funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF): Research Funding Program of the General Secretariat for Research and Technology: SYN11_10_19 NBCA. Investing in Knowledge Society through the European Social Fund. The DKFZ Study was supported by the DKFZ.; EMBRACE was supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo were supported by an NIHR Grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust were supported by an NIHR Grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft were supported by Cancer Research UK Grant C5047/A8385. Ros Eeles was also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. FCCC: the authors acknowledge the support from The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. was funded by 5U01CA113916, R01CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) was supported by the German Cancer Aid (Grant No. 110837, Rita K. Schmutzler). This work was supported by the European Regional Development Fund and Free State of Saxony, Germany (LIFE: Leipzig Research Centre for Civilization Diseases, Project Numbers 713-241202, 713-241202, 14505/2470, 14575/2470). GEMO: the study was supported by the Ligue Nationale Contre le Cancer; the Association "Le cancer du sein, parlons-en!" Award; the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" Program and the French National Institute of Cancer (INCa). GEORGETOWN: CI received support from the Non-therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI Grant P30-CA051008), the Fisher Center for Hereditary Cancer and Clinical GenomicsResearch, and Swing Fore the Cure. G-FAST: Bruce Poppe is a Senior Clinical Investigator of FWO. Mattias Van Heetvelde obtained funding from IWT. HCSC was supported by a Grant RD12/0036/0006 and 15/00059 from ISCIII (Spain), partially supported by European Regional Development FEDER Funds. The HEBCS was financially supported by the Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society and the Sigrid Juselius Foundation. HEBON Study was supported by the Dutch Cancer Society Grants NKI1998-1854, NKI2004-3088, and NKI2007-3756, the Netherlands Organization of Scientific Research Grant NWO 91109024, the Pink Ribbon Grants 110005 and 2014-187.WO76, the BBMRI Grant NWO 184.021.007/CP46, and the Transcan Grant JTC 2012 Cancer 12-054. HEBON thanks the Registration Teams of Dutch Cancer Registry (IKNL; S. Siesling, J. Verloop) and the Dutch Pathology database (PALGA; L. Overbeek) for their help in part of the data collection. HRBCP was supported by the Hong Kong Sanatorium and Hospital, Dr. Ellen Li Charitable Foundation, The Kerry Group Kuok Foundation, National Institute of Health 1R 03CA130065, and North California Cancer Center. Hungarian Breast and Ovarian Cancer Study (HUNBOCS) was supported by Hungarian Research Grants KTIA-OTKA CK-80745 and OTKA K-112228. ICO: Contract Grant Sponsor: Asociacion Espanola Contra el Cancer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia. Contract Grant Numbers: ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, PIE13/00022, 2009SGR290, and 2014SGR364. The IHCC was supported by Grant PBZ_KBN_122/P05/2004.; The ILUH Group was supported by the Icelandic Association "Walking for Breast Cancer Research" and by the Landspitali University Hospital Research Fund. INHERIT: this work was supported by the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" Program: Grant No. CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade: Grant No. PSR-SIIRI-701. The PERSPECTIVE Project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (Grant GPH-129344), the Ministere de l'Economie, Science et Innovation du Quebec through Genome Quebec, and the Quebec Breast Cancer Foundation. IOVHBOCS was supported by Ministero della Salute and "5x1000" Istituto Oncologico Veneto Grant. IPOBCS: this study was in part supported by Liga Portuguesa Contra o Cancro. kConFab was supported by a Grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia. KOHBRA was supported by a Grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1020350). MAYO was supported by NIH Grants CA116167, CA192393, and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), and a Grant from the Breast Cancer Research Foundation. MCGILL: Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. MODSQUAD was supported by MH CZ: DRO (MMCI, 00209805) and by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101) to LF, and by Charles University in Prague Project UNCE204024 (MZ). MSKCC was supported by Grants from the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, and the Andrew Sabin Research Fund. NAROD: 1R01 CA149429-01. NCI: the research of Drs. MH Greene and PL Mai was supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by Support Services Contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc., Rockville, MD. NICCC was supported by Clalit Health Services in Israel. Some of its activities were supported by the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. NNPIO: this work has been supported by the Russian Federation for Basic Research (Grants 15-04-01744 and 16-54-00055). NRG Oncology: this study was supported by NRG Oncology Operations Grant Number U10 CA180868 as well as NRG SDMC Grant U10 CA180822, Gynecologic Oncology Group (GOG) Administrative Office and the GOG Tissue Bank (CA 27469), and the GOG Statistical and Data Center (CA 37517). Drs. Greene, Mai, and Savage were supported by Funding from the Intramural Research Program, NCI. OSUCCG was supported by the Ohio State University Comprehensive Cancer Center. PBCS: this work was supported by the Italian Association of Cancer Research (AIRC) [IG 2013 N.14477] and Tuscany Institute for Tumors (ITT) Grant 2014-2015-2016. SEABASS: Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06), and Cancer Research Initiatives Foundation. The SMC Team was in part sponsored by a Grant from the Israeli Cancer Association to the Israeli Consortium of Hereditary Breast Cancer.; SWE-BRCA Collaborators were supported by the Swedish Cancer Society. UCHICAGO was supported by NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032, and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance, and the Breast Cancer Research Foundation. OIO is an ACS Clinical Research Professor. UCLA: Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research Foundation. UCSF: UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UKFOCR was supported by a Project Grant from CRUK to Paul Pharoah. UPENN: National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855; Breast Cancer Research Foundation; Susan G. Komen Foundation for the Cure, Basser Research Center for BRCA. VFCTG: Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. WCP: Dr. Karlan was funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. NR 36 TC 0 Z9 0 U1 10 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JAN PY 2017 VL 161 IS 1 BP 117 EP 134 DI 10.1007/s10549-016-4018-2 PG 18 WC Oncology SC Oncology GA EI0TV UT WOS:000392188500012 PM 27796716 ER PT J AU Edelman, EJ Maisto, SA Hansen, NB Cutter, CJ Dziura, J Fiellin, LE O'Connor, PG Bedimo, R Gibert, C Marconi, VC Rimland, D Rodriguez-Barradas, MC Simberkoff, MS Justice, AC Bryant, KJ Fiellin, DA AF Edelman, E. Jennifer Maisto, Stephen A. Hansen, Nathan B. Cutter, Christopher J. Dziura, James Fiellin, Lynn E. O'Connor, Patrick G. Bedimo, Roger Gibert, Cynthia Marconi, Vincent C. Rimland, David Rodriguez-Barradas, Maria C. Simberkoff, Michael S. Justice, Amy C. Bryant, Kendall J. Fiellin, David A. TI The Starting Treatment for Ethanol in Primary care Trials (STEP Trials): Protocol for Three Parallel Multi-Site Stepped Care Effectiveness Studies for Unhealthy Alcohol Use in HIV-Positive Patients SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Multicenter study; Randomized controlled trial; Algorithms; HIV; Alcohol ID ACTIVE ANTIRETROVIRAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; BRIEF INTERVENTION; EMERGENCY-DEPARTMENT; HEPATITIS-C; MEDICATION ADHERENCE; NICOTINE DEPENDENCE; PROBABILITY SAMPLE; TREATMENT SERVICES; HARMFUL DRINKERS AB Unhealthy alcohol use is common among HN-positive patients, yet effective evidence-based treatments are rarely provided in clinical settings providing HIV care. Further, given patient variability in response to initial treatments, stepped care approaches may be beneficial. We describe the rationale, aims and study design for the current Starting Treatment for Ethanol in Primary care Trials (STEP Trials); three parallel randomized controlled effectiveness trials being conducted in five Infectious Disease Clinics. Participants meeting criteria for: 1) at-risk drinking, 2) moderate alcohol use with liver disease (MAID), or 3) alcohol use disorder (AUD) are randomized to integrated stepped care versus treatment as usual. For those with at-risk drinking or MALD, integrated stepped care starts with a one session brief intervention and follow-up 2-week telephone booster. Based on pre-specified nonresponse criteria, participants may be "stepped up" at week 4 to receive four sessions of motivational enhancement therapy (MET) and "stepped up" again at week 12 for addiction physician management (APM) and consideration of alcohol pharmacotherapy. For those with AUD, integrated stepped care begins with APM. Non-responders may be "stepped up" at week 4 to receive MET and again at week 12 for a higher level of care (e.g. intensive outpatient program). The primary outcome is alcohol consumption assessed at 24 weeks, and secondary outcome is the VACS Index, a validated measure of HIV morbidity and mortality risk. Results from the STEP Trials should inform future research and the implementation of interventions to address unhealthy alcohol use among HIV-positive individuals. (C) 2016 Elsevier Inc. All rights reserved. C1 [Edelman, E. Jennifer; Cutter, Christopher J.; Fiellin, Lynn E.; O'Connor, Patrick G.; Justice, Amy C.; Fiellin, David A.] Yale Univ, Sch Med, 367 Cedar St,ESH A, New Haven, CT 06510 USA. [Edelman, E. Jennifer; Hansen, Nathan B.; Fiellin, Lynn E.; Fiellin, David A.] Yale Univ, Sch Publ Hlth, Ctr Interdisciplinary Res AIDS, New Haven, CT 06510 USA. [Maisto, Stephen A.] Syracuse Univ, Syracuse, NY 13244 USA. [Hansen, Nathan B.] Univ Georgia, Coll Publ Hlth, Athens, GA 30602 USA. [Dziura, James] Yale Univ, Sch Publ Hlth, Yale Ctr Analyt Sci, New Haven, CT 06511 USA. [Bedimo, Roger] Vet Affairs North Texas Hlth Care Syst, Dallas, TX 75216 USA. [Bedimo, Roger] UT Southwestern, Dallas, TX 75216 USA. [Gibert, Cynthia] DC Vet Affairs Med Ctr, Washington, DC 20422 USA. [Gibert, Cynthia] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20422 USA. [Marconi, Vincent C.; Rimland, David] Atlanta Vet Affairs Med Ctr, Decatur, GA 30033 USA. [Marconi, Vincent C.; Rimland, David] Emory Univ, Sch Med, Decatur, GA 30033 USA. [Rodriguez-Barradas, Maria C.] Michael E DeBakey VA Med Ctr, Houston, TX 77030 USA. [Rodriguez-Barradas, Maria C.] Baylor Coll Med, Houston, TX 77030 USA. [Simberkoff, Michael S.] VA NY Harbor Healthcare Syst, New York, NY 10010 USA. [Simberkoff, Michael S.] NYU, Sch Med, New York, NY 10010 USA. [Justice, Amy C.] VA Connecticut Healthcare Syst, Vet Aging Cohort Study, West Haven, CT 06516 USA. [Bryant, Kendall J.] NIAAA, HIV AIDS Program, Bethesda, MD 20892 USA. EM ejennifer.edelman@yale.edu FU National Institute on Alcohol Abuse and Alcoholism [1U01AA020795, 2U01AA020790]; Yale-Drug Abuse, HIV, and Addiction Research Scholar [K12DA033312-02] FX This work was generously supported by funding from the National Institute on Alcohol Abuse and Alcoholism (1U01AA020795 and 2U01AA020790). EJ Edelman was supported as a Yale-Drug Abuse, HIV, and Addiction Research Scholar (National Institute on Drug Abuse K12DA033312-02) during this time. NR 77 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 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD JAN PY 2017 VL 52 BP 80 EP 90 DI 10.1016/j.cct.2016.11.008 PG 11 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA EI5VZ UT WOS:000392565700011 PM 27876616 ER PT J AU Pamela, KB Judd, EH Allan, BW Michael, CK Lorna, R Sara, D Phillip, W Nivedita, P Jeremy, B Stephen, J Ziya, K John, WK Chloe, M Andrew, CM AF Pamela, Burrows K. Judd, Hollander E. Allan, Wolfson B. Michael, Kurz C. Lorna, Richards Sara, DiFiore Phillip, Watts Nivedita, Patkar Jeremy, Brown Stephen, Jackman Ziya, Kirkali John, Kusek W. Chloe, Michel Andrew, Meltzer C. CA STONE Study Investigators TI Design and challenges of a randomized clinical trial of medical expulsive therapy (tamsulosin) for urolithiasis in the emergency department SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Urolithiasis; Kidney stones; Urinary stone disease; Medical expulsive therapy; Alpha-blocker; Emergency department ID KIDNEY-STONES; UNITED-STATES; MANAGEMENT; CALCULI; VISITS; TRENDS AB Urolithiasis or urinary stone disease has been estimated to affect about 1 in 11 Americans. Patients with urinary stone disease commonly present to the emergency department for management of their acute pain. In addition to providing analgesia, administration of drug (medical expulsive therapy) is often prescribed to assist passage of the urinary stone. In this methodology paper, we describe the design of a prospective, multi-center, randomized, double-blind placebo controlled clinical trial of the alpha-adrenergic blocker, tamsulosin, to evaluate its effectiveness as medical expulsive therapy. In addition, we describe the unique challenges of conducting a trial of this type within the setting of the emergency department. (C) 2016 Elsevier Inc. All rights reserved. C1 [Pamela, Burrows K.] George Washington Univ, Ctr Biostat, Milken Inst Sch Publ Hlth, 6110 Execut Blvd, Rockville, MD 20852 USA. [Judd, Hollander E.; Phillip, Watts] Thomas Jefferson Univ Hosp, Dept Emergency Med, 1020 Sansom St, Philadelphia, PA 19107 USA. [Allan, Wolfson B.; Sara, DiFiore; Stephen, Jackman] Univ Pittsburgh, Dept Emergency Med, Suite 400A Iroquois Bldg,3600 Forbes Ave, Pittsburgh, PA 15261 USA. [Michael, Kurz C.; Nivedita, Patkar] Univ Alabama Birmingham, Dept Emergency Med, 619 19th St South, Birmingham, AL 35249 USA. [Lorna, Richards; Jeremy, Brown; Chloe, Michel; Andrew, Meltzer C.] George Washington Univ, Med Fac Associates, Dept Emergency Med, 2120 L St NW, Washington, DC 20037 USA. [Ziya, Kirkali; John, Kusek W.] NIDDK, Div Kidney Urol & Hematol Dis, 6707 Democracy Blvd, Bethesda, MD 20892 USA. [Jeremy, Brown] NIGMS, Off Emergency Care Res, Bethesda, MD USA. EM pam_b@bsc.gwu.edu FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [U01 DK096037, RO1 DK071603, U34 DK090957] FX The STONE Study is supported by cooperative agreement U01 DK096037 from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (Pilot Study RO1 DK071603, Planning Grant U34 DK090957). The study is registered at clinicaltrials.gov (NCT00382265). NR 16 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD JAN PY 2017 VL 52 BP 91 EP 94 DI 10.1016/j.cct.2016.11.010 PG 4 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA EI5VZ UT WOS:000392565700012 ER PT J AU Zang, Q Mansouri, K Williams, AJ Judson, RS Allen, DG Casey, WM Kleinstreuer, NC AF Zang, Qingda Mansouri, Kamel Williams, Antony J. Judson, Richard S. Allen, David G. Casey, Warren M. Kleinstreuer, Nicole C. TI In Silico Prediction of Physicochemical Properties of Environmental Chemicals Using Molecular Fingerprints and Machine Learning SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID COMPUTATIONAL TOXICOLOGY RESOURCE; AQUEOUS SOLUBILITY; APPLICABILITY DOMAIN; ORGANIC-COMPOUNDS; QSPR MODELS; TOXCAST PROGRAM; BOILING POINTS; LOG-P; PERSPECTIVE; EXPOSURE AB There are little available toxicity data on the vast majority of chemicals in commerce. High-throughput screening (HTS) studies, such as those being carried out by the U.S. Environmental Protection Agency (EPA) ToxCast program in partnership with the federal Tox21 research program, can generate biological data to inform models for predicting potential toxicity. However, physicochemical properties are also needed to model environmental fate and transport, as well as exposure potential. The purpose of the present study was to generate an open-source quantitative structure property relationship (QSPR) workflow to predict a variety of physicochemical properties that would have cross-platform compatibility to integrate into existing cheminformatics workflows. In this effort, decades-old experimental property data sets available within the EPA EPI Suite were reanalyzed using modern cheminfoimatics workflows to develop updated QSPR models capable of supplying computationally efficient, open, and transparent HTS property predictions in support of environmental modeling efforts. Models were built using updated EPI Suite data sets for the prediction of six physicochemical properties: octanol water partition coefficient (logP), water solubility (logS), boiling point (BP), melting point (MP), vapor pressure (logVP), and bioconcentration factor (logBCF). The coefficient of determination (R-2) between the estimated values and experimental data for the six predicted properties ranged from 0.826 (MP) to 0.965 (BP), with model performance for five of the six properties exceeding those from the original EPI Suite models. The newly derived models can be employed for rapid estimation of physicochemical properties within an open-source HTS workflow to inform fate and toxicity prediction models of environmental chemicals. C1 [Zang, Qingda; Allen, David G.] Integrated Lab Syst Inc, Res Triangle Pk, NC 27709 USA. [Mansouri, Kamel; Williams, Antony J.; Judson, Richard S.] US EPA, Natl Ctr Computat Toxicol, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Casey, Warren M.; Kleinstreuer, Nicole C.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Kleinstreuer, NC (reprint author), 530 Davis Dr, Morrisville, NC 27560 USA. EM nicole.kleinstreuer@nih.gov OI Mansouri, Kamel/0000-0002-6426-8036; Kleinstreuer, Nicole/0000-0002-7914-3682 FU National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH) [HHSN273201500010C] FX We would like to express our deep appreciation to Dr. Ann Richard (EPA National Center for Computational Toxicology) and Dr. Shannon Bell (Integrated Laboratory Systems, Inc.) for their constructive suggestions for this manuscript. We also thank Ms. Catherine Sprankle (Integrated Laboratory Systems, Inc.) for editorial review. This project was funded in whole or in part with federal funds from the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH) under contract HHSN273201500010C to Integrated Laboratory Systems in support of NICEATM. NR 61 TC 0 Z9 0 U1 17 U2 17 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9596 EI 1549-960X J9 J CHEM INF MODEL JI J. Chem Inf. Model. PD JAN PY 2017 VL 57 IS 1 BP 36 EP 49 DI 10.1021/acs.jcim.6b00625 PG 14 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA EI7OK UT WOS:000392687400006 PM 28006899 ER PT J AU McAdams, TA Rijsdijk, FV Narusyte, J Ganiban, JM Reiss, D Spotts, E Neiderhiser, JM Lichtenstein, P Eley, TC AF McAdams, Tom A. Rijsdijk, Fruhling V. Narusyte, Jurgita Ganiban, Jody M. Reiss, David Spotts, Erica Neiderhiser, Jenae M. Lichtenstein, Paul Eley, Thalia C. TI Associations between the parent-child relationship and adolescent self-worth: a genetically informed study of twin parents and their adolescent children SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE Adolescence; parenting; parent-child relationships; children-of-twins; self-esteem ID GENOTYPE-ENVIRONMENT CORRELATION; OF-TWINS; PEER ATTACHMENT; PERCEIVED COMPETENCE; ANTISOCIAL-BEHAVIOR; CONDUCT DISTURBANCE; EXTENDED CHILDREN; MENTAL-HEALTH; ESTEEM; DEPRESSION AB BackgroundLow self-worth during adolescence predicts a range of emotional and behavioural problems. As such, identifying potential sources of influence on self-worth is important. Aspects of the parent-child relationship are often associated with adolescent self-worth but to date it is unclear whether such associations may be attributable to familial confounding (e.g. genetic relatedness). We set out to clarify the nature of relationships between parental expressed affection and adolescent self-worth, and parent-child closeness and adolescent self-worth. MethodsWe used data from the Twin and Offspring Study in Sweden, a children-of-twins sample comprising 909 adult twin pairs with adolescent children. Using these data we were able to apply structural equationmodels with which we could examine whether associations remained after accounting for genetic transmission. ResultsResults demonstrated that parent-child closeness and parental-expressed affection were both phenotypically associated with adolescent self-worth. Associations could not be attributed to genetic relatedness between parent and child. ConclusionsParent-child closeness and parental affection are associated with adolescent self-worth above and beyond effects attributable to genetic relatedness. Data were cross-sectional, so the direction of effects cannot be confirmed but findings support the notion that positive parent-child relationships increase adolescent self-worth. C1 [McAdams, Tom A.; Rijsdijk, Fruhling V.; Eley, Thalia C.] Kings Coll London, Inst Psychiat Psychol & Neurosci, MRC, Social Genet & Dev Psychiat Ctr, London, England. [Narusyte, Jurgita] Karolinska Inst, Div Insurance Med, Dept Clin Neurosci, Stockholm, Sweden. [Ganiban, Jody M.] George Washington Univ, Dept Psychol, Washington, DC 20052 USA. [Reiss, David] Yale Child Study Ctr, New Haven, CT USA. [Spotts, Erica] NIH, Off Behav & Social Sci Res, Bldg 10, Bethesda, MD 20892 USA. [Neiderhiser, Jenae M.] Penn State Univ, Dept Psychol, University Pk, PA 16802 USA. [Lichtenstein, Paul] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. EM tom.mcadams@kcl.ac.uk FU Wellcome Trust [107706/Z/15/Z]; Royal Society [107706/Z/15/Z]; Leverhulme Trust [RPG-210]; National Institute of Mental Health [R01MH54610]; National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London FX T.A.M. is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 107706/Z/15/Z). While working on this manuscript T.A.M. and T.C.E. were also supported by the Leverhulme Trust (RPG-210). The Twin and Offspring Study in Sweden was supported by Grant R01MH54610 from the National Institute of Mental Health. This study presents independent research part-funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The authors have declared that they have no competing or potential conflicts of interest. NR 61 TC 0 Z9 0 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9630 EI 1469-7610 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD JAN PY 2017 VL 58 IS 1 BP 46 EP 54 DI 10.1111/jcpp.12600 PG 9 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA EI4ZX UT WOS:000392504100008 PM 27426633 ER PT J AU Kaniski, F Enewold, L Thomas, A Malik, S Stevens, JL Harlan, LC AF Kaniski, Filip Enewold, Lindsey Thomas, Anish Malik, Shakuntala Stevens, Jennifer L. Harlan, Linda C. TI Temporal patterns of care and outcomes of non-small cell lung cancer patients in the United States diagnosed in 1996, 2005, and 2010 SO LUNG CANCER LA English DT Article DE Lung cancer; Treatment; Surgery; Radiation; Chemotherapy; Targeted therapy survival ID ELDERLY-PATIENTS; INSURANCE STATUS; SURGERY; CHEMOTHERAPY; CARBOPLATIN; DISPARITIES; POPULATION; CISPLATIN; TRENDS; NSCLC AB Introduction: Lung cancer remains a common and deadly cancer in the United States. This study evaluated factors associated with stage-specific cancer therapy and survival focusing on temporal trends and sociodemographic disparities. Methods: A random sample (n=3,318) of non-small cell lung cancer (NSCLC) patients diagnosed in 1996, 2005 and 2010, and reported to the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) program was analyzed. Logistic regression was utilized to identify factors associated with receipt of surgery among stage patients and chemotherapy among stage IIIB/IV patients. Cox proportional hazard regression was utilized to assess factors associated with all-cause mortality, stratified by stage. Results: Surgery among stage I/II patients decreased non-significantly overtime (1996: 78.8%; 2010: 68.5%; p = 0.18), whereas receipt of chemotherapy among stage IIIB/IV patients increased significantly overtime (1996: 36.1%; 2010: 51.2%; p < 0.01). Receipt of surgery (70-79 and >= 80 vs. <70: Odds Ratio(OR):0.31; 95% Confidence Interval (CI): 0.16-0.63 and OR:0.04; 95% CI: 0.02-0.10, respectively) and chemotherapy (>= 80 vs. <70: OR: 0.26; 95% CI:0.15-0.45) was less likely among older patients. Median survival improved non-significantly among stage patients from 51 to 64 months (p = 0.75) and significantly among patients from 4 to 5 months (p < 0.01). Conclusion: Treatment disparities were observed in both stage groups, notably among older patients. Among stage patients, survival did not change significantly possibly due to stable surgery utilization. Among stage IIIB/IV patients, although the use of chemotherapy increased and survival improved, the one-month increase in median survival highlights the need for addition research. Published by Elsevier Ireland Ltd. C1 [Kaniski, Filip; Enewold, Lindsey; Harlan, Linda C.] NCI, Div Canc Control & Populat Sci, Healthcare Delivery Res Program, Bethesda, MD 20892 USA. [Thomas, Anish] NCI, Ctr Canc Res, Thorac & Gastrointestinal Oncol Branch, Bethesda, MD 20892 USA. [Malik, Shakuntala] NCI, Div Canc Treatment & Diag, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Stevens, Jennifer L.] Informat Management Serv Inc, Rockville, MD 20852 USA. EM lindsey.enewold@nih.gov FU National Cancer Institute [HHSN261201000024C, HHSN261201000025C, HHSN261201000-032C, HHSN261201000027C, HHSN261201000026C, HHSN261-201000140C, HHSN261201000037C, HHSN261201000033C, HH-SN261201000034C, HHSN261201000035C, HHSN261201000-029C, HHSN261201000031C, HHSN261201000028C, HHSN261201000030C] FX This work was supported by National Cancer Institute contracts: HHSN261201000024C; HHSN261201000025C, HHSN261201000-032C, HHSN261201000027C, HHSN261201000026C, HHSN261-201000140C, HHSN261201000037C, HHSN261201000033C, HH-SN261201000034C, HHSN261201000035C, HHSN261201000-029C, HHSN261201000031C, HHSN261201000028C, and HHSN261201000030C. The authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors. This article was produced by employees of the US government as part of their official duties and, as such, is in the public domain in the United States of America. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. NR 31 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 EI 1872-8332 J9 LUNG CANCER JI Lung Cancer PD JAN PY 2017 VL 103 BP 66 EP 74 DI 10.1016/j.lungcan.2016.11.020 PG 9 WC Oncology; Respiratory System SC Oncology; Respiratory System GA EI7KP UT WOS:000392676900011 PM 28024699 ER PT J AU Lotta, LA Gulati, P Day, FR Payne, F Ongen, H van de Bunt, M Gaulton, KJ Eicher, JD Sharp, SJ Luan, JA Rolfe, ED Stewart, ID Wheeler, E Willems, SM Adams, C Yaghootkar, H Forouhi, NG Khaw, KT Johnson, AD Semple, RK Frayling, T Perry, JRB Dermitzakis, E McCarthy, MI Barroso, I Wareham, NJ Savage, DB Langenberg, C O'Rahilly, S Scott, RA AF Lotta, Luca A. Gulati, Pawan Day, Felix R. Payne, Felicity Ongen, Halit van de Bunt, Martijn Gaulton, Kyle J. Eicher, John D. Sharp, Stephen J. Luan, Jian'an Rolfe, Emanuella De Lucia Stewart, Isobel D. Wheeler, Eleanor Willems, Sara M. Adams, Claire Yaghootkar, Hanieh Forouhi, Nita G. Khaw, Kay-Tee Johnson, Andrew D. Semple, Robert K. Frayling, Timothy Perry, John R. B. Dermitzakis, Emmanouil McCarthy, Mark I. Barroso, Ines Wareham, Nicholas J. Savage, David B. Langenberg, Claudia O'Rahilly, Stephen Scott, Robert A. CA EPIC-InterAct Consortium Cambridge FPLD1 Consortium TI Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance SO NATURE GENETICS LA English DT Article ID CORONARY-ARTERY-DISEASE; BODY-FAT DISTRIBUTION; METABOLIC SYNDROME; DIABETES-MELLITUS; CARDIOMETABOLIC DISEASE; MYOCARDIAL-INFARCTION; TISSUE EXPANDABILITY; LIPOPROTEIN-LIPASE; ABDOMINAL OBESITY; WIDE ASSOCIATION AB Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin levels adjusted for BMI, lower HDL cholesterol levels and higher triglyceride levels) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms in common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognized molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link. C1 [Lotta, Luca A.; Day, Felix R.; Sharp, Stephen J.; Luan, Jian'an; Rolfe, Emanuella De Lucia; Stewart, Isobel D.; Willems, Sara M.; Forouhi, Nita G.; Perry, John R. B.; Wareham, Nicholas J.; Langenberg, Claudia; Scott, Robert A.] Univ Cambridge, MRC Epidemiol Unit, Cambridge, England. [Gulati, Pawan; Adams, Claire; Semple, Robert K.; Barroso, Ines; Savage, David B.; O'Rahilly, Stephen] Univ Cambridge, Metabol Res Labs, Cambridge, England. [Payne, Felicity; Wheeler, Eleanor; Barroso, Ines] Wellcome Trust Sanger Inst, Hinxton, England. [Ongen, Halit; Dermitzakis, Emmanouil] Univ Geneva, Sch Med, Dept Genet Med & Dev, Geneva, Switzerland. [van de Bunt, Martijn; McCarthy, Mark I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [van de Bunt, Martijn; McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Gaulton, Kyle J.] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. [Eicher, John D.; Johnson, Andrew D.] NHLBI, Populat Sci Branch, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [Yaghootkar, Hanieh; Frayling, Timothy] Univ Exeter, Sch Med, Royal Devon & Exeter Hosp, Genet Complex Traits,Inst Biomed & Clin Sci, Exeter, Devon, England. [Khaw, Kay-Tee] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. EM ib1@sanger.ac.uk; nick.wareham@mrc-epid.cam.ac.uk; dbs23@medschl.cam.ac.uk; claudia.langenberg@mrc-epid.cam.ac.uk; so104@medschl.cam.ac.uk; robert.scott@mrc-epid.cam.ac.uk RI Salamanca-Fernandez, Elena/R-5943-2016; Grioni, Sara/K-5320-2016; OI Salamanca-Fernandez, Elena/0000-0002-1795-2206; Grioni, Sara/0000-0002-5891-8426; Forouhi, Nita/0000-0002-5041-248X; Sacerdote, Carlotta/0000-0002-8008-5096; Payne, Felicity/0000-0003-4228-581X; Wheeler, Eleanor/0000-0002-8616-6444 FU UK Medical Research Council [MC_UU_12015/1, MC_PC_13046, MC_PC_13048, MR/L00002/1]; MRC Metabolic Diseases Unit [MC_UU_12012/5]; Cambridge NIHR Biomedical Research Centre; EU/EFPIA Innovative Medicines Initiative (EMIF grant ) [115372]; EU FP6 program [LSHM_CT_2006_037197]; Novo Nordisk; Wellcome Trust [107064, 090532, 098381, WT098051, 095515/Z/11/Z, 100574/Z/12/Z]; University of Oxford FX This study was funded by the UK Medical Research Council through grants MC_UU_12015/1, MC_PC_13046, MC_PC_13048 and MR/L00002/1. This work was supported by the MRC Metabolic Diseases Unit (MC_UU_12012/5) and the Cambridge NIHR Biomedical Research Centre and EU/EFPIA Innovative Medicines Initiative Joint Undertaking (EMIF grant 115372). Funding for the InterAct project was provided by the EU FP6 program (grant LSHM_CT_2006_037197). This work was funded, in part, through an EFSD Rising Star award to R.A.S. supported by Novo Nordisk. D.B.S. is supported by Wellcome Trust grant 107064. M.I.M. is a Wellcome Trust Senior Investigator and is supported by the following grants from the Wellcome Trust: 090532 and 098381. M.v.d.B. is supported by a Novo Nordisk postdoctoral fellowship run in partnership with the University of Oxford. I.B. is supported by Wellcome Trust grant WT098051. S.O'R. acknowledges funding from the Wellcome Trust (Wellcome Trust Senior Investigator Award 095515/Z/11/Z and Wellcome Trust Strategic Award 100574/Z/12/Z). NR 77 TC 3 Z9 3 U1 2 U2 2 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 JAN PY 2017 VL 49 IS 1 BP 17 EP 26 DI 10.1038/ng.3714 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA EG3WY UT WOS:000390976600007 PM 27841877 ER PT J AU Marshall, CR Marshall, CR Howrigan, DP Merico, D Thiruvahindrapuram, B Wu, WT Greer, DS Antaki, D Shetty, A Holmans, PA Pinto, D Gujral, M Brandler, WM Malhotra, D Wang, ZZ Fajarado, KVF Maile, MS Ripke, S Agartz, I Albus, M Alexander, M Amin, F Atkins, J Bacanu, SA Belliveau, RA Bergen, SE Ertalan, M Bevilacqua, E Bigdeli, TB Black, DW Bruggeman, R Buccola, NG Buckner, RL Bulik-Sullivan, B Byerley, W Cahn, W Cai, GQ Cairns, MJ Campion, D Cantor, RM Carr, VJ Carrera, N Catts, SV Chambert, KD Cheng, W Cloninger, CR Cohen, D Cormican, P Craddock, N Crespo-Facorro, B Crowley, JJ Curtis, D Davidson, M Davis, KL Degenhardt, F Del Favero, J DeLisi, LE Dikeos, D Dinan, T Djurovic, S Donohoe, G Drapeau, E Duan, J Dudbridge, F Eichhammer, P Eriksson, J Escott-Price, V Essioux, L Fanous, AH Farh, KH Farrell, MS Frank, J Franke, L Freedman, R Freimer, NB Friedman, JI Forstner, AJ Fromer, M Genovese, G Georgieva, L Gershon, ES Giegling, I Giusti-Rodriguez, P Godard, S Goldstein, JI Gratten, J de Haan, L Hamshere, ML Hansen, M Hansen, T Haroutunian, V Hartmann, AM Henskens, FA Herms, S Hirschhorn, JN Hoffinann, P Hofman, A Huang, H Ikeda, M Joa, I Kahler, AK Kahn, RS Kalaydjieva, L Karjalainen, J Kavanagh, D Keller, MC Kelly, BJ Kennedy, JL Kim, Y Knowles, JA Konte, B Laurent, C Lee, P Lee, SH Legge, SE Lerer, B Levy, DL Liang, KY Lieberman, J Lonnqvist, J Loughland, CM Magnusson, PKE Maher, BS Maier, W Mallet, J Mattheisen, M Mattingsdal, M McCarley, RW McDonald, C McIntosh, AM Meier, S Meijer, CJ Melle, I Mesholam-Gately, RI Metspalu, A Michie, PT Milani, L Milanova, V Mokrab, Y Morris, DW Muller-Myhsok, B Murphy, KC Murray, RM Myin-Germeys, I Nenadic, I Nertney, DA Nestadt, G Nicodemus, KK Nisenbaum, L Nordin, A O'Callaghan, E O'Dushlaine, C Oh, SY Olincy, A Olsen, L O'Neill, FA Van Os, J Pantelis, C Papadimitriou, GN Parkhomenko, E Pato, MT Paunio, T Perkins, DO Pers, TH Pietilainen, O Pimm, J Pocklington, AJ Powell, J Price, A Pulver, AE Purcell, SM Quested, D Rasmussen, HB Reichenberg, A Reimers, MA Richards, AL Roffman, JL Roussos, P Ruderfer, DM Salomaa, V Sanders, AR Savitz, A Schall, U Schulze, TG Schwab, SG Scolnick, EM Scott, RJ Seidman, LJ Shi, JX Silverman, JM Smoller, JW Soderman, E Spencer, CCA Stahl, EA Strengman, E Strohmaier, J Stroup, TS Suvisaari, J Svrakic, DM Szatkiewicz, JP Thirumalai, S Tooney, PA Veijola, J Visscher, PM Waddington, J Walsh, D Webb, BT Weiser, M Wildenauer, DB Williams, NM Williams, S Witt, SH Wolen, AR Wormley, BK Wray, NR Wu, JQ Zai, CC Adolfsson, R Andreassen, OA Blackwood, DHR Bramon, E Buxbaum, JD Cichon, S Collier, DA Corvin, A Daly, MJ Darvasi, A Domenici, E Esko, T Gejman, PV Gill, M Gurling, H Hultman, CM Iwata, N Jablensky, AV Jonsson, EG Kendler, KS Kirov, G Knight, J Levinson, DF Li, QQS McCarroll, SA McQuillin, A Moran, JL Mowry, BJ Nothen, MM Ophoff, RA Owen, MJ Palotie, A Pato, CN Petryshen, TL Posthuma, D Rietschel, M Riley, BP Rujescu, D Sklar, P St Clair, D Walters, JTR Werge, T Siillivan, PF O'Donovan, MC Scherer, SW Neale, BM Sebat, J AF Marshall, Christian R. Marshall, Christian R. Howrigan, Daniel P. Merico, Daniele Thiruvahindrapuram, Bhooma Wu, Wenting Greer, Douglas S. Antaki, Danny Shetty, Aniket Holmans, Peter A. Pinto, Dalila Gujral, Madhusudan Brandler, William M. Malhotra, Dheeraj Wang, Zhouzhi Fajarado, Karin V. Fuentes Maile, Michelle S. Ripke, Stephan Agartz, Ingrid Albus, Margot Alexander, Madeline Amin, Farooq Atkins, Joshua Bacanu, Silviu A. Belliveau, Richard A., Jr. Bergen, Sarah E. Ertalan, Marcelo Bevilacqua, Elizabeth Bigdeli, Tim B. Black, Donald W. Bruggeman, Richard Buccola, Nancy G. Buckner, Randy L. Bulik-Sullivan, Brendan Byerley, William Cahn, Wiepke Cai, Guiqing Cairns, Murray J. Campion, Dominique Cantor, Rita M. Carr, Vaughan J. Carrera, Noa Catts, Stanley V. Chambert, Kimberley D. Cheng, Wei Cloninger, C. Robert Cohen, David Cormican, Paul Craddock, Nick Crespo-Facorro, Benedicto Crowley, James J. Curtis, David Davidson, Michael Davis, Kenneth L. Degenhardt, Franziska Del Favero, Jurgen DeLisi, Lynn E. Dikeos, Dimitris Dinan, Timothy Djurovic, Srdjan Donohoe, Gary Drapeau, Elodie Duan, Jubao Dudbridge, Frank Eichhammer, Peter Eriksson, Johan Escott-Price, Valentina Essioux, Laurent Fanous, Ayman H. Farh, Kai-How Farrell, Martilias S. Frank, Josef Franke, Lude Freedman, Robert Freimer, Nelson B. Friedman, Joseph I. Forstner, Andreas J. Fromer, Menachem Genovese, Giulio Georgieva, Lyudmila Gershon, Elliot S. Giegling, Ina Giusti-Rodriguez, Paola Godard, Stephanie Goldstein, Jacqueline I. Gratten, Jacob de Haan, Lieuwe Hamshere, Marian L. Hansen, Mark Hansen, Thomas Haroutunian, Vahram Hartmann, Annette M. Henskens, Frans A. Herms, Stefan Hirschhorn, Joel N. Hoffinann, Per Hofman, Andrea Huang, Hailiang Ikeda, Masashi Joa, Inge Kahler, Anna K. Kahn, Rene S. Kalaydjieva, Luba Karjalainen, Juha Kavanagh, David Keller, Matthew C. Kelly, Brian J. Kennedy, James L. Kim, Yunjung Knowles, James A. Konte, Bettina Laurent, Claudine Lee, Phil Lee, S. Hong Legge, Sophie E. Lerer, Bernard Levy, Deborah L. Liang, Kung-Yee Lieberman, Jeffrey Lonnqvist, Jouko Loughland, Carmel M. Magnusson, Patrik K. E. Maher, Brion S. Maier, Wolfgang Mallet, Jacques Mattheisen, Manuel Mattingsdal, Morten McCarley, Robert W. McDonald, Colm McIntosh, Andrew M. Meier, Sandra Meijer, Carin J. Melle, Ingrid Mesholam-Gately, Raquelle I. Metspalu, Andres Michie, Patricia T. Milani, Lili Milanova, Vihra Mokrab, Younes Morris, Derek W. Muller-Myhsok, Bertram Murphy, Kieran C. Murray, Robin M. Myin-Germeys, Inez Nenadic, Igor Nertney, Deborah A. Nestadt, Gerald Nicodemus, Kristin K. Nisenbaum, Laura Nordin, Annelie O'Callaghan, Eadbhard O'Dushlaine, Colm Oh, Sang-Yun Olincy, Ann Olsen, Line O'Neill, F. Anthony Van Os, Jim Pantelis, Christos Papadimitriou, George N. Parkhomenko, Elena Pato, Michele T. Paunio, Tiina Perkins, Diana O. Pers, Tune H. Pietilainen, Olli Pimm, Jonathan Pocklington, Andrew J. Powell, John Price, Alkes Pulver, Ann E. Purcell, Shaun M. Quested, Digby Rasmussen, Henrik B. Reichenberg, Abraham Reimers, Mark A. Richards, Alexander L. Roffman, Joshua L. Roussos, Panos Ruderfer, Douglas M. Salomaa, Veikko Sanders, Alan R. Savitz, Adam Schall, Ulrich Schulze, Thomas G. Schwab, Sibylle G. Scolnick, Edward M. Scott, Rodney J. Seidman, Larry J. Shi, Jianxin Silverman, Jeremy M. Smoller, Jordan W. Soderman, Erik Spencer, Chris C. A. Stahl, Eli A. Strengman, Eric Strohmaier, Jana Stroup, T. Scott Suvisaari, Jaana Svrakic, Dragan M. Szatkiewicz, Jin P. Thirumalai, Srinivas Tooney, Paul A. Veijola, Juha Visscher, Peter M. Waddington, John Walsh, Dermot Webb, Bradley T. Weiser, Mark Wildenauer, Dieter B. Williams, Nigel M. Williams, Stephanie Witt, Stephanie H. Wolen, Aaron R. Wormley, Brandon K. Wray, Naomi R. Wu, Jing Qin Zai, Clement C. Adolfsson, Rolf Andreassen, Ole A. Blackwood, Douglas H. R. Bramon, Elvira Buxbaum, Joseph D. Cichon, Sven Collier, David A. Corvin, Aiden Daly, Mark J. Darvasi, Ariel Domenici, Enrico Esko, Tonu Gejman, Pablo V. Gill, Michael Gurling, Hugh Hultman, Christina M. Iwata, Nakao Jablensky, Assen V. Jonsson, Erik G. Kendler, Kenneth S. Kirov, George Knight, Jo Levinson, Douglas F. Li, Qingqin S. McCarroll, Steven A. McQuillin, Andrew Moran, Jennifer L. Mowry, Bryan J. Nothen, Markus M. Ophoff, Roel A. Owen, Michael J. Palotie, Aarno Pato, Carlos N. Petryshen, Tracey L. Posthuma, Danielle Rietschel, Marcella Riley, Brien P. Rujescu, Dan Sklar, Pamela St Clair, David Walters, James T. R. Werge, Thomas Siillivan, Patrick F. O'Donovan, Michael C. Scherer, Stephen W. Neale, Benjamin M. Sebat, Jonathan CA CNV Schizophrenia Working Grp Psychosis Endophenotypes TI Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects SO NATURE GENETICS LA English DT Article ID GENE; 16P11.2; AUTISM; RISK; CNVS; REARRANGEMENTS; DUPLICATIONS; PHENOTYPES; DISORDERS; MUTATIONS AB Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 x 10(-15)), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 x 10(-6)). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 x 10(-11)) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 x 10(-5)). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination. C1 [Marshall, Christian R.; Merico, Daniele; Thiruvahindrapuram, Bhooma; Wang, Zhouzhi; Scherer, Stephen W.] Hosp Sick Children, Ctr Appl Genom, Toronto, ON, Canada. [Marshall, Christian R.; Merico, Daniele; Thiruvahindrapuram, Bhooma; Wang, Zhouzhi; Scherer, Stephen W.] Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON, Canada. [Howrigan, Daniel P.; Ripke, Stephan; Bulik-Sullivan, Brendan; Farh, Kai-How; Fromer, Menachem; Goldstein, Jacqueline I.; Huang, Hailiang; Lee, Phil; Daly, Mark J.; Palotie, Aarno; Neale, Benjamin M.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Howrigan, Daniel P.; Ripke, Stephan; Belliveau, Richard A., Jr.; Bergen, Sarah E.; Bevilacqua, Elizabeth; Bulik-Sullivan, Brendan; Chambert, Kimberley D.; Fromer, Menachem; Genovese, Giulio; O'Dushlaine, Colm; Scolnick, Edward M.; Smoller, Jordan W.; Wolen, Aaron R.; Daly, Mark J.; McCarroll, Steven A.; Moran, Jennifer L.; Palotie, Aarno; Petryshen, Tracey L.; Neale, Benjamin M.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Wu, Wenting; Greer, Douglas S.; Antaki, Danny; Shetty, Aniket; Gujral, Madhusudan; Brandler, William M.; Malhotra, Dheeraj; Fajarado, Karin V. Fuentes; Maile, Michelle S.; Palotie, Aarno; Sebat, Jonathan] Univ Calif San Diego, Beyster Ctr Psychiat Genom, La Jolla, CA 92093 USA. [Wu, Wenting; Greer, Douglas S.; Antaki, Danny; Shetty, Aniket; Gujral, Madhusudan; Brandler, William M.; Malhotra, Dheeraj; Fajarado, Karin V. Fuentes; Maile, Michelle S.; Palotie, Aarno; Sebat, Jonathan] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Holmans, Peter A.; Carrera, Noa; Craddock, Nick; Escott-Price, Valentina; Georgieva, Lyudmila; Hamshere, Marian L.; Kavanagh, David; Legge, Sophie E.; Pocklington, Andrew J.; Richards, Alexander L.; Ruderfer, Douglas M.; Williams, Nigel M.; Kirov, George; Owen, Michael J.; Palotie, Aarno; Walters, James T. R.; O'Donovan, Michael C.] Cardiff Univ, Inst Psychol Med & Clin Neurosci, Sch Med, MRC Ctr Neuropsychiat Genet & Genom, Cardiff, S Glam, Wales. [Holmans, Peter A.; Craddock, Nick; Richards, Alexander L.; Owen, Michael J.; O'Donovan, Michael C.] Cardiff Univ, Natl Ctr Mental Hlth, Cardiff, S Glam, Wales. [Pinto, Dalila; Cai, Guiqing; Davis, Kenneth L.; Drapeau, Elodie; Friedman, Joseph I.; Haroutunian, Vahram; Parkhomenko, Elena; Reichenberg, Abraham; Silverman, Jeremy M.; Buxbaum, Joseph D.; Palotie, Aarno] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY USA. [Pinto, Dalila] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, Dept Genet & Genom Sci, Seaver Autism Ctr, New York, NY USA. [Malhotra, Dheeraj; Domenici, Enrico] F Hoffmann La Roche Ltd, Neurosci Discovery & Translat Area, Pharma Res & Early Dev, Basel, Switzerland. [Agartz, Ingrid; Djurovic, Srdjan; Mattingsdal, Morten; Melle, Ingrid; Andreassen, Ole A.; Jonsson, Erik G.] Univ Oslo, Inst Clin Med, KG Jebsen Ctr Psychosis Res, NORMENT, Oslo, Norway. [Agartz, Ingrid] Diakonhjemmet Hosp, Dept Psychiat, Oslo, Norway. [Agartz, Ingrid; Soderman, Erik; Jonsson, Erik G.] Karolinska Inst, Psychiat Sect, Dept Clin Neurosci, Stockholm, Sweden. [Albus, Margot] State Mental Hosp, Haar, Germany. [Alexander, Madeline; Laurent, Claudine; Levinson, Douglas F.] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Amin, Farooq] Emory Univ, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. [Amin, Farooq] Atlanta Vet Affairs Med Ctr, Dept Psychiat & Behav Sci, Atlanta, GA USA. [Atkins, Joshua; Cairns, Murray J.; Scott, Rodney J.; Tooney, Paul A.; Wu, Jing Qin] Univ Newcastle, Sch Biomed Sci & Pharm, Callaghan, NSW, Australia. [Atkins, Joshua] Hunter Med Res Inst, New Lambton, NSW, Australia. [Bacanu, Silviu A.; Bigdeli, Tim B.; Reimers, Mark A.; Webb, Bradley T.; Wolen, Aaron R.; Wormley, Brandon K.; Kendler, Kenneth S.; Palotie, Aarno; Riley, Brien P.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Psychiat, Richmond, VA USA. [Bergen, Sarah E.; Kahler, Anna K.; Magnusson, Patrik K. E.; Hultman, Christina M.; Siillivan, Patrick F.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Ertalan, Marcelo; Hansen, Thomas; Olsen, Line; Rasmussen, Henrik B.; Werge, Thomas] Mental Hlth Serv Copenhagen, Inst Biol Psychiat, Mental Hlth Ctr Set, Copenhagen, Denmark. [Ertalan, Marcelo; Hansen, Thomas; Mattheisen, Manuel; Olsen, Line; Rasmussen, Henrik B.; Palotie, Aarno; Werge, Thomas] iPSYCH, Lundbeck Fdn Initiat Integrat Psychiat Res, Aaarhus, Denmark. [Black, Donald W.] Univ Iowa, Carver Coll Med, Dept Psychiat, Iowa City, IA USA. [Bruggeman, Richard] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. [Buccola, Nancy G.] Louisiana State Univ, Hlth Sci Ctr, Sch Nursing, New Orleans, LA USA. [Buckner, Randy L.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Buckner, Randy L.; Roffman, Joshua L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Buckner, Randy L.; Roffman, Joshua L.; Petryshen, Tracey L.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr, Boston, MA 02114 USA. [Byerley, William] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Cahn, Wiepke; Kahn, Rene S.; Strengman, Eric; Ophoff, Roel A.] Univ Med Ctr Utrecht, Dept Psychiat, Rudolf Magnus Inst Neurosci, Utrecht, Netherlands. [Cai, Guiqing; Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Dept Human Genet, New York, NY 10029 USA. [Cairns, Murray J.; Carr, Vaughan J.; Catts, Stanley V.; Henskens, Frans A.; Lee, Phil; Loughland, Carmel M.; Michie, Patricia T.; Pantelis, Christos; Schall, Ulrich; Scott, Rodney J.; Tooney, Paul A.; Wu, Jing Qin; Jablensky, Assen V.; Palotie, Aarno] Schizophrenia Res Inst, Sydney, NSW, Australia. [Cairns, Murray J.; Henskens, Frans A.; Kelly, Brian J.; Loughland, Carmel M.; Schall, Ulrich; Tooney, Paul A.] Univ Newcastle, Prior Ctr Translat Neurosci & Mental Hlth, Newcastle, NSW, Australia. [Campion, Dominique; O'Neill, F. Anthony] Ctr Hosp Rouvray, Rouen, France. [Campion, Dominique; O'Neill, F. Anthony] INSERM U1079, Fac Med, Rouen, France. [Cantor, Rita M.; Ophoff, Roel A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Carr, Vaughan J.] Univ New S Wales, Sch Psychiat, Sydney, NSW, Australia. [Catts, Stanley V.] Univ Queensland, Royal Brisbane & Womens Hosp, Dept Psychiat, Brisbane, Qld, Australia. [Cheng, Wei] Univ N Carolina, Dept Comp Sci, Chapel Hill, NC USA. [Cloninger, C. Robert; Svrakic, Dragan M.; Palotie, Aarno] Washington Univ, Dept Psychiat, St Louis, MO USA. [Cohen, David] Pierre & Marie Curie Fac Med, AP HP, Dept Child & Adolescent Psychiat, Paris, France. [Cohen, David] Inst Intelligent Syst & Robot, Paris, France. [Cormican, Paul; Donohoe, Gary; Morris, Derek W.; Corvin, Aiden; Gill, Michael] Trinity Coll Dublin, Dept Psychiat, Neuropsychiat Genet Res Grp, Dublin, Ireland. [Crespo-Facorro, Benedicto] Univ Cantabria, Univ Hosp Marques de Valdecilla, Inst Formac & Invest Marques de Valdecilla, Santander, Spain. [Crespo-Facorro, Benedicto] Ctr Invest Biomed Red Salud Mental, Madrid, Spain. [Crowley, James J.; Farrell, Martilias S.; Giusti-Rodriguez, Paola; Kim, Yunjung; Szatkiewicz, Jin P.; Williams, Stephanie; Palotie, Aarno; Siillivan, Patrick F.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Curtis, David] Queen Mary Univ London, Dept Psychol Med, London, England. [Curtis, David; Pimm, Jonathan; Gurling, Hugh; McQuillin, Andrew] UCL, Div Psychiat, Mol Psychiat Lab, London, England. [Davidson, Michael; Weiser, Mark] Sheba Med Ctr, Dept Psychiat, Tel Hashomer, Israel. [Degenhardt, Franziska; Forstner, Andreas J.; Herms, Stefan; Hoffinann, Per; Hofman, Andrea; Cichon, Sven; Nothen, Markus M.; Palotie, Aarno] Univ Bonn, Inst Human Genet, Bonn, Germany. [Degenhardt, Franziska; Forstner, Andreas J.; Herms, Stefan; Hoffinann, Per; Hofman, Andrea; Cichon, Sven; Nothen, Markus M.; Palotie, Aarno] Life & Brain Ctr, Dept Genom, Bonn, Germany. [Del Favero, Jurgen] Univ Antwerp, VIB Dept Mol Genet, Applied Mol Genom Unit, Antwerp, Belgium. [DeLisi, Lynn E.; McCarley, Robert W.] Virginia Boston Hlth Care Syst, Brockton, MA USA. [DeLisi, Lynn E.; Levy, Deborah L.; McCarley, Robert W.; Mesholam-Gately, Raquelle I.; Seidman, Larry J.; Palotie, Aarno; Petryshen, Tracey L.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Dikeos, Dimitris; Papadimitriou, George N.] Univ Athens, Sch Med, Dept Psychiat 1, Athens, Greece. [Dinan, Timothy] Univ Coll Cork, Dept Psychiat, Cork, Ireland. [Djurovic, Srdjan] Oslo Univ Hosp, Dept Med Genet, Oslo, Norway. [Donohoe, Gary; Morris, Derek W.] Natl Univ Ireland Galway, Sch Psychol, Cognit Genet & Therapy Grp, Galway, Ireland. [Donohoe, Gary; Morris, Derek W.] Natl Univ Ireland Galway, Discipline Biochem, Galway, Ireland. [Duan, Jubao; Sanders, Alan R.; Gejman, Pablo V.] NorthShore Univ HealthSyst, Dept Psychiat & Behav Sci, Evanston, IL USA. [Duan, Jubao; Gershon, Elliot S.; Sanders, Alan R.; Gejman, Pablo V.; Palotie, Aarno] Univ Chicago, Dept Psychiat & Behav Neurosci, Chicago, IL 60637 USA. [Dudbridge, Frank] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London, England. [Eichhammer, Peter] Univ Regensburg, Dept Psychiat, Regensburg, Germany. [Eriksson, Johan] Folkhalsan Res Ctr, Helsinki, Finland. [Eriksson, Johan] Biomedicum Helsinki, Helsinki, Finland. [Eriksson, Johan] Biomedicum Helsinki, Helsinki, Finland. [Eriksson, Johan; Salomaa, Veikko] Natl Inst Hlth & Welf, Helsinki, Finland. [Eriksson, Johan] Univ Helsinki, Helsinki Univ Cent Hosp, Dept Gen Practice, Helsinki, Finland. [Essioux, Laurent] F Hoffmann La Roche & Cie AG, Pharma Res & Early Dev, Translat Technol & Bioinformat, Basel, Switzerland. [Fanous, Ayman H.] Washington Virginia Med Ctr, Mental Hlth Serv Line, Washington, DC USA. [Fanous, Ayman H.] Georgetown Univ, Dept Psychiat, Washington, DC USA. [Fanous, Ayman H.] Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA. [Fanous, Ayman H.; Knowles, James A.; Pato, Michele T.; Pato, Carlos N.] Univ So Calif, Keck Sch Med, Dept Psychiat, Los Angeles, CA 90033 USA. [Frank, Josef; Meier, Sandra; Schulze, Thomas G.; Strohmaier, Jana; Witt, Stephanie H.; Rietschel, Marcella] Heidelberg Univ, Dept Genet Epidemiol Psychiat, Cent Inst Mental Hlth, Med Fac Mannheim, Heidelberg, Germany. [Franke, Lude; Karjalainen, Juha] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Freedman, Robert; Olincy, Ann] Univ Colorado Denver, Dept Psychiat, Aurora, CO USA. [Freimer, Nelson B.; Ophoff, Roel A.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Ctr Neurobehav Genet, Los Angeles, CA 90024 USA. [Fromer, Menachem; Purcell, Shaun M.; Roussos, Panos; Ruderfer, Douglas M.; Stahl, Eli A.; Sklar, Pamela] Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY 10029 USA. [Fromer, Menachem; Lee, Phil; Smoller, Jordan W.; Palotie, Aarno; Neale, Benjamin M.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA USA. [Gershon, Elliot S.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Giegling, Ina; Hartmann, Annette M.; Konte, Bettina; Rujescu, Dan] Univ Halle, Dept Psychiat, Halle, Germany. [Giegling, Ina; Rujescu, Dan] Univ Munich, Dept Psychiat, Munich, Germany. [Godard, Stephanie] Hop La Pitie Salpetriere, Inst Myol, INSERM, Dept Human & Mol Genet, Paris, France. [Goldstein, Jacqueline I.; Hirschhorn, Joel N.; Huang, Hailiang; Pers, Tune H.; Price, Alkes; Stahl, Eli A.; Daly, Mark J.; Esko, Tonu; Palotie, Aarno; Neale, Benjamin M.] Broad Inst MIT & Harvard, Med & Populat Genet Program, Cambridge, MA USA. [Gratten, Jacob; Lee, S. Hong; Visscher, Peter M.; Wray, Naomi R.; Mowry, Bryan J.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [de Haan, Lieuwe; Meijer, Carin J.] Univ Amsterdam, Acad Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Hansen, Mark] Illumina Inc, La Jolla, CA USA. [Haroutunian, Vahram] JJ Peters Virginia Med Ctr, Bronx, NY USA. [Haroutunian, Vahram; Reichenberg, Abraham; Wolen, Aaron R.; Buxbaum, Joseph D.; Palotie, Aarno; Sklar, Pamela] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Henskens, Frans A.] Univ Newcastle, Sch Elect Engn & Comp Sci, Newcastle, NSW, Australia. [Herms, Stefan; Hoffinann, Per; Cichon, Sven; Palotie, Aarno] Univ Basel, Dept Biomed, Div Med Genet, Basel, Switzerland. [Hirschhorn, Joel N.; Esko, Tonu; McCarroll, Steven A.] Harvard Med Sch, Dept Genet, Boston, MA USA. [Hirschhorn, Joel N.; Pers, Tune H.; Esko, Tonu] Boston Childrens Hosp, Div Endocrinol, Boston, MA USA. [Hirschhorn, Joel N.; Pers, Tune H.; Esko, Tonu; Palotie, Aarno] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA. [Ikeda, Masashi; Iwata, Nakao] Fujita Hlth Univ, Dept Psychiat, Sch Med, Toyoake, Aichi, Japan. [Joa, Inge] Stavanger Univ Hosp, Dept Psychiat, Reg Ctr Clin Res Psychosis, Stavanger, Norway. [Kalaydjieva, Luba] Univ Western Australia, Med Res Ctr, Perth, WA, Australia. [Kalaydjieva, Luba; Jablensky, Assen V.] Univ Western Australia, Perkins Inst Med Res, Perth, WA, Australia. [Keller, Matthew C.] Univ Colorado, Dept Psychol, Boulder, CO USA. [Kennedy, James L.; Zai, Clement C.; Knight, Jo] Campbell Family Mental Hlth Res Inst, Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Kennedy, James L.; Zai, Clement C.; Knight, Jo] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Kennedy, James L.; Knight, Jo] Univ Toronto, Inst Med Sci, Toronto, ON, Canada. [Knowles, James A.; Pato, Michele T.; Palotie, Aarno; Pato, Carlos N.] Univ So Calif, Zilkha Neurogenet Inst, Keck Sch Med, Los Angeles, CA USA. [Laurent, Claudine] Pierre & Marie Curie Fac Med, Dept Child & Adolescent Psychiat, Paris, France. [Lerer, Bernard] Hadassah Hebrew Univ Med Ctr, Dept Psychiat, Jerusalem, Israel. [Levy, Deborah L.] McLean Hosp, Psychol Res Lab, Belmont, MA USA. [Liang, Kung-Yee] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Lieberman, Jeffrey; Stroup, T. Scott] Columbia Univ, Dept Psychiat, New York, NY USA. [Lonnqvist, Jouko; Suvisaari, Jaana] Natl Inst Hlth & Welf, Dept Mental Hlth, Helsinki, Finland. [Lonnqvist, Jouko; Suvisaari, Jaana] Natl Inst Hlth & Welf, Subst Abuse Serv, Helsinki, Finland. [Maher, Brion S.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Maier, Wolfgang] Univ Bonn, Dept Psychiat, Bonn, Germany. [Mallet, Jacques] Hop La Pitie Salpetriere, CNRS, Lab Genet Mol Neurotransmiss & Proc Neurodegenera, Paris, France. [Mattheisen, Manuel] Aarhus Univ, Dept Biomed, Aarhus, Denmark. [Mattheisen, Manuel] Aarhus Univ, ISEQ, Ctr Integrat Sequencing, Aarhus, Denmark. [Mattheisen, Manuel] Univ Bonn, Dept Genom Math, Bonn, Germany. [Mattingsdal, Morten] Sorlandet Hosp, Res Unit, Kristiansand, Norway. [McDonald, Colm] Natl Univ Ireland Galway, Dept Psychiat, Galway, Ireland. [McIntosh, Andrew M.; Blackwood, Douglas H. R.] Univ Edinburgh, Div Psychiat, Edinburgh, Midlothian, Scotland. [McIntosh, Andrew M.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Melle, Ingrid; Andreassen, Ole A.] Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway. [Mesholam-Gately, Raquelle I.; Seidman, Larry J.] Beth Israel Deaconess Med Ctr, Massachusetts Mental Hlth, Ctr Publ Psychiat Div, Boston, MA 02215 USA. [Metspalu, Andres; Milani, Lili; Esko, Tonu; Palotie, Aarno] Univ Tartu, Estonian Genome Ctr, Tartu, Estonia. [Michie, Patricia T.] Univ Newcastle, Sch Psychol, Newcastle, NSW, Australia. [Milanova, Vihra] Med Univ, First Psychiat Clin, Sofia, Bulgaria. [Mokrab, Younes; Collier, David A.] Eli Lilly & Co Ltd, Windlesham, Surrey, England. [Muller-Myhsok, Bertram] Max Planck Inst Psychiat, Munich, Germany. [Muller-Myhsok, Bertram] Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England. [Muller-Myhsok, Bertram] Cluster Syst Neurol SyNergy, Munich, Germany. [Murphy, Kieran C.] Royal Coll Surgeons Ireland, Dept Psychiat, Dublin, Ireland. [Murray, Robin M.; Powell, John] Kings Coll London, Inst Psychiat, London, England. [Myin-Germeys, Inez; Van Os, Jim] Maastricht Univ Med Ctr, South Limburg Mental Hlth Res & Teaching Network, EURON, Maastricht, Netherlands. [Nenadic, Igor] Jena Univ Hosp, Dept Psychiat & Psychotherapy, Jena, Germany. [Nertney, Deborah A.; Mowry, Bryan J.] Univ Queensland, Queensland Ctr Mental Hlth Res, Brisbane, Qld, Australia. [Nestadt, Gerald; Pulver, Ann E.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD USA. [Nicodemus, Kristin K.] Trinity Coll Dublin, Dept Psychiat, Dublin, Ireland. [Nisenbaum, Laura] Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN USA. [Nordin, Annelie; Adolfsson, Rolf] Umea Univ, Dept Clin Sci, Psychiat, Umea, Sweden. [O'Callaghan, Eadbhard] DETECT Early Intervent Serv Psychosis, Blackrock, Ireland. [Oh, Sang-Yun] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA. Queens Univ Belfast, Inst Clin Sci, Ctr Publ Hlth, Belfast, Antrim, North Ireland. [Van Os, Jim] Kings Coll London, Inst Psychiat, London, England. [Pantelis, Christos] Univ Melbourne, Melbourne Neuropsychiat Ctr, Melbourne, Vic, Australia. [Pantelis, Christos] Melbourne Hlth, Melbourne, Vic, Australia. [Paunio, Tiina; Pietilainen, Olli] Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland. [Perkins, Diana O.; Siillivan, Patrick F.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Pers, Tune H.] Tech Univ Denmark, Dept Syst Biol, Ctr Biol Sequence Anal, Kongens, Denmark. [Pietilainen, Olli] Univ Helsinki, Inst Mol Med Finland, FIMM, Helsinki, Finland. [Price, Alkes] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Quested, Digby] Univ Oxford, Dept Psychiat, Oxford, England. [Roussos, Panos; Sklar, Pamela] Icahn Sch Med Mt Sinai, Inst Multiscale Biol, New York, NY USA. [Savitz, Adam; Li, Qingqin S.] Janssen Res & Dev, Neurosci Therapeut Area, Raritan, NJ USA. [Schulze, Thomas G.] Univ Gottingen, Dept Psychiat & Psychotherapy, Gottingen, Germany. [Schwab, Sibylle G.] Univ Erlangen Nurnberg, Psychiat & Psychotherapy Clin, Erlangen, Germany. [Scott, Rodney J.] Hunter New England Hlth Serv, Newcastle, NSW, Australia. [Shi, Jianxin] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Silverman, Jeremy M.] Bronx Vet Affairs Med Ctr, Res & Dev, New York, NY USA. [Spencer, Chris C. A.] Wellcome Trust Ctr Human Genet, Oxford, England. [Strengman, Eric] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [Thirumalai, Srinivas] Berkshire Healthcare NHS Fdn Trust, Bracknell, Berks, England. [Veijola, Juha] Univ Oulu, Dept Psychiat, Oulu, Finland. [Veijola, Juha] Univ Hosp Oulu, Dept Psychiat, Oulu, Finland. [Waddington, John] Royal Coll Surgeons Ireland, Mol & Cellular Therapeut, Dublin, Ireland. [Walsh, Dermot] Hlth Res Board, Dublin, Ireland. [Wildenauer, Dieter B.; Jablensky, Assen V.] Univ Western Australia, Sch Psychiat & Clin Neurosci, Perth, WA, Australia. [Bramon, Elvira] UCL, Div Psychiat, London, England. [Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY USA. [Cichon, Sven] Res Ctr Juelich, Inst Neurosci & Med INM 1, Julich, Germany. [Collier, David A.] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London, England. [Darvasi, Ariel] Hebrew Univ Jerusalem, Dept Genet, Jerusalem, Israel. [Domenici, Enrico] Univ Trento, Ctr Integrat Biol, Trento, Italy. [Jablensky, Assen V.] Univ Western Australia, Sch Psychiat & Clin Neurosci, Ctr Clin Res Neuropsychiat, Perth, WA, Australia. [Petryshen, Tracey L.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Posthuma, Danielle] Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Funct Genom, Neurosci Campus Amsterdam, Amsterdam, Netherlands. [Posthuma, Danielle] Vrije Univ Amsterdam, Med Ctr Amsterdam, Dept Complex Trait Genet, Neurosci Campus Amsterdam, Amsterdam, Netherlands. [Posthuma, Danielle] Erasmus Univ, Dept Child & Adolescent Psychiat, Med Ctr, Rotterdam, Netherlands. [St Clair, David] Univ Aberdeen, Inst Med Sci, Aberdeen, Scotland. [Palotie, Aarno; Werge, Thomas] Univ Copenhagen, Dept Clin Med, Copenhagen, Denmark. [Scherer, Stephen W.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Scherer, Stephen W.] Univ Toronto, McLaughlin Ctr, Toronto, ON, Canada. [Sebat, Jonathan] Univ Calif San Diego, Dept Cellular & Mol Med, San Diego, CA 92103 USA. RI Scherer, Stephen /B-3785-2013; Pantelis, Christos/H-7722-2014; Powell, John/G-4412-2011; OI Scherer, Stephen /0000-0002-8326-1999; Visscher, Peter/0000-0002-2143-8760; Dinan, Timothy/0000-0002-2316-7220; McIntosh, Andrew/0000-0002-0198-4588; Knight, Joanne/0000-0002-7148-1660; Pantelis, Christos/0000-0002-9565-0238; Powell, John/0000-0001-6124-439X; Jonsson, Erik/0000-0001-8368-6332; Webb, Bradley/0000-0002-0576-5366; Domenici, Enrico/0000-0001-7436-6919; murray, robin/0000-0003-0829-0519; Adolfsson, Rolf/0000-0001-9785-8473 FU US National Institute of Mental Health (NIMH) [U01 MH094421] FX Core funding for the Psychiatric Genomics Consortium is from the US National Institute of Mental Health (NIMH, U01 MH094421). We thank T. Lehner, A. Addington and G. Senthil (NIMH). The work of the contributing groups was supported by numerous grants from governmental and charitable bodies as well as philanthropic donation. Details are provided in the Supplementary Note. NR 36 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 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD JAN PY 2017 VL 49 IS 1 BP 27 EP 35 DI 10.1038/ng.3725 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA EG3WY UT WOS:000390976600008 ER PT J AU Chu, AY Deng, X Fisher, VA Drong, A Zhang, Y Feitosa, MF Liu, CT Weeks, O Choh, AC Duan, Q Dyer, TD Eicher, JD Guo, XQ Heard-Costa, NL Kacprowski, T Kent, JW Lange, LA Liu, XG Lohman, K Lu, LY Mahajan, A O'Connell, JR Parihar, A Peralta, JM Smith, AV Zhang, Y Homuth, G Kissebah, AH Kullberg, J Laqua, R Launer, LJ Nauck, M Olivier, M Peyser, PA Terry, JG Wojczynski, MK Yao, J Bielak, LF Blangero, J Borecki, IB Bowden, DW Carr, JJ Czerwinski, SA Ding, JZ Friedrich, N Gudnason, V Harris, TB Ingelsson, E Johnson, AD Kardia, SLR Langefeld, CD Lind, L Liu, YM Mitchell, BD Morris, AP Mosley, TH Rotter, JI Shuldiner, AR Towne, B Volzke, H Wallaschofski, H Wilson, JG Allison, M Lindgren, CM Goessling, W Cupples, LA Steinhauser, ML Fox, CS AF Chu, Audrey Y. Deng, Xuan Fisher, Virginia A. Drong, Alexander Zhang, Yang Feitosa, Mary F. Liu, Ching-Ti Weeks, Olivia Choh, Audrey C. Duan, Qing Dyer, Thomas D. Eicher, John D. Guo, Xiuqing Heard-Costa, Nancy L. Kacprowski, Tim Kent, Jack W., Jr. Lange, Leslie A. Liu, Xinggang Lohman, Kurt Lu, Lingyi Mahajan, Anubha O'Connell, Jeffrey R. Parihar, Ankita Peralta, Juan M. Smith, Albert V. Zhang, Yi Homuth, Georg Kissebah, Ahmed H. Kullberg, Joel Laqua, Rene Launer, Lenore J. Nauck, Matthias Olivier, Michael Peyser, Patricia A. Terry, James G. Wojczynski, Mary K. Yao, Jie Bielak, Lawrence F. Blangero, John Borecki, Ingrid B. Bowden, Donald W. Carr, John Jeffrey Czerwinski, Stefan A. Ding, Jingzhong Friedrich, Nele Gudnason, Vilmunder Harris, Tamara B. Ingelsson, Erik Johnson, Andrew D. Kardia, Sharon L. R. Langefeld, Carl D. Lind, Lars Liu, Yongmei Mitchell, Braxton D. Morris, Andrew P. Mosley, Thomas H., Jr. Rotter, Jerome I. Shuldiner, Alan R. Towne, Bradford Voelzke, Henry Wallaschofski, Henri Wilson, James G. Allison, Matthew Lindgren, Cecilia M. Goessling, Wolfram Cupples, L. Adrienne Steinhauser, Matthew L. Fox, Caroline S. TI Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation SO NATURE GENETICS LA English DT Article ID INCIDENT CARDIOVASCULAR-DISEASE; METABOLIC RISK-FACTORS; ALL-CAUSE MORTALITY; CARDIOMETABOLIC RISK; VISCERAL ADIPOSITY; SUBCUTANEOUS FAT; SUSCEPTIBILITY; HYPERTENSION; QUALITY; BIOLOGY AB Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopicfat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 x 10(-8); false discovery rate < 1 %). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease. C1 [Chu, Audrey Y.; Eicher, John D.; Johnson, Andrew D.; Cupples, L. Adrienne; Fox, Caroline S.] NHLBIs Framingham Heart Study, Framingham, MA USA. [Chu, Audrey Y.] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Chu, Audrey Y.; Zhang, Yang; Weeks, Olivia; Goessling, Wolfram; Steinhauser, Matthew L.; Fox, Caroline S.] Harvard Med Sch, Boston, MA 02115 USA. [Deng, Xuan; Fisher, Virginia A.; Liu, Ching-Ti; Heard-Costa, Nancy L.; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Drong, Alexander; Mahajan, Anubha; Morris, Andrew P.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Zhang, Yang; Steinhauser, Matthew L.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Zhang, Yang; Weeks, Olivia; Goessling, Wolfram; Steinhauser, Matthew L.] Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 USA. [Feitosa, Mary F.; Wojczynski, Mary K.; Borecki, Ingrid B.] Washington Univ, Dept Genet, St Louis, MO 63110 USA. [Choh, Audrey C.; Towne, Bradford] Wright State Univ, Boonshoft Sch Med, Dept Populat & Publ Hlth Sci, Div Epidemiol & Biostat, Dayton, OH 45435 USA. [Duan, Qing; Lange, Leslie A.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Dyer, Thomas D.; Peralta, Juan M.; Blangero, John] Univ Texas Hlth Sci Ctr San Antonio, South Texas Diabet & Obes Inst, Brownsville, TX USA. [Dyer, Thomas D.; Peralta, Juan M.; Blangero, John] Univ Texas Rio Grande Valley, Brownsville, TX USA. [Guo, Xiuqing; Yao, Jie; Rotter, Jerome I.] UCLA Med Ctr, Dept Pediat, Inst Translat Genom & Populat Sci, LABioMed Harbor, Torrance, CA USA. [Kacprowski, Tim; Homuth, Georg] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Kacprowski, Tim; Nauck, Matthias; Friedrich, Nele; Voelzke, Henry] German Ctr Cardiovasc Res DZHK, Greifswald, Germany. [Kent, Jack W., Jr.; Olivier, Michael] Texas Biomed Res Inst, Dept Genet, TOPS Nutr & Obes Res Ctr, San Antonio, TX USA. [Liu, Xinggang; O'Connell, Jeffrey R.; Parihar, Ankita; Mitchell, Braxton D.; Shuldiner, Alan R.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Lohman, Kurt; Ding, Jingzhong; Liu, Yongmei] Wake Forest Sch Med, Winston Salem, NC USA. [Lohman, Kurt; Lu, Lingyi; Langefeld, Carl D.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Smith, Albert V.; Gudnason, Vilmunder] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmunder] Univ Iceland, Fac Med, Reykjavik, Iceland. [Zhang, Yi; Kissebah, Ahmed H.; Olivier, Michael] Med Coll Wisconsin, Biotechnol & Bioengn Ctr, TOPS Obes & Metab Res Ctr, Dept Psychol, Milwaukee, WI 53226 USA. [Kullberg, Joel; Lind, Lars] Uppsala Univ, Sect Radiol, Dept Surg Sci, Uppsala, Sweden. [Laqua, Rene] Univ Hosp Berne, Dept Neuroradiol, Bern, Switzerland. [Launer, Lenore J.; Harris, Tamara B.] NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Nauck, Matthias; Friedrich, Nele; Wallaschofski, Henri] Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany. [Peyser, Patricia A.; Bielak, Lawrence F.; Kardia, Sharon L. R.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Terry, James G.; Carr, John Jeffrey] Vanderbilt Univ, Med Ctr, Dept Cardiovasc Med, Dept Radiol & Radiol Sci, Nashville, TN USA. [Terry, James G.; Carr, John Jeffrey] Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Nashville, TN USA. [Bowden, Donald W.] Wake Forest Univ Hlth Sci, Ctr Genom & Personalized Med Res, Winston Salem, NC USA. [Bowden, Donald W.] Wake Forest Univ, Sch Med, Ctr Diabet Res, Dept Biochem, Winston Salem, NC 27109 USA. [Bowden, Donald W.] Wake Forest Univ, Sch Med, Ctr Human Genom, Winston Salem, NC 27109 USA. [Czerwinski, Stefan A.] Univ Texas Hlth Sci Ctr UTHealth, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Brownsville Campus, Brownsville, TX USA. [Ding, Jingzhong] Wake Forest Sch Med, Gerontol & Geriatr Med, Winston Salem, NC USA. [Ingelsson, Erik] Uppsala Univ, Mol Epidemiol & Sci Life Lab, Dept Med Sci, Uppsala, Sweden. [Ingelsson, Erik] Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA. [Liu, Yongmei] Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Mitchell, Braxton D.] Baltimore Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD USA. [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England. [Mosley, Thomas H., Jr.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Voelzke, Henry] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Voelzke, Henry] German Ctr Diabet Res DZD, Greifswald, Germany. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Allison, Matthew] Univ Calif San Diego, Sch Med, Dept Family Med & Publ Hlth, Div Prevent Med, San Diego, CA 92103 USA. [Lindgren, Cecilia M.] Univ Oxford, Big Data Inst, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford, England. [Goessling, Wolfram] Harvard Stem Cell Inst, Cambridge, MA USA. [Goessling, Wolfram] Harvard Med Sch, Brigham & Womens Hosp, Div Gastroenterol, Boston, MA USA. [Goessling, Wolfram] Dana Farber Canc Inst, Boston, MA 02115 USA. [Goessling, Wolfram; Steinhauser, Matthew L.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Steinhauser, Matthew L.] Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, 75 Francis St, Boston, MA 02115 USA. [Chu, Audrey Y.; Fox, Caroline S.] Merck Res Labs, Boston, MA 02115 USA. EM audrey.chu@nih.gov; msteinhauser@partners.org; foxca@nhlbi.nih.gov RI Feitosa, Mary/K-8044-2012 OI Allison, Matthew/0000-0003-0777-8272; Carr, John/0000-0002-4398-8237; Mitchell, Braxton/0000-0003-4920-4744; Feitosa, Mary/0000-0002-0933-2410 FU NHLBI NIH HHS [R01 HL117078]; NIDDK NIH HHS [R01 DK106236] NR 27 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 JAN PY 2017 VL 49 IS 1 BP 125 EP 130 DI 10.1038/ng.3738 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA EG3WY UT WOS:000390976600018 PM 27918534 ER PT J AU Markland, AD Jelovsek, JE Whitehead, WE Newman, DK Andy, UU Dyer, K Harm-Ernandes, I Cichowski, S McCormick, J Rardin, C Sutkin, G Shaffer, A Meikle, S AF Markland, A. D. Jelovsek, J. E. Whitehead, W. E. Newman, D. K. Andy, U. U. Dyer, K. Harm-Ernandes, I. Cichowski, S. McCormick, J. Rardin, C. Sutkin, G. Shaffer, A. Meikle, S. CA Pelvic Floor Disorders Network TI Improving biofeedback for the treatment of fecal incontinence in women: implementation of a standardized multi-site manometric biofeedback protocol SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Article DE anal sphincter exercises; anorectal manometry; factorial design; fecal incontinence; manometry-assisted biofeedback; pelvic floor disorders; randomized placebo-controlled trial; treatment fidelity; urge resistance training ID OBJECTIVE STRUCTURED ASSESSMENT; RANDOMIZED CONTROLLED-TRIAL; ANAL INCONTINENCE; TECHNICAL SKILL; SURGICAL RESIDENTS; NATIONAL INSTITUTE; EXERCISES; TRAINEES; WORKSHOP; DESIGN AB BackgroundStandardized training and clinical protocols using biofeedback for the treatment of fecal incontinence (FI) are important for clinical care. Our primary aims were to develop, implement, and evaluate adherence to a standardized protocol for manometric biofeedback to treat FI. MethodsIn a Pelvic Floor Disorders Network (PFDN) trial, participants were enrolled from eight PFDN clinical centers across the United States. A team of clinical and equipment experts developed biofeedback software on a novel tablet computer platform for conducting standardized anorectal manometry with separate manometric biofeedback protocols for improving anorectal muscle strength, sensation, and urge resistance. The training protocol also included education on bowel function, anal sphincter exercises, and bowel diary monitoring. Study interventionists completed online training prior to attending a centralized, standardized certification course. For the certification, expert trainers assessed the ability of the interventionists to perform the protocol components for a paid volunteer who acted as a standardized patient. Postcertification, the trainers audited interventionists during trial implementation to improve protocol adherence. Key ResultsTwenty-four interventionists attended the in-person training and certification, including 46% advanced practice registered nurses (11/24), 50% (12/24) physical therapists, and 4% physician assistants (1/24). Trainers performed audio audits for 88% (21/24), representing 84 audited visits. All certified interventionists met or exceeded the prespecified 80% pass rate for the audit process, with an average passing rate of 93%. Conclusions & InferencesA biofeedback protocol can be successfully imparted to experienced pelvic floor health care providers from various disciplines. Our process promoted high adherence to a standard protocol and is applicable to many clinical settings. C1 [Markland, A. D.; McCormick, J.] Univ Alabama Birmingham, Dept Med, Div Gerontol Geriatr & Palliat Care, 700 19th St South, Birmingham, AL 35294 USA. [Markland, A. D.; McCormick, J.] Birmingham Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Birmingham, AL USA. [Jelovsek, J. E.] Cleveland Clin, Obstet Gynecol & Womens Hlth Inst, Cleveland, OH 44106 USA. [Whitehead, W. E.] Univ North Carolina Chapel Hill, Div Gastroenterol & Hepatol, Dept Med, Chapel Hill, NC USA. [Whitehead, W. E.] Univ North Carolina Chapel Hill, Div Urogynecol, Dept Obstet & Gynecol, Chapel Hill, NC USA. [Newman, D. K.] Univ Penn, Dept Surg, Perelman Sch Med, Div Urol, Philadelphia, PA 19104 USA. [Andy, U. U.] Univ Penn, Dept Obstet & Gynecol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Dyer, K.] Kaiser Permanente, Dept Obstet & Gynecol, San Diego, CA USA. [Harm-Ernandes, I.] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Cichowski, S.] Univ New Mexico, Hlth Sci Ctr, Dept Obstet & Gynecol, Albuquerque, NM 87131 USA. [Cichowski, S.] Univ New Mexico, Hlth Sci Ctr, Dept Surg, Albuquerque, NM 87131 USA. [Rardin, C.] Brown Univ, Alpert Med Sch, Dept Obstet & Gynecol, Providence, RI 02912 USA. [Sutkin, G.] Univ Pittsburgh, Med Ctr, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Shaffer, A.] RTI Int, Res Triangle Pk, NC USA. [Meikle, S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. EM amarkland@uabmc.edu OI Markland, Alayne/0000-0002-6567-6744 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U10 HD054215, U10 HD041261, U10 HD069013, U10 HD054214, U10 HD041267, U10 HD069025, U10 HD069010, U10 HD069006, U01 HD069031]; National Institutes of Health Office of Research on Women's Health FX Supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U10 HD054215, U10 HD041261, U10 HD069013, U10 HD054214, U10 HD041267, U10 HD069025, U10 HD069010, U10 HD069006, U01 HD069031) and the National Institutes of Health Office of Research on Women's Health. NR 19 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1350-1925 EI 1365-2982 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD JAN PY 2017 VL 29 IS 1 AR UNSP e12906 DI 10.1111/nmo.12906 PG 7 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA EI4YM UT WOS:000392500000009 ER PT J AU Sapra, KJ Chaurasia, AK Hutcheon, JA Ahrens, KA AF Sapra, Katherine J. Chaurasia, Ashok K. Hutcheon, Jennifer A. Ahrens, Katherine A. TI Reconstructing a Pregnancy Cohort to Examine Potential Selection Bias in Studies on Racial Disparities in Preterm Delivery SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE preterm birth; racial disparities; loss to follow-up; selection bias; collider bias; induced termination ID NEW-YORK-CITY; LEFT TRUNCATION; UNITED-STATES; ABORTION SERVICES; BERKSONS BIAS; MISSING DATA; OUTCOMES; BIRTH; TIME AB BackgroundEpidemiologic studies examining preconception risk factors on perinatal outcomes are typically restricted to livebirths. By including only non-terminated pregnancies, estimates for the underlying pregnancy cohort may be subject to selection bias. We examined if potential selection bias due to induced termination by maternal race may result in different estimates of the non-Hispanic black - non-Hispanic white risk ratio (RR) for preterm delivery (PTD) among a reconstructed pregnancy cohort (pseudo-pregnancy cohort'). MethodsUsing New York City registries of 1.6 million livebirths, spontaneous terminations, and induced terminations among non-Hispanic black and non-Hispanic white women (2000-12), we multiply imputed PTD (<37 weeks) and early PTD (<32 weeks) outcomes for induced terminations based on maternal race, age, parity, marital status, nativity, and medical care payer to construct the pseudo-pregnancy cohort. ResultsAmong non-Hispanic black and non-Hispanic white women, 55% and 19% of pregnancies ended in induced termination and 13% and 8% resulted in PTD, respectively. Although several factors were associated with both PTD and induced termination, PTD RRs in the birth (RR 1.64, 95% confidence interval (CI) 1.62, 1.66) and pseudo-pregnancy (RR 1.63, 95% CI 1.56, 1.71) cohorts were similar. However, early PTD RR was somewhat larger in the birth (RR 2.80, 95% CI 2.71, 2.89) than pseudo-pregnancy (RR 2.47, 95% CI 2.23, 2.73) cohort. ConclusionsUsing birth certificate data - thereby excluding induced terminations - to estimate the PTD racial disparity did not produce biased estimates. Our data suggest observed PTD disparities likely are not artefacts of selection bias due to induced termination. C1 [Sapra, Katherine J.] Weill Cornell Med Coll, Dept Obstet & Gynecol, New York, NY 10065 USA. [Chaurasia, Ashok K.] Univ Waterloo, Sch Publ Hlth & Hlth Syst, Waterloo, ON, Canada. [Hutcheon, Jennifer A.] Univ British Columbia, Dept Obstet & Gynaecol, Vancouver, BC, Canada. [Ahrens, Katherine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Rockville, MD USA. EM kjs2004@med.cornell.edu FU Intramural NIH HHS [Z99 HD999999] NR 33 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 EI 1365-3016 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD JAN PY 2017 VL 31 IS 1 BP 55 EP 63 DI 10.1111/ppe.12322 PG 9 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA EI5BX UT WOS:000392509800009 PM 27794171 ER PT J AU Mao, CY Yang, J Wang, H Zhang, SY Yang, ZH Luo, HY Li, F Shi, MM Liu, YT Zhuang, ZP Du, P Wang, YH Shi, CH Xu, YM AF Mao, Cheng-yuan Yang, Jing Wang, Hui Zhang, Shu-yu Yang, Zhi-hua Luo, Hai-yang Li, Fang Shi, Mengmeng Liu, Yu-tao Zhuang, Zheng-ping Du, Pan Wang, Yao-he Shi, Chang-he Xu, Yu-ming TI SMPD1 variants in Chinese Han patients with sporadic Parkinson's disease SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Parkinson's disease; SMPD1; Variant; Chinese population ID ENZYME GENE SMPD1; ACID SPHINGOMYELINASE; P.L302P MUTATION; SIGNAL PEPTIDE; RISK-FACTOR AB Introduction: A founder mutation, p.L302P, in sphingomyelin phosphodiesterase 1, acid lysosomal (SMPD1), causing Niemann-Pick disease, a recessive lysosomal storage disorder, was reported to be associated with increased risk of Parkinson's disease (PD) in Ashkenazi Jewish population. Several other studies about the association between SMPD1 variants and PD were performed afterward in other populations. However, the results on the role of SMPD1 mutations for PD have been conflicting. This study aimed to investigate the role of mutations in SMPD1 in Chinese PD patients. Methods: We sequenced all the exons of this gene in 512 Chinese Han cases with sporadic Parkinson's disease and 495 matched healthy control subjects. Results: We identified Leu-Ala (Val) repeat variants and six known single nucleotide variants (p.A36V, p.D212D, p.P332R, p.G508R, p.P533L, p.T544T) in SMPD1 in both patients and normal controls. Case control analysis showed the association between Leu-Ala (Val) repeat variants in SMPD1 and Chinese Han patients with PD (chi(2) = 8.771, p = 0.012), and the allele with less than seven LeuAla (Val) repeats may increase the risk of PD (p = 0.010). Conclusion: We identified association between Leu-Ala (Val) repeat variants in SMPD1 and Chinese Han patients with sporadic Parkinson's disease. Our results provide further support for the role of lysosomal pathways in PD development. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Mao, Cheng-yuan; Yang, Jing; Wang, Hui; Zhang, Shu-yu; Yang, Zhi-hua; Luo, Hai-yang; Li, Fang; Shi, Mengmeng; Liu, Yu-tao; Shi, Chang-he; Xu, Yu-ming] Zhengzhou Univ, Affiliated Hosp 1, Dept Neurol, 1 Jian She East Rd, Zhengzhou 450000, Henan, Peoples R China. [Mao, Cheng-yuan; Yang, Jing; Wang, Hui; Zhang, Shu-yu; Yang, Zhi-hua; Luo, Hai-yang; Li, Fang; Shi, Mengmeng; Shi, Chang-he] Zhengzhou Univ, Affiliated Hosp 1, Inst Clin Med, Zhengzhou 450000, Henan, Peoples R China. [Zhuang, Zheng-ping] NINDS, Surg Neurol Branch, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Du, Pan; Wang, Yao-he] Zhengzhou Univ, Affiliated Hosp 1, Int Joint Res Lab Cell & Gene Therapy Henan Prov, 1 Jian She East Rd, Zhengzhou 450000, Henan, Peoples R China. EM shichanghe@gmail.com; xuyuming@zzu.edu.cn FU National Natural Science Foundation of China [81530037, 81471158, U1404311, 81600946]; Medical Science and Technique Foundation of Henan Province [201503038]; Key Scientific Research Projects of Universities in Henan Province [16A320052] FX This work was supported by grant 81530037 and 81471158 from the National Natural Science Foundation of China (to Dr. Yu-ming Xu), grant U1404311 from the National Natural Science Foundation of China (to Dr. Chang-he Shi), grant 81600946 from the National Natural Science Foundation of China (to Dr. Jing Yang), grant 201503038 from the Medical Science and Technique Foundation of Henan Province (to Dr. Yu-tao Liu), grant 16A320052 from the Key Scientific Research Projects of Universities in Henan Province (to Dr. Yu-tao Liu). We would like to thank the patients and normal controls for their participation in this study. NR 12 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 EI 1873-5126 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD JAN PY 2017 VL 34 BP 59 EP 61 DI 10.1016/j.parkreldis.2016.10.014 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA EI7NN UT WOS:000392685000011 PM 27814975 ER PT J AU Luine, V Gomez, J Beck, K Bowman, R AF Luine, Victoria Gomez, Juan Beck, Kevin Bowman, Rachel TI Sex differences in chronic stress effects on cognition in rodents SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE Cognition; Resilience; Sex differences; Spatial memory; Stress ID CHRONIC RESTRAINT STRESS; SPATIAL MEMORY PERFORMANCE; FEMALE RATS; OBJECT RECOGNITION; MAZE PERFORMANCE; HIPPOCAMPUS; ANXIETY; IMPAIRMENTS; MODULATION; MONOAMINES AB Chronic stress causes deleterious changes in physiological function in systems ranging from neural cells in culture to laboratory rodents, sub-human primates and humans. It is notable, however, that the vast majority of research in this area has been conducted in males. In this review, we provide information about chronic stress effects on cognition in female rodents and contrast it with responses in male rodents. In general, females show cognitive resilience to chronic stressors which impair male cognitive function using spatial tasks including the radial arm maze, radial arm water maze, Morris water maze, Y-maze and object placement. Moreover, stress often enhances female performance in some of these cognitive tasks. Memory in females is not affected by stress in non spatial memory tasks like recognition memory and temporal order recognition meihory while males show impaired memory following stress. We discuss possible bases for these sex-dependent differences including the use of different strategies by the sexes to solve cognitive tasks. Whether the sex differences result from changes in non-mnemonic factors is also considered. Sex-dependent differences in alcohol and drug influences on stress responses are also described. Finally, the role of neurally derived estradiol in driving sex differences and providing resilience to stress in females is shown. The importance of determining the nature and extent of sex differences in stress responses is that such differences may provide vital information for understanding why some stress related diseases have different incidence rates between the sexes and for developing novel therapeutic treatments. (C) 2016 Elsevier Inc. All rights reserved. C1 [Luine, Victoria] CUNY Hunter Coll, Dept Psychol, 695 Pk Ave, New York, NY 10065 USA. [Gomez, Juan] NIDA, Biobehav Imaging & Mol Neuropsychopharmacol, Baltimore, MD 21224 USA. [Beck, Kevin] VA NJ Hlth Care Syst, Neurobehav Res Lab, E Orange, NJ 07018 USA. [Beck, Kevin] Rutgers New Jrersey Med Sch, Dept Pharmacol Physiol & Neurosci, Newark, NJ 07103 USA. [Bowman, Rachel] Sacred Heart Univ, Dept Psychol, Fairfield, CT 06825 USA. EM vluine@hunter.cuny.edu FU NIH [GM60654, GM60665, MD007599]; City University of New York; PSC-CUNY FX Experimental work discussed in this review was supported by NIH grants GM60654 (VL), GM60665 (VL) and MD007599 (HC), the City University of New York and PSC-CUNY. The authors thank the many undergraduate and graduate students who participated in the research. NR 54 TC 0 Z9 0 U1 8 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD JAN PY 2017 VL 152 SI SI BP 13 EP 19 DI 10.1016/j.pbb.2016.08.005 PG 7 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA EI7MU UT WOS:000392683000003 PM 27566290 ER PT J AU Priddy, BM Carmack, SA Thomas, LC Vendruscolo, JCM Koob, GF Vendruscolo, LF AF Priddy, Brittany M. Carmack, Stephanie A. Thomas, Lisa C. Vendruscolo, Janaina C. M. Koob, George F. Vendruscolo, Leandro F. TI Sex, strain, and estrous cycle influences on alcohol drinking in rats SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE Alcohol use disorders; Alcoholism; Gender differences; Genetic differences; Ethanol; Drug addiction ID CONDITIONED TASTE-AVERSION; ANXIETY-RELATED BEHAVIORS; SPRAGUE-DAWLEY RATS; ADULT WISTAR RATS; ETHANOL DRINKING; FEMALE RATS; VOLUNTARY CONSUMPTION; GENDER-DIFFERENCES; DAILY PATTERNS; ADOLESCENT AB Although women appear to be more vulnerable to alcohol-induced pathophysiology than men, the neurobiological basis for sex differences is largely unknown, partially because most studies on alcohol drinking are conducted in male subjects only. The present study examined sex differences in alcohol consumption in two rat strains, Long Evans and Wistar, using multiple behavioral paradigms. The effects of the estrous cycle on alcohol consumption were monitored throughout the study. The results indicated that females drank more alcohol than males when given either continuous or intermittent access to alcohol (vs. Water) in their home cages (voluntary drinking). Under operant conditions, no sex or strain differences were found in drinking prior to development of alcohol dependence. However, upon dependence induction by chronic, intermittent alcohol vapor exposure, Wistar rats of both sexes substantially escalated their alcohol intake compared with their nondependent drinking levels, whereas Long Evans rats only exhibited a moderate escalation of drinking. Under these conditions, the estrous cycle had no effect on alcohol drinking in any strain and drinking model. Thus, strain, sex, and drinking conditions interact to modulate nondependent and dependent alcohol drinking. The present results emphasize the importance of including sex and strain as biological variables in exploring individual differences in alcohol drinking and dependence. Published by Elsevier Inc. C1 [Priddy, Brittany M.; Carmack, Stephanie A.; Thomas, Lisa C.; Vendruscolo, Janaina C. M.; Koob, George F.; Vendruscolo, Leandro F.] NIDA, Neurobiol Addict Sect, NIH, Baltimore, MD USA. EM leandro.vendruscolo@nih.gov FU National Institute on Drug Abuse, Intramural Research Program FX The National Institute on Drug Abuse, Intramural Research Program supported this work. The authors thank Michael Arends for editorial assistance. NR 39 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 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD JAN PY 2017 VL 152 SI SI BP 61 EP 67 DI 10.1016/j.pbb.2016.08.001 PG 7 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA EI7MU UT WOS:000392683000009 PM 27498303 ER PT J AU Rothe, J Frey, O Madangopal, R Rickus, J Hierlemann, A AF Rothe, Joerg Frey, Olivier Madangopal, Rajtarun Rickus, Jenna Hierlemann, Andreas TI Robust Functionalization of Large Microelectrode Arrays by Using Pulsed Potentiostatic Deposition SO SENSORS LA English DT Article DE electrodeposition; microelectrode array; pulse potential waveform; voltage pulses; pulsed potentiostatic deposition; complementary metal-oxide-semiconductor (CMOS); platinum; gold; poly(phenylenediamine) PPD; poly(ethylenedioxythiophene) PEDOT ID GLUCOSE-OXIDASE; POLY(3,4-ETHYLENEDIOXYTHIOPHENE) FILM; ELECTRODES; BIOSENSORS; POLYMERS; PLATFORM; GOLD; ACID AB Surface modification of microelectrodes is a central step in the development of microsensors and microsensor arrays. Here, we present an electrodeposition scheme based on voltage pulses. Key features of this method are uniformity in the deposited electrode coatings, flexibility in the overall deposition area, i.e., the sizes and number of the electrodes to be coated, and precise control of the surface texture. Deposition and characterization of four different materials are demonstrated, including layers of high-surface-area platinum, gold, conducting polymer poly(ethylenedioxythiophene), also known as PEDOT, and the non-conducting polymer poly(phenylenediamine), also known as PPD. The depositions were conducted using a fully integrated complementary metal-oxide-semiconductor (CMOS) chip with an array of 1024 microelectrodes. The pulsed potentiostatic deposition scheme is particularly suitable for functionalization of individual electrodes or electrode subsets of large integrated microelectrode arrays: the required deposition waveforms are readily available in an integrated system, the same deposition parameters can be used to functionalize the surface of either single electrodes or large arrays of thousands of electrodes, and the deposition method proved to be robust and reproducible for all materials tested. C1 [Rothe, Joerg; Frey, Olivier; Hierlemann, Andreas] Swiss Fed Inst Technol, Dept Biosyst Sci & Engn, Bio Engn Lab, Mattenstr 26, CH-4058 Basel, Switzerland. [Madangopal, Rajtarun; Rickus, Jenna] Purdue Univ, Bindley Biosci Ctr, Physiol Sensing Facil, Agr & Biol Engn,Biomed Engn, W Lafayette, IN 47907 USA. [Madangopal, Rajtarun; Rickus, Jenna] Purdue Univ, Birck Nanotechnol Ctr, W Lafayette, IN 47907 USA. [Madangopal, Rajtarun] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Rothe, J (reprint author), Swiss Fed Inst Technol, Dept Biosyst Sci & Engn, Bio Engn Lab, Mattenstr 26, CH-4058 Basel, Switzerland. EM joergenmarode@gmail.com; olivier.frey@insphero.com; rajtarun.madangopal@nih.gov; rickus@purdue.edu; andreas.hierlemann@bsse.ethz.ch RI Hierlemann, Andreas/A-7046-2008 OI Hierlemann, Andreas/0000-0002-3838-2468 FU ERC [267351]; Swiss National Science Foundation [142440]; Indiana Clinical and Translational Sciences Institute; National Institutes of Health, National Center for Research Resources, Clinical and Translational Sciences Award [RR025761]; National Institutes of Health, National Institute of General Medical Sciences [8R21GM103467-03] FX We acknowledge the ZMB (Zentrum fur Mikroskopie) of the University of Basel, Switzerland, for taking the SEM pictures (Figures 3, 5b, 6 and S3). Financial support through the ERC Advanced Grant 267351 "NeuroCMOS" and individual support for Olivier Frey through the Swiss National Science Foundation (Ambizione Grant 142440) is acknowledged. Rajtarun Madangopal was supported by the Indiana Clinical and Translational Sciences Institute funded, in part by Grant # RR025761 from the National Institutes of Health, National Center for Research Resources, Clinical and Translational Sciences Award; and by the National Institutes of Health, National Institute of General Medical Sciences (Grant # 8R21GM103467-03). NR 32 TC 0 Z9 0 U1 1 U2 1 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1424-8220 J9 SENSORS-BASEL JI Sensors PD JAN PY 2017 VL 17 IS 1 AR 22 DI 10.3390/s17010022 PG 13 WC Chemistry, Analytical; Electrochemistry; Instruments & Instrumentation SC Chemistry; Electrochemistry; Instruments & Instrumentation GA EJ2DV UT WOS:000393021000022 ER PT J AU Kongnyuy, M Sidana, A George, AK Muthigi, A Iyera, A Ho, R Chelluri, R Mertan, F Frye, TP Su, D Merino, MJ Choyke, PL Wood, BJ Pinto, PA Turkbey, B AF Kongnyuy, Michael Sidana, Abhinav George, Arvin K. Muthigi, Akhil Iyera, Amogh Ho, Richard Chelluri, Raju Mertan, Francesca Frye, Thomas P. Su, Daniel Merino, Maria J. Choyke, Peter L. Wood, Bradford J. Pinto, Peter A. Turkbey, Baris TI Tumor contact with prostate capsule on magnetic resonance imaging: A potential biomarker for staging and prognosis SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article DE Biomarker; Capsule; Magnetic resonance imaging; Lymph node; Prostatic neoplasms ID FUSION-GUIDED BIOPSY; RADICAL PROSTATECTOMY; BIOCHEMICAL RECURRENCE; INTEROBSERVER AGREEMENT; SURGICAL OUTCOMES; CANCER; MRI; PROBABILITY; EXTENSION; ACCURACY AB Background: The high-spatial resolution of multiparametric magnetic resonance imaging (mpMRI) has improved the detection of clinically significant prostate cancer. mpMRI characteristics (extraprostatic extension [EPE], number of lesions, etc.) may predict final pathological findings (positive lymph node [pLN] and pathological ECE [pECE]) and biochemical recurrence (BCR). Tumor contact length (TCL) on MRI, defined as the length of a lesion in contact with the prostatic capsule, is a novel marker with promising early results. We aimed to evaluate TCL as a predictor of +pathological EPE (+pEPE), +pathological LN (+pLN), and BCR in patients undergoing robotic assisted laparoscopic radical prostatectomy. Materials and methods: A review was performed of a prospectively maintained single-institution database of men with prostate cancer who underwent prostate mpMRI followed by robotic-assisted laparoscopic radical prostatectomy without prior therapy from 2007 to 2015. TCL was measured using T2-weighted magnetic resonance images. Logistic and Cox regression analysis were used to assess associations of clinical, imaging, and histopathological variables with pEPE, pLN, and BCR. Receiver operating characteristic curves were used to characterize and compare TCL performance with Partin tables. Results: There were 87/379 (23.0%) +pEPE, 18/384 (4.7%) +pLN, and 33/371 (8.9%) BCR patients. Patients with adverse pathology/ oncologic outcomes had longer TCL compared to those without adverse outcomes (+pEPE: 19.8 vs. 10.1 mm, P < 0.0001, +pLN: 38.0 vs. 11.7 mm, P < 0.0001, and BCR: 19.2 vs. 11.2 mm, P = 0.001). On multivariate analysis, TCL remained a predictor of +pEPE (odds ratio: 1.04, P = 0.001), +pLN (odds ratio: 1.07, P < 0.0001), and BCR (hazard ratio: 1.03, P = 0.02). TCL thresholds for predicting +pEPE and +pLN were 12.5 and 19.7 mm, respectively. TCL alone was found to have good predictive ability for +pEPE and +PLN (pEPE: TCLAUC: 0.71 vs. Partin(AUC): 0.66, P = 0.21; pLN:TCLAUC: 0.77 vs. Partin(AUC): 0.88, P = 0.04). Conclusion: We demonstrate that TCL is an independent predictor of +pEPE, +pLN, and BCR. If validated, this imaging biomarker may facilitate and inform patient counseling and decision-making. Published by Elsevier Inc. C1 [Kongnyuy, Michael; Sidana, Abhinav; George, Arvin K.; Muthigi, Akhil; Iyera, Amogh; Ho, Richard; Chelluri, Raju; Frye, Thomas P.; Su, Daniel; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Mertan, Francesca; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Wood, Bradford J.] NCI, Ctr Intervent Oncol, Bethesda, MD 20892 USA. [Wood, Bradford J.] NIH, Ctr Clin, Bethesda, MD 20892 USA. EM speeditomike@gmail.com NR 27 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 1078-1439 EI 1873-2496 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD JAN PY 2017 VL 35 IS 1 AR 30.e1 DI 10.1016/j.urolone.2016.07.013 PG 8 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA EI6YW UT WOS:000392644700005 ER PT J AU Muthigi, A Sidana, A George, AK Kongnyuy, M Maruf, M Valayil, S Wood, BJ Pinto, PA AF Muthigi, Akhil Sidana, Abhinav George, Arvin K. Kongnyuy, Michael Maruf, Mahir Valayil, Subin Wood, Bradford J. Pinto, Peter A. TI Current beliefs and practice patterns among urologists regarding prostate magnetic resonance imaging and magnetic resonance-targeted biopsy SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article DE Prostate cancer; Multiparametric MRI; MR-targeted biopsy; Survey; Trends ID FUSION BIOPSY; MULTIPARAMETRIC MRI; GUIDED BIOPSY; CANCER; ROBOTICS; HISTORY; SECTION; MEN AB Introduction and objective: Multiparametric magnetic resonance imaging (MRI) and magnetic resonance (MR) -targeted biopsy have a growing role in the screening and evaluation of prostate cancer. We aim to evaluate the current knowledge, attitude, and practice patterns of urologists regarding this new technique. Methods: An anonymous online questionnaire was designed to collect information on urologists' beliefs and use of prostate multiparametric MRI and MR-targeted biopsy. The survey was sent to members of the Society of Urologic Oncology, the Endourological Society, and European Association of Urology. Multivariate logistic regression analysis was performed to determine predictors for use of prostate MRI and MR-targeted biopsy. Results: A total of 302 responses were received (Endourological Society: 175, European Association of Urology: 23, and Society of Urologic Oncology: 104). Most respondents (83.6%) believe MR-targeted biopsy to be moderately to extremely beneficial in the evaluation of prostate cancer. Overall, 85.7% of responders use prostate MRI in their practice, and 63.0% use MR-targeted biopsy. The 2 most common settings for use of MR-targeted biopsy include patients with history of prior negative biopsy result (96.3%) and monitoring patients on active surveillance (72.5%). In those who do not use MR-targeted biopsy, the principal reasons were lack of necessary infrastructure (64.1%) and prohibitive costs (48.1%). On multivariate logistic regression analysis, practice in an academic setting (1.86 [1.02-3.40], P = 0.043) and performing greater than 25 radical prostatectomies per year (2.32 [1.18-4.56], P = 0.015) remained independent predictors for using MR-targeted biopsy. Conclusions: Most respondents of our survey look favorably on use of prostate MRI and MR-targeted biopsy in clinical practice. Over time, reduction in fixed costs and easier access to equipment may lead to further dissemination of this novel and potentially transformative technology. Published by Elsevier Inc. C1 [Muthigi, Akhil; Sidana, Abhinav; George, Arvin K.; Kongnyuy, Michael; Maruf, Mahir; Valayil, Subin; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Wood, Bradford J.] NCI, Ctr Intervent Oncol, Bethesda, MD 20892 USA. [Wood, Bradford J.] NIH, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM akhilmuth@gmail.com FU Intramural Research Program of the National Institutes of Health (NIH); National Cancer Institute, Center for Cancer Research; Center for Interventional Oncology; NIH; Pfizer Inc.; Doris Duke Charitable Foundation; Alexandria Real Estate Equities, Inc.; Howard Hughes Medical Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research, and the Center for Interventional Oncology. NIH and Philips Healthcare have a cooperative research and development agreement. NIH and Philips share intellectual property in the field. This research was also made possible through the National Institutes of Health Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc., The Doris Duke Charitable Foundation, The Alexandria Real Estate Equities, Inc. and Mr. and Mrs. Joel S. Marcus, and the Howard Hughes Medical Institute, as well as other private donors. For a complete list, please visit the Foundation website at http://fnih.org/work/education-training-0/medical-research-scholars-prog ram. NR 27 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 1078-1439 EI 1873-2496 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD JAN PY 2017 VL 35 IS 1 DI 10.1016/j.urolonc.2016.08.008 PG 7 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA EI6YW UT WOS:000392644700011 ER PT J AU Cookson, MR AF Cookson, Mark R. TI RNA-binding proteins implicated in neurodegenerative diseases SO WILEY INTERDISCIPLINARY REVIEWS-RNA LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; X MENTAL-RETARDATION; MESSENGER-RNA; ALZHEIMERS-DISEASE; SPINOCEREBELLAR ATAXIA; HEXANUCLEOTIDE REPEAT; NEUROLOGICAL DISEASE; MICRORNA BIOGENESIS; PARKINSONS-DISEASE AB Gene expression is regulated at many levels, including after generation of the primary RNA transcript from DNA but before translation into protein. Such post-translational gene regulation occurs via the action of a multitude of RNA binding proteins and include varied actions from splicing to regulation of association with the translational machinery. Primary evidence that such processes might contribute to disease mechanisms in neurodegenerative disorders comes from the observation of mutations in RNA binding proteins, particularly in diseases in the amyotrophic lateral sclerosis-frontotemporal dementia spectrum and in some forms of ataxia and tremor. The bulk of evidence from recent surveys of the types of RNA species that are affected in these disorders suggests a global deregulation of control rather than a very small number of RNA species, although why some groups of neurons are sensitive to these changes is not well understood. Overall, these data suggest that neurodegeneration can be initiated by mutations in RNA binding proteins and, as a corollary, that neurons are particularly sensitive to loss of control of gene expression at the post-transcriptional level. Such observations have implications not only for understanding the nature of neurodegenerative disorders but also how we might intervene therapeutically in these diseases. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. C1 [Cookson, Mark R.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM cookson@mail.nih.gov FU Intramural Research Program of the National Institute on Aging, NIH FX This work was supported by the Intramural Research Program of the National Institute on Aging, NIH. NR 102 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1757-7004 EI 1757-7012 J9 WIRES RNA JI Wiley Interdiscip. Rev.-RNA PD JAN-FEB PY 2017 VL 8 IS 1 AR UNSP e1397 DI 10.1002/wrna.1397 PG 13 WC Cell Biology SC Cell Biology GA EI5CR UT WOS:000392512000013 ER PT J AU Grammatikakis, I Abdelmohsen, K Gorospe, M AF Grammatikakis, Ioannis Abdelmohsen, Kotb Gorospe, Myriam TI Posttranslational control of HuR function SO WILEY INTERDISCIPLINARY REVIEWS-RNA LA English DT Review ID RNA-BINDING PROTEIN; KINASE-C-DELTA; STABILIZING FACTOR HUR; MESSENGER-RNA; BREAST-CANCER; POSTTRANSCRIPTIONAL REGULATION; REPLICATIVE SENESCENCE; CENTROSOME FUNCTION; OXIDATIVE STRESS; NUCLEAR EXPORT AB The RNA-binding protein HuR (human antigen R) associates with numerous transcripts, coding and noncoding, and controls their splicing, localization, stability, and translation. Through its regulation of target transcripts, HuR has been implicated in cellular events including proliferation, senescence, differentiation, apoptosis, and the stress and immune responses. In turn, HuR influences processes such as cancer and inflammation. HuR function is primarily regulated through posttranslational modifications that alter its subcellular localization and its ability to bind target RNAs; such modifications include phosphorylation, methylation, ubiquitination, NEDDylation, and proteolytic cleavage. In this review, we describe the modifications that impact upon HuR function on gene expression programs and disease states. (C) 2016 The Authors. WIREs RNA published by Wiley Periodicals, Inc. C1 [Grammatikakis, Ioannis; Abdelmohsen, Kotb; Gorospe, Myriam] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. EM abdelmohsenk@grc.nia.nih.gov FU NIA-IRP, NIH FX This work was supported in its entirety by the NIA-IRP, NIH. NR 100 TC 2 Z9 2 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1757-7004 EI 1757-7012 J9 WIRES RNA JI Wiley Interdiscip. Rev.-RNA PD JAN-FEB PY 2017 VL 8 IS 1 AR UNSP e1372 DI 10.1002/wrna.1372 PG 11 WC Cell Biology SC Cell Biology GA EI5CR UT WOS:000392512000007 ER PT J AU Grossman, JH Crist, RM Clogston, JD AF Grossman, Jennifer H. Crist, Rachael M. Clogston, Jeffrey D. TI Early Development Challenges for Drug Products Containing Nanomaterials SO AAPS JOURNAL LA English DT Article DE drug delivery; drug development; nanomedicine; preclinical; targeted delivery ID FIELD-FLOW FRACTIONATION; GOLD NANOPARTICLES; IN-VITRO; SIZE-DISTRIBUTION; TARGETED DRUG; NANOMEDICINES; PEG; PHARMACOKINETICS; ACTIVATION; LIPOSOMES AB The vast majority of drug product candidates in early development fail to progress to clinics. This is true for products containing nanomaterials just as for other types of pharmaceuticals. Early development pathways should therefore place high priority on experiments that help candidates fail faster and less expensively. Nanomedicines fail for many reasons, but some are more avoidable than others. Some of the points of failure are not considerations in the development of small molecules or biopharmaceuticals, and so may be unexpected, even to those with previous experience bringing drug products to the clinic. This article reviews experiments that have proven useful in providing "go/no-go" decision-making data for nanomedicines in early preclinical development. Of course, the specifics depend on the particulars of the drug product and the nanomaterial type, and not every product shares the same development pathway or the same potential points of failure. Here, we focus on challenges that differ from those in the development of traditional small molecule therapeutics, and on experiments that reveal deficiencies that can only be corrected by essentially starting over-altering the nanomedicine to an extent that all previous characterization and proof-of-concept testing must be repeated. Conducting these experiments early in the development process can save significant resources and time and allow developers to focus on derisked candidates with a greater likelihood of ultimate success. C1 [Grossman, Jennifer H.; Crist, Rachael M.; Clogston, Jeffrey D.] Leidos Biomed Res Inc, Nanotechnol Characterizat Lab, Canc Res Technol Program, Frederick Natl Lab Canc Res, 8560 Progress Dr,Wing D,Rm 1003, Frederick, MD 21702 USA. RP Grossman, JH (reprint author), Leidos Biomed Res Inc, Nanotechnol Characterizat Lab, Canc Res Technol Program, Frederick Natl Lab Canc Res, 8560 Progress Dr,Wing D,Rm 1003, Frederick, MD 21702 USA. EM jennifer.grossman@fnlcr.nih.gov RI Crist, Rachael/K-7603-2012; Nanotechnology Characterization Lab, NCL/K-8454-2012 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. The authors thank the scientists and staff of the Nanotechnology Characterization Lab (NCL), with special thanks to Scott McNeil, Stephan Stern, Marina Dobrovolskaia, and Magdalena Scully for helpful discussions and Allen Kane for assistance with figures. NR 55 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD JAN PY 2017 VL 19 IS 1 BP 92 EP 102 DI 10.1208/s12248-016-9980-4 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EI1BR UT WOS:000392210900009 PM 27612680 ER PT J AU Mazor, R Addissie, S Jang, YJ Tai, CH Rose, J Hakim, F Pastan, I AF Mazor, Ronit Addissie, Selamawit Jang, Youjin Tai, Chin-Hsien Rose, Jeremy Hakim, Fran Pastan, Ira TI Role of HLA-DP in the Presentation of Epitopes from the Truncated Bacterial PE38 Immunotoxin SO AAPS JOURNAL LA English DT Article DE DP; epitope prediction; HLA class II; in silico; MHC class II; T-cell epitopes ID T-CELL EPITOPES; MHC CLASS-II; IN-SILICO PREDICTION; RESTRICTION ELEMENTS; VACCINE DEVELOPMENT; RECOMBINANT IMMUNOTOXIN; IMMUNODOMINANT ANTIGEN; PSEUDOMONAS EXOTOXIN; BINDING-SPECIFICITY; PERIPHERAL-BLOOD AB Identification of helper T-cell epitopes is important in many fields of medicine. We previously used an experimental approach to identify T-cell epitopes in PE38, a truncated bacterial toxin used in immunotoxins. Here, we evaluated the ability of antibodies to DR, DP, or DQ to block T-cell responses to PE38 epitopes in 36 PBMC samples. We predicted the binding affinities of peptides to DR, DP, and DQ alleles using computational tools and analyzed their ability to predict the T-cell epitopes. We found that HLA-DR is responsible for 65% of the responses, DP 24%, and DQ 4%. One epitope that is presented in 20% of the samples (10/50) is entirely DP restricted and was not predicted to bind to DR or DP reference alleles using binding algorithms. We conclude that DP has an important role in helper T-cell response to PE38. C1 [Mazor, Ronit; Addissie, Selamawit; Jang, Youjin; Tai, Chin-Hsien; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 5106, Bethesda, MD 20892 USA. [Rose, Jeremy; Hakim, Fran] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 5106, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research [ZO1 BC008753-26] FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (Project # ZO1 BC008753-26). We thank Dr. Zuben Sauna for his helpful comments in reviewing the manuscript. NR 60 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 JAN PY 2017 VL 19 IS 1 BP 117 EP 129 DI 10.1208/s12248-016-9986-y PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EI1BR UT WOS:000392210900012 PM 27796910 ER PT J AU Park, Y Pacitto, A Bayliss, T Cleghorn, LAT Wang, Z Hartman, T Arora, K Ioerger, TR Sacchettini, J Rizzi, M Donini, S Blundell, TL Ascher, DB Rhee, K Breda, A Zhou, N Dartois, V Jonnala, SR Via, LE Mizrahi, V Epemolu, O Stojanovski, L Simeons, F Osuna-Cabello, M Ellis, L MacKenzie, CJ Smith, ARC Davis, SH Murugesan, D Buchanan, KI Turner, PA Huggett, M Zuccotto, F Rebollo-Lopez, MJ Lafuente-Monasterio, MJ Sanz, O Diaz, GS Lelievre, J Ballell, L Selenski, C Axtman, M Ghidelli-Disse, S Pflaumer, H Bosche, M Drewes, G Freiberg, GM Kurnick, MD Srikumaran, M Kempf, DJ Green, SR Ray, PC Read, K Wyatt, P Barry, CE Boshoff, HI AF Park, Yumi Pacitto, Angela Bayliss, Tracy Cleghorn, Laura A. T. Wang, Zhe Hartman, Travis Arora, Kriti Ioerger, Thomas R. Sacchettini, Jim Rizzi, Menico Donini, Stefano Blundell, Tom L. Ascher, David B. Rhee, Kyu Breda, Ardala Zhou, Nian Dartois, Veronique Jonnala, Surendranadha Reddy Via, Laura E. Mizrahi, Valerie Epemolu, Ola Stojanovski, Laste Simeons, Fred Osuna-Cabello, Maria Ellis, Lucy MacKenzie, Claire J. Smith, Alasdair R. C. Davis, Susan H. Murugesan, Dinakaran Buchanan, Kirsteen I. Turner, Penelope A. Huggett, Margaret Zuccotto, Fabio Jose Rebollo-Lopez, Maria Jose Lafuente-Monasterio, Maria Sanz, Olalla Santos Diaz, Gracia Lelievre, Joel Ballell, Lluis Selenski, Carolyn Axtman, Matthew Ghidelli-Disse, Sonja Pflaumer, Hannah Boesche, Markus Drewes, Gerard Freiberg, Gail M. Kurnick, Matthew D. Srikumaran, Myron Kempf, Dale J. Green, Simon R. Ray, Peter C. Read, Kevin Wyatt, Paul Barry, Clifton E., III Boshoff, Helena I. TI Essential but Not Vulnerable: Indazole Sulfonamides Targeting Inosine Monophosphate Dehydrogenase as Potential Leads against Mycobacterium tuberculosis SO ACS INFECTIOUS DISEASES LA English DT Article DE target validation; IMPDH; guanine; purine salvage; Mycobacterium tuberculosis; indazole sulfonamide ID PROTEIN STABILITY; METABOLITE CONCENTRATIONS; MUTATIONS; BIOSYNTHESIS; INHIBITORS; METABOLOMICS; DUPLICATION; EXPRESSION; COMPLEXES; DISCOVERY AB A potent, noncytotoxic indazole sulfonamide was identified by high-throughput screening of >100,000 synthetic compounds for activity against Mycobacterium tuberculosis (Mtb). This noncytotoxic compound did not directly inhibit cell wall biogenesis but triggered a slow lysis of Mtb cells as measured by release of intracellular green fluorescent protein (GFP). Isolation of resistant mutants followed by whole-genome sequencing showed an unusual gene amplification of a 40 gene region spanning from Rv3371 to Rv3411c and in one case a potential promoter mutation upstream of guaB2 (Rv3411c) encoding inosine monophosphate dehydrogenase (IMPDH). Subsequent biochemical validation confirmed direct inhibition of IMPDH by an uncompetitive mode of inhibition, and growth inhibition could be rescued by supplementation with guanine, a bypass mechanism for the IMPDH pathway. Beads containing immobilized indazole sulfonamides specifically interacted with IMPDH in cell lysates. X-ray crystallography of the IMPDH IMP inhibitor complex revealed that the primary interactions of these compounds with IMPDH were direct pi pi interactions with the IMP substrate. Advanced lead compounds in this series with acceptable pharmacokinetic properties failed to show efficacy in acute or chronic murine models of tuberculosis (TB). Time kill experiments in vitro suggest that sustained exposure to drug concentrations above the minimum inhibitory concentration (MIC) for 24 h were required for a tidal effect, levels that have been difficult to achieve in vivo. Direct measurement of guanine levels in resected lung tissue from tuberculosis-infected animals and patients revealed 0.5-2 mM concentrations in caseum and normal lung tissue. The high lesional levels of guanine and the slow lytic, growth-rate-dependent effect of IMPDH inhibition pose challenges to developing drugs against this target for use in treating TB. C1 [Park, Yumi; Arora, Kriti; Jonnala, Surendranadha Reddy; Via, Laura E.; Barry, Clifton E., III; Boshoff, Helena I.] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Pacitto, Angela; Blundell, Tom L.; Ascher, David B.] Univ Cambridge, Dept Biochem, Cambridge CB2 1GA, England. [Bayliss, Tracy; Cleghorn, Laura A. T.; Epemolu, Ola; Stojanovski, Laste; Simeons, Fred; Osuna-Cabello, Maria; Ellis, Lucy; MacKenzie, Claire J.; Smith, Alasdair R. C.; Davis, Susan H.; Murugesan, Dinakaran; Buchanan, Kirsteen I.; Turner, Penelope A.; Huggett, Margaret; Zuccotto, Fabio; Green, Simon R.; Ray, Peter C.; Read, Kevin; Wyatt, Paul] Univ Dundee, Coll Life Sci, Drug Discovery Unit, James Black Ctr, Dundee DD1 5EH, Scotland. [Wang, Zhe; Hartman, Travis; Rhee, Kyu] Weill Cornell Med Coll, Div Infect Dis, Dept Med, New York, NY 10065 USA. [Ioerger, Thomas R.] Texas A&M Univ, Dept Comp Sci & Engn, College Stn, TX 77843 USA. [Sacchettini, Jim; Breda, Ardala; Zhou, Nian] Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA. [Rizzi, Menico; Donini, Stefano] Univ Piemonte Orientale, Dipartimento Sci Farmaco, Via Bovio 6, I-28100 Novara, Italy. [Dartois, Veronique] Rutgers State Univ, New Jersey Med Sch, Publ Hlth Res Inst, Newark, NJ 07103 USA. [Via, Laura E.; Barry, Clifton E., III] Univ Cape Town, Inst Infect Dis & Mol Med, MRC NHLS UCT Mol Mycobacteriol Res Unit, ZA-7700 Rondebosch, South Africa. [Jose Rebollo-Lopez, Maria; Jose Lafuente-Monasterio, Maria; Sanz, Olalla; Santos Diaz, Gracia; Lelievre, Joel; Ballell, Lluis] GlaxoSmithKline, Dis Developing World, Calle Severo Ochoa 2, Madrid 28760, Spain. [Selenski, Carolyn; Axtman, Matthew] GlaxoSmithKline, 5 Crescent Dr, Philadelphia, PA 19112 USA. [Ghidelli-Disse, Sonja; Pflaumer, Hannah; Boesche, Markus; Drewes, Gerard] GlaxoSmithKline, Mol Discovery Res, Cellzome GmbH, Meyerhofstr 1, D-69117 Heidelberg, Germany. [Freiberg, Gail M.; Kurnick, Matthew D.; Srikumaran, Myron; Kempf, Dale J.] AbbVie Mol Characterizat, 1 North Waukegan Rd, N Chicago, IL 60064 USA. RP Boshoff, HI (reprint author), NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hboshoff@niaid.nih.gov RI Zuccotto, Fabio/E-7144-2017 OI Zuccotto, Fabio/0000-0002-3888-7423 FU Intramural Research Program of NIAID; Foundation for the National Institutes of Health; Bill & Melinda Gates Foundation; South African Medical Research Council; NHMRC [APP1072476]; Newton Fund RCUK-CONFAP Grant - Medical Research Council (MRC); Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG) [MR/M026302/1]; Wellcome Trust FX This work was funded, in part, by the Intramural Research Program of NIAID and in part by grants from the Foundation for the National Institutes of Health with support from the Bill & Melinda Gates Foundation (to C.E.B. III, V.M., and P.W.), and the South African Medical Research Council (to V.M.). D.B.A. was supported by an NHMRC C. J. Martin Fellowship (APP1072476). D.B.A. and T.L.B received funding from the Newton Fund RCUK-CONFAP Grant awarded by The Medical Research Council (MRC) and Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG) (MR/M026302/1). P.W. received joint funding from the Bill and Melinda Gates Foundation and Wellcome Trust for A Centre of Excellence for Lead Optimisation for Diseases of the Developing World. We acknowledge Beth Fischer and Vinod Nair for help with electron microscopy. NR 58 TC 2 Z9 2 U1 4 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 2373-8227 J9 ACS INFECT DIS JI ACS Infect. Dis. PD JAN PY 2017 VL 3 IS 1 BP 18 EP 33 DI 10.1021/acsinfecdis.6b00103 PG 16 WC Chemistry, Medicinal; Infectious Diseases SC Pharmacology & Pharmacy; Infectious Diseases GA EI1TH UT WOS:000392260300003 PM 27704782 ER PT J AU Liu, JY Bruhn, DF Lee, RB Zheng, Z Janusic, T Scherbakov, D Scherman, MS Boshoff, HI Das, S Rakesh Waidyarachchi, SL Brewer, TA Gracia, B Yang, L Bollinger, J Robertson, GT Meibohm, B Lenaerts, AJ Ainsa, J Bottger, EC Lee, RE AF Liu, Jiuyu Bruhn, David F. Lee, Robin B. Zheng, Zhong Janusic, Tana Scherbakov, Dimitri Scherman, Michael S. Boshoff, Helena I. Das, Sourav Rakesh Waidyarachchi, Samanthi L. Brewer, Tiffany A. Gracia, Begona Yang, Lei Bollinger, John Robertson, Gregory T. Meibohm, Bernd Lenaerts, Anne J. Ainsa, Jose Boettger, Erik C. Lee, Richard E. TI Structure-Activity Relationships of Spectinamide Antituberculosis Agents: A Dissection of Ribosomal Inhibition and Native Efflux Avoidance Contributions SO ACS INFECTIOUS DISEASES LA English DT Article DE structure-activity relationship; spectinamide; spectinomycin; antituberculosis; efflux pump; efficacy ID MYCOBACTERIUM-TUBERCULOSIS; SPECTINOMYCIN MODIFICATION; IN-VITRO; CHEMISTRY; ANTIBIOTICS; DERIVATIVES; ANALOGS AB Spectinamides are a novel class of antitubercular agents with the potential to treat drug-resistant tuberculosis infections. Their antitubercular activity is derived from both ribosomal affinity and their ability to overcome intrinsic efflux mediated by the Mycobacterium tuberculosis Rv1258c efflux pump. This study explores the structure-activity relationships through analysis of 50 targeted spectinamides. Compounds are evaluated for ribosomal translational inhibition, MIC activity in Rv1258c efflux pump deficient and wild type tuberculosis strains, and efficacy in an acute model of tuberculosis infection. The results of this study show a narrow structure-activity relationship, consistent with a tight ribosome-binding pocket and strict structural requirements to overcome native efflux. Rationalization of ribosomal inhibition data using molecular dynamics simulations showed stable complex formation for halogenated spectinamides consistent with the long post antibiotic effects observed. The lead spectinamides identified in this study demonstrated potent MIC activity against MDR and XDR tuberculosis and had desirable antitubercular class specific features including low protein binding, low microsomal metabolism, no cytotoxicity, and significant reductions in bacterial burdens in the lungs of mice infected with M. tuberculosis. The structure-activity relationships detailed here emphasize the need to examine efflux-mediated resistance in the design of antituberculosis drugs and demonstrate that it is possible to overcome intrinsic efflux with synthetic modification. The ability to understand the structure requirements for this class has produced a variety of new substituted spectinamides, which may provide useful alternative candidates and promote the further development of this class. C1 [Liu, Jiuyu; Bruhn, David F.; Lee, Robin B.; Zheng, Zhong; Das, Sourav; Rakesh; Waidyarachchi, Samanthi L.; Brewer, Tiffany A.; Yang, Lei; Bollinger, John; Lee, Richard E.] St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, 262 Danny Thomas Pl,MS 1000, Memphis, TN 38105 USA. [Janusic, Tana; Scherbakov, Dimitri; Boettger, Erik C.] Univ Zurich, Natl Zentrum Mykobakterien, Inst Med Mikrobiol, Ramistr 71,Gloriastr 30-32, CH-8006 Zurich, Switzerland. [Scherman, Michael S.; Robertson, Gregory T.; Lenaerts, Anne J.] Colorado State Univ, Dept Microbiol, Mycobacterial Res Labs, 1682 Campus Delivery, Ft Collins, CO 80523 USA. [Boshoff, Helena I.] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, 33 North Dr, Bethesda, MD 20814 USA. [Brewer, Tiffany A.; Meibohm, Bernd] Univ Tennessee, Hlth Sci Ctr, Dept Pharmaceut Sci, 881 Madison Ave, Memphis, TN 38163 USA. [Gracia, Begona; Ainsa, Jose] Univ Zaragoza, Dept Microbiol Med Prevent & Salud Publ, E-50009 Zaragoza, Spain. [Gracia, Begona; Ainsa, Jose] Univ Zaragoza, BIFI, E-50009 Zaragoza, Spain. [Gracia, Begona; Ainsa, Jose] CIBER Enfermedades Resp CIBERES, Zaragoza 50009, Spain. RP Lee, RE (reprint author), St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, 262 Danny Thomas Pl,MS 1000, Memphis, TN 38105 USA. EM Richard.lee@stjude.org RI Robertson, Gregory/E-1601-2017; Lenaerts, Anne/F-1353-2017 OI Robertson, Gregory/0000-0001-7157-4034; FU National Institutes of Health [AI090810, OD016226]; American Lebanese Syrian Associated Charities (ALSAC), St. Jude Children's Research Hospital; Intramural Research Program of NIAID FX This research was supported by funding from the National Institutes of Health (Grants AI090810 and OD016226) and the American Lebanese Syrian Associated Charities (ALSAC), St. Jude Children's Research Hospital. This work was also funded, in part, by the Intramural Research Program of NIAID. NR 30 TC 0 Z9 0 U1 2 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 2373-8227 J9 ACS INFECT DIS JI ACS Infect. Dis. PD JAN PY 2017 VL 3 IS 1 BP 72 EP 88 DI 10.1021/acsinfecdis.6b00158 PG 17 WC Chemistry, Medicinal; Infectious Diseases SC Pharmacology & Pharmacy; Infectious Diseases GA EI1TH UT WOS:000392260300008 PM 28081607 ER PT J AU Ai, T Willett, R Williams, J Ding, R Wilson, DJ Xie, JS Kim, DH Puertollano, R Chen, LQ AF Ai, Teng Willett, Rose Williams, Jessica Ding, Rui Wilson, Daniel J. Xie, Jiashu Kim, Do-Hyung Puertollano, Rosa Chen, Liqiang TI N-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)benzamides: Antiproliferative Activity and Effects on mTORC1 and Autophagy SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Autophagy; autophagy modulator; mTOR; pancreatic cancer; anticancer agents ID PANCREATIC-CANCER CELLS; INITIATING KINASE ULK1; TUMOR-GROWTH; IN-VIVO; INHIBITORS; DISCOVERY; POTENT; VPS34; P53; PROGRESSION AB Guided by antiproliferative activity in MIA PaCa-2 cells, we have performed preliminary structure activity relationship studies on N-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)benzamides. Two selected compounds showed submicromolar antiproliferative activity and good metabolic stability. Both compounds reduced mTORC1 activity and increased autophagy at the basal level. In addition, they disrupted autophagic flux by interfering with mTORC1 reactivation and clearance of LC3-II under starvation/refeed conditions, as evidenced by accumulation of LC3-II and abnormal LC3 labeled punctae. Therefore, N-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)benzamides may represent a new class of autophagy modulators that possesses potent anticancer activity and potentially a novel mechanism of action. C1 [Ai, Teng; Williams, Jessica; Ding, Rui; Wilson, Daniel J.; Xie, Jiashu; Chen, Liqiang] Univ Minnesota, Acad Hlth Ctr, Ctr Drug Design, Minneapolis, MN 55455 USA. [Willett, Rose; Puertollano, Rosa] NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Kim, Do-Hyung] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. RP Chen, LQ (reprint author), Univ Minnesota, Acad Hlth Ctr, Ctr Drug Design, Minneapolis, MN 55455 USA. EM chenx462@umn.edu FU Center for Drug Design in the Academic Health Center of the University of Minnesota; Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI); National Institute of General Medical Sciences (NIGMS) [R01GM097057] FX This work was supported by the Center for Drug Design in the Academic Health Center of the University of Minnesota (to L. C.). R.W. and RP. were supported by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI). D.-H.K. was supported by the National Institute of General Medical Sciences (NIGMS) (R01GM097057). We thank Dr. Huaqing Cui for the initial synthesis of compound 1. NR 24 TC 0 Z9 0 U1 4 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-5875 J9 ACS MED CHEM LETT JI ACS Med. Chem. Lett. PD JAN PY 2017 VL 8 IS 1 BP 90 EP 95 DI 10.1021/acsmedchemlett.6b00392 PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA EH8UM UT WOS:000392047900015 PM 28105281 ER PT J AU Pajtler, KW Mack, SC Ramaswamy, V Smith, CA Witt, H Smith, A Hansford, JR von Hoff, K Wright, KD Hwang, E Frappaz, D Kanemura, Y Massimino, M Faure-Conter, C Modena, P Tabori, U Warren, KE Holland, EC Ichimura, K Giangaspero, F Castel, D von Deimling, A Kool, M Dirks, PB Grundy, RG Foreman, NK Gajjar, A Korshunov, A Finlay, J Gilbertson, RJ Ellison, DW Aldape, KD Merchant, TE Bouffet, E Pfister, SM Taylor, MD AF Pajtler, Kristian W. Mack, Stephen C. Ramaswamy, Vijay Smith, Christian A. Witt, Hendrik Smith, Amy Hansford, Jordan R. von Hoff, Katja Wright, Karen D. Hwang, Eugene Frappaz, Didier Kanemura, Yonehiro Massimino, Maura Faure-Conter, Cecile Modena, Piergiorgio Tabori, Uri Warren, Katherine E. Holland, Eric C. Ichimura, Koichi Giangaspero, Felice Castel, David von Deimling, Andreas Kool, Marcel Dirks, Peter B. Grundy, Richard G. Foreman, Nicholas K. Gajjar, Amar Korshunov, Andrey Finlay, Jonathan Gilbertson, Richard J. Ellison, David W. Aldape, Kenneth D. Merchant, Thomas E. Bouffet, Eric Pfister, Stefan M. Taylor, Michael D. TI The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants SO ACTA NEUROPATHOLOGICA LA English DT Article DE Ependymoma; Subgroups; RELA; YAP1; Treatment; Trial; Posterior fossa ID POSTERIOR-FOSSA EPENDYMOMAS; CENTRAL-NERVOUS-SYSTEM; CHILDRENS ONCOLOGY GROUP; IN-VIVO; POSTOPERATIVE CHEMOTHERAPY; PEDIATRIC EPENDYMOMA; RECURRENT EPENDYMOMA; PROGNOSTIC-FACTORS; STEM-CELLS; SUPRATENTORIAL AB Multiple independent genomic profiling efforts have recently identified clinically and molecularly distinct subgroups of ependymoma arising from all three anatomic compartments of the central nervous system (supratentorial brain, posterior fossa, and spinal cord). These advances motivated a consensus meeting to discuss: (1) the utility of current histologic grading criteria, (2) the integration of molecular-based stratification schemes in future clinical trials for patients with ependymoma and (3) current therapy in the context of molecular subgroups. Discussion at the meeting generated a series of consensus statements and recommendations from the attendees, which comment on the prognostic evaluation and treatment decisions of patients with intracranial ependymoma (WHO Grade II/III) based on the knowledge of its molecular subgroups. The major consensus among attendees was reached that treatment decisions for ependymoma (outside of clinical trials) should not be based on grading (II vs III). Supratentorial and posterior fossa ependymomas are distinct diseases, although the impact on therapy is still evolving. Molecular subgrouping should be part of all clinical trials henceforth. C1 [Pajtler, Kristian W.; Witt, Hendrik; Kool, Marcel; Pfister, Stefan M.] German Canc Res Ctr, Div Pediat Neurooncol, Heidelberg, Germany. [Pajtler, Kristian W.; Witt, Hendrik; Pfister, Stefan M.] Univ Heidelberg Hosp, Dept Pediat Oncol Hematol & Immunol, Heidelberg, Germany. [Pajtler, Kristian W.; Witt, Hendrik; Kool, Marcel; Pfister, Stefan M.] German Canc Consortium DKTK, Heidelberg, Germany. [Mack, Stephen C.] Cleveland Clin, Dept Stem Cell Biol & Regenerat Med, Lerner Res Inst, Cleveland, OH 44106 USA. [Mack, Stephen C.] Case Western Reserve Univ, Dept Mol Med, Cleveland Clin, Lerner Coll Med, Cleveland, OH 44106 USA. [Ramaswamy, Vijay; Smith, Christian A.; Dirks, Peter B.; Taylor, Michael D.] Hosp Sick Children, Div Neurosurg, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON, Canada. [Ramaswamy, Vijay] Hosp Sick Children, Div Hematol Oncol, Toronto, ON, Canada. [Smith, Amy] Arnold Palmer Hosp, Orlando, FL USA. [von Hoff, Katja] Royal Childrens Hosp, Melbourne, Vic, Australia. [von Hoff, Katja] Univ Med Ctr Hamburg Eppendorf, Dept Pediat Hematol & Oncol, Hamburg, Germany. [Wright, Karen D.; Gajjar, Amar] St Jude Childrens Res Hosp, Dept Oncol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Hwang, Eugene] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. [Frappaz, Didier; Faure-Conter, Cecile] Pediat Neurooncol Ctr Leon Berard, Lyon, France. [Kanemura, Yonehiro] Osaka Natl Hosp, Dept Neurosurg, Osaka, Japan. [Kanemura, Yonehiro] Osaka Natl Hosp, Inst Clin Res, Osaka, Japan. [Massimino, Maura] Fdn IRCCS Ist Nazl Tumori, Milan, Italy. [Modena, Piergiorgio] S Anna Gen Hosp, Genet Lab, Pathol Unit, Como, Italy. [Warren, Katherine E.] NCI, NIH, Bethesda, MD 20892 USA. [Holland, Eric C.] Fred Hutchinson Canc Res Ctr, Div Human Biol, 1124 Columbia St, Seattle, WA 98104 USA. [Ichimura, Koichi] Natl Canc Ctr, Res Inst, Div Brain Tumor Translat Res, Tokyo, Japan. [Giangaspero, Felice] Sapienza Univ, Dept Radiol Sci Oncol & Anat Pathol, Rome, Italy. [Castel, David] Univ Paris Saclay, Gustave Roussy Univ Paris Sud, Dept Cancerol Enfant & Adolescent, Villejuif, France. [Castel, David] Gustave Roussy Univ Paris Sud, Vectorol & Therapeut Anticancereuses UMR8203, CNRS, Univ Paris Saclay, Villejuif, France. [von Deimling, Andreas; Korshunov, Andrey] Heidelberg Univ, Dept Neuropathol, Heidelberg, Germany. [von Deimling, Andreas; Korshunov, Andrey] German Canc Res Ctr, Clin Cooperat Unit Neuropathol, Heidelberg, Germany. [Grundy, Richard G.] Univ Nottingham, Sch Med, Childrens Brain Tumour Res Ctr, Nottingham, England. [Foreman, Nicholas K.] Univ Colorado Denver, Dept Pediat, Aurora, CO USA. [Finlay, Jonathan] Nationwide Childrens Hosp, Columbus, OH USA. [Finlay, Jonathan] Ohio State Univ, Columbus, OH 43210 USA. [Gilbertson, Richard J.] Univ Cambridge, CRUK Cambridge Inst, Li Ka Shing Ctr, Cambridge, England. [Ellison, David W.] St Jude Childrens Res Hosp, Dept Pathol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Aldape, Kenneth D.] Univ Toronto, Lab Med & Pathobiol, Toronto, ON, Canada. [Merchant, Thomas E.] St Jude Childrens Res Hosp, Dept Radiol Sci, 332 N Lauderdale St, Memphis, TN 38105 USA. RP Pfister, SM (reprint author), German Canc Res Ctr, Div Pediat Neurooncol, Heidelberg, Germany.; Pfister, SM (reprint author), Univ Heidelberg Hosp, Dept Pediat Oncol Hematol & Immunol, Heidelberg, Germany.; Pfister, SM (reprint author), German Canc Consortium DKTK, Heidelberg, Germany.; Taylor, MD (reprint author), Hosp Sick Children, Div Neurosurg, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON, Canada. EM s.pfister@dkfz.de; mdtaylor@sickkids.ca RI von Deimling, Andreas/F-7774-2013; OI von Deimling, Andreas/0000-0002-5863-540X; Foreman, Nicholas/0000-0003-4848-4801; Grundy, Richard/0000-0002-2585-2539 FU NCI NIH HHS [P01 CA096832] NR 40 TC 1 Z9 1 U1 5 U2 5 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 JAN PY 2017 VL 133 IS 1 BP 5 EP 12 DI 10.1007/s00401-016-1643-0 PG 8 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA EI0AX UT WOS:000392134900002 PM 27858204 ER PT J AU Silver, RM Myatt, L Hauth, JC Leveno, KJ Peaceman, AM Ramin, SM Samuels, P Saade, G Sorokin, Y Clifton, RG Reddy, UM AF Silver, Robert M. Myatt, Leslie Hauth, John C. Leveno, Kenneth J. Peaceman, Alan M. Ramin, Susan M. Samuels, Philip Saade, George Sorokin, Yoram Clifton, Rebecca G. Reddy, Uma M. TI Cell-Free Total and Fetal DNA in First Trimester Maternal Serum and Subsequent Development of Preeclampsia SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE preeclampsia; cell-free DNA; placenta; fetal fraction ID INTRAUTERINE GROWTH RESTRICTION; PLACENTAL EPIGENETIC SIGNATURE; LOW-RISK; PLASMA; PREGNANCY; PREDICTION; GENE; QUANTIFICATION; 2ND-TRIMESTER; PREVENTION AB Objective The objective of this study was to assess the relationship between first trimester cell-free total and fetal DNA in maternal plasma and the subsequent development of preeclampsia. Study Design Nested case-control study of patients enrolled in the Combined Antioxidant and Preeclampsia Prediction Studies prediction study of 175 women who did and 175 women who did not develop preeclampsia. The predictive values of cell-free total and fetal DNA and the subsequent development of preeclampsia were measured using receiver operating characteristic curves. Results Cell-free total DNA was higher in African American (median; 25-75%; 6.15; 0.14-28.73; p = 0.02) and Hispanic (4.95; 0.20-26.82; p = 0.037) compared with white women (2.33; 0.03-13.10). Levels of cell-free total DNA were also associated with maternal body mass index (BMI) (p = 0.02). Cell-free total DNA levels were similar between women who later developed preeclampsia (3.52; 0.11-25.3) and controls (3.74; 0.12-21.14, p = 0.96). Conclusion There is no significant difference in levels of cell-free total DNA in the first trimester in women who subsequently develop preeclampsia. Levels of cell-free total DNA in the first trimester are increased in African American and Hispanic compared with white women, and levels increase with increasing BMI. C1 [Silver, Robert M.; Myatt, Leslie; Hauth, John C.; Leveno, Kenneth J.; Peaceman, Alan M.; Ramin, Susan M.; Samuels, Philip; Saade, George; Sorokin, Yoram; Clifton, Rebecca G.; Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. [Silver, Robert M.] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Myatt, Leslie] Univ Cincinnati, Cincinnati, OH USA. [Hauth, John C.] Univ Alabama Birmingham, Birmingham, AL USA. [Leveno, Kenneth J.] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. [Peaceman, Alan M.] Northwestern Univ, Chicago, IL USA. [Ramin, Susan M.] Univ Texas Hlth Sci Ctr Houston, Childrens Mem Hermann Hosp, Houston, TX 77030 USA. [Samuels, Philip] Ohio State Univ, Columbus, OH 43210 USA. [Saade, George] Univ Texas Med Branch, Galveston, TX 77555 USA. [Sorokin, Yoram] Wayne State Univ, Detroit, MI USA. [Clifton, Rebecca G.] George Washington Univ, Ctr Biostat, Washington, DC USA. RP Silver, RM (reprint author), 30 N 1900 E 2B200 SOM, Salt Lake City, UT 84132 USA. EM bob.silver@hsc.utah.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD34208, HD27869, HD40485, HD40560, HD40544, HD34116, HD40512, HD21410, HD40545, HD40500, HD27915, HD34136, HD27860, HD53118, HD53097, HD27917, HD36801]; National Heart, Lung, Blood Institute; National Center for Research Resources [M01 RR00080, UL1 RR024153, UL1 RR024989] FX The project described was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (HD34208, HD27869, HD40485, HD40560, HD40544, HD34116, HD40512, HD21410, HD40545, HD40500, HD27915, HD34136, HD27860, HD53118, HD53097, HD27917, and HD36801); the National Heart, Lung, Blood Institute; and the National Center for Research Resources (M01 RR00080, UL1 RR024153, UL1 RR024989). Comments and views of the authors do not necessarily represent the views of the NICHD, NHLBI, or NCRR. NR 31 TC 0 Z9 0 U1 4 U2 4 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 EI 1098-8785 J9 AM J PERINAT JI Am. J. Perinatol. PD JAN PY 2017 VL 34 IS 2 BP 191 EP 198 DI 10.1055/s-0035-1570383 PG 8 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA EI1RS UT WOS:000392256200013 PM 27398706 ER PT J AU Oh, H Baumrind, S Korn, EL Dugoni, S Boero, R Aubert, M Boyd, R AF Oh, Heesoo Baumrind, Sheldon Korn, Edward L. Dugoni, Steven Boero, Roger Aubert, Maryse Boyd, Robert TI A retrospective study of Class II mixed-dentition treatment SO ANGLE ORTHODONTIST LA English DT Article DE Class II malocclusion; Mixed dentition; Early treatment; Retrospective study ID RANDOMIZED CLINICAL-TRIAL; TWIN-BLOCK APPLIANCE; MALOCCLUSION; ORTHODONTICS; MULTICENTER; ARCH AB Objective: To consider the effectiveness of early treatment using one mixed-dentition approach to the correction of moderate and severe Class II malocclusions. Materials and Methods: Three groups of Class II subjects were included in this retrospective study: an early treatment (EarlyTx) group that first presented at age 7 to 9.5 years (n = 54), a late treatmeht (LateTx) group whose first orthodontic visit occurred between ages 12 and 15 (n = 58), and an untreated Class II (UnTx) group to assess the pretreatment comparability of the two treated groups (n = 51). Thirteen conventional cephalometric measurements were reported for each group and Class II molar severity was measured on the study casts of the EarlyTx and LateTx groups. Results: Successful Class II correction was observed in approximately three quarters of both the EarlyTx group and the LateTx group at the end of treatment. EarlyTx patients had fewer permanent teeth extracted than did the LateTx patients (5.6% vs 37.9%, P < .001) and spent less time in full bonded appliance therapy in the permanent dentition than did LateTx patients (1.7 +/- 0.8 vs 2.6 +/- 0.7years, P < .001). When supervision time is included, the EarlyTx group had longer total treatment time and averaged more visits than did the LateTx group (53.1 +/- 18.8 vs 33.7 +/- 8.3, P < .0001). Fifty-five percent of the LateTx extraction cases involved removal of the maxillary first premolars only and were finished in a Class II molar relationship. Conclusion: EarlyTx comprehensive mixed-dentition treatment was an effective modality for early correction of Class II malocclusions. C1 [Oh, Heesoo; Baumrind, Sheldon; Dugoni, Steven; Boero, Roger; Aubert, Maryse; Boyd, Robert] Univ Pacific, Arthur A Dugoni Sch Dent, Dept Orthodont, 155 Fifth St, San Francisco, CA 94103 USA. [Baumrind, Sheldon] Univ Pacific, Arthur A Dugoni Sch Dent, Craniofacial Res Instrumentat Lab, San Francisco, CA USA. [Korn, Edward L.] NCI, Biometr Res Program, NIH, Bethesda, MD 20892 USA. RP Oh, H (reprint author), Univ Pacific, Arthur A Dugoni Sch Dent, Dept Orthodont, 155 Fifth St, San Francisco, CA 94103 USA. EM hoh@pacific.edu FU grant of Orthodontic Faculty Development Fellowship Award from the American Association of Orthodontists Foundation; Full Time Faculty Teaching (FFT) Fellowship Award from the American Association of Orthodontists FX This study was supported in part by a grant of Orthodontic Faculty Development Fellowship Award from the American Association of Orthodontists Foundation and a three-year, Full Time Faculty Teaching (FFT) Fellowship Award from the American Association of Orthodontists. NR 15 TC 0 Z9 0 U1 2 U2 2 PU E H ANGLE EDUCATION RESEARCH FOUNDATION, INC PI NEWTON N PA 1615 BEACON ST, NEWTON N, MA 02468-1507 USA SN 0003-3219 EI 1945-7103 J9 ANGLE ORTHOD JI Angle Orthod. PD JAN PY 2017 VL 87 IS 1 BP 56 EP 67 DI 10.2319/012616-72.1 PG 12 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA EI1RA UT WOS:000392254400008 PM 27391205 ER PT J AU Kraus, VB Collins, JE Hargrove, D Losina, E Nevitt, M Katz, JN Wang, SX Sandell, LJ Hoffmann, SC Hunter, DJ AF Kraus, Virginia Byers Collins, Jamie E. Hargrove, David Losina, Elena Nevitt, Michael Katz, Jeffrey N. Wang, Susanne X. Sandell, Linda J. Hoffmann, Steven C. Hunter, David J. CA OA Biomarkers Consortium TI Predictive validity of biochemical biomarkers in knee osteoarthritis: data from the FNIH OA Biomarkers Consortium SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID SUBCHONDRAL BONE; HIP-OSTEOARTHRITIS; ARTICULAR-CARTILAGE; COLLAGEN-SYNTHESIS; MOLECULAR MARKERS; IIA PROCOLLAGEN; C-TELOPEPTIDE; PROGRESSION; SERUM; TURNOVER AB Objective To investigate a targeted set of biochemical biomarkers as predictors of clinically relevant osteoarthritis (OA) progression. Methods Eighteen biomarkers were measured at baseline, 12 months (M) and 24 M in serum (s) and/or urine (u) of cases (n=194) from the OA initiative cohort with knee OA and radiographic and persistent pain worsening from 24 to 48 M and controls (n=406) not meeting both end point criteria. Primary analyses used multivariable regression models to evaluate the association between biomarkers (baseline and time-integrated concentrations (TICs) over 12 and 24 M, transposed to z values) and case status, adjusted for age, sex, body mass index, race, baseline radiographic joint space width, Kellgren-Lawrence grade, pain and pain medication use. For biomarkers with adjusted p<0.1, the c-statistic (area under the curve (AUC)), net reclassification index and the integrated discrimination improvement index were used to further select for hierarchical multivariable discriminative analysis and to determine the most predictive and parsimonious model. Results The 24 M TIC of eight biomarkers significantly predicted case status (ORs per 1 SD change in biomarker): sCTXI 1.28, sHA 1.22, sNTXI 1.25, uC2C-HUSA 1.27, uCTXII, 1.37, uNTXI 1.29, uCTXl alpha 1.32, uCTXI beta 1.27. 24 M TIC of uCTXII (1.47-1.72) and uC2C-Human Urine Sandwich Assay (HUSA) (1.36-1.50) both predicted individual group status (pain worsening, joint space loss and their combination). The most predictive and parsimonious combinatorial model for case status consisted of 24 M TIC uCTXII, sHA and sNTXI (AUC 0.667 adjusted). Baseline uCTXII and uCTXI alpha both significantly predicted case status (OR 1.29 and 1.20, respectively). Conclusions Several systemic candidate biomarkers hold promise as predictors of pain and structural worsening of OA. C1 [Kraus, Virginia Byers] Duke Mol Physiol Inst, Box 104775,300 North Duke St, Durham, NC 27701 USA. [Kraus, Virginia Byers] Duke Univ, Sch Med, Div Rheumatol, Durham, NC USA. [Collins, Jamie E.; Losina, Elena] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Hargrove, David] LabCorp Clin Trials, San Leandro, CA USA. [Nevitt, Michael; Katz, Jeffrey N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Wang, Susanne X.] AbbVie, N Chicago, IL USA. [Sandell, Linda J.] Washington Univ, Dept Orthopaed Surg, Musculoskeletal Res Ctr, St Louis, MO USA. [Hoffmann, Steven C.] Fdn Natl Inst Hlth, Bethesda, MD USA. [Hunter, David J.] Royal North Shore Hosp, Dept Rheumatol, Sydney, NSW, Australia. [Hunter, David J.] Univ Sydney, Kolling Inst, Inst Bone & Joint Res, Sydney, NSW, Australia. RP Kraus, VB (reprint author), Duke Mol Physiol Inst, Box 104775,300 North Duke St, Durham, NC 27701 USA. EM vbk@duke.edu FU Foundations for National Institutes of Health (FNIH) OA Biomarkers Consortium; AbbVie; Amgen; Arthritis Foundation; Bioiberica S.A.; DePuy Mitek; Flexion Therapeutics; GlaxoSmithKline; Merck Serono; Rottapharm \ Madaus; Sanofi; Stryker; Pivotal OAI MRI Analyses study; NIH NHLBI [HHSN2682010000]; National Institutes of Health [N01 AR 2 2258, N01 AR 2 2259, N01-AR-2-2260, N01-AR-2-2261, N01-AR-2-2262]; Merck Research Laboratories; Novartis Pharmaceuticals Corporation; Pfizer FX In-kind donations to support biochemical testing was provided by Alere, ARTIALIS S.A., BioVendor-Laboratorni medicina a.s., IBEX Pharmaceuticals, Immunodiagnostic Systems and Quidel Corporation. Scientific and financial support for the Foundations for National Institutes of Health (FNIH) OA Biomarkers Consortium and the study are made possible through grants, direct and in-kind contributions provided by: AbbVie, Amgen, Arthritis Foundation, Bioiberica S.A., DePuy Mitek, Flexion Therapeutics, GlaxoSmithKline, Merck Serono, Rottapharm vertical bar Madaus, Sanofi, Stryker, The Pivotal OAI MRI Analyses study, NIH NHLBI HHSN2682010000. We thank the Osteoarthritis Research Society International for their leadership and expertise on the FNIH OA Biomarker Consortium project. The osteoarthritis initiative (OAI) is a public-private partnership comprising five contracts (N01 AR 2 2258, N01 AR 2 2259, N01-AR-2-2260, N01-AR-2-2261 and N01-AR-2-2262) funded by the National Institutes of Health. Funding partners include Merck Research Laboratories, Novartis Pharmaceuticals Corporation, GlaxoSmithKline and Pfizer. Private sector funding for the Consortium and CAI is managed by the FNIH. The statistical analysis and writing of this article was independent from and not contingent upon approval from the study sponsors or kit suppliers. NR 35 TC 3 Z9 3 U1 3 U2 3 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 JAN PY 2017 VL 76 IS 1 BP 186 EP 195 DI 10.1136/annrheumdis-2016-209252 PG 10 WC Rheumatology SC Rheumatology GA EI3XG UT WOS:000392425200027 PM 27296323 ER PT J AU Baez, A Shiloach, J AF Baez, Antonino Shiloach, Joseph TI Increasing dissolved-oxygen disrupts iron homeostasis in production cultures of Escherichia coli SO ANTONIE VAN LEEUWENHOEK INTERNATIONAL JOURNAL OF GENERAL AND MOLECULAR MICROBIOLOGY LA English DT Article DE NADPH concentration; ROS accumulation; RyhB::mutant; SodA, SodB, SodC regulation ID HIGH CELL-DENSITY; MITOCHONDRIAL ELECTRON-TRANSPORT; ZINC SUPEROXIDE-DISMUTASE; AMINO-ACID BIOSYNTHESIS; QUINOLINATE SYNTHETASE; HYDROGEN-PEROXIDE; CONTAINING ENZYME; OXIDATIVE STRESS; SITE; TOXICITY AB The damaging effect of high oxygen concentration on growth of Escherichia coli is well established. Over-oxygenation increases the intracellular concentration of reactive oxygen species (ROS), causing the destruction of the [4Fe-4S] cluster of dehydratases and limiting the biosynthesis of both branched-chain amino acids and nicotinamide adenine dinucleotide. A key enzyme that reduces the damaging effect of superoxide is superoxide dismutase (SOD). Its transcriptional regulation is controlled by global transcription regulators that respond to changes in oxygen and iron concentrations and pH. Production of biological compounds from E. coli is currently achieved using cultures grown to high cell densities which require oxygen-enriched air supply. It is, therefore, important to study the effect of over-oxygenation on E. coli metabolism and the bacterial protecting mechanism. The effect of over-oxygenation on the superoxide dismutase regulation system was evaluated in cultures grown in a bioreactor by increasing the oxygen concentration from 30 to 300 % air saturation. Following the change in the dissolved oxygen (DO), the expression of sodC, the periplasmic CuZn-containing SOD, and sodA, the cytosolic Mn-containing SOD, was higher in all the tested strains, while the expression of the sodB, the cytosolic Fe-containing SOD, was lower. The down-regulation of the sodB was found to be related to the activation of the small RNA RyhB. It was revealed that iron homeostasis, in particular ferric iron, was involved in the RyhB activation and in sodB regulation but not in sodA. Supplementation of amino acids to the culture medium reduced the intracellular ROS accumulation and reduced the activation of both SodA and SodC following the increase in the oxygen concentration. The study provides evidence that at conditions of over-oxygenation, sodA and sodC are strongly regulated by the amount of ROS, in particular superoxide; and sodB is regulated by iron availability through the small RNA RyhB. In addition, information on the impact of NADH, presence of amino acids and type of iron on SOD regulation, and consequently, on the ROS concentration is provided. C1 [Baez, Antonino] BUAP, CICM, Lab Ecol Mol Microbiana, IC, Puebla, Mexico. [Shiloach, Joseph] NIDDK, Biotechnol Core Lab, NIH, Bethesda, MD 20892 USA. RP Shiloach, J (reprint author), NIDDK, Biotechnol Core Lab, NIH, Bethesda, MD 20892 USA. EM antonino.baez@correo.buap.mx; Josephs@niddk.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX Funding was provided by the intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 48 TC 0 Z9 0 U1 6 U2 6 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0003-6072 EI 1572-9699 J9 ANTON LEEUW INT J G JI Antonie Van Leeuwenhoek PD JAN PY 2017 VL 110 IS 1 BP 115 EP 124 DI 10.1007/s10482-016-0781-7 PG 10 WC Microbiology SC Microbiology GA EI0SL UT WOS:000392184800012 PM 27757702 ER PT J AU Marmisolle, I Martinez, J Liu, JE Mastrogiovanni, M Fergusson, MM Rovira, II Castro, L Trostchansky, A Moreno, M Cao, L Finkel, T Quijano, C AF Marmisolle, Ines Martinez, Jennyfer Liu, Jie Mastrogiovanni, Mauricio Fergusson, Maria M. Rovira, Ilsa I. Castro, Laura Trostchansky, Andres Moreno, Maria Cao, Liu Finkel, Toren Quijano, Celia TI Reciprocal regulation of acetyl-CoA carboxylase 1 and senescence in human fibroblasts involves oxidant mediated p38 MAPK activation SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE Lipid synthesis; Acetyl-CoA carboxylase I; Cellular senescence; DNA damage response; Reactive oxygen species (ROS); p38 MAPK ID FATTY-ACID SYNTHASE; DNA-DAMAGE; MITOCHONDRIAL-FUNCTION; CELLULAR SENESCENCE; STEM-CELLS; IN-VIVO; PROLIFERATION; CANCER; ATM; PHOSPHORYLATION AB We sought to explore the fate of the fatty acid synthesis pathway in human fibroblasts exposed to DNA damaging agents capable of inducing senescence, a state of irreversible growth arrest. Induction of premature senescence by doxorubicin or hydrogen peroxide led to a decrease in protein and mRNA levels of acetyl-CoA carboxylase 1 (ACC1), the enzyme that catalyzes the rate-limiting step in fatty-acid biosynthesis. ACC1 decay accompanied the activation of the DNA damage response (DDR), and resulted in decreased lipid synthesis. A reduction in protein and mRNA levels of ACC1 and in lipid synthesis was also observed in human primary fibroblasts that underwent replicative senescence. We also explored the consequences of inhibiting fatty acid synthesis in proliferating non-transformed cells. Using shRNA technology, we knocked down ACC1 in human fibroblasts. Interestingly, this metabolic perturbation was sufficient to arrest proliferation and trigger the appearance of several markers of the DDR and increase senescence associated beta-galactosidase activity. Reactive oxygen species and p38 mitogen activated protein kinase phosphorylation participated in the induction of senescence. Similar results were obtained upon silencing of fatty acid synthase (FAS) expression. Together our results point towards a tight coordination of fatty acid synthesis and cell proliferation in human fibroblasts. (C) 2016 Elsevier Inc. All rights reserved. C1 [Marmisolle, Ines; Martinez, Jennyfer; Mastrogiovanni, Mauricio; Castro, Laura; Trostchansky, Andres; Quijano, Celia] Univ Republica, Ctr Free Radical & Biomed Res, Fac Med, Montevideo 11800, Uruguay. [Marmisolle, Ines; Martinez, Jennyfer; Mastrogiovanni, Mauricio; Castro, Laura; Trostchansky, Andres; Quijano, Celia] Univ Republica, Fac Med, Dept Bioquim, Montevideo, Uruguay. [Liu, Jie; Fergusson, Maria M.; Rovira, Ilsa I.; Cao, Liu; Finkel, Toren] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. [Moreno, Maria] Univ Republica, Fac Med, Inst Higiene, Dept Desarrollo Biotecnol,Lab Vaccine Res, Montevideo, Uruguay. [Cao, Liu] China Med Univ, Key Lab Med Cell Biol, Minist Educ, Shenyang, Peoples R China. RP Quijano, C (reprint author), Univ Republica, Ctr Free Radical & Biomed Res, Fac Med, Montevideo 11800, Uruguay.; Quijano, C (reprint author), Univ Republica, Fac Med, Dept Bioquim, Montevideo, Uruguay.; Finkel, T (reprint author), NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. EM finkelt@nhlbi.nih.gov; celiq@fmed.edu.uy FU NIH; Fondo Clemente Estable-ANII [FCE_6381]; CSIC I + D [47]; Programa de Desarrollo de las Ciencias Basicas (PEDE-CIBA); Espacio Interdisciplinario Centros; UDELAR; CSIC grupos I + D [767, 563]; CSIC Iniciacion; ANII FX This work was supported by NIH Intramural funds awarded to TF; Fondo Clemente Estable-ANII (FCE_6381) and CSIC I + D 2012 (ID 47) and Programa de Desarrollo de las Ciencias Basicas (PEDE-CIBA) to CQ; Espacio Interdisciplinario Centros, UDELAR 2015 to CQ LC and AT; CSIC grupos I + D 2014 (767) to LC; CSIC grupos I + D 2014 (563) to AT and CSIC Iniciacion to IM and JM. IM and JM have scholarships from the ANII. NR 48 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 EI 1096-0384 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JAN 1 PY 2017 VL 613 BP 12 EP 22 DI 10.1016/j.abb.2016.10.016 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA EI5VM UT WOS:000392564400002 PM 27983949 ER PT J AU Beyer, AM Zinkevich, N Miller, B Liu, Y Wittenburg, AL Mitchell, M Galdieri, R Sorokin, A Gutterman, DD AF Beyer, Andreas M. Zinkevich, Natalya Miller, Bradley Liu, Yanping Wittenburg, April L. Mitchell, Michael Galdieri, Ralph Sorokin, Andrey Gutterman, David D. TI Transition in the mechanism of flow-mediated dilation with aging and development of coronary artery disease SO BASIC RESEARCH IN CARDIOLOGY LA English DT Article DE Vasodilation; Coronary artery disease; Flow-mediated dilation; Microvasculature ID NITRIC-OXIDE; ENDOTHELIAL DYSFUNCTION; HYDROGEN-PEROXIDE; HUMAN MICROCIRCULATION; RESISTANCE VESSELS; RESPONSES; VASODILATION; PRESSURE; ARTERIOLES; HYPERCHOLESTEROLEMIA AB In microvessels of patients with coronary artery disease (CAD), flow-mediated dilation (FMD) is largely dependent upon the endothelium-derived hyperpolarizing factor H2O2. The goal of this study is to examine the influence of age and presence or absence of disease on the mechanism of FMD. Human coronary or adipose arterioles (similar to 150 mu m diameter) were prepared for videomicroscopy. The effect of inhibiting COX [indomethacin (Indo) or NOS (L-NAME), eliminating H2O2 (polyethylene glycol-catalase (PEG-CAT)] or targeting a reduction in mitochondrial ROS with scavengers/inhibitors [Vitamin E ((mt)Vitamin E); phenylboronic acid ((mt)PBA)] was determined in children aged 0-18 years; young adults 19-55 years; older adults >55 years without CAD, and similarly aged adults with CAD. Indo eliminated FMD in children and reduced FMD in younger adults. This response was mediated mainly by PGI(2), as the prostacyclin-synthase-inhibitor trans-2-phenyl cyclopropylamine reduced FMD in children and young adults. L-NAME attenuated dilation in children and younger adults and eliminated FMD in older adults without CAD, but had no effect on vessels from those with CAD, where mitochondria-derived H2O2 was the primary mediator. The magnitude of dilation was reduced in older compared to younger adults independent of CAD. Exogenous treatment with a sub-dilator dose of NO blocked FMD in vessels from subjects with CAD, while prolonged inhibition of NOS in young adults resulted in a phenotype similar to that observed in disease. The mediator of coronary arteriolar FMD evolves throughout life from prostacyclin in youth, to NO in adulthood. With the onset of CAD, NO-inhibitable release of H2O2 emerges as the exclusive mediator of FMD. These findings have implications for use of pharmacological agents, such as nonsteroidal anti-inflammatory agents in children and the role of microvascular endothelium in cardiovascular health. C1 [Beyer, Andreas M.; Zinkevich, Natalya; Miller, Bradley; Sorokin, Andrey; Gutterman, David D.] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. [Beyer, Andreas M.; Wittenburg, April L.] Med Coll Wisconsin, Dept Physiol, Cardiovasc Ctr, HRC H4875,8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. [Zinkevich, Natalya] Carroll Univ, Dept Hlth & Med, Waukesha, WI USA. [Liu, Yanping] NIGMS, NIH, Bethesda, MD USA. [Mitchell, Michael] Childrens Hosp Wisconsin, Wauwatosa, WI USA. [Galdieri, Ralph] Wheaton Franciscan Healthcare, Wheaton, IL USA. [Gutterman, David D.] Clement J Zablocki VA Med Ctr Milwaukee, Milwaukee, WI USA. RP Beyer, AM (reprint author), Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA.; Beyer, AM (reprint author), Med Coll Wisconsin, Dept Physiol, Cardiovasc Ctr, HRC H4875,8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM abeyer@mcw.edu OI Beyer, Andreas /0000-0001-9129-7492 FU National Institutes of Health [R01-HL-113612, R21-OD-018306]; Clinical and Translational Science Award (CTSA) program of NCATS [8UL1TR000055] FX This work was supported by National Institutes of Health Grants R01-HL-113612 (to D. D. Gutterman), R21-OD-018306 (to A. M. Beyer). We received support from the Clinical and Translational Science Award (CTSA) program of NCATS for writing assistance (Glenn Krakower Grant 8UL1TR000055). NR 41 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0300-8428 EI 1435-1803 J9 BASIC RES CARDIOL JI Basic Res. Cardiol. PD JAN PY 2017 VL 112 IS 1 AR 5 DI 10.1007/s00395-016-0594-x PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EI2IM UT WOS:000392310300005 PM 27995364 ER PT J AU Shi, M O'Brien, KM Sandler, DP Taylor, JA Zaykin, DV Weinberg, CR AF Shi, Min O'Brien, Katie M. Sandler, Dale P. Taylor, Jack A. Zaykin, Dmitri V. Weinberg, Clarice R. TI Previous GWAS hits in relation to young-onset breast cancer SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Young-onset breast cancer; Genome-wide association study; Single-nucleotide polymorphism; Family-based genetic methods; Log-linear models; Genetic risk score ID GENOME-WIDE ASSOCIATION; COMMON GENETIC-VARIANTS; SUSCEPTIBILITY LOCI; RISK-FACTORS; AFRICAN-AMERICAN; COHORT CONSORTIUM; BAYESIAN-APPROACH; UNITED-STATES; IDENTIFIES 2; WOMEN AB Genome-wide association studies (GWAS) have identified dozens of single-nucleotide polymorphisms (SNPs) associated with breast cancer. Few studies focused on young-onset breast cancer, which exhibits etiologic and tumor-type differences from older-onset disease. Possible confounding by prenatal effects of the maternal genome has also not been considered. Using a family-based design for breast cancer before age 50, we assessed the relationship between breast cancer and 77 GWAS-identified breast cancer risk SNPs. We estimated relative risks (RR) for inherited and maternally mediated genetic effects. We also used published RR estimates to calculate genetic risk scores and model joint effects. Seventeen of the candidate SNPs were nominally associated with young-onset breast cancer in our 1296 non-Hispanic white affected families (uncorrected p value < 0.05). Top-ranked SNPs included rs3803662-A (TOX3, RR = 1.39; p = 7.0 x 10(-6)), rs12662670-G (ESR1, RR = 1.56; p = 5.7 x 10(-4)), rs2981579-A (FGFR2, RR = 1.24; p = 0.002), and rs999737-G (RAD51B, RR = 1.37; p = 0.003). No maternally mediated effects were found. A risk score based on all 77 SNPs indicated that their overall relationship to young-onset breast cancer risk was more than additive (additive-fit p = 2.2 x 10(-7)) and consistent with a multiplicative joint effect (multiplicative-fit p = 0.27). With the multiplicative formulation, the case sister's genetic risk score exceeded that of her unaffected sister in 59% of families. The results of this family-based study indicate that no effects of previously identified risk SNPs were explained by prenatal effects of maternal variants. Many of the known breast cancer risk variants were associated with young-onset breast cancer, with evidence that TOX3, ESR1, FGFR2, and RAD51B are important for young-onset disease. C1 [Shi, Min; O'Brien, Katie M.; Zaykin, Dmitri V.; Weinberg, Clarice R.] NIEHS, Biostat & Computat Biol Branch, 111 TW Alexander Dr, Durham, NC 27709 USA. [Sandler, Dale P.; Taylor, Jack A.] NIEHS, Epidemiol Branch, 111 TW Alexander Fr, Durham, NC 27709 USA. RP Weinberg, CR (reprint author), NIEHS, Biostat & Computat Biol Branch, 111 TW Alexander Dr, Durham, NC 27709 USA. EM weinber2@niehs.nih.gov OI taylor, jack/0000-0001-5303-6398; Sandler, Dale/0000-0002-6776-0018 FU Intramural Research Program of the NIH; National Institute of Environmental Health Sciences [Z01-ES044005, Z01-ES102245]; Susan G. Komen for the Cure [FAS0703856] FX This work was supported by the Intramural Research Program of the NIH, the National Institute of Environmental Health Sciences (project Z01-ES044005 to DPS and project Z01-ES102245 to CRW) and Susan G. Komen for the Cure (grant FAS0703856 to CRW). NR 81 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JAN PY 2017 VL 161 IS 2 BP 333 EP 344 DI 10.1007/s10549-016-4053-z PG 12 WC Oncology SC Oncology GA EI3IZ UT WOS:000392385100014 PM 27848153 ER PT J AU Cassler, NM Brownell, I AF Cassler, N. M. Brownell, I. TI PD-1 checkpoint blockade is an emerging treatment for Merkel cell carcinoma SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Editorial Material ID PEMBROLIZUMAB C1 [Cassler, N. M.] Walter Reed Natl Mil Med Ctr, Dept Dermatol, 8901 Wisconsin Ave, Bethesda, MD 20889 USA. [Brownell, I.] NCI, Dermatol Branch, NIH, 10 Ctr Dr,13N202, Bethesda, MD 20892 USA. RP Brownell, I (reprint author), NCI, Dermatol Branch, NIH, 10 Ctr Dr,13N202, Bethesda, MD 20892 USA. EM isaac.brownell@nih.gov OI Brownell, Isaac/0000-0002-0090-9914 NR 4 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-0963 EI 1365-2133 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD JAN PY 2017 VL 176 IS 1 BP 18 EP 18 DI 10.1111/bjd.14828 PG 1 WC Dermatology SC Dermatology GA EI4OV UT WOS:000392474100028 PM 28098367 ER PT J AU Nathan, N Burke, K Moss, J Darling, TN AF Nathan, N. Burke, K. Moss, J. Darling, T. N. TI A diagnostic and management algorithm for individuals with an isolated skin finding suggestive of tuberous sclerosis complex SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Letter ID CONSENSUS CONFERENCE; RECOMMENDATIONS C1 [Nathan, N.; Darling, T. N.] Uniformed Serv Univ Hlth Sci, Dept Dermatol, Bethesda, MD 20814 USA. [Nathan, N.; Moss, J.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Burke, K.] Madigan Army Med Ctr, Dept Dermatol, Tacoma, WA 98431 USA. RP Darling, TN (reprint author), Uniformed Serv Univ Hlth Sci, Dept Dermatol, Bethesda, MD 20814 USA. EM thomas.darling@usuhs.edu OI Darling, Thomas/0000-0002-5161-1974 FU National Institutes of Health (NIH), National Heart, Lung, and Blood Institute, Bethesda, MD, U.S.A.; NIH; Pfizer Inc.; Doris Duke Charitable Foundation; Alexandria Real Estate Equities, Inc.; Howard Hughes Medical Institute; Doris Duke Charitable Foundation [2014088] FX J.M. was supported by the Intramural Research Program, National Institutes of Health (NIH), National Heart, Lung, and Blood Institute, Bethesda, MD, U.S.A. This research was made possible 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 Pfizer Inc., the Doris Duke Charitable Foundation, the Alexandria Real Estate Equities, Inc., and Mr and Mrs Joel S. Marcus, and the Howard Hughes Medical Institute, as well as other private donors. This work was supported by Grant 2014088 from the Doris Duke Charitable Foundation. NR 14 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-0963 EI 1365-2133 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD JAN PY 2017 VL 176 IS 1 BP 220 EP 223 DI 10.1111/bjd.14724 PG 4 WC Dermatology SC Dermatology GA EI4OV UT WOS:000392474100053 PM 27167640 ER PT J AU Kunos, CA Chu, E Beumer, JH Sznol, M Ivy, SP AF Kunos, Charles A. Chu, Edward Beumer, Jan H. Sznol, Mario Ivy, S. Percy TI Phase I trial of daily triapine in combination with cisplatin chemotherapy for advanced-stage malignancies SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Triapine; Cisplatin; Phase I clinical trial; Advanced malignancies; Dose-limiting toxicity; Maximum tolerated dose; Oral bioavailability ID RIBONUCLEOTIDE REDUCTASE INHIBITION; HUMAN CERVICAL CANCERS; 3-AMINOPYRIDINE-2-CARBOXALDEHYDE THIOSEMICARBAZONE 3-AP; ONCOLOGY-GROUP; RADIATION AB Advanced-stage malignancies have increased deoxyribonucleotide demands in DNA replication and repair, making deoxyribonucleotide supply a potential exploitable target for therapy based on ribonucleotide reductase (RNR) inhibition. A dose-finding phase I trial was conducted of intravenous (i.v.) triapine, a small-molecule RNR inhibitor, and cisplatin chemotherapy in patients with advanced-stage solid tumor malignancies. Patients received dose-finding levels of i.v. triapine (48-96 mg/m(2)) and i.v. cisplatin (20-75 mg/m(2)) on 1 of 3 different schedules. The primary endpoint was to identify the maximum tolerated dose of a triapine-cisplatin combination. Secondary endpoints included the rate of triapine-cisplatin objective response and the pharmacokinetics and bioavailability of a single oral triapine dose. (Clinicaltrials.gov number, NCT00024323). The MTD was 96 mg/m(2) triapine daily days 1-4 and 75 mg/m(2) cisplatin split over day 2 and day 3. Frequent grade 3 or 4 adverse events included fatigue, dyspnea, leukopenia, thrombocytopenia, and electrolyte abnormalities. No objective responses were observed; 5 (50%) of 10 patients treated at the MTD had stable disease. Pharmacokinetics indicated an oral triapine bioavailability of 88%. The triapine-cisplatin combination may be given safely in patients with advanced-stage solid tumor malignancies. On the basis of these results, a phase I trial adequately powered to evaluate oral triapine bioavailability in women with advanced-stage uterine cervix or vulvar cancers is underway. C1 [Kunos, Charles A.; Ivy, S. Percy] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Chu, Edward; Beumer, Jan H.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Beumer, Jan H.] Univ Pittsburgh, Inst Canc, Canc Therapeut Program, Pittsburgh, PA USA. [Beumer, Jan H.] Univ Pittsburgh, Sch Pharm, Pittsburgh, PA USA. [Sznol, Mario] Yale Univ, Sch Med, New Haven, CT USA. [Sznol, Mario] Yale Canc Ctr, New Haven, CT USA. [Kunos, Charles A.] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag,NIH, 9609 Med Ctr Dr,MSC 9739, Bethesda, MD 20892 USA. RP Kunos, CA (reprint author), NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA.; Kunos, CA (reprint author), NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag,NIH, 9609 Med Ctr Dr,MSC 9739, Bethesda, MD 20892 USA. EM charles.kunos@nih.gov OI Beumer, Jan/0000-0002-8978-9401 FU Vion Pharmaceuticals, Incorporated [CLI-021] FX This study was funded by Vion Pharmaceuticals, Incorporated (Contract Number CLI-021). NR 19 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 EI 1432-0843 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD JAN PY 2017 VL 79 IS 1 BP 201 EP 207 DI 10.1007/s00280-016-3200-x PG 7 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA EI2MX UT WOS:000392322700022 PM 27878356 ER PT J AU Dao, K Lu, YM Peer, CJ Figg, WD Stadelmann, R Burnier, M Buclin, T Kissling, S AF Dao, Kim Lu, Yimin Peer, Cody J. Figg, William D. Stadelmann, Raphael Burnier, Michel Buclin, Thierry Kissling, Sebastien TI Pharmacokinetics of lenalidomide during high cut-off dialysis in a patient with multiple myeloma and renal failure SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE High-flux dialysis; High cut-off membrane; Lenalidomide; Pharmacokinetics ID HEMODIALYSIS; DEXAMETHASONE AB High cut-off dialysis, increasingly used in multiple myeloma patients, is susceptible to influence anticancer drug elimination. We report about lenalidomide disposition in a patient on high cut-off dialysis for renal failure secondary to myeloma cast nephropathy. The patient received a higher dosage of lenalidomide (5 mg b.i.d.), owing to concerns about a potential decrease in lenalidomide exposure during dialysis sessions. A set of blood samples was taken in order to develop a pharmacokinetic model accounting for lenalidomide concentrations in this setting. According to our model, the area under the curve was 3273 A mu g h/L, i.e., 60% higher than expected under usual dosage (25 mg q.d.) with normal renal function. Despite this, the patient did not develop major hematological toxicity. Lenalidomide doses of 5 mg b.i.d. led to high exposure in a patient with renal failure undergoing high cut-off dialysis. Yet, the dosage of 5 mg q.d. recommended in conventional dialysis would probably be adequate in such patients. C1 [Dao, Kim; Buclin, Thierry] Univ Lausanne Hosp, CHUV, Dept Labs, Div Clin Pharmacol,Biomed, Rue Bugnon 17, CH-1011 Lausanne, Switzerland. [Dao, Kim; Lu, Yimin; Stadelmann, Raphael; Burnier, Michel; Buclin, Thierry; Kissling, Sebastien] Univ Lausanne, Rue Bugnon 17, CH-1011 Lausanne, Switzerland. [Lu, Yimin; Burnier, Michel; Kissling, Sebastien] Univ Lausanne Hosp, Dept Med, Serv Nephrol, Lausanne, Switzerland. [Peer, Cody J.; Figg, William D.] NCI, Clin Pharmacol Program, Ctr Canc Res, Bethesda, MD 20892 USA. [Stadelmann, Raphael] Univ Lausanne Hosp, Dept Oncol, Div Hematol, Lausanne, Switzerland. RP Dao, K (reprint author), Univ Lausanne Hosp, CHUV, Dept Labs, Div Clin Pharmacol,Biomed, Rue Bugnon 17, CH-1011 Lausanne, Switzerland.; Dao, K (reprint author), Univ Lausanne, Rue Bugnon 17, CH-1011 Lausanne, Switzerland. EM kim.dao@chuv.ch; Yimin.Lu@unil.ch; cody.peer@nih.gov; wf13e@nih.gov; Raphael.Stadelmann@chuv.ch; Michel.Burnier@chuv.ch; Thierry.Buclin@chuv.ch; Sebastien.Kissling@chuv.ch OI Dao, Kim/0000-0002-6033-3435 NR 9 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 EI 1432-0843 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD JAN PY 2017 VL 79 IS 1 BP 215 EP 218 DI 10.1007/s00280-016-3219-z PG 4 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA EI2MX UT WOS:000392322700024 PM 27988790 ER PT J AU Shirota, H Klinman, DM Ito, SE Ito, H Kubo, M Ishioka, C AF Shirota, Hidekazu Klinman, Dennis M. Ito, Shuku-ei Ito, Hiroyasu Kubo, Masato Ishioka, Chikashi TI IL4 from T Follicular Helper Cells Downregulates Antitumor Immunity SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID DRAINING LYMPH-NODES; TUMOR MICROENVIRONMENT; ESTABLISHED MELANOMA; PULMONARY METASTASIS; DENDRITIC CELLS; GASTRIC-CANCER; BREAST-CANCER; NKT CELLS; IN-VIVO; ROLES AB Immune cells constitute a large fraction of the tumor microenvironment and modulate tumor progression. Clinical data indicate that chronic inflammation is present at tumor sites and that IL4 in particular is upregulated. Here, we demonstrate that T follicular helper (Tfh) cells arise in tumor-draining lymph nodes where they produce an abundance of IL4. Deletion of IL4-expressing Tfh cells improves antitumor immunity, delays tumor growth, and reduces the generation of immunosuppressive myeloid cells in the lymph nodes. These findings suggest that IL4 from Tfh cells affects antitumor immunity and constitutes an attractive therapeutic target to reduce immunosuppression in the tumor microenvironment, and thus enhance the efficacy of cancer immunotherapy. Cancer Immunol Res; (C) 2016 AACR. C1 [Shirota, Hidekazu; Ito, Shuku-ei; Ishioka, Chikashi] Tohoku Univ Hosp, Dept Clin Oncol, Sendai, Miyagi, Japan. [Klinman, Dennis M.] NCI, Canc & Inflammat Program, Frederick, MD 21701 USA. [Ito, Hiroyasu] Gifu Univ, Dept Informat Clin Med, Grad Sch Med, Gifu, Japan. [Kubo, Masato] Tokyo Univ Sci, Res Inst Biol Sci, Div Mol Pathol, Chiba, Japan. RP Shirota, H (reprint author), Tohoku Univ Hosp, Aoba Ku, 1-1 Seiryo Machi, Sendai, Miyagi 9808574, Japan. EM hidekazu.shirota.e1@tohoku.ac.jp FU Intramural Research Program of the National Cancer Institute of the National Institutes of Health, USA; Ministry of Education, Culture, Sports, Science and Technology (MEXT) KAKENHI, Japan FX This work was supported by the Intramural Research Program of the National Cancer Institute of the National Institutes of Health, USA and the Ministry of Education, Culture, Sports, Science and Technology (MEXT) KAKENHI, Japan. NR 52 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 2326-6066 EI 2326-6074 J9 CANCER IMMUNOL RES JI Cancer Immunol. Res. PD JAN PY 2017 VL 5 IS 1 BP 61 EP 71 DI 10.1158/2326-6066.CIR-16-0113 PG 11 WC Oncology; Immunology SC Oncology; Immunology GA EI1MD UT WOS:000392240600007 PM 27920023 ER PT J AU Layh-Schmitt, G Lu, SJ Navid, F Brooks, SR Lazowick, E Davis, KM Montagna, C Gadina, M Colbert, RA AF Layh-Schmitt, Gerlinde Lu, Shajia Navid, Fatemeh Brooks, Stephen R. Lazowick, Emily Davis, Kathryn M. Montagna, Cristina Gadina, Massimo Colbert, Robert A. TI Generation and differentiation of induced pluripotent stem cells reveal ankylosing spondylitis risk gene expression in bone progenitors SO CLINICAL RHEUMATOLOGY LA English DT Article DE Bone; Rheumatic diseases; Spondyloarthritis; Tissues ormodels ID IMMUNE-MEDIATED DISEASES; AXIAL SPONDYLOARTHRITIS; AMINOPEPTIDASES; SCLEROSIS; PROTEINS; INSIGHTS; LINES; NRF2 AB Axial spondyloarthritis (axSpA), which encompasses ankylosing spondylitis, is a complex genetic disease. Aberrant bone formation is a key feature of pathogenesis that can lead to ankylosis of the spine. Our objective is to determine, whether genes whose variants confer susceptibility to AS are expressed in bone progenitors like mesenchymal stem cells (MSCs). Since MSCs from bone marrow is difficult to obtain, we first examined, whether MSCs can be derived from induced pluripotent stem cells (iPSCs). Dermal fibroblasts of two axSpA patients and one healthy control were reprogrammed into iPSCs using a Sendai virus vector encoding pluripotency genes. Pluripotency of iPSCs was examined by embryoid body formation and by testing for stem cell specific gene and protein expression using RT-PCR and immuno fluorescence. iPSCs were differentiated into MSCs by a TGF inhibitor. MSCs were characterized by flow cytometry using lineage specific antibodies and by their capacity to develop into chondrocytes, adipocytes, and osteoblasts in lineage-specific medium. RNA-seq was applied to determine genome-wide gene expression patterns in MSCs, iPSCs, and blood. We show for the first time, that expression levels of several AS susceptibility genes (EDIL3, ANO6, HAPLN1, ANTXR2) involved in bone formation are significantly elevated in MSCs (2-15-fold; p <= 0.05) compared to blood or iPSCs and demonstrate that iPSC-derived MSCs can be differentiated into osteoblasts, chondrocytes, and adipocytes. We conclude, MSCs generated from patient fibroblast-derived iPSC lines are useful tools for studying functional genomics of risk genes associated with bone formation in AS pathogenesis. C1 [Layh-Schmitt, Gerlinde; Navid, Fatemeh; Lazowick, Emily; Colbert, Robert A.] NIAMS, Pediat Translat Res Branch, NIH, Bldg 10 CRC,Rm 1-5132,10 Ctr Dr MSC 1102, Bethesda, MD 20892 USA. [Lu, Shajia; Davis, Kathryn M.; Gadina, Massimo] NIAMS, Translat Immunol Sect, Off Sci & Technol, NIH, Bethesda, MD USA. [Brooks, Stephen R.] NIAMS, Biodata Min & Discovery Sect, Off Sci & Technol, NIH, Bethesda, MD USA. [Montagna, Cristina] Albert Einstein Coll Med, Dept Genet, Bronx, NY 10467 USA. RP Layh-Schmitt, G (reprint author), NIAMS, Pediat Translat Res Branch, NIH, Bldg 10 CRC,Rm 1-5132,10 Ctr Dr MSC 1102, Bethesda, MD 20892 USA. EM Layhschmittg@mail.nih.gov; lushajia@ep.niams.nih.gov; navidf2@mail.nih.gov; stephen.brooks@nih.gov; emily.lazowick@nih.gov; davis.kathrynm@gmail.com; cristina.montagna@einstein.yu.edu; gadinama@mail.nih.gov; colbertr@mail.nih.gov FU NIAMS Intramural Research Program [Z01 AR041184] FX 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 Gustavo Gutierrez-Cruz, NIAMS, National Instututes of Health, for his assistance with the RNA-seq technology. This work was supported by the NIAMS Intramural Research Program, Z01 AR041184. NR 43 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0770-3198 EI 1434-9949 J9 CLIN RHEUMATOL JI Clin. Rheumatol. PD JAN PY 2017 VL 36 IS 1 BP 143 EP 154 DI 10.1007/s10067-016-3469-5 PG 12 WC Rheumatology SC Rheumatology GA EI2IA UT WOS:000392309000019 PM 27864696 ER PT J AU Rathbun, AM Yau, MS Shardell, M Stuart, EA Hochberg, MC AF Rathbun, Alan M. Yau, Michelle S. Shardell, Michelle Stuart, Elizabeth A. Hochberg, Marc C. TI Depressive symptoms and structural disease progression in knee osteoarthritis: data from the Osteoarthritis Initiative SO CLINICAL RHEUMATOLOGY LA English DT Article DE Bone; Cartilage; Epidemiology; Osteoarthritis ID RHEUMATOID-ARTHRITIS; RISK-FACTORS; OLDER-ADULTS; PAIN; METAANALYSIS; STRESS; PREVALENCE; CHALLENGES; MANAGEMENT; PHENOTYPES AB Depressive symptoms are associated with increases in pain and functional limitations in knee osteoarthritis (OA). The aim was to determine whether depressive symptoms are also associated with greater structural knee OA progression. Four years of annual radiographic and clinical assessments from the Osteoarthritis Initiative were analyzed. The Center for Epidemiological Studies Depression Scale was used to identify depressive symptoms (threshold = >= 16) at the baseline visit. Propensity scores were used to match participants with and without baseline depressive symptoms on multiple potential confounders. Assessment of radiographic knee OA was based on changes in individual radiographic features, which included osteophyte (OST) grade and joint space narrowing (JSN) grade. Mixed effect models were used to examine structural progression between depressed and non-depressed participants with definitive radiographic knee OA. Depressive symptoms were significantly associated with a higher risk of OST progression (odds ratio [OR] = 1.74; 95% confidence interval [CI]: 1.01, 3.00) and a non-significant lower risk of JSN progression (OR = 0.40; 95% CI: 0.14, 1.15) 1 year after baseline. Conversely, there was a non-significant lower risk of OST progression (OR = 0.71; 95% CI: 0.28, 1.79) and higher risk of JSN progression (OR = 1.89; 95% CI: 0.71, 5.06) from year 3 to year 4 of follow-up. However, the patterns of OST progression and JSN progression were not significantly different between the depressed and non-depressed (P = 0.25 and 0.15, respectively). The findings provide no evidence that depressive symptoms have a detectable effect on changes in radiographic disease severity in knee OA. C1 [Rathbun, Alan M.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, 660 W Redwood St,Howard Hall Suite 200, Baltimore, MD 21201 USA. [Yau, Michelle S.] Harvard Med Sch, Hebrew SeniorLife Inst Aging Res, Boston, MA USA. [Shardell, Michelle] NIA, Translat Gerontol Branch, Bethesda, MD 20892 USA. [Stuart, Elizabeth A.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Hochberg, Marc C.] Univ Maryland, Sch Med, Dept Med, Div Rheumatol & Clin Immunol, Baltimore, MD 21201 USA. RP Rathbun, AM (reprint author), Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, 660 W Redwood St,Howard Hall Suite 200, Baltimore, MD 21201 USA. EM arathbun@epi.umaryland.edu FU National Institute on Aging [T32 AG000262] FX This research was supported by a training grant (T32 AG000262) from the National Institute on Aging. NR 40 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 0770-3198 EI 1434-9949 J9 CLIN RHEUMATOL JI Clin. Rheumatol. PD JAN PY 2017 VL 36 IS 1 BP 155 EP 163 DI 10.1007/s10067-016-3495-3 PG 9 WC Rheumatology SC Rheumatology GA EI2IA UT WOS:000392309000020 PM 27957619 ER PT J AU Saloustros, E Salpea, P Starost, M Liu, S Faucz, FR London, E Szarek, E Song, WJ Hussain, M Stratakis, CA AF Saloustros, Emmanouil Salpea, Paraskevi Starost, Matthew Liu, Sissi Faucz, Fabio R. London, Edra Szarek, Eva Song, Woo-Jin Hussain, Mehboob Stratakis, Constantine A. TI Prkar1a gene knockout in the pancreas leads to neuroendocrine tumorigenesis SO ENDOCRINE-RELATED CANCER LA English DT Article DE mouse model; neuroendocrine tumors; pancreas; metastasis; PRKAR1A ID SUBUNIT TYPE 1A; CARNEY COMPLEX; REGULATORY SUBUNIT; MOLECULAR-GENETICS; DOWN-REGULATION; TUMORS; ENDOCRINE; CELLS; DIFFERENTIATION; MUTATIONS AB Carney complex (CNC) is a rare disease associated with multiple neoplasias, including a predisposition to pancreatic tumors; it is caused most frequently by the inactivation of the PRKAR1A gene, a regulator of the cyclic AMP (cAMP)-dependent kinase (PKA). The method used was to create null alleles of prkar1a in mouse cells expressing pdx1 (Delta-Prkar1a). We found that these mice developed endocrine or mixed endocrine/acinar cell carcinomas with 100% penetrance by the age of 4-5 months. Malignant behavior of the tumors was seen as evidenced by stromal invasion and metastasis to locoregional lymph nodes. Histologically, most tumors exhibited an organoid pattern as seen in the islet-cell tumors. Biochemically, the lesions exhibited high PKA activity, as one would expect from deleting prkar1a. The primary neuroendocrine nature of these tumor cells was confirmed by immunohistochemical staining and electron microscopy, the latter revealing the characteristic granules. Although the Delta-Prkar1a mice developed hypoglycemia after overnight fasting, insulin and glucagon levels in the plasma were normal. Negative immunohistochemical staining for the most commonly produced peptides (insulin, c-peptide, glucagon, gastrin and somatostatin) suggested that these tumors were non-functioning. We hypothesize that the recently identified multipotent pdx1+/insulin- cell in adult pancreas, gives rise to endocrine or mixed endocrine/acinar pancreatic malignancies with complete prkar1a deficiency. In conclusion, this mouse model supports the role of prkar1a as a tumor suppressor gene in the pancreas and points to the PKA pathway as a possible therapeutic target for these lesions. C1 [Saloustros, Emmanouil; Salpea, Paraskevi; Liu, Sissi; Faucz, Fabio R.; London, Edra; Szarek, Eva; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet PDEGEN, NIH, Bethesda, MD USA. [Saloustros, Emmanouil; Salpea, Paraskevi; Liu, Sissi; Faucz, Fabio R.; London, Edra; Szarek, Eva; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Endocrinol Inter Inst Training Program, NIH, Bethesda, MD USA. [Starost, Matthew] NIH, Diagnost & Res Serv Branch, DVR, ORS, Bldg 10, Bethesda, MD 20892 USA. [Song, Woo-Jin; Hussain, Mehboob] Johns Hopkins Univ, Div Metab, Dept Pediat, Baltimore, MD USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet PDEGEN, NIH, Bethesda, MD USA.; Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Endocrinol Inter Inst Training Program, NIH, Bethesda, MD USA. EM stratakc@mail.nih.gov FU research project of Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA [Z01-HD008920]; National Institutes of Health [DK101591, DK081472, DK079637]; Hellenic Society of Medical Oncology FX This work was supported by the research project Z01-HD008920 (Principal Investigator: Dr Constantine A Stratakis) of the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA, by the DK101591, DK081472, DK079637 grants (Principal Investigator: Mehboob Hussain) of the National Institutes of Health and by a grant from the Hellenic Society of Medical Oncology (to Dr Saloustros). NR 32 TC 0 Z9 0 U1 1 U2 1 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 JAN PY 2017 VL 24 IS 1 BP 31 EP 40 DI 10.1530/ERC-16-0443 PG 10 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA EI1BC UT WOS:000392209000006 PM 27803029 ER PT J AU Gruzieva, O Xu, CJ Breton, CV Annesi-Maesano, I Anto, JM Auffray, C Ballereau, S Bellander, T Bousquet, J Bustamante, M Charles, MA de Kluizenaar, Y den Dekker, HT Duijts, L Felix, JF Gehring, U Guxens, M Jaddoe, VVW Jankipersadsing, SA Merid, SK Kere, J Kumar, A Lemonnier, N Lepeule, J Nystad, W Page, CM Panasevich, S Postma, D Slama, R Sunyer, J Soderhall, C Yao, J London, SJ Pershagen, G Koppelman, GH Melen, E AF Gruzieva, Olena Xu, Cheng-Jian Breton, Carrie V. Annesi-Maesano, Isabella Anto, Josep M. Auffray, Charles Ballereau, Stephane Bellander, Tom Bousquet, Jean Bustamante, Mariona Charles, Marie-Aline de Kluizenaar, Yvonne den Dekker, Herman T. Duijts, Liesbeth Felix, Janine F. Gehring, Ulrike Guxens, Monica Jaddoe, Vincent V. W. Jankipersadsing, Soesma A. Merid, Simon Kebede Kere, Juha Kumar, Ashish Lemonnier, Nathanael Lepeule, Johanna Nystad, Wenche Page, Christian Magnus Panasevich, Sviatlana Postma, Dirkje Slama, Remy Sunyer, Jordi Soderhall, Cilla Yao, Jin London, Stephanie J. Pershagen, Goran Koppelman, Gerard H. Melen, Erik TI Epigenome-Wide Meta-Analysis of Methylation in Children Related to Prenatal NO2 Air Pollution Exposure SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID POLYCYCLIC AROMATIC-HYDROCARBONS; DNA METHYLATION; QUANTILE NORMALIZATION; RESPIRATORY HEALTH; OXIDATIVE STRESS; MATERNAL SMOKING; CORD BLOOD; EARLY-LIFE; ASTHMA; ASSOCIATION AB BACKGROUND: Prenatal exposure to air pollution is considered to be associated with adverse effects on child health. This may partly be mediated by mechanisms related to DNA methylation. OBJECTIVES: We investigated associations between exposure to air pollution, using nitrogen dioxide (NO2) as marker, and epigenome-wide cord blood DNA methylation. METHODS: We meta-analyzed the associations between NO2 exposure at residential addresses during pregnancy and cord blood DNA methylation (Illumina 450K) in four European and North American studies (n = 1,508) with subsequent look-up analyses in children ages 4 (n = 733) and 8 (n = 786) years. Additionally, we applied a literature-based candidate approach for antioxidant and anti-inflammatory genes. To assess influence of exposure at the transcriptomics level, we related mRNA expression in blood cells to NO2 exposure in 4- (n = 111) and 16-year-olds (n = 239). RESULTS: We found epigenome-wide significant associations [false discovery rate (FDR) p < 0.05] between maternal NO2 exposure during pregnancy and DNA methylation in newborns for 3 CpG sites in mitochondria-related genes: cg12283362 (LONP1), cg24172570 (3.8 kbp upstream of HIBADH), and cg08973675 (SLC25A28). The associations with cg08973675 methylation were also significant in the older children. Further analysis of antioxidant and anti-inflammatory genes revealed differentially methylated CpGs in CAT and TPO in newborns (FDR p < 0.05). NO2 exposure at the time of biosampling in childhood had a significant impact on CAT and TPO expression. CONCLUSIONS: NO2 exposure during pregnancy was associated with differential offspring DNA methylation in mitochondria-related genes. Exposure to NO2 was also linked to differential methylation as well as expression of genes involved in antioxidant defense pathways. C1 [Gruzieva, Olena; Merid, Simon Kebede; Pershagen, Goran; Melen, Erik] Inst Environm Med, Karolinska Inst, Nobelsvag 13, S-E17177 Stockholm, Sweden. [Xu, Cheng-Jian] Univ Groningen, Univ Med Ctr Groningen, Groningen Res Inst Asthma & COPD GRIAC, Groningen, Netherlands. [Xu, Cheng-Jian] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Breton, Carrie V.] Univ Southern Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Annesi-Maesano, Isabella] INSERM, Dept Epidemiol Allerg & Resp Dis, Paris, France. [Bustamante, Mariona] ISGlobal, Ctr Res Environm Epidemiol CREAL, Barcelona, Spain. [Anto, Josep M.] IMIM Hosp Mar Med Res Inst, Barcelona, Spain. [Anto, Josep M.; Gehring, Ulrike; Jaddoe, Vincent V. W.; Merid, Simon Kebede; Kumar, Ashish] UPF, Barcelona, Spain. [Anto, Josep M.; Guxens, Monica; Sunyer, Jordi] CIBERESP, Barcelona, Spain. [Auffray, Charles; Ballereau, Stephane; Lemonnier, Nathanael] Univ Lyon, European Inst Syst Biol & Med, Lyon, France. [Bellander, Tom; Pershagen, Goran; Melen, Erik] Stockholm Cty Council, Ctr Occupat & Environm Med, Stockholm, Sweden. [Bousquet, Jean] Univ Montpellier, CHU Montpellier, Montpellier, France. [Bustamante, Mariona; Jankipersadsing, Soesma A.; Kumar, Ashish] Barcelona Inst Sci & Technol, Ctr Genom Regulat CRG, Barcelona, Spain. [Charles, Marie-Aline] Univ Paris 05, INSERM, CRESS UMR1153, Ctr Rech Epidemiol & Stat Sorbonne Paris Cite,Ear, Villejuif, France. [de Kluizenaar, Yvonne] Netherlands Org Appl Sci Res TNO, Delft, Netherlands. [Jaddoe, Vincent V. W.] Generat R Study Grp, Delft, Netherlands. [Felix, Janine F.] Univ Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Duijts, Liesbeth; Jaddoe, Vincent V. W.] Univ Med Ctr, Med Ctr, Erasmus MC, Dept Pediat, Rotterdam, Netherlands. [Ballereau, Stephane; Jankipersadsing, Soesma A.] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. [Auffray, Charles; Felix, Janine F.; Jankipersadsing, Soesma A.; Kumar, Ashish] Erasmus Univ Med Centre, Sophia Childrens Hosp, Dept Child & Adolescent Psychiat Psychol, Rotterdam, Netherlands. [den Dekker, Herman T.; Jaddoe, Vincent V. W.; Lepeule, Johanna] Karolinska Inst, Dept Biosci Nutr, Stockholm, Sweden. [Duijts, Liesbeth; Guxens, Monica] Swiss Trop & Publ Hlth Inst, Dept Publ Hlth Epidemiol, Unit Chron Dis Epidemiol, Basel, Switzerland. [Kumar, Ashish] Univ Basel, Basel, Switzerland. [Annesi-Maesano, Isabella; Bellander, Tom; Bousquet, Jean; de Kluizenaar, Yvonne] INSERM, Team Environm Epidemiol, Grenoble, France. [Bustamante, Mariona; Gehring, Ulrike] Univ Grenoble Alpes, IAB U1209, Grenoble, France. [Annesi-Maesano, Isabella; Anto, Josep M.; Bellander, Tom; Charles, Marie-Aline] Norwegian Inst Publ Hlth, Div Phys & Mental Hlth, Oslo, Norway. [Gehring, Ulrike; Kere, Juha; Postma, Dirkje; Soderhall, Cilla; London, Stephanie J.] Karolinska Inst, Dept Women & Childrens Hlth, Stockholm, Sweden. [Auffray, Charles; Bustamante, Mariona; den Dekker, Herman T.] NIEHS, Div Intramural Res, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. [Anto, Josep M.; Bousquet, Jean; Jaddoe, Vincent V. W.; Jankipersadsing, Soesma A.] Univ Groningen, Univ Med Ctr Groningen, Dept Pediat Pulmonol & Pediat Allergol, GRIAC,Beatrix Childrens Hosp, Groningen, Netherlands. [Guxens, Monica; Kere, Juha] Childrens Hosp, Stockholm, Sweden. RP Gruzieva, O (reprint author), Inst Environm Med, Karolinska Inst, Nobelsvag 13, S-E17177 Stockholm, Sweden. EM olena.gruzieva@ki.se OI London, Stephanie/0000-0003-4911-5290 FU NIEHS NIH HHS [P30 ES007048] NR 57 TC 3 Z9 3 U1 6 U2 6 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JAN PY 2017 VL 125 IS 1 BP 104 EP 110 DI 10.1289/EHP36 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA EI0WD UT WOS:000392195000014 PM 27448387 ER PT J AU Houck, KA Judson, RS Knudsen, TB Martin, MT Richard, AM Crofton, KM Simeonov, A Paules, RS Bucher, JR Thomas, RS AF Houck, Keith A. Judson, Richard S. Knudsen, Thomas B. Martin, Matthew T. Richard, Ann M. Crofton, Kevin M. Simeonov, Anton Paules, Richard S. Bucher, John R. Thomas, Russell S. TI Comment on "On the Utility of ToxCast (TM) and ToxPi as Methods for Identifying New Obesogens" SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Letter ID ESTROGEN-RECEPTOR; PPAR-GAMMA; CHEMICALS; ASSAYS; PROGRAM; MODEL C1 [Houck, Keith A.; Judson, Richard S.; Knudsen, Thomas B.; Martin, Matthew T.; Richard, Ann M.; Crofton, Kevin M.; Thomas, Russell S.] US EPA, Natl Ctr Computat Toxicol, Off Res & Dev, Res Triangle Pk, NC 27705 USA. [Simeonov, Anton] NIH, Natl Ctr Advancing Translat Sci, US Dept HHS, Bldg 10, Bethesda, MD 20892 USA. [Paules, Richard S.; Bucher, John R.] NIEHS, Natl Toxicol Program, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. RP Thomas, RS (reprint author), US EPA, Natl Ctr Computat Toxicol, Off Res & Dev, Res Triangle Pk, NC 27705 USA. EM thomas.russell@epa.gov NR 16 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 JAN PY 2017 VL 125 IS 1 BP A8 EP A11 DI 10.1289/EHP881 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA EI0WD UT WOS:000392195000028 PM 28055944 ER PT J AU Rosenthal, J Balakrishnan, K Bruce, N Chambers, D Graham, J Jack, D Kline, L Masera, O Mehta, S Mercado, IR Neta, G Pattanayak, S Puzzolo, E Petach, H Punturieri, A Rubinstein, A Sage, M Sturke, R Shankar, A Sherr, K Smith, K Yadama, G AF Rosenthal, Joshua Balakrishnan, Kalpana Bruce, Nigel Chambers, David Graham, Jay Jack, Darby Kline, Lydia Masera, Omar Mehta, Sumi Ruiz Mercado, Ilse Neta, Gila Pattanayak, Subhrendu Puzzolo, Elisa Petach, Helen Punturieri, Antonello Rubinstein, Adolfo Sage, Michael Sturke, Rachel Shankar, Anita Sherr, Kenny Smith, Kirk Yadama, Gautam TI Implementation Science to Accelerate Clean Cooking for Public Health SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID EVALUATING COMPLEX INTERVENTIONS; RESEARCH-COUNCIL GUIDANCE; SUSTAINED USE; SERVICES RESEARCH; GLOBAL BURDEN; STOVE USE; COOKSTOVES; DYNAMICS; FRAMEWORK; BARRIERS AB Clean cooking has emerged as a major concern for global health and development because of the enormous burden of disease caused by traditional cookstoves and fires. The World Health Organization has developed new indoor air quality guidelines that few homes will be able to achieve without replacing traditional methods with modern clean cooking technologies, including fuels and stoves. However, decades of experience with improved stove programs indicate that the challenge of modernizing cooking in impoverished communities includes a complex, multi-sectoral set of problems that require implementation research. The National Institutes of Health, in partnership with several government agencies and the Global Alliance for Clean Cookstoves, has launched the Clean Cooking Implementation Science Network that aims to address this issue. In this article, our focus is on building a knowledge base to accelerate scale-up and sustained use of the cleanest technologies in low-and middle-income countries. Implementation science provides a variety of analytical and planning tools to enhance effectiveness of clinical and public health interventions. These tools are being integrated with a growing body of knowledge and new research projects to yield new methods, consensus tools, and an evidence base to accelerate improvements in health promised by the renewed agenda of clean cooking. C1 [Rosenthal, Joshua; Kline, Lydia; Sturke, Rachel] NIH, Div Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 16, Bethesda, MD 20892 USA. [Balakrishnan, Kalpana] Sri Ramachandra Univ, Dept Environm Hlth Engn, Madras, Tamil Nadu, India. [Bruce, Nigel] Univ Liverpool, Dept Publ Hlth & Policy, Liverpool, Merseyside, England. [Chambers, David; Neta, Gila] NCI, NIH, Rockville, MD USA. [Graham, Jay] George Washington Univ, Dept Environm & Occupat Hlth, Washington, DC USA. [Jack, Darby] Columbia Univ, Dept Environm Hlth Sci, New York, NY USA. [Masera, Omar; Ruiz Mercado, Ilse] Univ Nacl Autonoma Mexico, Inst Invest Ecosistemas, Morelia, Michoacan, Mexico. [Mehta, Sumi] Global Alliance Clean Cookstoves, Washington, DC USA. [Pattanayak, Subhrendu] Duke Univ, Sanford Sch Publ Policy, Durham, NC USA. [Pattanayak, Subhrendu] Duke Univ, Nicholas Sch Environm, Durham, NC 27708 USA. [Puzzolo, Elisa] Global LPG Partnership, New York, NY USA. [Petach, Helen] US Agcy Int Dev, Washington, DC USA. [Punturieri, Antonello] NHLBI, Rockville, MD USA. [Rubinstein, Adolfo] Inst Clin Hlth Effectiveness, Buenos Aires, DF, Argentina. [Sage, Michael] Ctr Dis Control & Prevent, Atlanta, GA USA. [Shankar, Anita] Johns Hopkins Univ, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. [Sherr, Kenny] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Smith, Kirk] Univ Calif Berkeley, Dept Global Environm Hlth, Berkeley, CA 94720 USA. [Yadama, Gautam] Washington Univ, George Warren Brown Sch Social Work, St Louis, MO USA. RP Rosenthal, J (reprint author), NIH, Div Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 16, Bethesda, MD 20892 USA. EM joshua.rosenthal@nih.gov FU NIH Common Fund FX Funding for the ISN has been provided through an award from the NIH Common Fund. NR 50 TC 0 Z9 0 U1 14 U2 14 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JAN PY 2017 VL 125 IS 1 BP A3 EP A7 DI 10.1289/EHP1018 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA EI0WD UT WOS:000392195000027 PM 28055947 ER PT J AU Mutlu, E Cristy, T Graves, SW Hooth, MJ Waidyanatha, S AF Mutlu, Esra Cristy, Tim Graves, Steven W. Hooth, Michelle J. Waidyanatha, Suramya TI Characterization of aqueous formulations of tetra- and pentavalent forms of vanadium in support of test article selection in toxicology studies SO ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH LA English DT Article DE Sodium metavanadate; Vanadyl sulfate; Pentavalent vanadium; Tetravalent vanadium; Speciation; Oxovanadate; Oxidovanadate ID MASS-SPECTROMETRY; VANADATE; V-51; NMR; CHEMISTRY; DECAVANADATE; TOXICITY; SPECTROSCOPY; EQUILIBRIA; COMPLEXES AB Tetravalent (V-IV) and pentavalent (V-V) forms of vanadium were selected for testing by the National Toxicology Program via drinking water exposure due to potential human exposure. To aid in the test article selection, drinking water formulations (125-2000 mg/L) of vanadyl sulfate (V-IV), sodium orthovanadate, and sodium metavanadate (V-V) were characterized by ultraviolet/visible (UV/VIS) spectroscopy, mass spectrometry (MS), or V-51 nuclear magnetic resonance (NMR) spectroscopy. Aqueous formulations of orthovanadate, metavanadate, and vanadyl sulfate in general were basic, neutral, and acidic, respectively. Changes in vanadium speciation were investigated by adjusting formulation pH to acidic, neutral, or basic. There was no visible difference in UV/VIS spectra of pentavalent forms. NMR and MS analyses showed that the predominant oxidovanadate species in both ortho- and metavanadate formulations at basic and acidic pH, respectively, were the monomer and decamer, while, a mixture of oxidovanadates were present at neutral pH. Oxidovanadate species were not observed in vanadyl sulfate formulations at acidic pH but were observed at basic pH suggesting conversion of V-IV to V-V. These data suggest that formulations of both ortho- and metavanadate form similar oxidovanadate species in acidic, neutral and basic pH and exist mainly in the V-V form while vanadyl sulfate exists mainly as V-IV in acidic pH. Therefore, the formulation stability overtime was investigated only for sodium metavanadate and vanadyl sulfate. Drinking water formulations (50 and 2000 mg/L) of metavanadate (pH 7) and vanadyl sulfate (pH 3.5) were ae92 % of target concentration up to 42 days at 5 A degrees C and ambient temperature demonstrating the utility in toxicology studies. C1 [Mutlu, Esra; Hooth, Michelle J.; Waidyanatha, Suramya] NIEHS, Div Natl Toxicol Program, POB 12233,Mail Drop K2-07, Res Triangle Pk, NC 27709 USA. [Cristy, Tim; Graves, Steven W.] Battelle Mem Inst, 505 King Ave, Columbus, OH 43201 USA. RP Waidyanatha, S (reprint author), NIEHS, Div Natl Toxicol Program, POB 12233,Mail Drop K2-07, Res Triangle Pk, NC 27709 USA. EM waidyanathas@niehs.nih.gov FU National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, US Department of Health and Human Services [HHSN273201000016C] FX The authors are grateful to Mr. Brad Collins and Dr. Georgia Roberts for their review of this manuscript. This work was performed for the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, US Department of Health and Human Services, under contract no. HHSN273201000016C. NR 58 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0944-1344 EI 1614-7499 J9 ENVIRON SCI POLLUT R JI Environ. Sci. Pollut. Res. PD JAN PY 2017 VL 24 IS 1 BP 405 EP 416 DI 10.1007/s11356-016-7803-x PG 12 WC Environmental Sciences SC Environmental Sciences & Ecology GA EH9QK UT WOS:000392105700039 PM 27726079 ER PT J AU Miller, LR Marks, C Becker, JB Hurn, PD Chen, WJ Woodruff, T McCarthy, MM Sohrabji, F Schiebinger, L Wetherington, CL Makris, S Arnold, AP Einstein, G Miller, VM Sandberg, K Maier, S Cornelison, TL Clayton, JA AF Miller, Leah R. Marks, Cheryl Becker, Jill B. Hurn, Patricia D. Chen, Wei-Jung Woodruff, Teresa McCarthy, Margaret M. Sohrabji, Farida Schiebinger, Londa Wetherington, Cora Lee Makris, Susan Arnold, Arthur P. Einstein, Gillian Miller, Virginia M. Sandberg, Kathryn Maier, Susan Cornelison, Terri L. Clayton, Janine A. TI Considering sex as a biological variable in preclinical research SO FASEB JOURNAL LA English DT Review DE gender; methods; sex influences; sex differences ID MOUSE MODELS; BRAIN; BEHAVIOR; DISEASE; NUMBER; GENES AB In June 2015, the National Institutes of Health (NIH) released a Guide notice (NOT-OD-15-102) that highlighted the expectation of the NIH that the possible role of sex as a biologic variable be factored into research design, analyses, and reporting of vertebrate animal and human studies. Anticipating these guidelines, the NIH Office of Research on Women's Health, in October 2014, convened key stakeholders to discuss methods and techniques for integrating sex as a biologic variable in preclinical research. The workshop focused on practical methods, experimental design, and approaches to statistical analyses in the use of both male and female animals, cells, and tissues in preclinical research. Workshop participants also considered gender as a modifier of biology. This article builds on the workshop and is meant as a guide to preclinical investigators as they consider methods and techniques for inclusion of both sexes in preclinical research and is not intended to prescribe exhaustive/specific approaches for compliance with the new NIH policy.-Miller, L.R., Marks, C., Becker, J. B., Hurn, P. D., Chen, W.-J., Woodruff, T., McCarthy, M. M., Sohrabji, F., Schiebinger, L., Wetherington, C. L., Makris, S., Arnold, A. P., Einstein, G., Miller, V. M., Sandberg, K., Maier, S., Cornelison, T. L., Clayton, J. A. Considering sex as a biological variable in preclinical research. C1 [Miller, Leah R.; Maier, Susan; Cornelison, Terri L.; Clayton, Janine A.] NCI, Off Res Womens Hlth, Bethesda, MD 20892 USA. [Marks, Cheryl] NCI, Div Canc Biol, Bethesda, MD 20892 USA. [Wetherington, Cora Lee] NIDA, NIH, Bethesda, MD 20892 USA. [Becker, Jill B.] Univ Michigan, Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA. [Hurn, Patricia D.] Univ Michigan, Sch Nursing, Ann Arbor, MI 48109 USA. [Chen, Wei-Jung; Sohrabji, Farida] Texas A&M Hlth Sci Ctr, Dept Neurosci & Expt Therapeut, Bryan, TX USA. [Woodruff, Teresa] Northwestern Univ, Womens Hlth Res Inst, Chicago, IL 60611 USA. [McCarthy, Margaret M.] Univ Maryland, Dept Pharmacol, Baltimore, MD 21201 USA. [Schiebinger, Londa] Stanford Univ, Hist Sci, Stanford, CA 94305 USA. [Makris, Susan] US EPA, Off Res & Dev, Natl Ctr Environm Assessment, Washington, DC 20460 USA. [Arnold, Arthur P.] Univ Calif Los Angeles, Dept Integrat Biol & Physiol, Los Angeles, CA USA. [Arnold, Arthur P.] Univ Calif Los Angeles, Brain Res Inst, Neuroendocrinol Lab, Los Angeles, CA 90024 USA. [Einstein, Gillian] Univ Toronto, Dept Psychol, Toronto, ON, Canada. [Einstein, Gillian] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Einstein, Gillian] Womens Coll Res Inst, Toronto, ON, Canada. [Miller, Virginia M.] Mayo Clin, Dept Surg & Physiol, Rochester, MN USA. [Miller, Virginia M.] Mayo Clin, Dept Biomed Engn, Rochester, MN USA. [Sandberg, Kathryn] Georgetown Univ, Med Ctr, Dept Med, Washington, DC 20007 USA. [Sandberg, Kathryn] Georgetown Univ, Med Ctr, Ctr Study Sex Differences Hlth Aging & Dis, Washington, DC 20007 USA. RP Miller, LR (reprint author), NIH, Off Res Womens Hlth, 6707 Democracy Blvd,Suite 400, Bethesda, MD 20892 USA. EM leah.miller@nih.gov FU NHLBI NIH HHS [R01 HL119380]; NIA NIH HHS [P50 AG044170] NR 22 TC 1 Z9 1 U1 3 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD JAN PY 2017 VL 31 IS 1 BP 29 EP 34 DI 10.1096/fj.201600781R PG 6 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA EI0PW UT WOS:000392177600006 PM 27682203 ER PT J AU Raefsky, SM Mattson, MP AF Raefsky, Sophia M. Mattson, Mark P. TI Adaptive responses of neuronal mitochondria to bioenergetic challenges: Roles in neuroplasticity and disease resistance SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Review DE 3-hydroxybutyrate; Aerobic exercise; Autophagy; CREB; Hormesis; Intermittent fasting; Mitochondrial biogenesis; PGC-1 alpha ID TRAUMATIC BRAIN-INJURY; CORTICAL SYNAPTIC TERMINALS; REDUCES OXIDATIVE STRESS; TRANSGENIC MOUSE MODEL; CYTOCHROME-C-OXIDASE; AMYLOID BETA-PEPTIDE; GROWTH-FACTOR-I; ALZHEIMERS-DISEASE; PARKINSONS-DISEASE; CEREBRAL-ISCHEMIA AB An important concept in neurobiology is "neurons that fire together, wire together" which means that the formation and maintenance of synapses is promoted by activation of those synapses. Very similar to the effects of the stress of exercise on muscle cells, emerging findings suggest that neurons respond to activity by activating signaling pathways (e.g., Ca2+, CREB, PGC-1 alpha, NF-kappa B) that stimulate mitochondrial biogenesis and cellular stress resistance. These pathways are also activated by aerobic exercise and food deprivation, two bioenergetic challenges of fundamental importance in the evolution of the brains of all mammals, including humans. The metabolic 'switch' in fuel source from liver glycogen store-derived glucose to adipose cell-derived fatty acids and their ketone metabolites during fasting and sustained exercise, appears to be a pivotal trigger of both brain intrinsic and peripheral organ-derived signals that enhance learning and memory and underlying synaptic plasticity and neurogenesis. Brain-intrinsic extracellular signals include the excitatory neurotransmitter glutamate and the neurotrophic factor BDNF, and peripheral signals may include the liver-derived ketone 3-hydroxybutyrate and the muscle cell-derived protein irisin. Emerging findings suggest that fasting, exercise and an intellectually challenging lifestyle can protect neurons against the dysfunction and degeneration that they would otherwise suffer in acute brain injuries (stroke and head trauma) and neurodegenerative disorders including Alzheimer's, Parkinson's and Huntington's disease. Among the prominent intracellular responses of neurons to these bioenergetic challenges are up-regulation of antioxidant defenses, autophagy/mitophagy and DNA repair. A better understanding of such fundamental hormesis-based adaptive neuronal response mechanisms is expected to result in the development and implementation of novel interventions to promote optimal brain function and healthy brain aging. C1 [Raefsky, Sophia M.; Mattson, Mark P.] NIA, Lab Neurosci, Baltimore, MD 21224 USA. [Mattson, Mark P.] Johns Hopkins Univ, Dept Neurosci, Sch Med, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Lab Neurosci, 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. We thank Kristen Alexander for help with the preparation of illustrations. NR 205 TC 0 Z9 0 U1 28 U2 28 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 JAN PY 2017 VL 102 BP 203 EP 216 DI 10.1016/j.freeradbiomed.2016.11.045 PG 14 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA EI3AG UT WOS:000392361200017 PM 27908782 ER PT J AU Warren, WC Hillier, LW Tomlinson, C Minx, P Kremitzki, M Graves, T Markovic, C Bouk, N Pruitt, KD Thibaud-Nissen, F Schneider, V Mansour, TA Brown, CT Zimin, A Hawken, R Abrahamsen, M Pyrkosz, AB Morisson, M Fillon, V Vignal, A Chow, W Howe, K Fulton, JE Miller, MM Lovell, P Mello, CV Wirthlin, M Mason, AS Kuo, R Burt, DW Dodgson, JB Cheng, HH AF Warren, Wesley C. Hillier, LaDeana W. Tomlinson, Chad Minx, Patrick Kremitzki, Milinn Graves, Tina Markovic, Chris Bouk, Nathan Pruitt, Kim D. Thibaud-Nissen, Francoise Schneider, Valerie Mansour, Tamer A. Brown, C. Titus Zimin, Aleksey Hawken, Rachel Abrahamsen, Mitch Pyrkosz, Alexis B. Morisson, Mireille Fillon, Valerie Vignal, Alain Chow, William Howe, Kerstin Fulton, Janet E. Miller, Marcia M. Lovell, Peter Mello, Claudio V. Wirthlin, Morgan Mason, Andrew S. Kuo, Richard Burt, David W. Dodgson, Jerry B. Cheng, Hans H. TI A New Chicken Genome Assembly Provides Insight into Avian Genome Structure SO G3-GENES GENOMES GENETICS LA English DT Article DE Gallus gallus; genome assembly; MHC ID LEUKOCYTE RECEPTOR COMPLEX; LTR RETROTRANSPOSONS; GENE; SEQUENCE; MAP; IDENTIFICATION; ALIGNMENT; SOFTWARE; RESOURCE; DOMESTICATION AB The importance of the Gallus gallus (chicken) as a model organism and agricultural animal merits a continuation of sequence assembly improvement efforts. We present a new version of the chicken genome assembly (Gallus_gallus-5.0; GCA_000002315.3), built from combined long single molecule sequencing technology, finished BACs, and improved physical maps. In overall assembled bases, we see a gain of 183 Mb, including 16.4 Mb in placed chromosomes with a corresponding gain in the percentage of intact repeat elements characterized. Of the 1.21 Gb genome, we include three previously missing autosomes, GGA30, 31, and 33, and improve sequence contig length 10-fold over the previous Gallus_gallus-4.0. Despite the significant base representation improvements made, 138 Mb of sequence is not yet located to chromosomes. When annotated for gene content, Gallus_gallus-5.0 shows an increase of 4679 annotated genes (2768 noncoding and 1911 protein-coding) over those in Gallus_gallus-4.0. We also revisited the question of what genes are missing in the avian lineage, as assessed by the highest quality avian genome assembly to date, and found that a large fraction of the original set of missing genes are still absent in sequenced bird species. Finally, our new data support a detailed map of MHC-B, encompassing two segments: one with a highly stable gene copy number and another in which the gene copy number is highly variable. The chicken model has been a critical resource for many other fields of study, and this new reference assembly will substantially further these efforts. C1 [Warren, Wesley C.; Hillier, LaDeana W.; Tomlinson, Chad; Minx, Patrick; Kremitzki, Milinn; Graves, Tina; Markovic, Chris] Washington Univ, Sch Med, McDonnell Genome Inst, 4444 Forest Pk Blvd, St Louis, MO 63108 USA. [Bouk, Nathan; Pruitt, Kim D.; Thibaud-Nissen, Francoise; Schneider, Valerie] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Mansour, Tamer A.; Brown, C. Titus] Univ Calif Davis, Davis, CA 95616 USA. [Zimin, Aleksey] Univ Maryland, Inst Phys Sci & Technol, College Pk, MD 20742 USA. [Hawken, Rachel; Abrahamsen, Mitch] Cobb Vantress Inc, Siloam Springs, AR 72761 USA. [Pyrkosz, Alexis B.; Cheng, Hans H.] USDA ARS, Avian Dis & Oncol Lab, 3606 E Mt Hope Rd, E Lansing, MI 48823 USA. [Morisson, Mireille; Fillon, Valerie; Vignal, Alain] Univ Toulouse, Genet Physiol & Syst Elevage, INRA, Auzeville Castanet Tolos, France. [Chow, William; Howe, Kerstin] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Fulton, Janet E.] Hy Line Int, Dallas, IA 50063 USA. [Miller, Marcia M.] Beckman Res Inst, Duarte, CA 91010 USA. [Lovell, Peter; Mello, Claudio V.; Wirthlin, Morgan] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97239 USA. [Mason, Andrew S.; Kuo, Richard; Burt, David W.] Univ Edinburgh, Roslin Inst, Roslin EH25 9RG, Midlothian, Scotland. [Mason, Andrew S.; Kuo, Richard; Burt, David W.] Univ Edinburgh, Royal Dick Sch Vet Studies, Roslin EH25 9RG, Midlothian, Scotland. [Dodgson, Jerry B.] Michigan State Univ, Dept Microbiol & Mol Genet, E Lansing, MI 48824 USA. RP Warren, WC (reprint author), Washington Univ, Sch Med, McDonnell Genome Inst, 4444 Forest Pk Blvd, St Louis, MO 63108 USA.; Cheng, HH (reprint author), USDA ARS, Avian Dis & Oncol, 4279 E Mt Hope Rd, E Lansing, MI 48823 USA. EM wwarren@wustl.edu; hcheng@msu.edu OI Mansour, Tamer/0000-0002-4747-4241 FU United States Department of Agriculture-Agricultural Research Service [20136701521357]; NIH, National Library of Medicine FX We thank the McDonnell Genome Institute sequencing production group for all sequencing support. We acknowledge funding from the United States Department of Agriculture-Agricultural Research Service 20136701521357 to W.C.W. The work of NIH authors was supported by the Intramural Research Program of the NIH, National Library of Medicine. NR 51 TC 0 Z9 0 U1 8 U2 8 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD JAN PY 2017 VL 7 IS 1 BP 109 EP 117 DI 10.1534/g3.116.035923 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA EI0YE UT WOS:000392200800010 PM 27852011 ER PT J AU Bulger, DA Fukushige, T Yun, SJ Semple, RK Hanover, JA Krause, MW AF Bulger, David A. Fukushige, Tetsunari Yun, Sijung Semple, Robert K. Hanover, John A. Krause, Michael W. TI Caenorhabditis elegans DAF-2 as a Model for Human Insulin Receptoropathies SO G3-GENES GENOMES GENETICS LA English DT Article DE DAF-2; INSR; CRISPR; Million Mutation Project; dauer ID FACTOR I RECEPTOR; SEQUENCE ALIGNMENT; SIGNALING PATHWAY; PROTEIN FUNCTION; DAUER FORMATION; TUMOR-CELLS; C-ELEGANS; MUTATIONS; RESISTANCE; GENE AB Human exome sequencing has dramatically increased the rate of identification of disease-associated polymorphisms. However, examining the functional consequences of those variants has created an analytic bottleneck. Insulin-like signaling in Caenorhabditis elegans has long provided a model to assess consequences of human insulin signaling mutations, but this has not been evaluated in the context of current genetic tools. We have exploited strains derived from the Million Mutation Project (MMP) and gene editing to explore further the evolutionary relationships and conservation between the human and C. elegans insulin receptors. Of 40 MMP alleles analyzed in the C. elegans insulin-like receptor gene DAF-2, 35 exhibited insulin-like signaling indistinguishable from wild-type animals, indicating tolerated mutations. Five MMP alleles proved to be novel dauer-enhancing mutations, including one new allele in the previously uncharacterized C-terminus of DAF-2. CRISPR-Cas9 genome editing was used to confirm the phenotypic consequence of six of these DAF-2 mutations and to replicate an allelic series of known human disease mutations in a highly conserved tyrosine kinase active site residue, demonstrating the utility of C. elegans for directly modeling human disease. Our results illustrate the challenges associated with prediction of the phenotypic consequences of amino acid substitutions, the value of assaying mutant isoform function in vivo, and how recently developed tools and resources afford the opportunity to expand our understanding even of highly conserved regulatory modules such as insulin signaling. This approach may prove generally useful for modeling phenotypic consequences of candidate human pathogenic mutations in conserved signaling and developmental pathways. C1 [Bulger, David A.; Fukushige, Tetsunari; Yun, Sijung; Krause, Michael W.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20878 USA. [Hanover, John A.] NIDDK, Lab Mol & Cellular Biol, NIH, Bethesda, MD 20892 USA. [Bulger, David A.; Semple, Robert K.] Univ Cambridge, Inst Metab Sci, Cambridge CB2 0QQ, England. RP Bulger, DA (reprint author), Univ Cambridge, Inst Metab Sci, Cambridge CB2 0QQ, England. EM dab68@cam.ac.uk OI Bulger, David/0000-0002-4234-9193 FU National Institutes of Health (NIH) Office of Research Infrastructure Programs [P40 OD010440]; NIH, National Institute of Diabetes and Digestive and Kidney Diseases; NIH Oxford-Cambridge Scholars Program; Wellcome Trust [WT098498]; United Kingdom National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre FX We thank Phillip Gorden and Michelle Bond for useful discussions and comments, Andy Golden for CRISPR-Cas9 advice and reagents, Fred Dyda for assistance with structural models and insights, Thomas Brodigan for technical help throughout the project, and Wormbase (http://www.wormbase.org/). Some strains were provided by the Caenorhabditis Genetics Center (CGC), which is funded by National Institutes of Health (NIH) Office of Research Infrastructure Programs (P40 OD010440). This work utilized the computational resources of the NIH High Performing Computation (HPC) Biowulf cluster (http://hpc.nih.gov). This work was supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. D.A.B. was supported by the NIH Oxford-Cambridge Scholars Program. R.K.S. was supported by the Wellcome Trust [grant number WT098498], and the United Kingdom National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. NR 45 TC 0 Z9 0 U1 4 U2 4 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD JAN PY 2017 VL 7 IS 1 BP 257 EP 268 DI 10.1534/g3.116.037184 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA EI0YE UT WOS:000392200800022 PM 27856697 ER PT J AU Rotman, Y Sanyal, AJ AF Rotman, Yaron Sanyal, Arun J. TI Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease SO GUT LA English DT Article ID PLACEBO-CONTROLLED TRIAL; RANDOMIZED CLINICAL-TRIAL; ACTIVATED RECEPTOR DELTA; TYPE-2 DIABETES-MELLITUS; GLUCAGON-LIKE PEPTIDE-1; DE-NOVO LIPOGENESIS; CHRONIC HEPATITIS-C; HCC MOUSE MODEL; BILE-ACID; INSULIN-RESISTANCE AB Given the high prevalence and rising incidence of nonalcoholic fatty liver disease (NAFLD), the absence of approved therapies is striking. Although the mainstay of treatment of NAFLD is weight loss, it is hard to maintain, prompting the need for pharmacotherapy as well. A greater understanding of disease pathogenesis in recent years was followed by development of new classes of medications, as well as potential repurposing of currently available agents. NAFLD therapies target four main pathways. The dominant approach is targeting hepatic fat accumulation and the resultant metabolic stress. Medications in this group include peroxisome proliferator-activator receptor agonists (eg, pioglitazone, elafibranor, saroglitazar), medications targeting the bile acid-farnesoid X receptor axis (obeticholic acid), inhibitors of de novo lipogenesis (aramchol, NDI-010976), incretins (liraglutide) and fibroblast growth factor (FGF)-21 or FGF-19 analogues. A second approach is targeting the oxidative stress, inflammation and injury that follow the metabolic stress. Medications from this group include antioxidants (vitamin E), medications with a target in the tumour necrosis factor a pathway (emricasan, pentoxifylline) and immune modulators (amlexanox, cenicriviroc). A third group has a target in the gut, including antiobesity agents such as orlistat or gut microbiome modulators (IMM-124e, faecal microbial transplant, solithromycin). Finally, as the ongoing injury leads to fibrosis, the harbinger of liver-related morbidity and mortality, antifibrotics (simtuzumab and GR-MD-02) will be an important element of therapy. It is very likely that in the next few years several medications will be available to clinicians treating patients with NAFLD across the entire spectrum of disease. C1 [Rotman, Yaron] NIDDK, Liver & Energy Metab Unit, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Sanyal, Arun J.] Virginia Commonwealth Univ, Sch Med, Dept Internal Med, Div Gastroenterol Hepatol & Nutr, Richmond, VA USA. RP Rotman, Y (reprint author), NIDDK, Liver & Energy Metab Unit, Liver Dis Branch, NIH, 10 Ctr Dr,Bldg 10,Room 9C434,MSC 1800, Bethesda, MD 20892 USA. EM rotmany@niddk.nih.gov FU NIDDK Intramural Research Program FX NIDDK Intramural Research Program. NR 131 TC 3 Z9 3 U1 7 U2 7 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 JAN PY 2017 VL 66 IS 1 BP 180 EP 190 DI 10.1136/gutjnl-2016-312431 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EI1YN UT WOS:000392282900021 PM 27646933 ER PT J AU Hyman, DM Sill, MW Lankes, HA Piekarz, R Shahin, MS Ridgway, MR Backes, F Tenney, ME Mathews, CA Hoffman, JS Aghajanian, C Hensley, ML AF Hyman, David M. Sill, Michael W. Lankes, Heather A. Piekarz, Richard Shahin, Mark S. Ridgway, Mildred R. Backes, Floor Tenney, Meaghen E. Mathews, Cara A. Hoffman, James S. Aghajanian, Carol Hensley, Martee L. TI A phase 2 study of alisertib (MLN8237) in recurrent or persistent uterine leiomyosarcoma: An NRG Oncology/Gynecologic Oncology Group study 0231D SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Alisertib; Aurora kinase; Uterine leiomyosarcoma ID GEMCITABINE PLUS DOCETAXEL; SOFT-TISSUE SARCOMAS; CELL LUNG-CANCER; II TRIAL; CTLA-4 BLOCKADE; CLINICAL-TRIALS; AURORA KINASE; DOXORUBICIN; IFOSFAMIDE; LEIOMYOMAS AB Objective. This two-stage Phase II study assessed the activity of single agent alisertib in patients with recurrent/persistent uterine leiomyosarcoma (uLMS). Methods. Eligibility criteria included histologically-confirmed, recurrent or persistent uLMS, age >= 18, 1-2 prior cytotoxic regimens, and RECIST version 1.1 measurable disease. The primary objective of the study was to evaluate the efficacy of alisertib through the frequency of patients with objective tumor responses and the frequency who survived event-free for at least 6 months (EFS6). The endpoints for EFS were RECIST progression, death, or beginning a subsequent therapy. The null hypothesis jointly specified the probability of a patient experiencing,a tumor response,to less than or.equal to 5% and the probability of a patient surviving event-free for at least 6 months to less than or equal to 20%. A two-stage design was used with a target accrual of 23 patients for stage 1 and 47 pts. cumulative for stage 2. Confidence intervals do not correct for multiplicity. Results. Twenty-three patients were enrolled with two patients excluded on central histology review, yielding 21 eligible patients. Median age was 61 years. Prior treatment was either 1 cytotoxic regimen (71.4%) or 2 (28.6%). The most common treatment related AEs (grade 3 or worse) were anemia Hensley et al. (2008a), leulcopenia Hensley et al. (2008b), neutropenia Ailald et al (2007), thrombocytopenia Huang et al. (2012), mucositis Hensley et al. (2008a), diarrhea Huang et al. (2012), and palmer-planter syndrome Zivanovic et at (2012). There were no objective responses (0%; 90% CI: 0-10.4%). Best response was stable disease (38.1%); 12 patients had progressive disease (57.1%). EFS6 was 0% (90% CI: 0-10.4%). Median PFS and OS were 1.7 (90% CI: 1.4-32) and 14.5 months (90% CI: 7.6 - NA), respectively. Conclusion. Alisertib did not demonstrate clinically meaningful single agent activity in previously treated uLMS. (C) 2016 Elsevier Inc. All rights reserved. C1 [Hyman, David M.; Aghajanian, Carol; Hensley, Martee L.] Mem Sloan Kettering Canc Ctr, 300 East 60th St, New York, NY 10065 USA. [Sill, Michael W.; Lankes, Heather A.] NRG Oncol Stat & Date Management Ctr, Buffalo, NY 14263 USA. [Piekarz, Richard] NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. [Shahin, Mark S.] Jefferson Hlth, Abington Hosp, Abington, PA 19001 USA. [Ridgway, Mildred R.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Backes, Floor] Ohio State Univ, Wexner Med Ctr, Hilliard, OH 43026 USA. [Tenney, Meaghen E.] Univ Chicago Med & Biol Sci, Gynecol Oncol, Chicago, IL 60637 USA. [Mathews, Cara A.] Women & Infants Hosp Rhode Isl, Providence, RI 02905 USA. Hosp Cent Connecticut, New Britain, CT 06050 USA. [Hoffman, James S.; Aghajanian, Carol; Hensley, Martee L.] Weill Cornell Med Coll, New York, NY 10065 USA. [Hoffman, James S.] Baystate Med, Springfield, MA USA. RP Hyman, DM (reprint author), Mem Sloan Kettering Canc Ctr, 300 East 60th St, New York, NY 10065 USA. EM hymand@mskcc.org; msill@gogstats.org; hlankes@gogstats.org; rpiekarz@nih.gov; mshahin@abingtonhealth.org; mridgway@umc.edu; Floor.Backes@osumc.edu; mtenney@bsd.uchicago.edu; cmathews@wihri.org; James.HoffmanMD@baystatehealth.org; aghajanc@mskcc.org; heasleym@mskcc.org FU National Cancer Institute grant NRG Oncology SDMC grant [U10 CA180822]; National Cancer Institute grant NRG Oncology Operations grant [U10CA 180868]; National Institutes of Health [P30 CA008748]; Millennium Pharmaceuticals FX This study was supported by National Cancer Institute grants NRG Oncology SDMC grant U10 CA180822 and the NRG Oncology Operations grant U10CA 180868. DH was supported by National Institutes of Health grant P30 CA008748. The authors would like to thank Millennium Pharmaceuticals for their support of this research. NR 37 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 JAN PY 2017 VL 144 IS 1 BP 96 EP 100 DI 10.1016/j.ygyno.2016-10.036 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA EI3CJ UT WOS:000392367000018 PM 28094040 ER PT J AU Hosokawa, K Kajigaya, S Feng, XM Desierto, MJ Ibanez, MDF Weinstein, ORB Scheinberg, P Townsley, DM Young, NS AF Hosokawa, Kohei Kajigaya, Sachiko Feng, Xingmin Desierto, Marie J. Ibanez, Maria del Pilar Fernandez Weinstein, Olga Rios Barbara Scheinberg, Phillip Townsley, Danielle M. Young, Neal S. TI A plasma microRNA signature as a biomarker for acquired aplastic anemia SO HAEMATOLOGICA LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; ACUTE MYELOID-LEUKEMIA; T-CELL DEVELOPMENT; MULTIPLE-SCLEROSIS; CIRCULATING MICRORNAS; MYELODYSPLASTIC SYNDROMES; EXTRACELLULAR MICRORNA; CARDIOVASCULAR-DISEASE; FLOW-CYTOMETRY; C-MYB AB A plastic anemia is an acquired bone marrow failure characterized by marrow hypoplasia, a paucity of hematopoietic stem and progenitor cells, and pancytopenia of the peripheral blood, due to immune attack on the bone marrow. In aplastic anemia, a major challenge is to develop immune biomarkers to monitor the disease. We measured circulating microRNAs in plasma samples of aplastic anemia patients in order to identify disease-specific microRNAs. A total of 179 microRNAs were analyzed in 35 plasma samples from 13 aplastic anemia patients, 11 myelodysplastic syndrome patients, and 11 healthy controls using the Serum/Plasma Focus microRNA Polymerase Chain Reaction Panel. Subsequently, 19 microRNAs from the discovery set were investigated in the 108 plasma samples from 41 aplastic anemia patients, 24 myelodysplastic syndrome patients, and 43 healthy controls for validation, confirming that 3 microRNAs could be validated as dysregulated (>1.5-fold change) in aplastic anemia, compared to healthy controls. MiR-150-5p (induction of T-cell differentiation) and miR-146b-5p (involvement in the feedback regulation of innate immune response) were elevated in aplastic anemia plasma, whereas miR-1 was decreased in aplastic anemia. By receiver operating characteristic curve analysis, we developed a logistic model with these 3 microRNAs that enabled us to predict the probability of a diagnosis of aplastic anemia with an area under the curve of 0.86. Dysregulated expression levels of the microRNAs became normal after immunosuppressive therapy at 6 months. Specifically, miR-150-5p expression was significantly reduced after successful immunosuppressive therapy, but did not change in non-responders. We propose 3 novel plasma biomarkers in aplastic anemia, in which miR-150-5p, miR-146b-5p, and miR-1 can serve for diagnosis and miR-150-5p for disease monitoring. Clinicaltrials.gov identifiers: 00260689, 00217594, 00961064. C1 [Hosokawa, Kohei; Kajigaya, Sachiko; Feng, Xingmin; Desierto, Marie J.; Ibanez, Maria del Pilar Fernandez; Weinstein, Olga Rios Barbara; Scheinberg, Phillip; Townsley, Danielle M.; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Hosokawa, K (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. EM kohei.hosokawa@nih.gov FU Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute, USA FX This research was supported by the Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute, USA. NR 64 TC 1 Z9 1 U1 2 U2 2 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD JAN PY 2017 VL 102 IS 1 BP 69 EP 78 DI 10.3324/haematol.2016.151076 PG 10 WC Hematology SC Hematology GA EJ0SW UT WOS:000392921800019 PM 27658437 ER PT J AU Oseni, AO Qureshi, WT Almahmoud, MF Bertoni, AG Bluemke, DA Hundley, WG Lima, JAC Herrington, DM Soliman, EZ AF Oseni, Abdullahi O. Qureshi, Waqas T. Almahmoud, Mohamed F. Bertoni, Alain G. Bluemke, David A. Hundley, William G. Lima, Joao A. C. Herrington, David M. Soliman, Elsayed Z. TI Left ventricular hypertrophy by ECG versus cardiac MRI as a predictor for heart failure SO HEART LA English DT Article ID ELECTROCARDIOGRAPHIC CRITERIA; CARDIOVASCULAR EVENTS; ATHEROSCLEROSIS; MASS; ASSOCIATION; ETHNICITY; RISK; RECLASSIFICATION; DETERMINANTS; OUTCOMES AB Objective To determine if there is a significant difference in the predictive abilities of left ventricular hypertrophy (LVH) detected by ECG-LVH versus LVH ascertained by cardiac MRI-LVH in a model similar to the Framingham Heart Failure Risk Score (FHFRS). Methods This study included 4745 (mean age 61 +/- 10 years, 53.5% women, 61.7% non-whites) participants in the Multi-Ethnic Study of Atherosclerosis. ECG-LVH was defined using Cornell voltage product while MRI-LVH was derived from left ventricular mass. Cox proportional hazard regression was used to examine the association between ECG-LVH and MRI-LVH with incident heart failure (HF). Harrell's concordance C-index was used to estimate the predictive ability of the model when either ECG-LVH or MRI-LVH was included as one of its components. Results ECG-LVH was present in 291 (6.1%), while MRI-LVH was present in 499 (10.5%) of the participants. Both ECG-LVH (HR 2.25, 95% CI 1.38 to 3.69) and MRI-LVH (HR 3.80, 95% CI 1.56 to 5.63) were predictive of HF. The absolute risk of developing HF was 8.81% for MRI-LVH versus 2.26% for absence of MRI-LVH with a relative risk of 3.9. With ECG-LVH, the absolute risk of developing HF 6.87% compared with 2.69% for absence of ECG-LVH with a relative risk of 2.55. The ability of the model to predict HF was better with MRI-LVH (C-index 0.871, 95% CI 0.842 to 0.899) than with ECG-LVH (C-index 0.860, 95% CI 0.833 to 0.888) (p<0.0001). Conclusions ECG-LVH and MRI-LVH are predictive of HF. Substituting MRI-LVH for ECG-LVH improves the predictive ability of a model similar to the FHFRS. C1 [Oseni, Abdullahi O.; Qureshi, Waqas T.; Almahmoud, Mohamed F.; Hundley, William G.; Herrington, David M.; Soliman, Elsayed Z.] Wake Forest Sch Med, Cardiol Sect, Dept Internal Med, Med Ctr Blvd, Winston Salem, NC 27157 USA. [Bertoni, Alain G.; Soliman, Elsayed Z.] Wake Forest Sch Med, Dept Epidemiol & Prevent, Med Ctr Blvd, Winston Salem, NC 27157 USA. [Bluemke, David A.] NIH, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Lima, Joao A. C.] Johns Hopkins Sch Med, Dept Radiol, Baltimore, MD USA. RP Oseni, AO (reprint author), Wake Forest Sch Med, Cardiol Sect, Dept Internal Med, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM aoseni@wakehealth.edu OI Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169]; National Center for Research Resources [UL1-TR-000040, UL1-TR-001079] FX This research was supported by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168 and N01-HC-95169 from the National Heart, Lung, and Blood Institute and by grants UL1-TR-000040 and UL1-TR-001079 from National Center for Research Resources. NR 27 TC 0 Z9 0 U1 2 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1355-6037 EI 1468-201X J9 HEART JI Heart PD JAN PY 2017 VL 103 IS 1 BP 49 EP 54 DI 10.1136/heartjnl-2016-309516 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EI1BU UT WOS:000392211200011 PM 27486144 ER PT J AU Wong, KCL Summers, RM Kebebew, E Yao, JH AF Wong, Ken C. L. Summers, Ronald M. Kebebew, Electron Yao, Jianhua TI Pancreatic Tumor Growth Prediction With Elastic-Growth Decomposition, Image-Derived Motion, and FDM-FEM Coupling SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE Tumor growth prediction; image-based model personalization; nonlinear solid mechanics; elastic-growth decomposition; FDM-FEM coupling ID NEUROENDOCRINE TUMORS; LINDAU-DISEASE; MODEL; DIFFUSION; CANCER; MASS AB Pancreatic neuroendocrine tumors are abnormal growths of hormone-producing cells in the pancreas. Unlike the brain which is protected by the skull, the pancreas can be significantly deformed by its surrounding organs. Consequently, the tumor shape differences observable from images at different time points arise from both tumor growth and pancreatic motion, and tumor growth model personalization may be compromised if such motion is ignored. Therefore, we incorporate pancreatic motion information derived from deformable image registration in model personalization. For more accurate mechanical interactions between tumor growth and pancreatic motion, elastic-growth decomposition is used with a hyperelastic constitutive law to model the mass effect, which allows growth modeling while conserving the mechanical properties. Furthermore, a way of coupling the finite difference method and the finite element method is proposed to greatly reduce the computation time. With both 2-[F-18]-fluoro-2-deoxy-D-glucose positron emission tomographic and contrast-enhanced computed tomographic images, functional, structural, and motion data are combined for a patient-specific model. Experiments on synthetic and clinical data show the importance of image-derived motion on estimating pathophysiologically plausible mechanical properties and the promising performance of our framework. From seven patient data sets, the recall, precision, Dice coefficient, relative volume difference, and average surface distance between the personalized tumor growth simulations and the measurements were 83.2 +/- 8.8%, 86.9 +/- 8.3%, 84.4 +/- 4.0%, 13.9 +/- 9.8%, and 0.6 +/- 0.1 mm, respectively. C1 [Wong, Ken C. L.; Summers, Ronald M.; Yao, Jianhua] NIH, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Yao, JH (reprint author), NIH, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM jyao@cc.nih.gov FU Intramural Research Program of the National Institutes of Health Clinical Center FX This work was funded by the Intramural Research Program of the National Institutes of Health Clinical Center. Asterisk indicates corresponding author. NR 39 TC 0 Z9 0 U1 1 U2 1 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 EI 1558-254X J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD JAN PY 2017 VL 36 IS 1 BP 111 EP 123 DI 10.1109/TMI.2016.2597313 PG 13 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA EI3UR UT WOS:000392418000010 PM 27529869 ER PT J AU Bouhrara, M Bonny, JM Ashinsky, BG Maring, MC Spencer, RG AF Bouhrara, Mustapha Bonny, Jean-Marie Ashinsky, Beth G. Maring, Michael C. Spencer, Richard G. TI Noise Estimation and Reduction in Magnetic Resonance Imaging Using a New Multispectral Nonlocal Maximum-likelihood Filter SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE Brain; MRI; Multispectral filtering; Nonlocal maximum likelihood filter; Nonlocal means filter; Rician noise ID RICIAN NOISE; MR-IMAGES; BAYESIAN-ANALYSIS; HUMAN BRAIN; ALGORITHM; VARIANCE; MCDESPOT; ROBUST; DECAY AB Denoising of magnetic resonance (MR) images enhances diagnostic accuracy, the quality of image manipulations such as registration and segmentation, and parameter estimation. The first objective of this paper is to introduce a new, high-performance, nonlocal filter for noise reduction in MR image sets consisting of progressively-weighted, that is, multispectral, images. This filter is a multispectral extension of the nonlocal maximum likelihood filter (NLML). Performance was evaluated on synthetic and in-vivo T-2- and T-1-weighted brain imaging data, and compared to the nonlocal-means(NLM) and its multispectral version, that is, MS-NLM, and the nonlocal maximum likelihood(NLML) filters. Visual inspectionof filtered images and quantitative analyses showed that all filters provided substantial reduction of noise. Further, as expected, the use of multispectral information improves filtering quality. In addition, numerical and experimental analyses indicated that the new multispectral NLML filter, MS-NLML, demonstrated markedly less blurring and loss of image detail than seen with the other filters evaluated. In addition, since noise standard deviation (SD) is an important parameter for all of these nonlocal filters, a multispectral extension of the method of maximum likelihood estimation (MLE) of noise amplitude is presented and compared to both local and nonlocal MLE methods. Numerical and experimental analyses indicated the superior performance of this multispectral method for estimation of noise SD. C1 [Bouhrara, Mustapha; Ashinsky, Beth G.; Maring, Michael C.; Spencer, Richard G.] NIA, NIH, Baltimore, MD 21214 USA. [Bonny, Jean-Marie] INRA, QuaPA UR370, F-63122 St Genes Champanelle, France. RP Bouhrara, M; Spencer, RG (reprint author), NIA, NIH, Baltimore, MD 21214 USA. EM bouhraram@mail.nih.gov; jeanmarie.bonny@clermont.inra.fr; beth.ashinsky@gmail.com; michael.maring@nih.gov; spencer@helix.nih.gov FU Intramural Research Program of the NIH, National Institute on Aging FX This work was supported by the Intramural Research Program of the NIH, National Institute on Aging. Asterisk indicates corresponding author. NR 41 TC 0 Z9 0 U1 4 U2 4 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 EI 1558-254X J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD JAN PY 2017 VL 36 IS 1 BP 181 EP 193 DI 10.1109/TMI.2016.2601243 PG 13 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA EI3UR UT WOS:000392418000016 PM 27552743 ER PT J AU Puttnam, R Davis, BR Pressel, SL Whelton, PK Cushman, WC Louis, GT Margolis, KL Oparil, S Williamson, J Ghosh, A Einhorn, PT Barzilay, JI AF Puttnam, Rachel Davis, Barry R. Pressel, Sara L. Whelton, Paul K. Cushman, William C. Louis, Gail T. Margolis, Karen L. Oparil, Suzanne Williamson, Jeffrey Ghosh, Alokananda Einhorn, Paula T. Barzilay, Joshua I. CA Antihypertensive Lipid-Lowering Tr TI Association of 3 Different Antihypertensive Medications With Hip and Pelvic Fracture Risk in Older Adults Secondary Analysis of a Randomized Clinical Trial SO JAMA INTERNAL MEDICINE LA English DT Article ID BONE-MINERAL DENSITY; LIPID-LOWERING TREATMENT; HEART-ATTACK TRIAL; THIAZIDE DIURETICS; BLOOD-PRESSURE; OSTEOPOROSIS; BLOCKERS; HEALTH; ALLHAT; COHORT AB IMPORTANCE On the basis of observational studies, the use of thiazide diuretics for the treatment of hypertension is associated with reduced fracture risk compared with nonuse. Data from randomized clinical trials are lacking. OBJECTIVE To examine whether the use of thiazide diuretics for the treatment of hypertension is associated with reduced fracture risk compared with nonuse. DESIGN, SETTING, AND PARTICIPANTS Using Veterans Affairs and Medicare claims data, this study examined hip and pelvic fracture hospitalizations in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial participants randomized to first-step therapy with a thiazide-type diuretic (chlorthalidone), a calcium channel blocker (amlodipine besylate), or an angiotensin-converting enzyme inhibitor (lisinopril). Recruitment was from February 1994 to January 1998; in-trial follow-up ended in March 2002. The mean follow-up was 4.9 years. Posttrial follow-up was conducted through the end of 2006, using passive surveillance via national databases. For this secondary analysis, which used an intention-to-treat approach, data were analyzed from February 1, 1994, through December 31, 2006. MAIN OUTCOMES AND MEASURES Hip and pelvic fracture hospitalizations. RESULTS A total of 22 180 participants (mean [SD] age, 70.4 [6.7] years; 43.0% female; and 49.9% white non-Hispanic, 31.2% African American, and 19.1% other ethnic groups) were followed for up to 8 years (mean [SD], 4.9 [1.5] years) during masked therapy. After trial completion, 16 622 participants for whom claims data were available were followed for up to 5 additional years (mean [SD] total follow-up, 7.8 [3.1] years). During the trial, 338 fractures occurred. Participants randomized to receive chlorthalidone vs amlodipine or lisinopril had a lower risk of fracture on adjusted analyses (hazards ratio [HR], 0.79; 95% CI, 0.63-0.98; P = .04). Risk of fracture was significantly lower in participants randomized to receive chlorthalidone vs lisinopril (HR, 0.75; 95% CI, 0.58-0.98; P = .04) but not significantly different compared with those randomized to receive amlodipine (HR, 0.82; 95% CI, 0.63-1.08; P = .17). During the entire trial and posttrial period of follow-up, the cumulative incidence of fractures was nonsignificantly lower in participants randomized to receive chlorthalidone vs lisinopril or amlodipine (HR, 0.87; 95% CI, 0.74-1.03; P = .10) and vs each medication separately. In sensitivity analyses, when 1 year after randomization was used as the baseline (to allow for the effects of medications on bone to take effect), similar results were obtained for in-trial and in-trial plus posttrial follow-up. CONCLUSIONS AND RELEVANCE These findings from a large randomized clinical trial provide evidence of a beneficial effect of thiazide-type diuretic therapy in reducing hip and pelvic fracture risk compared with treatment with other antihypertensive medications. C1 [Puttnam, Rachel; Barzilay, Joshua I.] Kaiser Permanente Georgia, Div Endocrinol, Atlanta, GA USA. [Davis, Barry R.; Pressel, Sara L.; Ghosh, Alokananda] Univ Texas Houston, Sch Publ Hlth, Coordinating Ctr Clin Trials, Houston, TX USA. [Whelton, Paul K.] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA. [Cushman, William C.] Vet Affairs Med Ctr, Prevent Med Sect, Memphis, TN USA. [Louis, Gail T.] Tulane Univ, Res Off, New Orleans, LA 70118 USA. [Margolis, Karen L.] HealthPartners Inst Educ & Res, Minneapolis, MN USA. [Oparil, Suzanne] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Williamson, Jeffrey] Wake Forest Univ, Sch Med, J Paul Sticht Ctr Aging, Winston Salem, NC 27109 USA. [Einhorn, Paula T.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. RP Barzilay, JI (reprint author), Kaiser Permanente Georgia, 3650 Steve Reynolds Blvd, Duluth, GA 30096 USA. EM joshua.barzilay@kp.org OI Papademetriou, Vasilios/0000-0002-2882-2757 FU National Heart, Lung, and Blood Institute [NO1-HC-35130, HHSN268201100036C]; Pfizer Inc. FX This research was supported by contracts NO1-HC-35130 and HHSN268201100036C from the National Heart, Lung, and Blood Institute. The ALLHAT investigators acknowledge contributions of study medications supplied by Pfizer Inc (amlodipine and doxazosin), AstraZeneca (atenolol and lisinopril), and Bristol- Myers Squibb (pravastatin) and financial support provided by Pfizer Inc. No specific funding was allocated for the work presented in this article. NR 30 TC 2 Z9 2 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JAN PY 2017 VL 177 IS 1 BP 67 EP 76 DI 10.1001/jamainternmed.2016.6821 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA EI0WN UT WOS:000392196200018 PM 27893045 ER PT J AU Inoue-Choi, M Liao, LM Reyes-Guzman, C Hartge, P Caporaso, N Freedman, ND AF Inoue-Choi, Maki Liao, Linda M. Reyes-Guzman, Carolyn Hartge, Patricia Caporaso, Neil Freedman, Neal D. TI Association of Long-term, Low-Intensity Smoking With All-Cause and Cause-Specific Mortality in the National Institutes of Health-AARP Diet and Health Study SO JAMA INTERNAL MEDICINE LA English DT Article ID CORONARY-HEART-DISEASE; CIGARETTE-SMOKING; LUNG-CANCER; INTERMITTENT SMOKING; NONDAILY SMOKERS; UNITED-STATES; LIGHT; RISK; WOMEN; TIME AB IMPORTANCE A growing proportion of US smokers now smoke fewer than 10 cigarettes per day (CPD), and that proportion will likely rise in the future. The health effects of smoking only a few CPD over one's lifetime are less understood than are the effects of heavier smoking, although many smokers believe that their level is modest. OBJECTIVE To evaluate the associations of long-term smoking of fewer than 1 or 1 to 10 CPD (low intensity) with all-cause and cause-specific mortality compared with never smoking cigarettes. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study of 290 215 adults in the National Institutes of Health-AARP (formerly known as the American Association of Retired Persons) Diet and Health Study who were aged 59 to 82 years in calendar years 2004-2005 (baseline). Data were gathered with a questionnaire assessing lifetime cigarette smoking history. Hazard ratios (HRs) and 95% CIs were determined for all-cause mortality and cause-specific mortality through the end of 2011. Hazard ratios and 95% CIs were estimated using Cox proportional hazards regression models using age as the underlying time metric and adjusted for sex, race/ ethnicity, educational level, physical activity, and alcohol intake. Data analysis was conducted from December 15, 2015, to September 30, 2016. EXPOSURES Current and historical smoking intensity during 9 previous age periods (from <15 years to >= 70 years) over the lifetime assessed on the 2004-2005 questionnaire. MAIN OUTCOMES AND MEASURES All-cause and cause-specific mortality among current, former, and never smokers. RESULTS Of the 290 215 cohort participants who completed the 2004-2005 questionnaire, 168 140 were men (57.9%); the mean (SD) age was 71 (5.3) years (range, 59-82 years). Most people who smoked fewer than 1 or 1 to 10 CPD at baseline reported smoking substantially higher numbers of CPD earlier in their lives. Nevertheless, 159 (9.1%) and 1493 (22.5%) of these individuals reported consistently smoking fewer than 1 or 1 to 10 CPD in each age period that they smoked, respectively. Relative to never smokers, consistent smokers of fewer than 1 CPD (HR, 1.64; 95% CI, 1.07-2.51) and 1 to 10 CPD (HR, 1.87; 95% CI, 1.64-2.13) had a higher all-cause mortality risk. Associations were similar in women and men for all-cause mortality and were observed across a range of smoking-related causes of death, with an especially strong association with lung cancer (HR, 9.12; 95% CI, 2.92-28.47, and HR, 11.61; 95% CI, 8.25-16.35 for <1 and 1-10 CPD, respectively). Former smokers who had consistently smoked fewer than 1 or 1 to 10 CPD had progressively lower risks with younger age at cessation. For example, the HRs for consistent smokers of fewer than 1 and 1 to 10 CPD who quit at 50 years or older were 1.44 (95% CI, 1.12-1.85) and 1.42 (95% CI, 1.27-1.59), respectively. CONCLUSIONS AND RELEVANCE This study provides evidence that individuals who smoke fewer than 1 or 1 to 10 CPD over their lifetime have higher mortality risks than never smokers and would benefit from cessation. These results provide further evidence that there is no risk-free level of exposure to tobacco smoke. C1 [Inoue-Choi, Maki; Liao, Linda M.; Hartge, Patricia; Caporaso, Neil; Freedman, Neal D.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Reyes-Guzman, Carolyn] US FDA, Off Sci, Ctr Tobacco Prod, Silver Spring, MD USA. RP Inoue-Choi, M (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,6E346, Rockville, MD 20850 USA. EM maki.inoue-choi@nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology Genetics FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology & Genetics. NR 33 TC 2 Z9 2 U1 3 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JAN PY 2017 VL 177 IS 1 BP 87 EP 95 DI 10.1001/jamainternmed.2016.7511 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA EI0WN UT WOS:000392196200021 PM 27918784 ER PT J AU Simons-Morton, B Haynie, D O'Brien, F Lipsky, L Bible, J Liu, DP AF Simons-Morton, Bruce Haynie, Denise O'Brien, Fearghal Lipsky, Leah Bible, Joe Liu, Danping TI Variability in measures of health and health behavior among emerging adults 1 year after high school according to college status SO JOURNAL OF AMERICAN COLLEGE HEALTH LA English DT Article DE College health; college students; diet; driving; exercise; mental health; physical health; substance use ID UNITED-STATES; YOUNG ADULTHOOD; PHYSICAL-ACTIVITY; NUTRIENT INTAKE; MARIJUANA USE; DIET QUALITY; ALCOHOL-USE; ADOLESCENTS; PREVALENCE; DRINKING AB Objective: To examine changes in health behaviors among US emerging adults 1 year after high school. Participants: The national sample of participants (N = 1,927), including those attending 4-year college/university (n = 884), 2-year colleges/technical schools (n = 588), and no college (n = 455), participated in annual spring surveys 2013-2014. Methods: Health behaviors were assessed the last year of high school and first year of college; differences by college status controlling for previous-year values were estimated using regression analyses. Results: Relative to 4-year college attendees, those attending technical school/community college were less likely to binge drink (odds ratio [OR] = 0.57, confidence interval [CI] = 0.38-0.86) but more likely to speed (OR = 1.26, CI = 1.0-2.84), consume sodas (OR = 1.57, CI = 1.0-2.47), and report lower family satisfaction (p <. 01), with marginally more physical and depressive symptoms. College nonattendees reported more DWI (driving while intoxicated; OR = 1.60, CI = 1.05-2.47), soda drinking (OR = 2.51, CI = 1.76-3.59), oversleeping (OR = 4.78, CI = 3.65-8.63), and less family satisfaction (p <. 04). Conclusions: Health risk behaviors among emerging adults varied by college status. C1 [Simons-Morton, Bruce; Haynie, Denise; O'Brien, Fearghal; Lipsky, Leah] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, 6100 Execut Blvd 7B13Q, Bethesda, MD 20892 USA. [Bible, Joe; Liu, Danping] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, 6100 Execut Blvd 7B13Q, Bethesda, MD 20892 USA. RP Simons-Morton, B (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, 6100 Execut Blvd 7B13Q, Bethesda, MD 20892 USA. EM mortonb@mail.nih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617; Haynie, Denise/0000-0002-8270-6079; Lipsky, Leah/0000-0003-2645-4388 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Heart, Lung and Blood Institute (NHLBI); National Institute on Alcohol Abuse and Alcoholism (NIAAA); Maternal and Child Health Bureau (MCHB) of the Health Resources and Services Administration (HRSA); National Institute on Drug Abuse (NIDA) [HHSN275201200001I] FX This research was supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and by the National Heart, Lung and Blood Institute (NHLBI), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and Maternal and Child Health Bureau (MCHB) of the Health Resources and Services Administration (HRSA), with supplemental support from the National Institute on Drug Abuse (NIDA) (contract number HHSN275201200001I). Intramural researchers were responsible for the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. NR 48 TC 0 Z9 0 U1 9 U2 9 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0744-8481 EI 1940-3208 J9 J AM COLL HEALTH JI J. Am. Coll. Health PY 2017 VL 65 IS 1 BP 58 EP 66 DI 10.1080/07448481.2016.1238384 PG 9 WC Education & Educational Research; Public, Environmental & Occupational Health SC Education & Educational Research; Public, Environmental & Occupational Health GA EI6TA UT WOS:000392628500007 PM 27661849 ER PT J AU McCormack, SE Chesi, A Mitchell, JA Roy, SM Cousminer, DL Kalkwarf, HJ Lappe, JM Gilsanz, V Oberfield, SE Shepherd, JA Mahboubi, S Winer, KK Kelly, A Grant, SFA Zemel, BS AF McCormack, Shana E. Chesi, Alessandra Mitchell, Jonathan A. Roy, Sani M. Cousminer, Diana L. Kalkwarf, Heidi J. Lappe, Joan M. Gilsanz, Vicente Oberfield, Sharon E. Shepherd, John A. Mahboubi, Soroosh Winer, Karen K. Kelly, Andrea Grant, Struan F. A. Zemel, Babette S. TI Relative Skeletal Maturation and Population Ancestry in Nonobese Children and Adolescents SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE SKELETAL MATURATION; GROWTH; POPULATION ANCESTRY; PEDIATRIC ENDOCRINOLOGY; BONE AGE ID PREDICTING ADULT HEIGHT; URBAN SOUTH-AFRICA; BONE MASS; REFERENCE CURVES; MINERAL DENSITY; SECULAR TRENDS; FRACTURE RISK; UNITED-STATES; BODY-FAT; AGE AB More rapid skeletal maturation in African-American (AA) children is recognized and generally attributed to an increased prevalence of obesity. The objective of the present study was to evaluate the effects of population ancestry on relative skeletal maturation in healthy, non-obese children and adolescents, accounting for body composition and sexual maturation. To do this, we leveraged a multiethnic, mixed-longitudinal study with annual assessments for up to 7 years (The Bone Mineral Density in Childhood Study and its ancillary cohort) conducted at five US clinical centers. Participants included 1592 children, skeletally immature (45% females, 19% AA) who were aged 5 to 17 years at study entry. The primary outcome measure was relative skeletal maturation as assessed by hand-wrist radiograph. Additional covariates measured included anthropometrics, body composition by dual-energy X-ray absorptiometry (DXA), and Tanner stage of sexual maturation. Using mixed effects longitudinal models, without covariates, advancement in relative skeletal maturation was noted in self-reported AA girls (approximate to 0.33 years, p<0.001) and boys (approximate to 0.43 years, p<0.001). Boys and girls of all ancestry groups showed independent positive associations of height, lean mass, fat mass, and puberty with relative skeletal maturation. The effect of ancestry was attenuated but persistent after accounting for covariates: for girls, 0.19 years (ancestry by self-report, p=0.02) or 0.29 years (ancestry by admixture, p=0.004); and for boys, 0.20 years (ancestry by self-report, p=0.004), or 0.29 years (ancestry by admixture, p=0.004). In summary, we conclude that advancement in relative skeletal maturation was associated with AA ancestry in healthy, non-obese children, independent of growth, body composition, and puberty. Further research into the mechanisms underlying this observation may provide insights into the regulation of skeletal maturation. (c) 2016 American Society for Bone and Mineral Research. C1 [McCormack, Shana E.; Roy, Sani M.; Kelly, Andrea; Grant, Struan F. A.] Childrens Hosp Philadelphia, Div Endocrinol & Diabet, 3401 Civ Ctr Blvd,Suite 11NW, Philadelphia, PA 19104 USA. [McCormack, Shana E.; Mitchell, Jonathan A.; Kelly, Andrea; Grant, Struan F. A.; Zemel, Babette S.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Chesi, Alessandra; Cousminer, Diana L.; Grant, Struan F. A.] Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA. [Mitchell, Jonathan A.; Zemel, Babette S.] Childrens Hosp Philadelphia, Div Gastroenterol Hepatol & Nutr, Philadelphia, PA 19104 USA. [Kalkwarf, Heidi J.] Cincinnati Childrens Hosp Med Ctr, Div Gastroenterol Hepatol & Nutr, Cincinnati, OH 45229 USA. [Lappe, Joan M.] Creighton Univ, Dept Med, Div Endocrinol, Omaha, NE 68178 USA. [Gilsanz, Vicente] Childrens Hosp Los Angeles, Dept Radiol, Los Angeles, CA 90027 USA. [Oberfield, Sharon E.] Columbia Univ, Med Ctr, Dept Pediat, Div Pediat Endocrinol Diabet & Metab, New York, NY USA. [Shepherd, John A.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA USA. [Mahboubi, Soroosh] Childrens Hosp Philadelphia, Dept Radiol, Philadelphia, PA 19104 USA. [Winer, Karen K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, PGNB, Bethesda, MD USA. RP McCormack, SE (reprint author), Childrens Hosp Philadelphia, Div Endocrinol & Diabet, 3401 Civ Ctr Blvd,Suite 11NW, Philadelphia, PA 19104 USA. EM mccormacks1@email.chop.edu OI Mitchell, Jonathan/0000-0003-3765-2419 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [N01-HD-1-3228, N01-HD-1-3329, N01-HD-1-3330, N01-HD-1-3331, N01-HD-1-3332, N01-HD-1-3333]; CTSA program [8 UL1 TR000077]; Pediatric Endocrine Society Clinical Scholars Award; Children's Hospital of Philadelphia Metabolism, Nutrition, and Development Research Affinity Group Pilot and Feasibility Grant; [R01 HD58886]; [R01 HD076321]; [R01 HD058886]; [DK094723-01]; [DK102659-01] FX The BMDCS study was funded by R01 HD58886 and R01 HD076321; the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) contracts (N01-HD-1-3228, N01-HD-1-3329, N01-HD-1-3330, N01-HD-1-3331, N01-HD-1-3332, N01-HD-1-3333); the CTSA program Grant 8 UL1 TR000077. Additional support was provided by: R01 HD058886 (SFAG); DK094723-01; DK102659-01; Pediatric Endocrine Society Clinical Scholars Award; Children's Hospital of Philadelphia Metabolism, Nutrition, and Development Research Affinity Group Pilot and Feasibility Grant (SEM). NR 44 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD JAN PY 2017 VL 32 IS 1 BP 115 EP 124 DI 10.1002/jbmr.2914 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EH7YU UT WOS:000391989400014 PM 27419386 ER PT J AU Brigida, I Chiriaco, M Di Cesare, S Cittaro, D Di Matteo, G Giannelli, S Lazarevic, D Zoccolillo, M Stupka, E Jenkner, A Francalanci, P Livadiotti, S Morawski, A Ravell, J Lenardo, M Cancrini, C Aiuti, A Finocchi, A AF Brigida, Immacolata Chiriaco, Maria Di Cesare, Silvia Cittaro, Davide Di Matteo, Gigliola Giannelli, Stefania Lazarevic, Dejan Zoccolillo, Matteo Stupka, Elia Jenkner, Alessandro Francalanci, Paola Livadiotti, Susanna Morawski, Aaron Ravell, Juan Lenardo, Michael Cancrini, Caterina Aiuti, Alessandro Finocchi, Andrea TI Large Deletion of MAGT1 Gene in a Patient with Classic Kaposi Sarcoma, CD4 Lymphopenia, and EBV Infection SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Letter DE MAGT1 deletion; Sequencing; Kaposi Sarcoma ID DEFICIENCY; DISEASE C1 [Brigida, Immacolata; Giannelli, Stefania; Zoccolillo, Matteo; Aiuti, Alessandro] Ist Sci San Raffaele, San Raffaele Telethon Inst Gene Therapy SR TIGET, Via Olgettina 60, I-20132 Milan, Italy. [Chiriaco, Maria; Di Matteo, Gigliola; Cancrini, Caterina; Finocchi, Andrea] Univ Roma Tor Vergata, Dept Syst Med, Rome, Italy. [Di Cesare, Silvia; Jenkner, Alessandro; Livadiotti, Susanna; Cancrini, Caterina; Finocchi, Andrea] Bambino Gesu Children Hosp, Dept Pediat, Div Immunol & Infect Dis, Rome, Italy. [Cittaro, Davide; Lazarevic, Dejan; Stupka, Elia] Hosp San Raffaele, Ctr Translat Genom & Bioinformat, Milan, Italy. [Francalanci, Paola] Bambino Gesu Children Hosp, Dept Pathol, Rome, Italy. [Morawski, Aaron; Ravell, Juan; Lenardo, Michael] NIAID, Mol Dev Immune Syst Sect, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Aiuti, Alessandro] IRCCS San Raffaele Sci Inst, Pediat Immunohematol & Bone Marrow Transplantat U, Milan, Italy. [Aiuti, Alessandro] Univ Vita Salute San Raffaele, Milan, Italy. RP Aiuti, A (reprint author), Ist Sci San Raffaele, San Raffaele Telethon Inst Gene Therapy SR TIGET, Via Olgettina 60, I-20132 Milan, Italy.; Finocchi, A (reprint author), Univ Roma Tor Vergata, Dept Syst Med, Rome, Italy.; Finocchi, A (reprint author), Bambino Gesu Children Hosp, Dept Pediat, Div Immunol & Infect Dis, Rome, Italy.; Aiuti, A (reprint author), IRCCS San Raffaele Sci Inst, Pediat Immunohematol & Bone Marrow Transplantat U, Milan, Italy.; Aiuti, A (reprint author), Univ Vita Salute San Raffaele, Milan, Italy. EM aiuti.alessandro@hsr.it; andrea.finocchi@uniroma2.it FU European Commission-Advanced Cell-based Therapies for the treatment of Primary Immunodeficiency [HEALTH-F5-2010-261387]; Italian TELETHON foundation [A1]; Italian Ministero della Salute [NET-2011-02350069, RF-2009-1485896 conv.055, GR-2011-02346985]; Fondazione Roma; Ospedale Pediatrico Bambino Gesu Ricerca Corrente [201602PI003708]; National Institute of Allergy and Infectious Diseases, National Institutes of Health FX The authors would like to thank the European Commission-Advanced Cell-based Therapies for the treatment of Primary Immunodeficiency (HEALTH-F5-2010-261387, CELL-PID to AA and AF), the Italian TELETHON foundation (TIGET Core grant A1), The Italian Ministero della Salute (Programma di rete, NET-2011-02350069), Fondazione Roma and Italian Ministero della Salute (RF-2009-1485896 conv.055), and Ospedale Pediatrico Bambino Gesu Ricerca Corrente (201602PI003708) to CC and AF. IB is supported by the Italian Ministero della Salute (GR-2011-02346985). This work was supported in part by the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 5 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD JAN PY 2017 VL 37 IS 1 BP 32 EP 35 DI 10.1007/s10875-016-0341-y PG 4 WC Immunology SC Immunology GA EI2DY UT WOS:000392298100011 PM 27770395 ER PT J AU Parta, M Cuellar-Rodriguez, J Freeman, AF Gea-Banacloche, J Holland, SM Hickstein, DD AF Parta, Mark Cuellar-Rodriguez, Jennifer Freeman, Alexandra F. Gea-Banacloche, Juan Holland, Steven M. Hickstein, Dennis D. TI Resolution of Multifocal Epstein-Barr Virus-Related Smooth Muscle Tumor in a Patient with GATA2 Deficiency Following Hematopoietic Stem Cell Transplantation SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE GATA2; Epstein-Barr virus ID SPORADIC MONOCYTOPENIA; AUTOSOMAL-DOMINANT; MONOMAC SYNDROME; ASSOCIATION; INFECTION; LEIOMYOSARCOMA; IMMUNOGLOBULIN; MUTATIONS; SARCOMA; CANCERS AB We performed allogeneic hematopoietic stem cell transplantation in a patient with GATA2 deficiency and an Epstein-Barr virus (EBV)-related spindle cell tumor involving the liver and possibly bone. He received a matched-related donor transplant with donor peripheral blood stem cells following a myeloablative conditioning regimen. He achieved rapid and high levels of donor engraftment and had complete reversal of the clinical and immunologic phenotype of MonoMAC/GATA2 deficiency and eradication of the EBV tumors after 3 years of follow-up. Thus, allogeneic hematopoietic stem cell transplant results in reconstitution of immunologic function and cure of EBV-associated malignancy in MonoMAC/GATA2 deficiency. C1 [Parta, Mark] Leidos Biomed Res Inc, Clin Res Directorate, Clin Monitoring Res Program, NCI Campus Frederick, Frederick, MD 21702 USA. [Cuellar-Rodriguez, Jennifer] Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Infect Dis, Mexico City, DF, Mexico. [Freeman, Alexandra F.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Gea-Banacloche, Juan; Hickstein, Dennis D.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Parta, M (reprint author), Leidos Biomed Res Inc, Clin Res Directorate, Clin Monitoring Res Program, NCI Campus Frederick, Frederick, MD 21702 USA. EM mark.parta@nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research; National Institute of Allergy and Infectious Diseases 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 by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by the National Institute of Allergy and Infectious Diseases. NR 27 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD JAN PY 2017 VL 37 IS 1 BP 61 EP 66 DI 10.1007/s10875-016-0360-8 PG 6 WC Immunology SC Immunology GA EI2DY UT WOS:000392298100015 PM 27924436 ER PT J AU Chakravorty, S Roh, SS Glass, J Smith, LE Simmons, AM Lund, K Lokhov, S Liu, X Xu, P Zhang, GL Via, LE Shen, QY Ruan, XL Yuan, X Zhu, HZ Viazovkina, E Shenai, S Rowneki, M Lee, JS Barry, CE Gao, Q Persing, D Kwiatkawoski, R Jones, M Gall, A Alland, D AF Chakravorty, Soumitesh Roh, Sandy S. Glass, Jennifer Smith, Laura E. Simmons, Ann Marie Lund, Kevin Lokhov, Sergey Liu, Xin Xu, Peng Zhang, Guolong Via, Laura E. Shen, Qingyu Ruan, Xianglin Yuan, Xing Zhu, Hong Zhu Viazovkina, Ekaterina Shenai, Shubhada Rowneki, Mazhgan Lee, Jong Seok Barry, Clifton E., III Gao, Qian Persing, David Kwiatkawoski, Robert Jones, Martin Gall, Alexander Alland, David TI Detection of Isoniazid-, Fluoroquinolone-, Amikacin-, and Kanamycin-Resistant Tuberculosis in an Automated, Multiplexed 10-Color Assay Suitable for Point-of-Care Use SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article DE 10-color assay; three-phase PCR; XDR-TB; point-of-care test ID LINE PROBE ASSAY; MYCOBACTERIUM-TUBERCULOSIS; MULTIDRUG-RESISTANT; DRUG-RESISTANCE; RIFAMPIN RESISTANCE; TREATMENT OUTCOMES; PULMONARY TUBERCULOSIS; OFLOXACIN RESISTANCE; HYBRIDIZATION ASSAY; GENETIC MUTATIONS AB Extensively drug-resistant (XDR) tuberculosis (TB) cannot be easily or quickly diagnosed. We developed a rapid, automated assay for the detection of XDR-TB plus resistance to the drug isoniazid (INH) for point-of-care use. Using a simple filter-based cartridge with an integrated sample processing function, the assay identified a wide selection of wild-type and mutant sequences associated with XDR-TB directly from sputum. Four new large-Stokes-shift fluorophores were developed. When these four Stokes-shift fluorophores were combined with six conventional fluorophores, 10-color probe detection in a single PCR tube was enabled. A new three-phase, double-nested PCR approach allowed robust melting temperature analysis with enhanced limits of detection (LODs). Finally, newly designed sloppy molecular beacons identified many different mutations using a small number of probes. The assay correctly distinguished wild-type sequences from 32 commonly occurring mutant sequences tested in gyrA, gyrB, katG, and rrs genes and the promoters of inhA and eis genes responsible for resistance to INH, the fluoroquinolone (FQ) drugs, amikacin (AMK), and kanamycin (KAN). The LOD was 300 CFU of Mycobacterium tuberculosis in 1 ml sputum. The rate of detection of heteroresistance by the assay was equivalent to that by Sanger sequencing. In a blind study of 24 clinical sputum samples, resistance mutations were detected in all targets with 100% sensitivity, with the specificity being 93.7 to 100%. Compared to the results of phenotypic susceptibility testing, the sensitivity of the assay was 75% for FQs and 100% each for INH, AMK, and KAN and the specificity was 100% for INH and FQ and 94% for AMK and KAN. Our approach could enable testing for XDR-TB in point-of-care settings, potentially identifying highly drug-resistant TB more quickly and simply than currently available methods. C1 [Chakravorty, Soumitesh; Roh, Sandy S.; Smith, Laura E.; Shenai, Shubhada; Rowneki, Mazhgan; Alland, David] Univ Med & Dent New Jersey, Dept Med, Newark, NJ 07103 USA. [Glass, Jennifer; Simmons, Ann Marie; Persing, David; Kwiatkawoski, Robert; Jones, Martin] Cepheid Inc, Sunnyvale, CA USA. [Lund, Kevin; Lokhov, Sergey; Viazovkina, Ekaterina; Gall, Alexander] Cepheid Inc, Bothell, WA USA. [Liu, Xin; Ruan, Xianglin; Yuan, Xing] Henan Prov Chest Hosp, Zhengzhou, Henan Province, Peoples R China. [Xu, Peng; Gao, Qian] Fudan Univ, Sch Basic Med Sci, Inst Biomed Sci, Key Lab Med Mol Virol,Minist Educ, Shanghai, Peoples R China. [Xu, Peng; Gao, Qian] Fudan Univ, Sch Basic Med Sci, Inst Med Microbiol, Shanghai, Peoples R China. [Zhang, Guolong; Shen, Qingyu; Zhu, Hong Zhu] SinoUS Int Res Ctr TB, Zhengzhou, Peoples R China. [Zhang, Guolong] Henan Publ Hlth Clin Ctr, Zhengzhou, Peoples R China. [Via, Laura E.; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Via, Laura E.; Barry, Clifton E., III] Univ Cape Town, Inst Infect Dis & Mol Med, Dept Pathol, Cape Town, South Africa. [Lee, Jong Seok] Int TB Res Ctr, Dept Microbiol, Chang Won, Gyeongsnag, South Korea. RP Chakravorty, S (reprint author), Univ Med & Dent New Jersey, Dept Med, Newark, NJ 07103 USA. EM chakraso@njms.rutgers.edu FU U.S. National Institutes of Health (NIH) [AI080653, AI111397]; South Korea and China; Intramural Research Program (IRP) of the National Institute of Allergy and Infectious Diseases, NIH; IRP's International Centers of Excellence in Research program's Sino-US International Research Center of Tuberculosis at the Henan Provincial Chest Hospital; Ministry of Science and Technology of China [2014DFA30340] FX This work was funded by U.S. National Institutes of Health (NIH) grants AI080653 and AI111397. Partial funding for the study in South Korea and China was provided by the Intramural Research Program (IRP) of the National Institute of Allergy and Infectious Diseases, NIH, and through IRP's International Centers of Excellence in Research program's Sino-US International Research Center of Tuberculosis at the Henan Provincial Chest Hospital and by the Ministry of Science and Technology of China (2014DFA30340). NR 57 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD JAN PY 2017 VL 55 IS 1 BP 183 EP 198 DI 10.1128/JCM.01771-16 PG 16 WC Microbiology SC Microbiology GA EH7QC UT WOS:000391966600023 PM 27807153 ER PT J AU Liu, BM AF Liu, Baoming TI Universal PCR Primers Are Critical for Direct Sequencing-Based Enterovirus Genotyping SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Letter DE enterovirus; genotyping; virus C1 [Liu, Baoming] NIAID, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Liu, BM (reprint author), NIAID, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM baoming.liu@nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH. NR 3 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 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD JAN PY 2017 VL 55 IS 1 BP 339 EP 340 DI 10.1128/JCM.01801-16 PG 2 WC Microbiology SC Microbiology GA EH7QC UT WOS:000391966600042 PM 28031445 ER PT J AU Jimmerson, LC Urban, TJ Truesdale, A Baouchi-Mokrane, F Kottilil, S Meissner, EG Sims, Z Langness, JA Hodara, A Aquilante, CL Kiser, JJ AF Jimmerson, Leah C. Urban, Thomas J. Truesdale, Aimee Baouchi-Mokrane, Fafa Kottilil, Shyam Meissner, Eric G. Sims, Zayani Langness, Jacob A. Hodara, Ariel Aquilante, Christina L. Kiser, Jennifer J. TI Variant Inosine Triphosphatase Phenotypes Are Associated With Increased Ribavirin Triphosphate Levels SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE Ribavirin triphosphate; ITPA activity; Pharmacogenetics; Pharmacogenomics; Intracellular pharmacology; SNPs; hemoglobin decline ID CHRONIC HEPATITIS-C; SUSTAINED VIROLOGICAL RESPONSE; SOFOSBUVIR PLUS RIBAVIRIN; INDUCED HEMOLYTIC-ANEMIA; SOLID-PHASE EXTRACTION; ITPA GENE PROTECT; COMBINATION THERAPY; VIRUS-INFECTION; PLASMA-CONCENTRATION; HCV INFECTION AB Individuals with lower inosine triphosphatase (ITPA) enzyme activity have a reduced likelihood of experiencing hemolytic anemia during hepatitis C virus (HCV) treatment containing ribavirin (RBV). Because ITPA degrades purines and RBV is a purine analogue, it is conceivable that ITPA activity may affect intracellular RBV concentrations. Here we assessed the association between ITPA activity phenotype and concentrations of RBV triphosphate (RBV-TP) in red blood cells (RBCs) during HCV treatment. RBV-TP was quantified in the RBCs of 177 HCV-infected individuals at a median (range) of 84 (19 to 336) days into HCV treatment that included RBV. Mean (SD) RBV-TP concentrations were 92.8 (51.6), 101.3 (53.5), 184.8 (84.5), and 197.7 (64.6) pmol/10(6) cells for 100%, 60%, 30%, and 10% ITPA activity groups, respectively. Overall, RBV-TP was approximately 2-fold higher in patients with 30% ITPA activity compared to 100% activity (P < .0001). Despite higher RBV-TP levels, individuals with variant ITPA phenotypes had less anemia. The 100% activity group had, on average, a -2.20 g/dL drop in hemoglobin vs -1.43 g/dL (P = .04) for 60% activity, -1.14 g/dL (P = .008) for 30% activity, and -0.70 g/dL (P = .06) for 10% activity. This finding of higher RBV-TP concentrations in RBCs in ITPA variants was unexpected given that ITPA activity-deficient individuals have a reduced likelihood of RBV-induced anemia. It also refutes the hypothesis that the mechanism by which ITPA variants are protected against anemia is due to lower RBV-TP levels in RBCs. C1 [Jimmerson, Leah C.; Langness, Jacob A.; Hodara, Ariel; Aquilante, Christina L.; Kiser, Jennifer J.] Univ Colorado Denver, Skaggs Sch Pharm & Pharmaceut Sci, Aurora, CO 80045 USA. [Langness, Jacob A.] Univ Colorado Hosp, Dept Pharm, Aurora, CO USA. [Urban, Thomas J.] Univ North Carolina Chapel Hill, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC USA. [Truesdale, Aimee; Baouchi-Mokrane, Fafa] Denver Hlth Med Ctr, Denver, CO USA. [Meissner, Eric G.] Med Univ South Carolina, Div Infect Dis, Dept Microbiol & Immunol, Charleston, SC USA. [Kottilil, Shyam] Univ Maryland, Div Clin Care & Res, Inst Human Virol, Baltimore, MD 21201 USA. [Kottilil, Shyam; Meissner, Eric G.; Sims, Zayani] NIH, Crit Care Med Dept, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Kiser, JJ (reprint author), Univ Colorado Denver, Skaggs Sch Pharm & Pharmaceut Sci, Aurora, CO 80045 USA. EM jennifer.kiser@ucdenver.edu NR 52 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0091-2700 EI 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD JAN PY 2017 VL 57 IS 1 BP 118 EP 124 DI 10.1002/jcph.783 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH8IB UT WOS:000392014300012 PM 27349952 ER PT J AU Lee, J Tofoleanu, F Pickard, FC Konig, G Huang, J Damjanovic, A Baek, M Seok, C Brooks, BR AF Lee, Juyong Tofoleanu, Florentina Pickard, Frank C. Konig, Gerhard Huang, Jing Damjanovic, Ana Baek, Minkyung Seok, Chaok Brooks, Bernard R. TI Absolute binding free energy calculations of CBClip host-guest systems in the SAMPL5 blind challenge SO JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN LA English DT Article DE Absolute binding free energy calculation; Hamiltonian replica exchange; Thermodynamic integration; Bennett's acceptance ratio; Double decoupling scheme; Host-guest complexes; Constant-pH simulation ID HYDRATION FREE-ENERGIES; BENNETTS ACCEPTANCE RATIO; PROTEIN-LIGAND BINDING; GENERAL FORCE-FIELD; MOLECULAR-DYNAMICS SIMULATIONS; REPLICA EXCHANGE METHOD; THERMODYNAMIC INTEGRATION; EXPLICIT SOLVENT; SUPRAMOLECULAR CHEMISTRY; PREDICTION CHALLENGE AB Herein, we report the absolute binding free energy calculations of CBClip complexes in the SAMPL5 blind challenge. Initial conformations of CBClip complexes were obtained using docking and molecular dynamics simulations. Free energy calculations were performed using thermodynamic integration (TI) with soft-core potentials and Bennett's acceptance ratio (BAR) method based on a serial insertion scheme. We compared the results obtained with TI simulations with soft-core potentials and Hamiltonian replica exchange simulations with the serial insertion method combined with the BAR method. The results show that the difference between the two methods can be mainly attributed to the van der Waals free energies, suggesting that either the simulations used for TI or the simulations used for BAR, or both are not fully converged and the two sets of simulations may have sampled difference phase space regions. The penalty scores of force field parameters of the 10 guest molecules provided by CHARMM Generalized Force Field can be an indicator of the accuracy of binding free energy calculations. Among our submissions, the combination of docking and TI performed best, which yielded the root mean square deviation of 2.94 kcal/mol and an average unsigned error of 3.41 kcal/mol for the ten guest molecules. These values were best overall among all participants. However, our submissions had little correlation with experiments. C1 [Lee, Juyong; Tofoleanu, Florentina; Pickard, Frank C.; Konig, Gerhard; Huang, Jing; Damjanovic, Ana; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20852 USA. [Huang, Jing] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 20852 USA. [Baek, Minkyung; Seok, Chaok] Seoul Natl Univ, Dept Chem, Seoul, South Korea. RP Lee, J (reprint author), NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20852 USA. EM juyong.lee@nih.gov RI Huang, Jing/G-5320-2011; OI Huang, Jing/0000-0001-9639-2907; Lee, Juyong/0000-0003-1174-4358 FU Intramural Research Program of the NIH, NHLBI FX The authors would like to thank R. Pastor for stimulating discussions. The research was supported by the Intramural Research Program of the NIH, NHLBI. Computational resources and services used in this work were provided by the LoBoS cluster of the National Institutes of Health. NR 83 TC 1 Z9 1 U1 2 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0920-654X EI 1573-4951 J9 J COMPUT AID MOL DES JI J. Comput.-Aided Mol. Des. PD JAN PY 2017 VL 31 IS 1 SI SI BP 71 EP 85 DI 10.1007/s10822-016-9968-2 PN 2 PG 15 WC Biochemistry & Molecular Biology; Biophysics; Computer Science, Interdisciplinary Applications SC Biochemistry & Molecular Biology; Biophysics; Computer Science GA EI2OH UT WOS:000392326500007 PM 27677749 ER PT J AU Tofoleanu, F Lee, J Pickard, FC Konig, G Huang, J Baek, M Seok, C Brooks, BR AF Tofoleanu, Florentina Lee, Juyong Pickard, Frank C. Koenig, Gerhard Huang, Jing Baek, Minkyung Seok, Chaok Brooks, Bernard R. TI Absolute binding free energies for octa-acids and guests in SAMPL5 Evaluating binding free energies for octa-acid and guest complexes in the SAMPL5 blind challenge SO JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN LA English DT Article DE Binding free energy simulations; Thermodynamic integration; Hamiltonian replica exchange; Bennett acceptance ratio; Double decoupling method; Molecular dynamics simulations; GalaxyDock-HG ID HYDRATION FREE-ENERGIES; SOLVATION FREE-ENERGIES; DEEP-CAVITY CAVITAND; LIGAND-BINDING; FORCE-FIELD; THERMODYNAMIC INTEGRATION; COMPUTER-SIMULATIONS; PK(A) CALCULATIONS; HYDROGEN-BONDS; AFFINITIES AB As part of the SAMPL5 blind prediction challenge, we calculate the absolute binding free energies of six guest molecules to an octa-acid (OAH) and to a methylated octa-acid (OAMe). We use the double decoupling method via thermodynamic integration (TI) or Hamiltonian replica exchange in connection with the Bennett acceptance ratio (HREM-BAR). We produce the binding poses either through manual docking or by using GalaxyDock-HG, a docking software developed specifically for this study. The root mean square deviations for our most accurate predictions are 1.4 kcal mol(-1) for OAH with TI and 1.9 kcal mol(-1) for OAMe with HREM-BAR. Our best results for OAMe were obtained for systems with ionic concentrations corresponding to the ionic strength of the experimental solution. The most problematic system contains a halogenated guest. Our attempt to model the sigma-hole of the bromine using a constrained off-site point charge, does not improve results. We use results from molecular dynamics simulations to argue that the distinct binding affinities of this guest to OAH and OAMe are due to a difference in the flexibility of the host. We believe that the results of this extensive analysis of host-guest complexes will help improve the protocol used in predicting binding affinities for larger systems, such as protein-substrate compounds. C1 [Tofoleanu, Florentina; Lee, Juyong; Pickard, Frank C.; Huang, Jing; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, 5635 Fishers Lane,T-900 Suite, Rockville, MD 20852 USA. [Koenig, Gerhard] Max Planck Inst Kohlenforsch, Mulheim, Germany. [Huang, Jing] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, 20 Penn St, Baltimore, MD 21201 USA. [Baek, Minkyung; Seok, Chaok] Seoul Natl Univ, Dept Chem, Seoul 08826, South Korea. RP Tofoleanu, F (reprint author), NHLBI, Lab Computat Biol, NIH, 5635 Fishers Lane,T-900 Suite, Rockville, MD 20852 USA. EM florentina.tofoleanu@nih.gov RI Huang, Jing/G-5320-2011; OI Huang, Jing/0000-0001-9639-2907; Lee, Juyong/0000-0003-1174-4358 FU National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health; NHLBI Intramural Lenfant Biomedical Fellowship FX The authors would like to thank Tim Miller, Richard Venable and John Legato for technical assistance. We would also like to thank Richard Pastor for very helpful discussions concerning the importance of accurately evaluating the ionic concentration. We extend our gratitude to Andrew C. Simmonett and Michael Lerner for helpful comments on the manuscript. This work was partially supported by the intramural research program of the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health and employed the high-performance computational capabilities of the LoBoS and Biowulf Linux clusters at the National Institutes of Health. (http://www.lobos.nih.gov and (http://biowulf.nih.gov). Florentina Tofoleanu, Juyong Lee and Frank Pickard have been supported by the NHLBI Intramural Lenfant Biomedical Fellowship. NR 74 TC 1 Z9 1 U1 2 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0920-654X EI 1573-4951 J9 J COMPUT AID MOL DES JI J. Comput.-Aided Mol. Des. PD JAN PY 2017 VL 31 IS 1 SI SI BP 107 EP 118 DI 10.1007/s10822-016-9965-5 PN 2 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Computer Science, Interdisciplinary Applications SC Biochemistry & Molecular Biology; Biophysics; Computer Science GA EI2OH UT WOS:000392326500009 PM 27696242 ER PT J AU Ito, T Hijioka, S Masui, T Kasajima, A Nakamoto, Y Kobayashi, N Komoto, I Hijioka, M Lee, L Igarashi, H Jensen, RT Imamura, M AF Ito, Tetsuhide Hijioka, Susumu Masui, Toshihiko Kasajima, Atsuko Nakamoto, Yuji Kobayashi, Noritoshi Komoto, Izumi Hijioka, Masayuki Lee, Lingaku Igarashi, Hisato Jensen, Robert Thomas Imamura, Masayuki TI Advances in the diagnosis and treatment of pancreatic neuroendocrine neoplasms in Japan SO JOURNAL OF GASTROENTEROLOGY LA English DT Review DE Pancreatic neuroendocrine neoplasm; Neuroendocrine tumor; Somatostatin receptor scintigraphy; In-111-octreoscan; Chromogranin A; EUS-FNA; WHO classification; NET G3; Molecular target therapy ID ENETS CONSENSUS GUIDELINES; FINE-NEEDLE-ASPIRATION; NEURON-SPECIFIC ENOLASE; SERUM CHROMOGRANIN-A; FOLLOW-UP; PROGNOSTIC-FACTORS; ENDOCRINE TUMORS; USEFUL MARKER; EUS-FNA; MANAGEMENT AB Several new developments have occurred in the field of pancreatic neuroendocrine neoplasm (PNEN) recently in Japan. First, the utility of chromogranin A (CgA), useful for the diagnosis and monitoring of the treatment response of neuroendocrine neoplasm (NEN), has been demonstrated in Japan. For PNEN diagnosis and treatment, grading and correct histological diagnosis according to the WHO 2010 classification is important. Regarding the histological diagnosis, the advent of endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) has enabled correct pathological diagnosis and suitable treatment for the affected tissue. Furthermore, EUS-FNA has also facilitates the assessment of the presence or absence of gene mutations. In addition, patients who have a well-differentiated neuroendocrine tumor (NET) showing a Ki-67 index of higher than 20 % according to the WHO 2010 classification, have also been identified, and their responses to treatment were found to be different from those of patients with poorly differentiated neuroendocrine carcinoma (NEC). Therefore, the concept of NET G3 was proposed. Additionally, somatostatin receptor type 2 is expressed in several cases of NET, and somatostatin receptor scintigraphy (In-111-octreoscan) has also been approved in Japan. This advancement will undoubtedly contribute to the localization diagnosis, the identification of remote metastasis, and assessments of the treatment responses of PNEN. Finally, regarding the treatment strategy for PNEN, the management of liver metastasis is important. The advent of novel molecular-targeted agents has dramatically improved the prognosis of advanced PNEN. Multimodality therapy that accounts for the tumor stage, degree of tumor differentiation, tumor volume, and speed of tumor growth is required. C1 [Ito, Tetsuhide; Hijioka, Masayuki; Lee, Lingaku; Igarashi, Hisato] Kyushu Univ, Grad Sch Med Sci, Dept Med & Bioregulatory Sci, Higashi Ku, Fukuoka 8128582, Japan. [Hijioka, Susumu] Aichi Canc Ctr Hosp, Dept Gastroenterol, Nagoya, Aichi, Japan. [Masui, Toshihiko] Kyoto Univ, Grad Sch Med, Dept Surg, Kyoto, Japan. [Kasajima, Atsuko] Tohoku Univ Hosp, Dept Pathol, Sendai, Miyagi, Japan. [Nakamoto, Yuji] Kyoto Univ, Grad Sch Med, Dept Diagnost Imaging & Nucl Med, Kyoto, Japan. [Kobayashi, Noritoshi] Yokohama City Univ, Grad Sch Med, Dept Oncol, Yokohama, Kanagawa, Japan. [Komoto, Izumi] Kansai Elect Power Hosp, Dept Surg, Osaka, Japan. [Jensen, Robert Thomas] NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. [Imamura, Masayuki] Kansai Elect Power Hosp, Neuroendocrine Tumor Ctr, Osaka, Japan. RP Ito, T (reprint author), Kyushu Univ, Grad Sch Med Sci, Dept Med & Bioregulatory Sci, Higashi Ku, Fukuoka 8128582, Japan. EM itopapa@intmed3.med.kyushu-u.ac.jp NR 60 TC 1 Z9 1 U1 5 U2 5 PU SPRINGER JAPAN KK PI TOKYO PA CHIYODA FIRST BLDG EAST, 3-8-1 NISHI-KANDA, CHIYODA-KU, TOKYO, 101-0065, JAPAN SN 0944-1174 EI 1435-5922 J9 J GASTROENTEROL JI J. Gastroenterol. PD JAN PY 2017 VL 52 IS 1 BP 9 EP 18 DI 10.1007/s00535-016-1250-9 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EH8ON UT WOS:000392031900002 PM 27539256 ER PT J AU Blackstock, OJ Moore, BA Berkenblit, GV Calabrese, SK Cunningham, CO Fiellin, DA Patel, VV Phillips, KA Tetrault, JM Shah, M Edelman, EJ AF Blackstock, Oni J. Moore, Brent A. Berkenblit, Gail V. Calabrese, Sarah K. Cunningham, Chinazo O. Fiellin, David A. Patel, Viraj V. Phillips, Karran A. Tetrault, Jeanette M. Shah, Minesh Edelman, E. Jennifer TI A Cross-Sectional Online Survey of HIV Pre-Exposure Prophylaxis Adoption Among Primary Care Physicians SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE HIV prevention; pre-exposure prophylaxis; primary care physicians; implementation ID UNITED-STATES; PROVIDERS KNOWLEDGE; ANTIRETROVIRAL PROPHYLAXIS; PRESCRIBING PRACTICES; INFECTED PATIENTS; HETEROSEXUAL MEN; SUBSTANCE USE; HIGH-RISK; PREVENTION; ATTITUDES AB Among health care providers, prescription of HIV pre-exposure prophylaxis (PrEP) has been low. Little is known specifically about primary care physicians (PCPs) with regard to PrEP awareness and adoption (i.e., prescription or referral), and factors associated with adoption. To assess PrEP awareness, PrEP adoption, and factors associated with adoption among PCPs. Cross-sectional online survey conducted in April and May 2015. Members of a national professional organization for academic primary care physicians (n = 266). PrEP awareness, PrEP adoption (ever prescribed or referred a patient for PrEP [yes/no]), provider and practice characteristics, and self-rated knowledge, attitudes, and beliefs associated with adoption. The survey response rate was 8.6 % (266/2093). Ninety-three percent of respondents reported prior awareness of PrEP. Of these, 34.9 % reported PrEP adoption. In multivariable analysis of provider and practice characteristics, compared with non-adopters, adopters were more likely to provide care to more than 50 HIV-positive patients (vs. 0, aOR = 6.82, 95 % CI 2.06-22.52). Compared with non-adopters, adopters were also more likely to report excellent, very good, or good self-rated PrEP knowledge (15.1 %, 33.7 %, 30.2 % vs. 2.5 %, 18.1 %, 23.8 %, respectively; p < 0.001) and to perceive PrEP as extremely safe (35.1 % vs. 10.7 %; p = 0.002). Compared with non-adopters, adopters were less likely to perceive PrEP as being moderately likely to increase risk behaviors ("risk compensation") (12.8 % vs. 28.8 %, p = 0.02). While most respondents were aware of PrEP, only one-third of PrEP-aware PCPs reported adoption. Adopters were more likely to have experience providing HIV care and to perceive PrEP as extremely safe, and were less likely to perceive PrEP use as leading to risk compensation. To enhance PCP adoption of PrEP, educational efforts targeting PCPs without HIV care experience should be considered, as well as training those with HIV care experience to be PrEP "clinical champions". Concerns about safety and risk compensation must also be addressed. C1 [Blackstock, Oni J.; Cunningham, Chinazo O.; Patel, Viraj V.] Albert Einstein Coll Med, Montefiore Med Ctr, 3300 Kossuth Ave, Bronx, NY 10467 USA. [Moore, Brent A.; Fiellin, David A.; Tetrault, Jeanette M.; Edelman, E. Jennifer] Yale Univ, Sch Med, New Haven, CT USA. [Berkenblit, Gail V.] Johns Hopkins Univ, Baltimore, MD USA. [Calabrese, Sarah K.; Fiellin, David A.; Edelman, E. Jennifer] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Phillips, Karran A.] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. [Shah, Minesh] Univ Illinois, Chicago, IL USA. RP Blackstock, OJ (reprint author), Albert Einstein Coll Med, Montefiore Med Ctr, 3300 Kossuth Ave, Bronx, NY 10467 USA. EM oblackst@montefiore.org OI Fiellin, David/0000-0002-4006-010X; Patel, Viraj/0000-0002-5603-9823 FU Yale Center for Clinical Investigation [UL1 TR000142]; Yale Drug Abuse, Addiction and HIV Research Scholar (DAHRS) [K12DA033312-03]; [K23MH102129]; [K01MH103080] FX This work was generously supported by Yale Center for Clinical Investigation (UL1 TR000142). E. Jennifer Edelman was funded as a Yale Drug Abuse, Addiction and HIV Research Scholar (DAHRS) during the writing of this manuscript (K12DA033312-03). Oni Blackstock is supported by K23MH102129 and Dr. Sarah Calabrese by K01MH103080. NR 40 TC 1 Z9 1 U1 13 U2 13 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 JAN PY 2017 VL 32 IS 1 BP 62 EP 70 DI 10.1007/s11606-016-3903-z PG 9 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EI0ZB UT WOS:000392203200015 PM 27778215 ER PT J AU Larsen, SE Bilenkin, A Tarasenko, TN Arjunaraja, S Stinson, JR McGuire, PJ Snow, AL AF Larsen, Sasha E. Bilenkin, Abegail Tarasenko, Tatiana N. Arjunaraja, Swadhinya Stinson, Jeffrey R. McGuire, Peter J. Snow, Andrew L. TI Sensitivity to Restimulation-Induced Cell Death Is Linked to Glycolytic Metabolism in Human T Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TRANSCRIPTION FACTOR; AEROBIC GLYCOLYSIS; GENE-EXPRESSION; FAS LIGAND; C-MYC; ACTIVATION; MEMORY; LYMPHOCYTES; GLUCOSE; DIFFERENTIATION AB Restimulation-induced cell death (RICD) regulates immune responses by restraining effector T cell expansion and limiting nonspecific damage to the host. RICD is triggered by re-engagement of the TCR on a cycling effector T cell, resulting in apoptosis. It remains unclear how RICD sensitivity is calibrated in T cells derived from different individuals or subsets. In this study we show that aerobic glycolysis strongly correlates with RICD sensitivity in human CD8(+) effector T cells. Reducing glycolytic activity or glucose availability rendered effector T cells significantly less sensitive to RICD. We found that active glycolysis specifically facilitates the induction of proapoptotic Fas ligand upon TCR restimulation, accounting for enhanced RICD sensitivity in highly glycolytic T cells. Collectively, these data indicate that RICD susceptibility is linked to metabolic reprogramming, and that switching back to metabolic quiescence may help shield T cells from RICD as they transition into the memory pool. C1 [Larsen, Sasha E.; Bilenkin, Abegail; Arjunaraja, Swadhinya; Stinson, Jeffrey R.; Snow, Andrew L.] Uniformed Serv Univ Hlth Sci, Dept Pharmacol & Mol Therapeut, Bethesda, MD 20814 USA. [Tarasenko, Tatiana N.; McGuire, Peter J.] NHGRI, Metab Infect & Immun Unit, NIH, Bethesda, MD 20892 USA. RP Snow, AL (reprint author), Uniformed Serv Univ Hlth Sci, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM andrew.snow@usuhs.edu FU National Institutes of Health [R01GM105821]; Uniformed Services University of the Health Sciences FX This work was supported by National Institutes of Health Grant R01GM105821 (to A.L.S.) and a Uniformed Services University of the Health Sciences grant (to S.E.L. and A.L.S.). NR 41 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 JAN 1 PY 2017 VL 198 IS 1 BP 147 EP 155 DI 10.4049/jimmunol.1601218 PG 9 WC Immunology SC Immunology GA EI3ON UT WOS:000392400800017 PM 27852741 ER PT J AU Malloy, AMW Ruckwardt, TJ Morabito, KM Lau-Kilby, AW Graham, BS AF Malloy, Allison M. W. Ruckwardt, Tracy J. Morabito, Kaitlyn M. Lau-Kilby, Annie W. Graham, Barney S. TI Pulmonary Dendritic Cell Subsets Shape the Respiratory Syncytial Virus-Specific CD8(+) T Cell Immunodominance Hierarchy in Neonates SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ANTIGEN-PRESENTING CELLS; ANTIVIRAL IMMUNITY; LYMPHOCYTE RESPONSES; INFLUENZA-VIRUS; VACCINIA VIRUS; CORD BLOOD; INDUCTION; MICE; INFECTION; DISTINCT AB Young infants are generally more susceptible to viral infections and experience more severe disease than do adults. CD8(+) T cells are important for viral clearance, and although often ineffective in neonates they can be protective when adequately stimulated. Using a murine CB6F1/ J hybrid model of respiratory syncytial virus (RSV) infection, we previously demonstrated that the CD8(+) T cell immunodominance hierarchy to two RSV-derived epitopes, K-d M2(82)-(90) and D-b M187-195, was determined by the age at infection. To determine whether age-dependent RSV-specific CD8(+) T cell responses could be modified through enhanced innate signaling, we used TLR4 or TLR9 agonist treatment at the time of infection, which remarkably changed the neonatal codominant response to an adult-like K-d M2(82-90) CD8(+) T cell immunodominant response. This shift was associated with an increase in the number of conventional dendritic cells, CD11b(+) and CD103(+) dendritic cells, in the lung-draining lymph node, as well as increased expression of the costimulatory molecule CD86. The magnitude of the K(d)M2(82-90) CD8(+) T cell response in TLR agonist-treated neonates could be blocked with Abs against CD80 and CD86. These studies demonstrate the age-dependent function of conventional dendritic cells, their role in determining immunodominance hierarchy, and epitope-specific CD8(+) T cell requirements for costimulation, all of which influence the immune response magnitude. The unique impact of TLR agonists on neonatal T cell responses is important to consider for RSV vaccines designed for young infants. C1 [Malloy, Allison M. W.; Lau-Kilby, Annie W.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Pediat, Lab Neonatal Infect & Immun, Bethesda, MD 20814 USA. [Malloy, Allison M. W.; Ruckwardt, Tracy J.; Morabito, Kaitlyn M.; Graham, Barney S.] NIAID, Viral Pathogenesis Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Malloy, AMW (reprint author), Uniformed Serv Univ Hlth Sci, 4301 Jones Bridge Rd,A3028, Bethesda, MD 20814 USA. EM allison.malloy@usuhs.edu FU Intramural Research Programs of the Vaccine Research Center, National Institutes of Health; Uniformed Services University of the Health Sciences Department of Pediatrics Grant [QP86GI-S24] FX This work was supported by the Intramural Research Programs of the Vaccine Research Center, National Institutes of Health and by Uniformed Services University of the Health Sciences Department of Pediatrics Grant QP86GI-S24. NR 63 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 JAN 1 PY 2017 VL 198 IS 1 BP 394 EP 403 DI 10.4049/jimmunol.1600486 PG 10 WC Immunology SC Immunology GA EI3ON UT WOS:000392400800040 PM 27895172 ER PT J AU Gera, N Swanson, KD Jin, T AF Gera, Nidhi Swanson, Kenneth D. Jin, Tian TI beta-Arrestin 1-dependent regulation of Rap2 is required for fMLP-stimulated chemotaxis in neutrophil-like HL-60 cells SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE GPCR; cell migration; GTPase ID FORMYL PEPTIDE RECEPTOR; PROTEASE-ACTIVATED RECEPTOR-2; SIGNAL-TRANSDUCTION PATHWAYS; HETEROTRIMERIC G-PROTEINS; GTP-BINDING PROTEIN; LIVING CELLS; MEDIATED ACTIVATION; EFFECTOR MOLECULES; LEADING-EDGE; RAS AB beta-Arrestins have emerged as key regulators of cytoskeletal rearrangement that are required for directed cell migration. Whereas it is known that beta-arrestins are required for formyl-Met-Leu-Phe receptor (FPR) recycling, less is known about their role in regulating FPR-mediated neutrophil chemotaxis. Here, we show that beta-arrestin 1 (ArrB1) coaccumulated with F-actin within the leading edge of neutrophil-like HL-60 cells during chemotaxis, and its knockdown resulted in markedly reduced migration within fMLP gradients. The small GTPase Ras-related protein 2 (Rap2) was found to bind ArrB1 under resting conditions but dissociated upon fMLP stimulation. The FPR-dependent activation of Rap2 required ArrB1 but was independent of G alpha(i) activity. Significantly, depletion of either ArrB1 or Rap2 resulted in reduced chemotaxis and defects in cellular repolarization within fMLP gradients. These data strongly suggest a model in which FPR is able to direct ArrB1 and other bound proteins that are required for lamellipodial extension to the leading edge in migrating neutrophils, thereby orientating and directing cell migration. C1 [Gera, Nidhi; Jin, Tian] NIAID, Chemotaxis Signal Sect, Immunogenet Lab, NIH, Rockville, MD USA. [Swanson, Kenneth D.] Beth Israel Deaconess Med Ctr, Dept Neurol, Div Neurooncol, Boston, MA 02215 USA. [Gera, Nidhi] Harvard Med Sch, Boston, MA USA. RP Gera, N (reprint author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Jin, T (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM nidhi_gera@hms.harvard.edu; tjin@niaid.nih.gov FU Intramural Research Program of the U.S. National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases [AI001156]; NIH National Heart, Lung, and Blood Institute [R01-HL116327] FX This work was supported by the Intramural Research Program of the U.S. National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases Grant AI001156 (to Tian Jin); and NIH National Heart, Lung, and Blood Institute Grant R01-HL116327 (to David E. Golan). The authors thank David E. Golan for his support of N.G. NR 81 TC 0 Z9 0 U1 1 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JAN PY 2017 VL 101 IS 1 BP 239 EP 251 DI 10.1189/jlb.2A1215-572R PG 13 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA EI0FN UT WOS:000392148500022 PM 27493245 ER PT J AU Myles, IA Zhao, M Nardone, G Olano, LR Reckhow, JD Saleem, D Break, TJ Lionakis, MS Myers, TG Gardina, PJ Kirkpatrick, CH Holland, SM Datta, SK AF Myles, Ian A. Zhao, Ming Nardone, Glenn Olano, Lisa R. Reckhow, Jensen D. Saleem, Danial Break, Timothy J. Lionakis, Michail S. Myers, Timothy G. Gardina, Paul J. Kirkpatrick, Charles H. Holland, Steven M. Datta, Sandip K. TI CD8(+) T cells produce a dialyzable antigen-specific activator of dendritic cells SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE transfer factor; cellular immunity; Tc17 ID DELAYED-TYPE HYPERSENSITIVITY; TRANSFER-FACTOR THERAPY; GUINEA-PIG; IN-VITRO; STAPHYLOCOCCUS-AUREUS; CANDIDA-ALBICANS; CENTRAL MEMORY; TC17 CELLS; RECEPTOR; IMMUNITY AB Cellular lysates from PPD+ donors have been reported to transfer tuberculin reactivity to naive recipients, but not diphtheria reactivity, and vice versa. A historically controversial topic, the terms "transfer factor" and "DLE" were used to characterize the reactivity-transferring properties of lysates. Intrigued by these reported phenomena, we found that the cellular extract derived from antigen-specific memory CD8(+) T cells induces IL-6 from antigen-matched APCs. This ultimately elicits IL-17 from bystander memory CD8(+) T cells. We have identified that dialyzable peptide sequences, S100a9, and the TCR beta chain from CD8(+) T cells contribute to the molecular nature of this activity. We further show that extracts from antigen-targeted T cells enhance immunity to Staphylococcus aureus and Candida albicans. These effects are sensitive to immunization protocols and extraction methodology in ways that may explain past discrepancies in the reproducibility of passive cellular immunity. C1 [Myles, Ian A.; Reckhow, Jensen D.; Saleem, Danial; Break, Timothy J.; Lionakis, Michail S.; Holland, Steven M.; Datta, Sandip K.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike,Bldg 33,Rm 2W10A, Bethesda, MD 20892 USA. [Zhao, Ming; Nardone, Glenn; Olano, Lisa R.] NIAID, Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Break, Timothy J.; Lionakis, Michail S.] NIAID, Genom Technol Sect, Res Technol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kirkpatrick, Charles H.] Univ Colorado, Hlth Sci Ctr, Denver, CO USA. RP Myles, IA (reprint author), NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike,Bldg 33,Rm 2W10A, Bethesda, MD 20892 USA. EM mylesi@niaid.nih.gov FU Intramural Research Program of NIAID; U.S. National Institutes of Health FX This work was supported by the Intramural Research Program of NIAID and the U.S. National Institutes of Health. The authors thank the patients, their families, and healthy participants for their assistance in this project. The authors also thank the NIAID Building 33 and 14BS veterinarians, animal care, and breeder technicians for their assistance on animal experiments; Drs. Bishop Hague and Elina Stregevsky for help with cell sorting; Dr. Francisco Otaizo-Carrasquero for help performing RNA-seq; Mark Kieh and Elim Cho for technical assistance; and Dawn Shaw, Towanda Carroll, Bevin Feutier, Emily Franks, Yuka Kanno, Kimberly Hilsen, Raynaldo Martin (NIAID), and Anthony St. Leger (NEI) for administrative assistance, as well as Mr. and Mrs. Topolino (NIAID) for their cooperation and sacrifice during the course of this project. NR 60 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JAN PY 2017 VL 101 IS 1 BP 307 EP 320 DI 10.1189/jlb.3A0216-082R PG 14 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA EI0FN UT WOS:000392148500028 PM 27515950 ER PT J AU Percopo, CM Brenner, TA Ma, M Kraemer, LS Hakeem, RMA Lee, JJ Rosenberg, HF AF Percopo, Caroline M. Brenner, Todd A. Ma, Michelle Kraemer, Laura S. Hakeem, Reem M. A. Lee, James J. Rosenberg, Helene F. TI SiglecF(+)Gr1(hi) eosinophils are a distinct subpopulation within the lungs of allergen-challenged mice SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE allergy; inflammation; flow cytometry; cytokines ID ALTERNATIVELY ACTIVATED MACROPHAGES; HYPODENSE EOSINOPHILS; BONE-MARROW; MOUSE EOSINOPHILS; FLOW-CYTOMETRY; INFLAMMATION; INFECTION; IMMUNITY; PROTEINS; LINEAGE AB Although eosinophils as a group are readily identified by their unique morphology and staining properties, flow cytometry provides an important means for identification of subgroups based on differential expression of distinct surface Ags. Here, we characterize an eosinophil sub-population defined by high levels of expression of the neutrophil Ag Gr1 (CD45(+)CD11c(-)SiglecF(+)Gr1(hi)). SiglecF(+)Gr1(hi) eosinophils, distinct from the canonical SiglecF(+)Gr1(-) eosinophil population, were detected in allergen-challenged wild-type and granule protein-deficient (EPX-/- and MBP-1(-/-)) mice, but not in the eosinophil-deficient Delta dblGATA strain. In contrast to Gr1(+) neutrophils, which express both cross-reacting Ags Ly6C and Ly6G, SiglecF(+)Gr1(hi) eosinophils from allergen-challenged lung tissue are uniquely Ly6G(+). Although indistinguishable from the more-numerous SiglecF(+)Gr1(-) eosinophils under light microscopy, FACS-isolated populations revealed prominent differences in cytokine contents. The lymphocyte-targeting cytokines CXCL13 and IL-27 were identified only in the SiglecF(+)Gr1(hi) eosinophil population (at 3.9 and 4.8 pg/10(6) cells, respectively), as was the prominent proinflammatory mediator IL-13 (72 pg/10(6) cells). Interestingly, bone marrow-derived (SiglecF(+)), cultured eosinophils include a more substantial Gr1(+) subpopulation (similar to 50%); Gr1(+) bmEos includes primarily a single Ly6C(+) and a smaller, double-positive (Ly6C(+)Ly6G(+)) population. Taken together, our findings characterize a distinct SiglecF(+)Gr1(hi) eosinophil subset in lungs of allergen-challenged, wild-type and granule protein-deficient mice. SiglecF(+)Gr1(hi) eosinophils from wild-type mice maintain a distinct subset of cytokines, including those active on B and T lymphocytes. These cytokines may facilitate eosinophil-mediated immunomodulatory responses in the allergen-challenged lung as well as in other distinct microenvironments. C1 [Percopo, Caroline M.; Brenner, Todd A.; Ma, Michelle; Kraemer, Laura S.; Rosenberg, Helene F.] NIAID, Inflammat Immunobiol Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Hakeem, Reem M. A.] NIAID, Mol Signal Transduct Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lee, James J.] Mayo Clin, Scottsdale, AZ USA. RP Rosenberg, HF (reprint author), NIAID, Inflammat Immunobiol Sect, Lab Allerg Dis, NIH, Bldg 10,Room 11C215,MSC 1883,9000 Rockville Pike, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov FU U.S. National Institutes of Health National Institute of Allergy and Infectious Diseases, Division of Intramural Research [AI 000941] FX This work was performed with support from the U.S. National Institutes of Health National Institute of Allergy and Infectious Diseases, Division of Intramural Research (Grant AI 000941) to H.F.R. We dedicate this work to our colleague, Dr. Kimberly Dyer, and send our wishes for her speedy recovery. NR 46 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JAN PY 2017 VL 101 IS 1 BP 321 EP 328 DI 10.1189/jlb.3A0416-166R PG 8 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA EI0FN UT WOS:000392148500029 PM 27531929 ER PT J AU Agrawal, K Hassoun, LA Foolad, N Pedersen, TL Sivamani, RK Newman, JW AF Agrawal, Karan Hassoun, Lauren A. Foolad, Negar Pedersen, Theresa L. Sivamani, Raja K. Newman, John W. TI Sweat lipid mediator profiling: a noninvasive approach for cutaneous research SO JOURNAL OF LIPID RESEARCH LA English DT Article DE oxidized lipids; endocannabinoids; ceramides; sphingolipids; skin; metabolic profiling; non-invasive sampling; atopic dermatitis ID TANDEM MASS-SPECTROMETRY; HIGH-RESOLUTION MODE; HUMAN ECCRINE SWEAT; ATOPIC-DERMATITIS; BARRIER FUNCTION; STRATUM-CORNEUM; HUMAN SKIN; METABOLOMICS; INFLAMMATION; CERAMIDES AB Recent advances in analytical and sweat collection techniques provide new opportunities to identify noninvasive biomarkers for the study of skin inflammation and repair. This study aims to characterize the lipid mediator profile including oxygenated lipids, endocannabinoids, and ceramides/sphingoid bases in sweat and identify differences in these profiles between sweat collected from nonlesional sites on the unflared volar forearm of subjects with and without atopic dermatitis (AD). Adapting routine procedures developed for plasma analysis, over 100 lipid mediators were profiled using LC-MS/MS and 58 lipid mediators were detected in sweat. Lipid mediator concentrations were not affected by sampling or storage conditions. Increases in concentrations of C30-C40 [NS] and [NdS] ceramides, and C18:1 sphingosine, were observed in the sweat of study participants with AD despite no differences being observed in transepidermal water loss between study groups, and this effect was strongest in men (P < 0.05, one-way ANOVA with Tukey's post hoc HSD). No differences in oxylipins and endocannabinoids were observed between study groups.(Jlr) Sweat mediator profiling may therefore provide a noninvasive diagnostic for AD prior to the presentation of clinical signs. C1 [Agrawal, Karan; Newman, John W.] Univ Calif Davis, Dept Nutr, Davis, CA 95616 USA. [Agrawal, Karan; Pedersen, Theresa L.; Newman, John W.] NIH, West Coast Metabol Ctr, Davis, CA 95616 USA. [Hassoun, Lauren A.; Foolad, Negar; Sivamani, Raja K.] Univ Calif Davis, Med Ctr, Sacramento, CA 95816 USA. [Pedersen, Theresa L.; Newman, John W.] ARS, USDA, Western Human Nutr Res Ctr, Davis, CA 95616 USA. RP Newman, JW (reprint author), Univ Calif Davis, Dept Nutr, Davis, CA 95616 USA.; Newman, JW (reprint author), NIH, West Coast Metabol Ctr, Davis, CA 95616 USA.; Newman, JW (reprint author), ARS, USDA, Western Human Nutr Res Ctr, Davis, CA 95616 USA. EM john.newman@ars.usda.gov FU National Institute of General Medical Sciences [T32-GM008799]; University of California-Davis Medical Student Research Fellowship from School of Medicine, University of California, Davis; US Department of Agriculture Intramural Project [2032-51530-022-00D]; National Institute of Diabetes and Digestive and Kidney Diseases [U24DK097154-01] FX This study was supported by National Institute of General Medical Sciences Grant T32-GM008799 (K.A.), the University of California-Davis Medical Student Research Fellowship from School of Medicine, University of California, Davis (L.A.H.), US Department of Agriculture Intramural Project 2032-51530-022-00D, and National Institute of Diabetes and Digestive and Kidney Diseases Grant U24DK097154-01 (J.W.N.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the US Department of Agriculture. The US Department of Agriculture is an equal opportunity provider and employer. The authors declare that they have no financial conflicts of interest. NR 49 TC 0 Z9 0 U1 4 U2 4 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 JAN PY 2017 VL 58 IS 1 BP 188 EP 195 DI 10.1194/jlr.M071738 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EI3RJ UT WOS:000392408700015 PM 27875258 ER PT J AU Cheng, Y Loh, YP Birch, NP AF Cheng, Yong Loh, Y. Peng Birch, Nigel P. TI Neuroserpin Attenuates H2O2-Induced Oxidative Stress in Hippocampal Neurons via AKT and BCL-2 Signaling Pathways SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE Oxidative stress; Reactive oxygen species; Protease inhibitor; Neuroprotection; Hippocampal neurons ID TISSUE-PLASMINOGEN ACTIVATOR; SERINE-PROTEASE INHIBITOR; RECEPTOR-RELATED PROTEIN; ALZHEIMER-DISEASE BRAIN; NERVOUS-SYSTEM; NEURODEGENERATIVE DISORDERS; MITOCHONDRIAL DYSFUNCTION; TRK RECEPTORS; CYTOCHROME-C; CELL-DEATH AB Oxidative stress plays a critical role in neuronal injury and is associated with various neurological diseases. Here, we explored the potential protective effect of neuroserpin against oxidative stress in primary cultured hippocampal neurons. Our results show that neuroserpin inhibits H2O2-induced neurotoxicity in hippocampal cultures as measured by WST, LDH release, and TUNEL assays. We found that neuroserpin enhanced the activation of AKT in cultures subjected to oxidative stress and that the AKT inhibitor Ly294002 blocked this neuroprotective effect. Neuroserpin increased the expression of the anti-apoptotic protein BCL-2 and blocked the activation of caspase-3. Neuroserpin did not increase the level of neuroprotection over levels seen in neurons transduced with a BCL-2 expression vector, and an inhibitor of Trk receptors, K252a, did not block neuroserpin's effect. Taken together, our study demonstrates that neuroserpin protects against oxidative stress-induced dysfunction and death of primary cultured hippocampal neurons through the AKT-BCL-2 signaling pathway through a mechanism that does not involve the Trk receptors and leads to inhibition of caspase-3 activation. C1 [Cheng, Yong; Loh, Y. Peng] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Birch, Nigel P.] Univ Auckland, Sch Biol Sci, Ctr Brain Res & Brain Res New Zealand, Rangahau Roro Aotearoa, 3a Symonds St 92019, Auckland 1142, New Zealand. RP Birch, NP (reprint author), Univ Auckland, Sch Biol Sci, Ctr Brain Res & Brain Res New Zealand, Rangahau Roro Aotearoa, 3a Symonds St 92019, Auckland 1142, New Zealand. EM n.birch@auckland.ac.nz FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Health and Human Development, National Institutes of Health, USA; Auckland Medical Research Foundation; University of Auckland FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Health and Human Development, National Institutes of Health, USA, and grants from the Auckland Medical Research Foundation and the University of Auckland to NPB. NR 59 TC 0 Z9 0 U1 4 U2 4 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 EI 1559-1166 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD JAN PY 2017 VL 61 IS 1 BP 123 EP 131 DI 10.1007/s12031-016-0807-7 PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA EH9ZL UT WOS:000392130800014 PM 27510267 ER PT J AU Narver, HL AF Narver, Heather L. TI Antimicrobial Stewardship in Laboratory Animal Facilities SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Review ID RESISTANT STAPHYLOCOCCUS-AUREUS; CRYSTALLINE-FREE ACID; SYSTEMIC ANTIMICROBIALS; SUGGESTED GUIDELINES; MACACA-MULATTA; MICE; STRATEGIES; PHARMACOKINETICS; ANTIBIOTICS; VETERINARY AB Bacterial resistance to antimicrobial drugs has become a global health crisis. Physicians and veterinarians are embracing the concept of 'antimicrobial stewardship' (AMS) to preserve the efficacy of antibiotics for future generations. Antimicrobials are used in laboratory animals to treat clinical disease, to protect populations that may be vulnerable to infection, and in research projects including studies of the microbiome and to influence expression in genetically engineered animals. This overview provides a critical look at the use of antimicrobials in contemporary vivaria, with special attention to rodents because they are the most commonly used species in research and because antimicrobial use in rodents is not straightforward. Improvements in antibiotic use are encouraged with the goal of decreasing bacterial resistance while continuing to provide quality clinical care and research support. Suggestions are framed by using the 5 Rs: Reduce, Refine, Replace, and Review antimicrobial use in the vivarium, and take Responsibility for the judicious use of antibiotics in research animals. C1 [Narver, Heather L.] NINDS, Anim Hlth & Care Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Narver, HL (reprint author), NINDS, Anim Hlth & Care Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM narverh@mail.nih.gov NR 36 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD JAN PY 2017 VL 56 IS 1 BP 6 EP 10 PG 5 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA EI1SQ UT WOS:000392258600002 ER PT J AU Tempero, M AF Tempero, Margaret TI New Year's Resolutions SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Editorial Material C1 [Tempero, Margaret] UCSF Pancreas Ctr, San Francisco, CA 94143 USA. [Tempero, Margaret] NCI, Clin Oncol Study Sect, Bethesda, MD 20892 USA. [Tempero, Margaret] Canc Prevent & Res Inst Texas, Sci Steering Comm, Austin, TX 78701 USA. [Tempero, Margaret] Canc Prevent & Res Inst Texas, Clin & Translat Study Sect, Austin, TX 78701 USA. [Tempero, Margaret] US FDA, Oncol Drug Advisory Comm, Rockville, MD 20857 USA. [Tempero, Margaret] UNMC Eppley Canc Ctr, Omaha, NE USA. [Tempero, Margaret] UCSF, Div Med Oncol, San Francisco, CA 94143 USA. [Tempero, Margaret] UCSF Helen Diller Family Comprehens Canc Ctr, Res Programs, San Francisco, CA USA. RP Tempero, M (reprint author), UCSF Pancreas Ctr, San Francisco, CA 94143 USA.; Tempero, M (reprint author), Canc Prevent & Res Inst Texas, Sci Steering Comm, Austin, TX 78701 USA.; Tempero, M (reprint author), Canc Prevent & Res Inst Texas, Clin & Translat Study Sect, Austin, TX 78701 USA.; Tempero, M (reprint author), UCSF, Div Med Oncol, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD JAN PY 2017 VL 15 IS 1 BP 1 EP 1 PG 1 WC Oncology SC Oncology GA EH8TT UT WOS:000392045900001 PM 28040714 ER PT J AU Park, YK Wang, LM Giampietro, A Lai, BB Lee, JE Ge, K AF Park, Young-Kwon Wang, Limin Giampietro, Anne Lai, Binbin Lee, Ji-Eun Ge, Kai TI Distinct Roles of Transcription Factors KLF4, Krox20, and Peroxisome Proliferator-Activated Receptor gamma in Adipogenesis SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article DE KLF4; Krox20; PPAR gamma; adipogenesis ID ADIPOCYTE DIFFERENTIATION; PPAR-GAMMA; HISTONE METHYLATION; ADIPOSE CONVERSION; EXPRESSION; FAT; MUSCLE; CELLS; GENE AB Much of our knowledge on adipogenesis comes from cell culture models of preadipocyte differentiation. Adipogenesis is induced by treating confluent preadipocytes with the adipogenic cocktail, which activates transcription factors (TFs) glucocorticoid receptor (GR) and CREB within minutes and increases expression of TFs C/EBP beta, C/EBP delta, KLF4, and Krox20 within hours. All of these TFs have been shown to be capable of promoting adipogenesis in culture when they are overexpressed. However, it has remained unclear whether endogenous KLF4 and Krox20 are required for adipogenesis in culture and in vivo. Using conditional knockout mice and derived white and brown preadipocytes, we show that endogenous KLF4 and Krox20 are dispensable for adipogenesis in culture and for brown adipose tissue development in mice. In contrast, the master adipogenic TF peroxisome proliferator-activated receptor gamma (PPAR gamma) is essential. These results challenge the existing model on transcriptional regulation in the early phase of adipogenesis and highlight the need of studying adipogenesis in vivo. C1 [Park, Young-Kwon; Wang, Limin; Giampietro, Anne; Lai, Binbin; Lee, Ji-Eun; Ge, Kai] NIDDK, Adipocyte Biol & Gene Regulat Sect, LERB, NIH, Bethesda, MD 20892 USA. RP Ge, K (reprint author), NIDDK, Adipocyte Biol & Gene Regulat Sect, LERB, NIH, Bethesda, MD 20892 USA. EM kai.ge@nih.gov FU Intramural Research Program of NIDDK, NIH, to K.G. FX This work was supported by the Intramural Research Program of NIDDK, NIH, to K.G. NR 24 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JAN PY 2017 VL 37 IS 2 AR UNSP e00554 DI 10.1128/MCB.00554-16 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EI1HM UT WOS:000392227700006 ER PT J AU Park, YK Ge, K AF Park, Young-Kwon Ge, Kai TI Glucocorticoid Receptor Accelerates, but Is Dispensable for, Adipogenesis SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article DE GR; adipogenesis; dexamethasone; glucocorticoid receptor ID TRANSCRIPTION FACTOR HOTSPOTS; PPAR-GAMMA EXPRESSION; BROWN ADIPOSE-TISSUE; ADIPOCYTE DIFFERENTIATION; PROTEIN; RESPONSIVENESS; BINDING; SWITCH; GENES; ALPHA AB Dexamethasone (DEX), a synthetic ligand for glucocorticoid receptor (GR), is routinely used to stimulate adipogenesis in culture. GR-depleted preadipocytes show adipogenesis defects 1 week after induction of differentiation. However, it has remained unclear whether GR is required for adipogenesis in vivo. By deleting GR in precursors of brown adipocytes, we found unexpectedly that GR is dispensable for brown adipose tissue development in mice. In culture, GR-deficient primary or immortalized white and brown preadipocytes showed severely delayed adipogenesis 1 week after induction of differentiation. However, when differentiation was extended to 3 weeks, GR-deficient preadipocytes showed levels of adipogenesis marker expression and lipid accumulation similar to those of the wild-type cells, indicating that DEX-bound GR accelerates, but is dispensable for, adipogenesis. Consistently, DEX accelerates, but is dispensable for, adipogenesis in culture. We show that DEX-bound GR accelerates adipogenesis by directly promoting the expression of adipogenic transcription factors CCAAT/enhancer-binding protein alpha (C/EBP alpha), C/EBP beta, C/EBP delta, KLF5, KLF9, and peroxisome proliferator-activated receptor gamma (PPARy gamma) in the early phase of differentiation. Mechanistically, DEX-bound GR recruits histone H3K27 acetyltransferase CBP to promote activation of C/EBP beta-primed enhancers of adipogenic genes. These results clarify the role of GR in adipogenesis in vivo and demonstrate that DEX-mediated activation of GR accelerates, but is dispensable for, adipogenesis. C1 [Park, Young-Kwon; Ge, Kai] NIDDK, Adipocyte Biol & Gene Regulat Sect, LERB, NIH, Bethesda, MD 20892 USA. RP Ge, K (reprint author), NIDDK, Adipocyte Biol & Gene Regulat Sect, LERB, NIH, Bethesda, MD 20892 USA. EM kai.ge@nih.gov FU Intramural Research Program of NIDDK, NIH FX This work was supported by the Intramural Research Program of NIDDK, NIH, to K.G. NR 31 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JAN PY 2017 VL 37 IS 2 AR UNSP e00260 DI 10.1128/MCB.00260-16 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EI1HM UT WOS:000392227700002 ER PT J AU Levin, R Hammond, GRV Balla, T De Camilli, P Fairn, GD Grinstein, S AF Levin, Roni Hammond, Gerald R. V. Balla, Tamas De Camilli, Pietro Fairn, Gregory D. Grinstein, Sergio TI Multiphasic dynamics of phosphatidylinositol 4-phosphate during phagocytosis SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID OXYSTEROL-BINDING-PROTEIN; PLASMA-MEMBRANE; TYROSINE PHOSPHORYLATION; CLASS-I; PHAGOSOMES; GOLGI; GAMMA; PHOSPHOINOSITIDES; RECEPTOR; CELLS AB We analyzed the distribution, fate, and functional role of phosphatidylinositol 4-phosphate (PtdIns4P) during phagosome formation and maturation. To this end, we used genetically encoded probes consisting of the PtdIns4P-binding domain of the bacterial effector SidM. PtdIns4P was found to undergo complex, multiphasic changes during phagocytosis. The phosphoinositide, which is present in the plasmalemma before engagement of the target particle, is transiently enriched in the phagosomal cup. Soon after the phagosome seals, PtdIns4P levels drop precipitously due to the hydrolytic activity of Sac2 and phospholipase C, becoming undetectable for similar to 10 min. PtdIns4P disappearance coincides with the emergence of phagosomal PtdIns3P. Conversely, the disappearance of PtdIns3P that signals the transition from early to late phagosomes is accompanied by resurgence of PtdIns4P, which is associated with the recruitment of phosphatidylinositol 4-kinase 2A. The reacquisition of PtdIns4P can be prevented by silencing expression of the kinase and can be counteracted by recruitment of a 4-phosphatase with a heterodimerization system. Using these approaches, we found that the secondary accumulation of PtdIns4P is required for proper phagosomal acidification. Defective acidification may be caused by impaired recruitment of Rab7 effectors, including RILP, which were shown earlier to displace phagosomes toward perinuclear lysosomes. Our results show multimodal dynamics of PtdIns4P during phagocytosis and suggest that the phosphoinositide plays important roles during the maturation of the phagosome. C1 [Levin, Roni; Grinstein, Sergio] Hosp Sick Children, Div Cell Biol, Toronto, ON M5G 1X8, Canada. [Levin, Roni; Fairn, Gregory D.; Grinstein, Sergio] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada. [Hammond, Gerald R. V.] Univ Pittsburgh, Sch Med, Dept Cell Biol, Pittsburgh, PA 15261 USA. [Balla, Tamas] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [De Camilli, Pietro] Yale Univ, Sch Med, Kavli Inst Neurosci, Howard Hughes Med Inst,Dept Neurosci, New Haven, CT 06510 USA. [De Camilli, Pietro] Yale Univ, Sch Med, Kavli Inst Neurosci, Howard Hughes Med Inst,Dept Cell Biol, New Haven, CT 06510 USA. [Fairn, Gregory D.] Univ Toronto, Dept Surg, Toronto, ON M5T 1P5, Canada. [Fairn, Gregory D.; Grinstein, Sergio] St Michaels Hosp, Keenan Res Ctr Biomed Sci, Toronto, ON M5B 1W8, Canada. RP Grinstein, S (reprint author), Hosp Sick Children, Div Cell Biol, Toronto, ON M5G 1X8, Canada.; Grinstein, S (reprint author), Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada.; Grinstein, S (reprint author), St Michaels Hosp, Keenan Res Ctr Biomed Sci, Toronto, ON M5B 1W8, Canada. EM sergio.grinstein@sickkids.ca FU University of Toronto; National Council for Science and Technology/Consejo Nacional de Ciencia y Tecnologia of Mexico; Canadian Institutes of Health Research [FDN-143202, MOP-133656]; Department of Cell Biology, University of Pittsburgh School of Medicine; intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health; National Institutes of Health [DK082700] FX R.L. is funded by the Connaught International Scholarship for Doctoral Students from the University of Toronto and by the National Council for Science and Technology/Consejo Nacional de Ciencia y Tecnologia of Mexico. This work was supported by Grant FDN-143202 from the Canadian Institutes of Health Research to S.G., Grant MOP-133656 from the Canadian Institutes of Health Research to G.D.F., funds from the Department of Cell Biology, University of Pittsburgh School of Medicine, to G.H., the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health to T.B., and Grant DK082700 from the National Institutes of Health to P.D.C. NR 54 TC 0 Z9 0 U1 4 U2 4 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JAN 1 PY 2017 VL 28 IS 1 BP 128 EP 140 DI 10.1091/mbc.E16-06-0451 PG 13 WC Cell Biology SC Cell Biology GA EI4VM UT WOS:000392491600014 PM 28035045 ER PT J AU Wang, J Ma, ZH Carr, SA Mertins, P Zhang, H Zhang, Z Chan, DW Ellis, MJC Townsend, RR Smith, RD McDermott, JE Chen, X Paulovich, AG Boja, ES Mesri, M Kinsinger, CR Rodriguez, H Rodland, KD Liebler, DC Zhang, B AF Wang, Jing Ma, Zihao Carr, Steven A. Mertins, Philipp Zhang, Hui Zhang, Zhen Chan, Daniel W. Ellis, Matthew J. C. Townsend, R. Reid Smith, Richard D. McDermott, Jason E. Chen, Xian Paulovich, Amanda G. Boja, Emily S. Mesri, Mehdi Kinsinger, Christopher R. Rodriguez, Henry Rodland, Karin D. Liebler, Daniel C. Zhang, Bing TI Proteome Profiling Outperforms Transcriptome Profiling for Coexpression Based Gene Function Prediction SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID BREAST-CANCER; PROTEOGENOMIC CHARACTERIZATION; EXPRESSION PROFILES; MICROARRAY DATA; RNA; NETWORKS; GENOME; QUANTIFICATION; ASSOCIATION; COMPLEMENT AB Coexpression of mRNAs under multiple conditions is commonly used to infer cofunctionality of their gene products despite well-known limitations of this "guilt-by-association" (GBA) approach. Recent advancements in mass spectrometry-based proteomic technologies have enabled global expression profiling at the protein level; however, whether proteome profiling data can outperform transcriptome profiling data for coexpression based gene function prediction has not been systematically investigated. Here, we address this question by constructing and analyzing mRNA and protein coexpression networks for three cancer types with matched mRNA and protein profiling data from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC). Our analyses revealed a marked difference in wiring between the mRNA and protein coexpression networks. Whereas protein coexpression was driven primarily by functional similarity between coexpressed genes, mRNA coexpression was driven by both cofunction and chromosomal colocalization of the genes. Functionally coherent mRNA modules were more likely to have their edges preserved in corresponding protein networks than functionally incoherent mRNA modules. Proteomic data strengthened the link between gene expression and function for at least 75% of Gene Ontology (GO) biological processes and 90% of KEGG pathways. A web application Gene2Net (http://cptac.gene2net.org) developed based on the three protein coexpression networks revealed novel gene-function relationships, such as linking ERBB2 (HER2) to lipid biosynthetic process in breast cancer, identifying PLG as a new gene involved in complement activation, and identifying AEBP1 as a new epithelial-mesenchymal transition (EMT) marker. Our results demonstrate that proteome profiling outperforms transcriptome profiling for coexpression based gene function prediction. Proteomics should be integrated if not preferred in gene function and human disease studies. C1 [Wang, Jing; Ma, Zihao; Zhang, Bing] Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Nashville, TN 37232 USA. [Wang, Jing; Ellis, Matthew J. C.; Zhang, Bing] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA. [Wang, Jing; Zhang, Bing] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Carr, Steven A.; Mertins, Philipp] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Zhang, Hui; Zhang, Zhen; Chan, Daniel W.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Ellis, Matthew J. C.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Townsend, R. Reid] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA. [Smith, Richard D.; McDermott, Jason E.; Rodland, Karin D.] Pacific Northwest Natl Lab, Div Biol Sci, Richland, WA 99352 USA. [Chen, Xian] Univ N Carolina, 130 Mason Farm Rd, Chapel Hill, NC 27599 USA. [Paulovich, Amanda G.] Fred Hutchinson Canc Res Ctr, Clin Res Div, 1100 Eastlake Ave East, Seattle, WA 98109 USA. [Boja, Emily S.; Mesri, Mehdi; Kinsinger, Christopher R.; Rodriguez, Henry] NCI, Off Canc Clin Prote Res, Bethesda, MD 20892 USA. [Liebler, Daniel C.] Vanderbilt Univ, Dept Biochem, Nashville, TN 37232 USA. [Liebler, Daniel C.] Vanderbilt Ingram Canc Ctr, Jim Ayers Inst Precancer Detect & Diag, Nashville, TN 37232 USA. RP Zhang, B (reprint author), Vanderbilt Univ, Dept Biomed Informat, Sch Med, 2525 West End Ave,Suite 1475, Nashville, TN 37203 USA. EM bing.zhang@vanderbilt.edu RI Smith, Richard/J-3664-2012 OI Smith, Richard/0000-0002-2381-2349 FU National Cancer Institute (NCI) CPTAC [U24CA159988, U24CA160034, U24CA160019, U24CA160036, U24CA160035]; Leidos Biomedical Research, Inc. [13XS029, 15X038]; Cancer Prevention & Research Institutes of Texas [RR160027]; McNair Medical Institute at Baylor College of Medicine; NCI CPTAC consortium FX This work was supported by National Cancer Institute (NCI) CPTAC awards U24CA159988, U24CA160034, U24CA160019, U24CA160036, and U24CA160035, and by contract 13XS029 and 15X038 from Leidos Biomedical Research, Inc. B.Z. and J.W. are partially supported by grant RR160027 from the Cancer Prevention & Research Institutes of Texas and funding from the McNair Medical Institute at Baylor College of Medicine. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work is supported by the NCI CPTAC consortium. A complete list of the consortium members can be found in supplemental Text S1. NR 55 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD JAN PY 2017 VL 16 IS 1 BP 121 EP 134 DI 10.1074/mcp.M116.060301 PG 14 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA EI0ZU UT WOS:000392205300010 PM 27836980 ER PT J AU Gipson, DS Kirkendall, ES Gumbs-Petty, B Quinn, T Steen, A Hicks, A McMahon, A Nicholas, S Zhao-Wong, A Taylor-Zapata, P Turner, M Herreshoff, E Jones, C Davis, JM Haber, M Hirschfeld, S AF Gipson, Debbie S. Kirkendall, Eric S. Gumbs-Petty, Brenda Quinn, Theresa Steen, A. Hicks, Amanda McMahon, Ann Nicholas, Savian Zhao-Wong, Anna Taylor-Zapata, Perdita Turner, Mark Herreshoff, Emily Jones, Charlotte Davis, Jonathan M. Haber, Margaret Hirschfeld, Steven TI Development of a Pediatric Adverse Events Terminology SO PEDIATRICS LA English DT Article ID ERRORS AB In 2009, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) established the Pediatric Terminology Harmonization Initiative to establish a core library of terms to facilitate the acquisition and sharing of knowledge between pediatric clinical research, practice, and safety reporting. A coalition of partners established a Pediatric Terminology Adverse Event Working Group in 2013 to develop a specific terminology relevant to international pediatric adverse event (AE) reporting. Pediatric specialists with backgrounds in clinical care, research, safety reporting, or informatics, supported by biomedical terminology experts from the National Cancer Institute's Enterprise Vocabulary Services participated. The multinational group developed a working definition of AEs and reviewed concepts (terms, synonyms, and definitions) from 16 pediatric clinical domains. The resulting AE terminology contains >1000 pediatric diseases, disorders, or clinical findings. The terms were tested for proof of concept use in 2 different settings: hospital readmissions and the NICU. The advantages of the AE terminology include ease of adoption due to integration with well-established and internationally accepted biomedical terminologies, a uniquely temporal focus on pediatric health and disease from conception through adolescence, and terms that could be used in both well-and underresourced environments. The AE terminology is available for use without restriction through the National Cancer Institute's Enterprise Vocabulary Services and is fully compatible with, and represented in, the Medical Dictionary for Regulatory Activities. The terminology is intended to mature with use, user feedback, and optimization. C1 [Gipson, Debbie S.; Herreshoff, Emily] Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA. [Kirkendall, Eric S.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Gumbs-Petty, Brenda; Quinn, Theresa; Steen, A.; Haber, Margaret] NCI, Enterprise Vocabulary Serv, Bethesda, MD 20892 USA. [Taylor-Zapata, Perdita] NICHHD, NIH, Bethesda, MD 20892 USA. [Hicks, Amanda] Univ Arkansas Med Sci, Div Biomed Informat, Little Rock, AR 72205 USA. [McMahon, Ann] US FDA, Off Pediat Therapeut, Bethesda, MD 20014 USA. [Nicholas, Savian; Zhao-Wong, Anna] Maintenance & Support Serv Org, Med Dictionary Regulatory Act, Mclean, VA USA. [Turner, Mark] Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England. [Jones, Charlotte] Nationwide Childrens Hosp, Neurol, Columbus, OH USA. [Davis, Jonathan M.] Tufts Univ, Tufts Med Ctr, Floating Hosp Children, Dept Pediat, Boston, MA 02111 USA. [Davis, Jonathan M.] Tufts Univ, Tufts Clin & Translat Sci Inst, Boston, MA 02111 USA. [Hirschfeld, Steven] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Quinn, T (reprint author), Enterprise Vocabulary Serv, 11300 Rockville Pike,Suite 1100, Rockville, MD 20852 USA. EM quinnt@mail.nih.gov FU National Children's Study [NC013003-001] FX This work was supported by National Children's Study interagency agreement NC013003-001. NR 14 TC 0 Z9 0 U1 2 U2 2 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 JAN PY 2017 VL 139 IS 1 AR e20160985 DI 10.1542/peds.2016-0985 PG 7 WC Pediatrics SC Pediatrics GA EH9WI UT WOS:000392122000013 ER PT J AU Burgess, S Cheng, LZ Gu, F Huang, JJ Huang, ZW Lin, SO Li, JS Li, W Qin, W Sun, YJ Zhou, SY Wei, WS Wu, Q Wang, HY Wang, XQ Xiong, JW Xi, JZ Yang, H Zhou, B Zhang, B AF Burgess, Shawn Cheng, Linzhao Gu, Feng Huang, Junjiu Huang, Zhiwei Lin, Shuo Li, Jinsong Li, Wei Qin, Wei Sun, Yujie Zhou Songyang Wei, Wensheng Wu, Qiang Wang, Haoyi Wang, Xiaoqun Xiong, Jing-Wei Xi, Jianzhong Yang, Hui Zhou, Bin Zhang, Bo TI Questions about NgAgo (vol 7, pg 913, 2016) SO PROTEIN & CELL LA English DT Correction C1 [Burgess, Shawn] NHGRI, NIH, Bethesda, MD 20892 USA. [Cheng, Linzhao] Johns Hopkins Univ, Sch Med, Dept Med, Div Hematol, Baltimore, MD 21205 USA. [Cheng, Linzhao] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Stem Cell Program, Baltimore, MD 21205 USA. [Gu, Feng] Wenzhou Med Univ, Hosp Eye, Ctr Vis Res, Wenzhou 325035, Peoples R China. [Huang, Junjiu; Zhou Songyang] Sun Yat Sen Univ, Sch Life Sci, Stem Cell & Funct Genom Lab, Guangzhou 510275, Guangdong, Peoples R China. [Huang, Zhiwei] Harbin Inst Technol, Ctr Life Sci, Harbin 150080, Peoples R China. [Lin, Shuo] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA. [Li, Jinsong; Zhou, Bin] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China. [Li, Wei; Wang, Haoyi] Chinese Acad Sci, Inst Zool, State Key Lab Stem Cell & Reprod Biol, Beijing 100101, Peoples R China. [Qin, Wei] Peking Univ, Shenzhen Grad Sch, Coll Chem Biol & Biotechnol, Shenzhen 518055, Peoples R China. [Sun, Yujie] PKU BIOPIC, Beijing 100871, Peoples R China. [Wei, Wensheng] Peking Univ, BIOPIC ICG CLS, Beijing 100871, Peoples R China. [Wei, Wensheng] Peking Univ, Sch Life Sci, Beijing 100871, Peoples R China. [Wu, Qiang] Shanghai Jiao Tong Univ, Ctr Comparat Biomed, Inst Syst Biomed, Shanghai 200240, Peoples R China. [Wang, Xiaoqun] Chinese Acad Sci, Inst Biophys, Beijing 100101, Peoples R China. [Xiong, Jing-Wei] Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. [Xi, Jianzhong] Peking Univ, Coll Engn, Beijing 100871, Peoples R China. [Yang, Hui] Shanghai Chinese Acad Sci, Inst Neurosci, Lab Dis Models Nonhuman Primates, Shanghai 200031, Peoples R China. [Zhang, Bo] Peking Univ, Coll Life Sci, Beijing 100871, Peoples R China. RP Cheng, LZ (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Div Hematol, Baltimore, MD 21205 USA.; Cheng, LZ (reprint author), Johns Hopkins Univ, Sch Med, Inst Cell Engn, Stem Cell Program, Baltimore, MD 21205 USA.; Lin, SO (reprint author), Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA.; Wang, HY (reprint author), Chinese Acad Sci, Inst Zool, State Key Lab Stem Cell & Reprod Biol, Beijing 100101, Peoples R China.; Wei, WS (reprint author), Peking Univ, BIOPIC ICG CLS, Beijing 100871, Peoples R China.; Wei, WS (reprint author), Peking Univ, Sch Life Sci, Beijing 100871, Peoples R China. EM LCheng2@jhmi.edu; shuolin@g.ucla.edu; wswei@pku.edu.cn; wanghaoyi@ioz.ac.cn NR 1 TC 0 Z9 0 U1 2 U2 2 PU HIGHER EDUCATION PRESS PI BEIJING PA NO 4 DEWAI DAJIE, BEIJING 100120, PEOPLES R CHINA SN 1674-800X EI 1674-8018 J9 PROTEIN CELL JI Protein Cell PD JAN PY 2017 VL 8 IS 1 BP 77 EP 77 DI 10.1007/s13238-016-0349-3 PG 1 WC Cell Biology SC Cell Biology GA EI2OA UT WOS:000392325800009 PM 27913985 ER PT J AU Serrano, KJ Thai, CL Greenberg, AJ Blake, KD Moser, RP Hesse, BW AF Serrano, Katrina J. Thai, Chan L. Greenberg, Alexandra J. Blake, Kelly D. Moser, Richard P. Hesse, Bradford W. TI Progress on Broadband Access to the Internet and Use of Mobile Devices in the United States: Tracking Healthy People 2020 Goals SO PUBLIC HEALTH REPORTS LA English DT Article DE Healthy People 2020; health information national trends survey; health communication; health information technology ID NATIONAL TRENDS SURVEY; INFORMATION AB Healthy People 2020 (HP2020) aims to improve population health outcomes through several objectives, including health communication and health information technology. We used 7 administrations of the Health Information National Trends Survey to examine HP2020 goals toward access to the Internet through broadband and mobile devices (N = 34080). We conducted descriptive analyses and obtained predicted marginals, also known as model-adjusted risks, to estimate the association between demographic characteristics and use of mobile devices. The HP2020 target (7.7% of the US population) for accessing the Internet through a cellular network was surpassed in 2014 (59.7%), but the HP2020 target (83.2%) for broadband access fell short (63.8%). Sex and age were associated with accessing the Internet through a cellular network throughout the years (Wald F test, P <.05). The increase in the percentage of people accessing the Internet through mobile devices presents an opportunity for technology-based health interventions that should be explored. C1 [Serrano, Katrina J.; Moser, Richard P.] NCI, Off Associate Director, Behav Res Program, Div Canc Control & Populat Sci,NIH, Rockville, MD USA. [Thai, Chan L.; Greenberg, Alexandra J.; Blake, Kelly D.; Hesse, Bradford W.] NCI, Hlth Commun & Informat Branch, Behav Res Program, Div Canc Control & Populat Sci,NIH, Rockville, MD USA. RP Serrano, KJ (reprint author), NIH, Off Associate Director, Behav Res Program, Div Canc Control & Populat Sci,NIH, 9609 Med Ctr Dr,3E538, Bethesda, MD 20892 USA. EM katrina.serrano@nih.gov NR 18 TC 0 Z9 0 U1 3 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0033-3549 EI 1468-2877 J9 PUBLIC HEALTH REP JI Public Health Rep. PD JAN-FEB PY 2017 VL 132 IS 1 BP 27 EP 31 DI 10.1177/0033354916679365 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EI3AW UT WOS:000392363100006 PM 28005473 ER PT J AU Nash, TE Bustos, JA Garcia, HH AF Nash, Theodore E. Bustos, Javier A. Garcia, Hector H. CA Cysticercosis Working Grp Peru TI Disease Centered Around Calcified Taenia solium Granuloma SO TRENDS IN PARASITOLOGY LA English DT Review ID SOLITARY CYSTICERCUS GRANULOMA; STATUS-EPILEPTICUS; PERILESIONAL EDEMA; NEUROCYSTICERCOSIS LESIONS; ANTIPARASITIC TREATMENT; CEREBRAL CALCIFICATION; MAGNETIC-RESONANCE; SEIZURE RECURRENCE; BRAIN EDEMA; EPILEPSY AB Taenia solium (the pork tapeworm) is present in most developing countries, where it is a frequent cause of seizures and other neurological disease. Parasitic larvae invade the human brain, establish, and eventually resolve, leaving a calcified scar. While these lesions are common in endemic regions, and most of these are clinically silent, a proportion of individuals with calcified cysticerci develop seizures from these lesions, and 30-65% of these cases are associated with perilesional edema (PE), likely due to host inflammation. This manuscript summarizes the importance, characteristics, natural history, and potential prevention and treatments of symptomatic calcified neurocysticercosis (NCC). C1 [Nash, Theodore E.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD USA. [Bustos, Javier A.; Garcia, Hector H.] Inst Nacl Ciencias Neurol, Unidad Cisticercosis, Lima, Peru. [Garcia, Hector H.] Univ Peruana Cayetano Heredia, Fac Ciencias & Filosofia, Dept Ciencias Celulares & Mol, Lima, Peru. RP Bustos, JA (reprint author), Inst Nacl Ciencias Neurol, Unidad Cisticercosis, Lima, Peru. EM javier.bustos@jhu.edu FU Intramural National Institutes of Allergy and Infectious diseases at the NIH; NIH-Fogarty International Center (FIC) Training Grant [D43TW001140]; Wellcome Trust Senior International Research Fellowship in Public Health and Tropical Medicine; NIAID-NIH [1R01A1116456] FX The support for this study was in part received from the Intramural National Institutes of Allergy and Infectious diseases at the NIH and by NIH-Fogarty International Center (FIC) Training Grant D43TW001140. H.G. is supported by a Wellcome Trust Senior International Research Fellowship in Public Health and Tropical Medicine. J.B. is supported by NIAID-NIH Grant 1R01A1116456. NR 72 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4922 EI 1471-5007 J9 TRENDS PARASITOL JI Trends Parasitol. PD JAN PY 2017 VL 33 IS 1 BP 65 EP 73 DI 10.1016/j.pt.2016.09.003 PG 9 WC Parasitology SC Parasitology GA EI5XN UT WOS:000392569700010 PM 27720140 ER PT J AU Resnik, DB Shamoo, AE AF Resnik, David B. Shamoo, Adil E. TI Reproducibility and Research Integrity SO ACCOUNTABILITY IN RESEARCH-POLICIES AND QUALITY ASSURANCE LA English DT Editorial Material ID PRECLINICAL RESEARCH; MISCONDUCT; QUALITY; HEALTH; AUDIT; ERROR C1 [Resnik, David B.] NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Shamoo, Adil E.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. RP Resnik, DB (reprint author), NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH) FX This research was supported, in part, by the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). It does not represent the views of the NIEHS, NIH, or the U.S. federal government. NR 41 TC 0 Z9 0 U1 8 U2 8 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0898-9621 EI 1545-5815 J9 ACCOUNT RES JI Account. Res. PY 2017 VL 24 IS 2 BP 116 EP 123 DI 10.1080/08989621.2016.1257387 PG 8 WC Medical Ethics SC Medical Ethics GA EH0US UT WOS:000391480000004 PM 27820655 ER PT J AU Goodman, RA Lochner, KA Thambisetty, M Wingo, TS Posner, SF Ling, SM AF Goodman, Richard A. Lochner, Kimberly A. Thambisetty, Madhav Wingo, Thomas S. Posner, Samuel F. Ling, Shari M. TI Prevalence of dementia subtypes in United States Medicare fee-for-service beneficiaries, 2011-2013 SO ALZHEIMERS & DEMENTIA LA English DT Article DE Alzheimer's disease; Dementia; Epidemiology; Medicare; Prevalence; Subtypes ID IDENTIFYING ALZHEIMERS-DISEASE; PUBLIC-HEALTH IMPACT; VASCULAR DEMENTIA; CLINICAL-CRITERIA; PRIMARY-CARE; LEWY BODIES; CLAIMS; EPIDEMIOLOGY; ACCURACY; RECOMMENDATIONS AB Introduction: Rapid growth of the older adult population requires greater epidemiologic characterization of dementia. We developed national prevalence estimates of diagnosed dementia and subtypes in the highest risk United States (US) population. Methods: We analyzed Centers for Medicare & Medicaid administrative enrollment and claims data for 100% of Medicare fee-for-service beneficiaries enrolled during 2011-2013 and age >= 68 years as of December 31, 2013 (n = 21.6 million). Results: Over 3.1 million (14.4%) beneficiaries had a claim for a service and/or treatment for any dementia subtype. Dementia not otherwise specified was the most common diagnosis (present in 92.9%). The most common subtype was Alzheimer's (43.5%), followed by vascular (14.5%), Lewy body (5.4%), frontotemporal (1.0%), and alcohol induced (0.7%). The prevalence of other types of diagnosed dementia was 0.2%. Discussion: This study is the first to document concurrent prevalence of primary dementia subtypes among this US population. The findings can assist in prioritizing dementia research, clinical services, and caregiving resources. (C) 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved. C1 [Goodman, Richard A.; Posner, Samuel F.] Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Goodman, Richard A.] Emory Univ, Sch Med, Dept Family & Prevent Med, Atlanta, GA 30322 USA. [Lochner, Kimberly A.; Ling, Shari M.] Ctr Medicare & Medicaid Serv, Baltimore, MD USA. [Thambisetty, Madhav] NIA, Clin & Translat Neurosci Unit, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. [Wingo, Thomas S.] Emory Univ, Sch Med, Dept Neurol & Human Genet, Atlanta, GA USA. [Wingo, Thomas S.] Atlanta VA Med Ctr, Div Neurol, Atlanta, GA USA. RP Goodman, RA (reprint author), Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA.; Goodman, RA (reprint author), Emory Univ, Sch Med, Dept Family & Prevent Med, Atlanta, GA 30322 USA. EM rgood02@emory.edu FU Department of Veteran's Affairs; National Institutes of Health FX To the best of our knowledge, no conflict of interest, financial, or other exists. Work related to this article by R.A.G, K.A.L., M.T., S.F.P., and S.M.L. was carried out in their official capacities as employees of the federal government and their respective HHS federal agencies. T.W.'s work is supported by grants from the Department of Veteran's Affairs and the National Institutes of Health. The findings and conclusions in this report are those of the authors and do not necessarily represent the official positions of the Centers for Disease Control and Prevention, Centers for Medicare & Medicaid Services, or Department of Veterans Affairs. NR 48 TC 0 Z9 0 U1 6 U2 6 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 JAN PY 2017 VL 13 IS 1 BP 28 EP 37 DI 10.1016/j.jalz.2016.04.002 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA EH6VP UT WOS:000391912300004 PM 27172148 ER PT J AU Klemen, ND Feingold, PL Goff, SL Hughes, MS Kammula, US Yang, JC Schrump, DS Rosenberg, SA Sherry, RM AF Klemen, Nicholas D. Feingold, Paul L. Goff, Stephanie L. Hughes, Marybeth S. Kammula, Udai S. Yang, James C. Schrump, David S. Rosenberg, Steven A. Sherry, Richard M. TI Metastasectomy Following Immunotherapy with Adoptive Cell Transfer for Patients with Advanced Melanoma SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID TUMOR-INFILTRATING LYMPHOCYTES; STAGE IV MELANOMA; METASTATIC MELANOMA; IPILIMUMAB; CANCER; SURVIVAL; NIVOLUMAB; RESECTION; CRITERIA AB Background. Immunotherapeutic treatment strategies including adoptive cell transfer (ACT) for metastatic melanoma are capable of mediating complete and durable responses, as well as partial responses and prolonged disease stabilization. Unfortunately, many patients ultimately develop progressive disease. The role of salvage metastasectomy in managing these patients has not been evaluated. Methods. Records of patients with metastatic melanoma treated with ACT at a single institution between 2000 and 2014 were reviewed. Patients with an objective response by RECIST criteria or disease stabilization of at least 6 months and who subsequently developed progressive melanoma and were managed with metastasectomy as the next therapeutic strategy were studied for progression-free survival (PFS) and overall survival (OS). Five additional clinical parameters were also reviewed for association with outcomes. Results. Of 115 patients treated with ACT who met our response criteria and then developed progressive disease, 26 (23%) had surgery. There were no mortalities related to surgical intervention. Median follow-up after surgery was 62 months. Median PFS after surgery was 11 months and five-year OS was 57%. The development of a new site of metastasis after ACT was associated with poor PFS and OS. Surgery after immunotherapy is safe. Long PFS and OS can be achieved by metastasectomy in selected patients with progressive melanoma following treatment with ACT. Clinical variables important for patient selection for metastasectomy after immunotherapy remain largely undefined. Improvements in immunotherapeutic treatment strategies may increase the role of surgery for patients with advanced disease. C1 [Klemen, Nicholas D.; Feingold, Paul L.; Goff, Stephanie L.; Hughes, Marybeth S.; Kammula, Udai S.; Yang, James C.; Schrump, David S.; Rosenberg, Steven A.; Sherry, Richard M.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Sherry, RM (reprint author), NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. EM SherryR@mail.nih.gov OI Feingold, Paul/0000-0002-3194-4309 NR 22 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD JAN PY 2017 VL 24 IS 1 BP 135 EP 141 DI 10.1245/s10434-016-5537-0 PG 7 WC Oncology; Surgery SC Oncology; Surgery GA EH1FZ UT WOS:000391510400022 PM 27638681 ER PT J AU Gipponi, M Baldelli, I Atzori, G Fregatti, P Murelli, F Pesce, M Margarino, C Depaoli, F Friedman, D AF Gipponi, Marco Baldelli, Ilaria Atzori, Giulia Fregatti, Piero Murelli, Federica Pesce, Marianna Margarino, Cecilia Depaoli, Francesca Friedman, Daniele TI Tumescent Anesthesia in Skin- and Nipple-sparing Mastectomy: Results of a Prospective Clinical Study SO ANTICANCER RESEARCH LA English DT Article DE Breast cancer; breast reconstruction; tumescent anesthesia ID MODIFIED RADICAL-MASTECTOMY; BLOOD-LOSS; IMMEDIATE RECONSTRUCTION; SUBCUTANEOUS MASTECTOMY; BREAST RECONSTRUCTION; LOCAL-ANESTHESIA; BURN SURGERY; ELECTROCAUTERY; RISK; LIPOSUCTION AB Background: The tumescent mastectomy technique has been used to facilitate dissection of subcutaneous tissue and mammary gland in order to reduce intraoperative bleeding and speed the operation. Patients and Methods: A prospective clinical study was performed on 30 female patients undergoing immediate breast reconstructions after skin-sparing mastectomy (SSM) or nipple-sparing mastectomy (NSM) in order to assess early postoperative complications, pain, and final esthetic outcome of skin flaps related to tumescent anesthesia (TA). Results: TA significantly speeded-up the operative procedure (131 +/- 49.99 vs. 180.5 +/- 67.15 min; p=0.03) achieving less skin damage compared to patients who did not have TA (p=0.045); moreover, no significant difference occurred with regard to the length of in-hospital stay and overall lymphatic drainage. Conclusion: The length of the operation as well as the final cosmetic outcome of skin flaps was significantly improved due to TA, with no appreciable side-effects. C1 [Gipponi, Marco; Atzori, Giulia; Fregatti, Piero; Murelli, Federica; Margarino, Cecilia; Depaoli, Francesca; Friedman, Daniele] Univ Genoa, Sch Med, San Martino Hosp, Breast Surg,Breast Unit, Genoa, Italy. [Baldelli, Ilaria; Pesce, Marianna] Univ Genoa, Sch Med, San Martino Hosp, Plast Surg,Breast Unit, Genoa, Italy. [Baldelli, Ilaria; Pesce, Marianna] Natl Canc Inst, Genoa, Italy. RP Gipponi, M (reprint author), IRCCS San Martino IST Genoa, Breast Unit, Lgo R Benzi 10, I-16132 Genoa, Italy. EM marco.gipponi@hsanmartino.it NR 24 TC 0 Z9 0 U1 2 U2 2 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 EI 1791-7530 J9 ANTICANCER RES JI Anticancer Res. PD JAN PY 2017 VL 37 IS 1 BP 349 EP 352 DI 10.21873/anticanres.11328 PG 4 WC Oncology SC Oncology GA EH7ND UT WOS:000391958800047 PM 28011513 ER PT J AU Benoit, BM Jariwala, N O'Connor, G Oetjen, LK Whelan, TM Werth, A Troxel, AB Sicard, H Zhu, LS Miller, C Takeshita, J McVicar, DW Kim, BS Rook, AH Wysocka, M AF Benoit, Bernice M. Jariwala, Neha O'Connor, Geraldine Oetjen, Landon K. Whelan, Timothy M. Werth, Adrienne Troxel, Andrea B. Sicard, Helene Zhu, Lisa Miller, Christopher Takeshita, Junko McVicar, Daniel W. Kim, Brian S. Rook, Alain H. Wysocka, Maria TI CD164 identifies CD4(+) T cells highly expressing genes associated with malignancy in Sezary syndrome: the Sezary signature genes, FCRL3, Tox, and miR-214 SO ARCHIVES OF DERMATOLOGICAL RESEARCH LA English DT Article DE Sezary syndrome; CD164; miR-214; FCRL3; Tox; KIR3DL2 ID MYCOSIS-FUNGOIDES; CUTANEOUS LYMPHOMA; CANCER CELLS; DIAGNOSIS; SURVIVAL; REVEALS; MARKER; PROLIFERATION; GANGLIOSIDE; LYMPHOCYTES AB Sezary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), is associated with a significantly shorter life expectancy compared to skin-restricted mycosis fungoides. Early diagnosis of SS is, therefore, key to achieving enhanced therapeutic responses. However, the lack of a biomarker(s) highly specific for malignant CD4(+) T cells in SS patients has been a serious obstacle in making an early diagnosis. We recently demonstrated the high expression of CD164 on CD4(+) T cells from Sezary syndrome patients with a wide range of circulating tumor burdens. To further characterize CD164 as a potential biomarker for malignant CD4(+) T cells, CD164(+) and CD164(-)CD4(+) T cells isolated from patients with high-circulating tumor burden, B2 stage, and medium/low tumor burden, B1-B0 stage, were assessed for the expression of genes reported to differentiate SS from normal controls, and associated with malignancy and poor prognosis. The expression of Sezary signature genes: T plastin, GATA-3, along with FCRL3, Tox, and miR-214, was significantly higher, whereas STAT-4 was lower, in CD164(+) compared with CD164(-)CD4(+) T cells. While Tox was highly expressed in both B2 and B1-B0 patients, the expression of Sezary signature genes, FCRL3, and miR-214 was associated predominantly with advanced B2 disease. High expression of CD164 mRNA and protein was also detected in skin from CTCL patients. CD164 was co-expressed with KIR3DL2 on circulating CD4(+) T cells from high tumor burden SS patients, further providing strong support for CD164 as a disease relevant surface biomarker. C1 [Benoit, Bernice M.; Jariwala, Neha; Werth, Adrienne; Zhu, Lisa; Miller, Christopher; Takeshita, Junko; Rook, Alain H.; Wysocka, Maria] Univ Penn, Dept Dermatol, Perelman Sch Med, 421 Curie Blvd,1049 BRB, Philadelphia, PA 19104 USA. [O'Connor, Geraldine; McVicar, Daniel W.] NCI, Canc & Inflammat Program, Frederick, MD 21701 USA. [Oetjen, Landon K.; Whelan, Timothy M.; Kim, Brian S.] Washington Univ, Dept Med, Div Dermatol, St Louis, MO USA. [Troxel, Andrea B.] Univ Penn, Dept Biostat & Epidemiol, Ctr Clin Epidemiol & Biostat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Sicard, Helene] Innate Pharma, Res & Drug Dev, Marseille, France. [Kim, Brian S.] Washington Univ, Dept Anesthesiol, St Louis, MO USA. [Kim, Brian S.] Washington Univ, Dept Pathol & Immunol, St Louis, MO USA. [Kim, Brian S.] Washington Univ, Div Biol & Biomed Sci, St Louis, MO USA. RP Wysocka, M (reprint author), Univ Penn, Dept Dermatol, Perelman Sch Med, 421 Curie Blvd,1049 BRB, Philadelphia, PA 19104 USA. EM mwysocka@mail.med.upenn.edu OI Troxel, Andrea/0000-0002-1393-3075 FU National Institute of Cancer [R21CA178424]; Translational Research Grant from the Leukemia and Lymphoma Society; National Institute of Arthritis and Musculoskeletal and Skin Diseases [K23-AR68433, K08-AR065577-03]; American Skin Association Research Grant; Intramural Research Program of the National Cancer Institute FX This work was supported by the National Institute of Cancer, R21CA178424 to M.W and A.H.R., Translational Research Grant from the Leukemia and Lymphoma Society to A.H.R, National Institute of Arthritis and Musculoskeletal and Skin Diseases, K23-AR68433 to J.T., and K08-AR065577-03 to B.S.K., American Skin Association Research Grant to B.S.K., and in part by the Intramural Research Program of the National Cancer Institute to D. McV. NR 45 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-3696 EI 1432-069X J9 ARCH DERMATOL RES JI Arch. Dermatol. Res. PD JAN PY 2017 VL 309 IS 1 BP 11 EP 19 DI 10.1007/s00403-016-1698-8 PG 9 WC Dermatology SC Dermatology GA EH8ZH UT WOS:000392060800002 PM 27766406 ER PT J AU Hoffman, AF Simpson, KJ Horvath, P Lovitt, C Silver, S Easton, E LaBarbera, DV Mendez, M Rothenberg, ME Seldin, J Wardwell-Swanson, J Fennell, M AF Hoffman, Ann F. Simpson, Kaylene J. Horvath, Peter Lovitt, Carrie Silver, Serena Easton, Evan LaBarbera, Daniel V. Mendez, Melissa Rothenberg, Mark E. Seldin, Jan Wardwell-Swanson, Judi Fennell, Myles TI SBI2 HCS/HCA 3D Imaging: Best Practices and Unmet Needs Colloquium SO ASSAY AND DRUG DEVELOPMENT TECHNOLOGIES LA English DT Article ID CULTURE; GENERATION; DISEASE; MODELS C1 [Hoffman, Ann F.] GlaxoSmithKline, 1250 S Collegeville Rd, Collegeville, PA 19426 USA. [Simpson, Kaylene J.] Peter MacCallum Canc Ctr, Parkville, Vic, Australia. [Horvath, Peter] Hungarian Acad Sci, Szeged, Hungary. [Lovitt, Carrie] Griffith Univ, Nathan, Qld 4111, Australia. [Silver, Serena] Novartis, Cambridge, MA USA. [Easton, Evan; Seldin, Jan] Greiner Bioone North Amer Inc, Monroe, NC USA. [LaBarbera, Daniel V.] Univ Colorado, Anschutz Med Campus, Denver, CO 80202 USA. [Mendez, Melissa] NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Rothenberg, Mark E.] Corning Inc, Corning, NY 14831 USA. [Wardwell-Swanson, Judi] InSphero Inc, Brunswick, ME USA. [Fennell, Myles] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. RP Hoffman, AF (reprint author), GlaxoSmithKline, 1250 S Collegeville Rd, Collegeville, PA 19426 USA. EM Ann.f.hoffman@gsk.com NR 15 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-658X EI 1557-8127 J9 ASSAY DRUG DEV TECHN JI ASSAY DRUG DEV. TECHNOL. PD JAN PY 2017 VL 15 IS 1 SI SI BP 1 EP 7 DI 10.1089/adt.2016.29054.afh PG 7 WC Biochemical Research Methods; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA EH5ZQ UT WOS:000391852300001 PM 28092461 ER PT J AU Battiwalla, M Hashmi, S Majhail, N Pavletic, S Savani, BN Shelburne, N AF Battiwalla, Minoo Hashmi, Shahrukh Majhail, Navneet Pavletic, Steven Savani, Bipin N. Shelburne, Nonniekaye TI National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: Developing Recommendations to Improve Survivorship and Long-Term Outcomes SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Editorial Material DE Late effects; Hematopoietic cell transplantation; Survivorship ID CONSENSUS DEVELOPMENT PROJECT; VERSUS-HOST-DISEASE; CLINICAL-TRIALS; RECIPIENT AGE; SURVIVAL; CRITERIA; PERIOD AB Continual advances in hematopoietic cell transplantation (HCT) have greatly improved early transplantation related mortality and broadened the applicability of this intense but curative therapy. With growing success there is increasing awareness of late complications, occurring >= 1 year after treatment, and their associated morbidity and mortality in HCT survivors. These late effects occur with a wide spectrum in terms of latency, intensity, reversibility, and lethality. There is a need to understand the biology, surveillance, management, and patient experience of HCT-related effects, as well as the health care and research infrastructure to manage this growing population. To address these needs, the National Cancer Institute and National:Heart.; Lung and Blood Institute cosponsored a 12-month initiative to identify barriers and knowledge gaps and to formulate research and practice recommendations. Six major areas of interest were identified: research methodology and study design, subsequent neoplasms, patient-centered outcomes, immune dysregulation and pathobiology, cardiovascular disease and associated risk factors, and health care delivery. These findings were presented during the 2016 workshop and revised based on public response. This report provides an overview of the National Institutes of Health HCT Late Effects Initiative process and recommendations. Published by Elsevier Inc. on behalf of the American Society for Blood and Marrow Transplantation. C1 [Battiwalla, Minoo] NHLBI, Hematol Branch, NIH, 10 Ctr Dr,Bldg 10 CRC,Room 5-3581, Bethesda, MD 20892 USA. [Hashmi, Shahrukh] Mayo Clin, Transplant Ctr, Rochester, MN USA. [Majhail, Navneet] Cleveland Clin, Blood & Marrow Transplant Program, Cleveland, OH 44106 USA. [Pavletic, Steven] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Hematol & Stem Cell Transplantat Sect, Nashville, TN USA. [Shelburne, Nonniekaye] NCI, Div Canc Control & Populat Sci, NIH, Rockville, MD USA. RP Battiwalla, M (reprint author), NHLBI, Hematol Branch, NIH, 10 Ctr Dr,Bldg 10 CRC,Room 5-3581, Bethesda, MD 20892 USA. EM battiwam@nhlbi.nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 19 TC 2 Z9 2 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JAN PY 2017 VL 23 IS 1 BP 6 EP 9 DI 10.1016/j.bbmt.2016.10.020 PG 4 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA EH8ST UT WOS:000392043300003 PM 27989931 ER PT J AU Shaw, BE Hahn, T Martin, PJ Mitchell, SA Petersdorf, EW Armstrong, GT Shelburne, N Storer, BE Bhatia, S AF Shaw, Bronwen E. Hahn, Theresa Martin, Paul J. Mitchell, Sandra A. Petersdorf, Effie W. Armstrong, Gregory T. Shelburne, Nonniekaye Storer, Barry E. Bhatia, Smita TI National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Research Methodology and Study Design Working Group Report SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE National Institutes of Health; consensus; Late effects; Hematopoietic cell transplantation ID BONE-MARROW-TRANSPLANTATION; CONGESTIVE-HEART-FAILURE; LONG-TERM SURVIVORS; SIGNIFICANT IMPROVEMENT; UNRELATED DONORS; RECIPIENT AGE; SOLID CANCERS; PREDICTORS; LEUKEMIA; MYELOMA AB The increasing numbers of hematopoietic cell transplantations (HCTs) performed each year, the changing demographics of HCT recipients, the introduction of new transplantation strategies, incremental improvement in survival, and the growing population of HCT survivors demand a comprehensive approach to examining the health and well-being of patients throughout life after HCT. This report summarizes strategies for the conduct of research on late effects after transplantation, including consideration of the study design and analytic approaches; methodologic challenges in handling complex phenotype data; an appreciation of the changing trends in the practice of transplantation; and the availability of biospecimens to support laboratory-based research. It is hoped that these concepts will promote continued research and facilitate the development of new approaches to address fundamental questions in transplantation outcomes. (C) 2017 American Society for Blood and Marrow Transplantation. C1 [Shaw, Bronwen E.] Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Hahn, Theresa] Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14263 USA. [Martin, Paul J.; Petersdorf, Effie W.] Univ Washington, Fred Hutchinson Canc Res Ctr, Dept Med, Div Clin Res, Seattle, WA 98195 USA. [Mitchell, Sandra A.] NCI, Outcomes Res Branch, Div Canc Control & Populat Sci, NIH, Rockville, MD USA. [Armstrong, Gregory T.] St Jude Childrens Res Hosp, Epidemiol & Canc Control, 332 N Lauderdale St, Memphis, TN 38105 USA. [Shelburne, Nonniekaye] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Storer, Barry E.] Fred Hutchinson Canc Res Ctr, Dept Med, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Bhatia, Smita] Univ Alabama Birmingham, Sch Med, Inst Canc Outcomes & Survivorship, 1600 S 7th Ave,Lowder Suite 500, Birmingham, AL 35233 USA. RP Bhatia, S (reprint author), Univ Alabama Birmingham, Sch Med, Inst Canc Outcomes & Survivorship, 1600 S 7th Ave,Lowder Suite 500, Birmingham, AL 35233 USA. EM sbhatia@peds.uab.edu FU National Heart, Lung and Blood Institute (NHLBI); National Cancer Institite (NCI) FX This initiative was sponsored jointly by the National Heart, Lung and Blood Institute (NHLBI) and the National Cancer Institite (NCI). NR 29 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 JAN PY 2017 VL 23 IS 1 BP 10 EP 23 DI 10.1016/j.bbmt.2016.08.018 PG 14 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA EH8ST UT WOS:000392043300004 PM 27590102 ER PT J AU Dietz, AC Duncan, CN Alter, BP Bresters, D Cowan, MJ Notarangelo, L Rosenberg, PS Shenoy, S Skinner, R Walters, MC Wagner, J Baker, KS Pulsipher, MA AF Dietz, Andrew C. Duncan, Christine N. Alter, Blanche P. Bresters, Dorine Cowan, Morton J. Notarangelo, Luigi Rosenberg, Philip S. Shenoy, Shalini Skinner, Roderick Walters, Mark C. Wagner, John Baker, K. Scott Pulsipher, Michael A. TI The Second Pediatric Blood and Marrow Transplant Consortium International Consensus Conference on Late Effects after Pediatric Hematopoietic Cell Transplantation: Defining the Unique Late Effects of Children Undergoing Hematopoietic Cell Transplantation for Immune Deficiencies, Inherited Marrow Failure Disorders, and Hemoglobinopathies SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Late effects; Pediatric allogeneic bone marrow transplantation; Marrow failure disorders; Immune deficiencies; Hemoglobinopathies ID NATIONAL-CANCER-INSTITUTE; LONG-TERM SURVIVORS; CHRONIC HEALTH CONDITIONS; SEVERE APLASTIC-ANEMIA; FANCONI-ANEMIA; CHILDHOOD-CANCER; INSTITUTE/PEDIATRIC BLOOD; ONCOLOGY GROUP; OUTCOMES; MALIGNANCIES AB An international consensus conference sponsored by the Pediatric Blood and Marrow Transplant consortium entitled "Late Effects Screening and Recommendations Following Allogeneic Hematopoietic Cell Transplant for Immune Deficiency and Nonmalignant Hematologic Disease" was held in Minneapolis, Minnesota on May 10, 2016 and May 11, 2016. The purpose of the conference was to address the unmet need for greater understanding of and the screening for long-term complications in the growing population of survivors of transplantation for nonmalignant disorders. The conference focused on transplantation for hemoglobinopathy, immune deficiency, and inherited bone marrow syndromes. A multidisciplinary group of experts in the disease areas and transplantation late effects presented the current state of understanding of how the underlying disease, pretransplantation therapies, and transplantation-related factors uniquely interact to influence the development of late toxicities. Recommendations were put forth by the group for the late effects screening of survivors of transplantation for these nonmalignant disorders. The findings and recommendations that came from this conference will be presented in a series of 6 additional manuscripts in the upcoming months. In this manuscript, we explore the need for screening practices specific to the survivors of transplantation for nonmalignant diseases and the methodologic challenges associated with the study of these patients. (C) 2017 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved. C1 [Dietz, Andrew C.; Pulsipher, Michael A.] Childrens Hosp Los Angeles, Childrens Ctr Canc & Blood Dis, Los Angeles, CA 90027 USA. [Duncan, Christine N.] Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA. [Alter, Blanche P.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Bresters, Dorine] Leiden Univ, Med Ctr, Willem Alexander Childrens Hosp, SCI Unit, Leiden, Netherlands. [Cowan, Morton J.] Univ Calif San Francisco, Dept Pediat Allergy Immunol, San Francisco, CA 94143 USA. [Cowan, Morton J.] Univ Calif San Francisco, Blood & Marrow Transplant Div, San Francisco, CA 94143 USA. [Notarangelo, Luigi] Harvard Med Sch, Boston Childrens Hosp, Div Immunol, Boston, MA USA. [Rosenberg, Philip S.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Shenoy, Shalini] Washington Univ, St Louis Childrens Hosp, St Louis, MO 63110 USA. [Skinner, Roderick] Great North Childrens Hosp, Newcastle Upon Tyne, Tyne & Wear, England. [Skinner, Roderick] Northern Inst Canc Res, Newcastle Upon Tyne, Tyne & Wear, England. [Walters, Mark C.] UCSF Benioff Childrens Hosp Oakland, Oakland, CA USA. [Wagner, John] Univ Minnesota, Blood & Marrow Transplant Program, Minneapolis, MN USA. [Baker, K. Scott] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. RP Pulsipher, MA (reprint author), Childrens Hosp Los Angeles, Div Hematol Oncol & Blood & Marrow Transplantat, 4650 Sunset Blvd,Mailstop 541, Los Angeles, CA 90027 USA. EM mpulsipher@chla.usc.edu FU National Institutes of Health [1R13CA159788-01, U01HL069254, R01 CA078938] FX This work was supported in part by grants from the National Institutes of Health (1R13CA159788-01 [to M.P., K.S.B.], U01HL069254 [to M.P.], R01 CA078938 [to S.B.], NR 36 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD JAN PY 2017 VL 23 IS 1 BP 24 EP 29 DI 10.1016/j.bbmt.2016.10.004 PG 6 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA EH8ST UT WOS:000392043300005 PM 27737772 ER PT J AU Rogawski, ET Platts-Mills, JA Seidman, JC John, S Mahfuz, M Ulak, M Shrestha, SK Soofi, SB Yori, PP Mduma, E Svensen, E Ahmed, T Lima, AAM Bhutta, ZA Kosek, MN Lang, DR Gottlieb, M Zaidi, AKM Kang, G Bessong, PO Houpt, ER Guerrant, RL AF Rogawski, Elizabeth T. Platts-Mills, James A. Seidman, Jessica C. John, Sushil Mahfuz, Mustafa Ulak, Manjeswori Shrestha, Sanjaya K. Soofi, Sajid Bashir Yori, Pablo Penataro Mduma, Estomih Svensen, Erling Ahmed, Tahmeed Lima, Aldo A. M. Bhutta, Zulfiqar A. Kosek, Margaret N. Lang, Dennis R. Gottlieb, Michael Zaidi, Anita K. M. Kang, Gagandeep Bessong, Pascal O. Houpt, Eric R. Guerrant, Richard L. TI Use of antibiotics in children younger than two years in eight countries: a prospective cohort study SO BULLETIN OF THE WORLD HEALTH ORGANIZATION LA English DT Article ID DIARRHEA; PEDIATRICS; COMMUNITY; STEWARDSHIP; RESISTANCE; MICROBIOTA; DISEASE; QUALITY AB Objective To describe the frequency and factors associated with antibiotic use in early childhood, and estimate the proportion of diarrhoea and respiratory illnesses episodes treated with antibiotics. Methods Between 2009 and 2014, we followed 2134 children from eight sites in Bangladesh, Brazil, India, Nepal, Pakistan, Peru, South Africa and the United Republic of Tanzania, enrolled in the MAL-ED birth cohort study. We documented all antibiotic use from mothers' reports at twice-weekly visits over the children's first two years of life. We estimated the incidence of antibiotic use and the associations of antibiotic use with child and household characteristics. We described treatment patterns for diarrhoea and respiratory illnesses, and identified factors associated with treatment and antibiotic class. Findings Over 1 346 388 total days of observation, 16 913 courses of antibiotics were recorded (an incidence of 4.9 courses per child per year), with the highest use in South Asia. Antibiotic treatment was given for 375/499 (75.2%) episodes of bloody diarrhoea and for 4274/9661 (44.2%) episodes of diarrhoea without bloody stools. Antibiotics were used in 2384/3943 (60.5%) episodes of fieldworker-confirmed acute lower respiratory tract illness as well as in 6608/16742 (39.5%) episodes of upper respiratory illness. Penicillins were used most frequently for respiratory illness, while antibiotic classes for diarrhoea treatment varied within and between sites. Conclusion Repeated antibiotic exposure was common early in life, and treatment of non-bloody diarrhoea and non-specific respiratory illnesses was not consistent with international recommendations. Rational antibiotic use programmes may have the most impact in South Asia, where antibiotic use was highest. C1 [Rogawski, Elizabeth T.; Platts-Mills, James A.; Houpt, Eric R.; Guerrant, Richard L.] Univ Virginia, Div Infect Dis & Int Hlth, POB 801379,Carter Harrison Res Bldg MR-6, Charlottesville, VA 22908 USA. [Seidman, Jessica C.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [John, Sushil; Kang, Gagandeep] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Mahfuz, Mustafa; Ahmed, Tahmeed] Int Ctr Diarrhoeal Dis Res, Dhaka, Bangladesh. [Ulak, Manjeswori] Tribhuvan Univ, Inst Med, Kathmandu, Nepal. [Shrestha, Sanjaya K.] Walter Reed AFRIMS Res Unit, Kathmandu, Nepal. [Soofi, Sajid Bashir; Bhutta, Zulfiqar A.; Zaidi, Anita K. M.] Aga Khan Univ, Karachi, Pakistan. [Yori, Pablo Penataro; Kosek, Margaret N.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Mduma, Estomih] Haydom Lutheran Hosp, Haydom, Tanzania. [Svensen, Erling] Univ Fed Ceara, Clin Res Unit, Fortaleza, Ceara, Brazil. [Lima, Aldo A. M.] Univ Fed Ceara, Inst Biomed, Fortaleza, Ceara, Brazil. [Lang, Dennis R.; Gottlieb, Michael] Fdn Natl Inst Hlth, Bethesda, MD USA. [Bessong, Pascal O.] Univ Venda, Thohoyandou, South Africa. RP Rogawski, ET (reprint author), Univ Virginia, Div Infect Dis & Int Hlth, POB 801379,Carter Harrison Res Bldg MR-6, Charlottesville, VA 22908 USA. EM etr5m@virginia.edu FU Fogarty International Center, National Institutes of Health [D43-TW009359] FX The Fogarty International Center, National Institutes of Health (D43-TW009359 to ETR) supported this work. NR 46 TC 0 Z9 1 U1 3 U2 3 PU WORLD HEALTH ORGANIZATION PI GENEVA 27 PA MARKETING AND DISSEMINATION, CH-1211 GENEVA 27, SWITZERLAND SN 0042-9686 EI 1564-0604 J9 B WORLD HEALTH ORGAN JI Bull. World Health Organ. PD JAN PY 2017 VL 95 IS 1 BP 49 EP 61 DI 10.2471/BLT.16.176123 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EH8RR UT WOS:000392040500014 PM 28053364 ER PT J AU Qadir, XV Clyne, M Lam, TK Khoury, MJ Schully, SD AF Qadir, Ximena V. Clyne, Mindy Lam, Tram Kim Khoury, Muin J. Schully, Sheri D. TI Trends in published meta-analyses in cancer research, 2008-2013 SO CANCER CAUSES & CONTROL LA English DT Article DE Meta-analysis; Database; Epidemiology; Clinical trials ID GENOME-WIDE ASSOCIATION; EPIDEMIOLOGY AB In order to capture trends in the contribution of epidemiology to cancer research, we describe an online meta-analysis database resource for cancer clinical and population research and illustrate trends and descriptive detail of cancer meta-analyses from 2008 through 2013. A total of 4,686 cancer meta-analyses met our inclusion criteria. During this 6-year period, a fivefold increase was observed in the yearly number of meta-analyses. Fifty-six percent of meta-analyses concerned observational studies, mostly of cancer risk, more than half of which were genetic studies. The major cancer sites were breast, colorectal, and digestive. This online database for Cancer Genomics and Epidemiology Navigator will be continuously updated to allow investigators to quickly navigate the meta-analyses emerging from cancer epidemiology studies and cancer clinical trials. C1 [Qadir, Ximena V.; Lam, Tram Kim; Khoury, Muin J.; Schully, Sheri D.] NCI, Div Canc Control & Populat Sci, NIH, 6100 Execut Blvd,Suite 2B03, Bethesda, MD 20892 USA. [Clyne, Mindy] Kelly Govt Serv, Troy, MI USA. [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. [Schully, Sheri D.] NIH, Off Dis Prevent, Bldg 10, Bethesda, MD 20892 USA. RP Schully, SD (reprint author), NCI, Div Canc Control & Populat Sci, NIH, 6100 Execut Blvd,Suite 2B03, Bethesda, MD 20892 USA.; Schully, SD (reprint author), NIH, Off Dis Prevent, Bldg 10, Bethesda, MD 20892 USA. EM schullys@mail.nih.gov FU Intramural NIH HHS [Z99 OD999999] NR 11 TC 0 Z9 0 U1 2 U2 2 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 JAN PY 2017 VL 28 IS 1 BP 5 EP 12 DI 10.1007/s10552-016-0830-6 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EH9CQ UT WOS:000392069700002 PM 27900614 ER PT J AU Bamishigbin, ON Schetter, CD Guardino, CM Stanton, AL Schafer, P Shalowitz, M Lanzi, RG Thorp, J Raju, T AF Bamishigbin, Olajide N. Schetter, Christine Dunkel Guardino, Christine M. Stanton, Annette L. Schafer, Peter Shalowitz, Madeleine Lanzi, Robin Gaines Thorp, John, Jr. Raju, Tonse CA Community Child Hlth Network TI Risk, Resilience, and Depressive Symptoms in Low-Income African American Fathers SO CULTURAL DIVERSITY & ETHNIC MINORITY PSYCHOLOGY LA English DT Article DE African American; fathers; risk; depression ID RANDOMIZED CLINICAL-TRIAL; POSTNATAL DEPRESSION; SOCIAL SUPPORT; MENTAL-HEALTH; PERCEIVED DISCRIMINATION; PSYCHOLOGICAL DISTRESS; PATERNAL INVOLVEMENT; COLLECTIVE EFFICACY; COPING STRATEGIES; MAJOR DEPRESSION AB Objective: Parental depression influences family health but research on low-income African American fathers is limited. The primary goal of the present study was to examine the role of paternal risk factors and resilience resources in predicting depressive symptoms in the year after birth of a child in a sample of African American fathers. We hypothesized that paternal risk factors (low socioeconomic status [SES], perceived stress, negative life events, racism, avoidant coping style) and resources (social support, self-esteem, collective efficacy, approach-oriented coping style) would predict depressive symptoms in fathers at 1 year postbirth controlling for depressive symptoms at 1 month postbirth. Method: African American fathers (n = 296) of predominantly low SES from 5 U.S. regions were interviewed at 1 and 12 months after birth of a child regarding potential risk factors, resilience resources, and depressive symptoms. Results: Depressive symptoms were low on average. However, hierarchical linear regression analyses revealed that avoidant coping style and experiences of racism predicted more depressive symptoms in fathers nearly a year after the birth of a child controlling for symptoms at 1 month. Conclusions: How fathers cope with stress and common everyday experiences of racism contributed to depressive symptoms in the year following birth of a child. Interventions that target race-related stressors and decrease avoidant coping may promote better outcomes in this important and understudied population. C1 [Bamishigbin, Olajide N.; Schetter, Christine Dunkel; Guardino, Christine M.; Stanton, Annette L.] Univ Calif Los Angeles, Dept Psychol, 1285A Franz Hall, Los Angeles, CA 90005 USA. [Schafer, Peter] New York Acad Med, New York, NY USA. [Shalowitz, Madeleine] North Shore Univ Hlth Syst, Chicago, IL USA. [Shalowitz, Madeleine] Univ Chicago, Chicago, IL 60637 USA. [Lanzi, Robin Gaines] Univ Alabama Birmingham, Dept Hlth Behav, Birmingham, AL USA. [Thorp, John, Jr.] Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC USA. [Raju, Tonse] Eunice Kennedy Shriver Natl Inst Child & Hlth Dev, Bethesda, MD USA. [Raju, Tonse] Community Child Hlth Network, Bethesda, MD USA. RP Bamishigbin, ON; Schetter, CD (reprint author), Univ Calif Los Angeles, Dept Psychol, 1285A Franz Hall, Los Angeles, CA 90005 USA. EM obamishigbin@ucla.edu; dunkel@psych.ucla.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U HD44207, U HD44219, U HD44226, U HD44245, U HD44253, U HD54791, U HD54019, U HD44226-05S1, U HD44245-06S1, R03 HD59584]; National Institute for Nursing Research [U NR008929] FX This article is a product of the Child Community Health Research Network (CCHN). Accordingly, the last designated author is the network itself preceded by the names of those on the writing team who directly prepared this article listed in the order the team judged best reflects their relative contributions. The CCHN was supported through cooperative agreements with the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U HD44207, U HD44219, U HD44226, U HD44245, U HD44253, U HD54791, U HD54019, U HD44226-05S1, U HD44245-06S1, R03 HD59584) and the National Institute for Nursing Research (U NR008929). For more information on CCHN network sites, see https://www.nichd.nih.gov/research/supported/Pages/cchn.aspx NR 71 TC 0 Z9 0 U1 4 U2 4 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 1099-9809 EI 1939-0106 J9 CULT DIVERS ETHN MIN JI Cult. Divers. Ethn. Minor. Psychol. PD JAN PY 2017 VL 23 IS 1 BP 70 EP 80 DI 10.1037/cdp0000088 PG 11 WC Ethnic Studies; Psychology, Social SC Ethnic Studies; Psychology GA EH9QW UT WOS:000392106900009 PM 27244219 ER PT J AU Jaso, BA Niciu, MJ Iadarola, ND Lally, N Richards, EM Park, M Ballard, ED Nugent, AC Machado-Vieira, R Zarate, CA AF Jaso, Brittany A. Niciu, Mark J. Iadarola, Nicolas D. Lally, Niall Richards, Erica M. Park, Minkyung Ballard, Elizabeth D. Nugent, Allison C. Machado-Vieira, Rodrigo Zarate, Carlos A., Jr. TI Therapeutic Modulation of Glutamate Receptors in Major Depressive Disorder SO CURRENT NEUROPHARMACOLOGY LA English DT Review DE alpha-amino-3-hydroxyl-5-methyl-4-isoxazoleproprionic acid (AMPA); antagonist; glutamate; major depressive disorder (MDD); metabotropic; N-methyl-D-aspartate (NMDA); negative allosteric modulator; positive allosteric modulator ID TREATMENT-RESISTANT DEPRESSION; ANTIDEPRESSANT-LIKE ACTIVITY; D-ASPARTATE ANTAGONIST; PROOF-OF-CONCEPT; ADD-ON TRIAL; RAPID-ACTING ANTIDEPRESSANT; RANDOMIZED CONTROLLED-TRIAL; RECEIVING HOSPICE CARE; SITE PARTIAL AGONIST; LOW-DOSE KETAMINE AB Current pharmacotherapies for major depressive disorder (MDD) have a distinct lag of onset that can prolong distress and impairment for patients, and real-world effectiveness trials further suggest that antidepressant efficacy is limited in many patients. All currently approved antidepressant medications for MDD act primarily through monoaminergic mechanisms, e.g., receptor/reuptake agonists or antagonists with varying affinities for serotonin, norepinephrine, or dopamine. Glutamate is the major excitatory neurotransmitter in the central nervous system, and glutamate and its cognate receptors are implicated in the pathophysiology of MDD, as well as in the development of novel therapeutics for this disorder. Since the rapid and robust antidepressant effects of the N-methyl-D-aspartate (NMDA) antagonist ketamine were first observed in 2000, other NMDA receptor antagonists have been studied in MDD. These have been associated with relatively modest antidepressant effects compared to ketamine, but some have shown more favorable characteristics with increased potential in clinical practice (for instance, oral administration, decreased dissociative and/or psychotomimetic effects, and reduced abuse/diversion liability). This article reviews the clinical evidence supporting the use of glutamate receptor modulators with direct affinity for cognate receptors: 1) non-competitive NMDA receptor antagonists (ketamine, memantine, dextromethorphan, AZD6765); 2) subunit (NR2B)-specific NMDA receptor antagonists (CP101,606/traxoprodil, MK-0657); 3) NMDA receptor glycine-site partial agonists (D-cycloserine, GLYX-13); and 4) metabotropic glutamate receptor (mGluR) modulators (AZD2066, RO4917523/basimglurant). Several other theoretical glutamate receptor targets with preclinical antidepressant-like efficacy, but that have yet to be studied clinically, are also briefly discussed; these include alpha-amino-3-hydroxyl-5-methyl-4isoxazoleproprionic acid (AMPA) agonists, mGluR2/3 negative allosteric modulators, and mGluR7 agonists. C1 [Jaso, Brittany A.; Niciu, Mark J.; Iadarola, Nicolas D.; Lally, Niall; Richards, Erica M.; Park, Minkyung; Ballard, Elizabeth D.; Nugent, Allison C.; Machado-Vieira, Rodrigo; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, 10 Ctr Dr,Bldg 10-CRC,Room 7-5545, Bethesda, MD 20892 USA. RP Zarate, CA (reprint author), CRC, 10 Ctr Dr,Unit 7 Southeast,Room 7-5342, 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) [NCT00088699, 04-M-0222]; NARSAD Independent Investigator Award; Brain & 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; NCT00088699, protocol 04-M-0222), by a NARSAD Independent Investigator Award to CAZ, and by a Brain & Behavior Mood Disorders Research Award to CAZ. A patent for the use of ketamine in depression has been awarded that lists CAZ among the inventors; he has assigned his rights on the patent to the U.S. government, but will share a percentage of any royalties that may be received by the government. All other authors have no conflict of interest to disclose, financial or otherwise. NR 102 TC 0 Z9 0 U1 12 U2 12 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1570-159X EI 1875-6190 J9 CURR NEUROPHARMACOL JI Curr. Neuropharmacol. PY 2017 VL 15 IS 1 BP 57 EP 70 DI 10.2174/1570159X14666160321123221 PG 14 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA EH6AX UT WOS:000391855800008 PM 26997505 ER PT J AU Diao, XX Carlier, J Zhu, MS Pang, SK Kronstrand, R Scheidweiler, KB Huestis, MA AF Diao, Xingxing Carlier, Jeremy Zhu, Mingshe Pang, Shaokun Kronstrand, Robert Scheidweiler, Karl B. Huestis, Marilyn A. TI In vitro and in vivo human metabolism of a new synthetic cannabinoid NM-2201 (CBL-2201) SO FORENSIC TOXICOLOGY LA English DT Article DE NM-2201; CBL-2201; Synthetic cannabinoid; In vitro human hepatocyte metabolism; High-resolution mass spectrometry; Authentic human urine specimen ID RESOLUTION MASS-SPECTROMETRY; HUMAN HEPATOCYTES; OXIDATIVE-METABOLISM; LIVER-MICROSOMES; 5-FLUORO ANALOG; DRUG DISCOVERY; HUMAN URINE; IDENTIFICATION; 3-N-BUTYLPHTHALIDE; BIOACTIVATION AB In 2014, NM-2201 (CBL-2201), a novel synthetic cannabinoid (SC), was detected by scientists at Russian and US laboratories. It has been already added to the list of scheduled drugs in Japan, Sweden and Germany. Unfortunately, no human metabolism data are currently available, which makes it challenging to confirm its intake, especially given that all SCs investigated thus far have been found to be extensively metabolized. The present study aims to recommend appropriate marker metabolites by investigating NM-2201 metabolism in human hepatocytes, and to confirm the results in authentic human urine specimens. For the metabolic stability assay, 1 A mu M NM-2201 was incubated in human liver microsomes (HLMs) for up to 1 h; for metabolite profiling, 10 A mu M of NM-2201 was incubated in human hepatocytes for 3 h. Two authentic urine specimens from NM-2201-positive cases were subjected to beta-glucuronidase hydrolysis prior to analysis. The identification of metabolites in hepatocyte samples and urine specimens was achieved with high-resolution mass spectrometry via information-dependent acquisition. NM-2201 was quickly metabolized in HLMs, with an 8.0-min half-life. In human hepatocyte incubation samples, a total of 13 NM-2201 metabolites were identified, generated mainly from ester hydrolysis and further hydroxylation, oxidative defluorination and subsequent glucuronidation. M13 (5-fluoro PB-22 3-carboxyindole) was found to be the major metabolite. In the urine specimens, the parent drug NM-2201 was not detected; M13 was the predominant metabolite after beta-glucuronidase hydrolysis. Therefore, based on the results of our study, we recommend M13 as a suitable urinary marker metabolite for confirming NM-2201 and/or 5F-PB-22 intake. C1 [Diao, Xingxing; Carlier, Jeremy; Scheidweiler, Karl B.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, Clin Pharmacol & Therapeut Branch, Intramural Res Program,NIH, 251 Bayview Blvd,Suite 200,Room 05A727, Baltimore, MD 21224 USA. [Zhu, Mingshe] Bristol Myers Squibb, Dept Biotransformat, Res & Dev, Princeton, NJ 08543 USA. [Pang, Shaokun] SCIEX Ltd, Redwood City, CA 94065 USA. [Kronstrand, Robert] Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, S-58758 Linkoping, Sweden. [Kronstrand, Robert] Linkoping Univ, Dept Drug Res, S-58185 Linkoping, Sweden. [Huestis, Marilyn A.] Univ Maryland, Sch Med, Baltimore, MD 21224 USA. RP Scheidweiler, KB (reprint author), NIDA, Chem & Drug Metab Sect, Clin Pharmacol & Therapeut Branch, Intramural Res Program,NIH, 251 Bayview Blvd,Suite 200,Room 05A727, Baltimore, MD 21224 USA. EM kscheidweiler@intra.nida.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health FX This research is supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NM-2201 was generously donated by the US Drug Enforcement Administration. We also appreciate help from Dr. Ariane Wohlfarth in performing the HLMs metabolic stability assays. NR 43 TC 2 Z9 2 U1 5 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1860-8965 EI 1860-8973 J9 FORENSIC TOXICOL JI Forensic Toxicol. PD JAN PY 2017 VL 35 IS 1 BP 20 EP 32 DI 10.1007/s11419-016-0326-9 PG 13 WC Toxicology SC Toxicology GA EH7EC UT WOS:000391934700003 PM 28286577 ER PT J AU Swortwood, MJ Newmeyer, MN Abulseoud, OA Andersson, M Barnes, AJ Scheidweiler, KB Huestis, MA AF Swortwood, Madeleine J. Newmeyer, Matthew N. Abulseoud, Osama A. Andersson, Maria Barnes, Allan J. Scheidweiler, Karl B. Huestis, Marilyn A. TI On-site oral fluid Delta(9)-tetrahydrocannabinol (THC) screening after controlled smoked, vaporized, and oral cannabis administration SO FORENSIC TOXICOLOGY LA English DT Article DE Cannabinoids; Oral fluid; On-site testing; Drager DrugTest (R) 5000; Alere (TM) DDS (R) 2; Driving under the influence of drugs (DUID) ID PHARMACOKINETIC PROPERTIES; TESTING DEVICES; DISPOSITION; METABOLITES; ALCOHOL; SMOKING; DRUGS; SERUM; USERS; RISK AB Increasing driving under the influence of cannabis cases is an important short-term consequence of cannabis legalization. On-site oral fluid (OF) testing devices provide advantages for roadside drug screening, because OF Delta(9)-tetrahydrocannabinol (THC) indicates more recent cannabis intake than urine, and it can be collected non-invasively by law enforcement personnel. THC presence in OF primarily results from oromucosal contamination during cannabis inhalation. To date, on-site OF devices were not investigated following edible cannabis. We evaluated sensitivity, specificity, and efficiency of the Drager DrugTest(A (R)) 5000 [DT5000] and Alere (TM) DDS(A (R))2 [DDS2] at various OF THC confirmatory cutoffs following controlled smoked, vaporized, and edible cannabis in frequent and occasional smokers. Times of last positive (t (last)) were evaluated for each device, cutoff, and smoking group. At a 5 A mu g/L OF THC confirmation cutoff, overall performance criteria exceeded the recommended 80% for both devices. At lower THC confirmation cutoffs (1-2 A mu g/L), true positive results were maximized but sensitivity was < 80%. When confirmation cutoffs were below manufacturers' screening cutoffs (5 A mu g/L DT5000, 25 A mu g/L DDS2), false negative results increased. No differences in t (last) were observed for DT5000 between the three administration routes, but later t (last) times were observed after smoking compared to vaporization with DDS2. Frequent smokers had significantly later median t (last) (5 h) compared to occasional smokers (1.5-3.5 h) for all conditions. There were no true positive results at 44 and 50 h with the DT5000 and DDS2, respectively. OF screening followed by confirmatory OF analysis is an important strategy for investigations of driving under the influence of drugs, with these data improving interpretation of cannabinoid OF results. C1 [Swortwood, Madeleine J.; Newmeyer, Matthew N.; Abulseoud, Osama A.; Andersson, Maria; Barnes, Allan J.; Scheidweiler, Karl B.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Swortwood, Madeleine J.] Sam Houston State Univ, Dept Forens Sci, Coll Criminal Justice, Huntsville, TX 77340 USA. [Newmeyer, Matthew N.] Univ Maryland, Toxicol Program, Baltimore, MD 21201 USA. [Huestis, Marilyn A.] Univ Maryland, Sch Med, 683 Shore Rd, Severna Pk, MD 21146 USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA.; Huestis, MA (reprint author), Univ Maryland, Sch Med, 683 Shore Rd, Severna Pk, MD 21146 USA. EM marilyn.huestis@gmail.com FU Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health FX The authors would like to thank Dr. Sandrine Pirard for her contribution to study design and the contributions of the clinical staffs of the Intramural Research Program, National Institute on Drug Abuse, and the Clinical Research Unit, Johns Hopkins Bayview Medical Center. This study was registered on clinicaltrials.gov (NCT02177513). Quantisal devices, Drager DrugTest 5000, and Alere DDS2 were provided by the manufacturers to NIH via Materials Transfer Agreements. This research was funded by the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health. MNN acknowledges the Graduate Partnership Program, NIH. NR 35 TC 0 Z9 0 U1 10 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1860-8965 EI 1860-8973 J9 FORENSIC TOXICOL JI Forensic Toxicol. PD JAN PY 2017 VL 35 IS 1 BP 133 EP 145 DI 10.1007/s11419-016-0348-3 PG 13 WC Toxicology SC Toxicology GA EH7EC UT WOS:000391934700015 ER PT J AU Riley, WT AF Riley, William T. TI Behavioral and Social Sciences at the National Institutes of Health: Methods, Measures, and Data Infrastructures as a Scientific Priority SO HEALTH PSYCHOLOGY LA English DT Editorial Material DE measurement; methodology; data integration; behavioral ontologies; big data ID INTERVENTIONS; TRIALS AB The National Institutes of Health Office of Behavioral and Social Sciences Research (OBSSR) recently released its strategic plan for 2017-2021. This plan focuses on three equally important strategic priorities: 1) improve the synergy of basic and applied behavioral and social sciences research, 2) enhance and promote the research infrastructure, methods, and measures needed to support a more cumulative and integrated approach to behavioral and social sciences research, and 3) facilitate the adoption of behavioral and social sciences research findings in health research and in practice. This commentary focuses on scientific priority two and future directions in measurement science, technology, data infrastructure, behavioral ontologies, and big data methods and analytics that have the potential to transform the behavioral and social sciences into more cumulative, data rich sciences that more efficiently build on prior research. C1 [Riley, William T.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Riley, WT (reprint author), NIH, Off Behav & Social Sci Res, 31 Ctr Dr,Bldg 31, Bethesda, MD 20892 USA. EM wiriley@mail.nih.gov NR 18 TC 0 Z9 0 U1 1 U2 1 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0278-6133 EI 1930-7810 J9 HEALTH PSYCHOL JI Health Psychol. PD JAN PY 2017 VL 36 IS 1 BP 5 EP 7 DI 10.1037/hea0000464 PG 3 WC Psychology, Clinical; Psychology SC Psychology GA EH9RE UT WOS:000392107700002 PM 28045300 ER PT J AU Barch, DM Pagliaccio, D AF Barch, Deanna M. Pagliaccio, David TI Consistency, Replication, and Meta-analyses of Altered Brain Activity in Unipolar Depression SO JAMA PSYCHIATRY LA English DT Editorial Material ID ANHEDONIA; MEMORY; FMRI C1 [Barch, Deanna M.] Washington Univ St Louis, Dept Psychol & Brain Sci, Box 1125,One Brookings Dr, St Louis, MO 63130 USA. [Barch, Deanna M.] Washington Univ St Louis, Dept Psychiat, St Louis, MO USA. [Barch, Deanna M.] Washington Univ St Louis, Dept Radiol, St Louis, MO USA. [Pagliaccio, David] NIMH, Emot & Dev Branch, Bethesda, MD 20892 USA. RP Barch, DM (reprint author), Washington Univ St Louis, Dept Psychol & Brain Sci, Box 1125,One Brookings Dr, St Louis, MO 63130 USA. EM dbarch@wustl.edu NR 7 TC 0 Z9 0 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD JAN PY 2017 VL 74 IS 1 BP 56 EP 57 DI 10.1001/jamapsychiatry.2016.2844 PG 2 WC Psychiatry SC Psychiatry GA EH9UQ UT WOS:000392117300012 PM 27829090 ER PT J AU Sudre, G Choudhuri, S Szekely, E Bonner, T Goduni, E Sharp, W Shaw, P AF Sudre, Gustavo Choudhuri, Saadia Szekely, Eszter Bonner, Teighlor Goduni, Elanda Sharp, Wendy Shaw, Philip TI Estimating the Heritability of Structural and Functional Brain Connectivity in Families Affected by Attention-Deficit/Hyperactivity Disorder SO JAMA PSYCHIATRY LA English DT Article ID SUPERIOR LONGITUDINAL FASCICULUS; DEFICIT HYPERACTIVITY DISORDER; WHITE-MATTER MICROSTRUCTURE; GENETIC-CONTROL; RESTING BRAIN; CHILDREN; DTI; NETWORK; ARCHITECTURE; ENDOPHENOTYPES AB IMPORTANCE Despite its high heritability, few risk genes have been identified for attention-deficit/hyperactivity disorder (ADHD). Brain-based phenotypes could aid gene discovery. There is a myriad of structural and functional connections that support cognition. Disruption of such connectivity is a key pathophysiologic mechanism for ADHD, and identifying heritable phenotypes within these connections could provide candidates for genomic studies. OBJECTIVE To identify the structural and functional connections that are heritable and pertinent to ADHD. DESIGN, SETTING, AND PARTICIPANTS Members of extended multigenerational families enriched for ADHD were evaluated. Structural connectivity was defined by diffusion tensor imaging (DTI) of white matter tract microstructure and functional connectivity through resting-state functional magnetic resonance imaging (rsfMRI). Heritability and association with ADHD symptoms were estimated in 24 extended multigenerational families enriched for ADHD (305 members with clinical phenotyping, 213 with DTI, and 193 with rsfMRI data). Findings were confirmed in 52 nuclear families (132 members with clinical phenotypes, 119 with DTI, and 84 with rsfMRI). The study and data analysis were conducted from April 1, 2010, to September 1, 2016. RESULTS In the 52 nuclear families, 86 individuals (65.2%) were male and the mean (SD) age at imaging was 20.9 (15.0) years; in the 24 multigenerational extended families, 145 individuals (47.5%) were male and mean age at imaging was 30.4 (19.7) years. Microstructural properties of white matter tracts connecting ipsilateral cortical regions and the corpus callosum were significantly heritable, ranging from total additive genetic heritability (h(2)) = 0.69 (SE, 0.13; P = .0000002) for radial diffusivity of the right superior longitudinal fasciculus to h(2) = 0.46 (SE, 0.15; P = .0009) for fractional anisotropy of the right inferior fronto-occipital fasciculus. Association with ADHD symptoms was found in several tracts, most strongly for the right superior longitudinal fasciculus (t = -3.05; P = .003). Heritable patterns of functional connectivity were detected within the default mode (h(2) = 0.36; SE, 0.16; cluster level significance, P < .002), cognitive control (h(2) = 0.32; SE, 0.15; P < .002), and ventral attention networks (h(2) = 0.36; SE, 0.16; P < .002). In all cases, subregions within each network showed heritable functional connectivity with the rest of that network. More symptoms of hyperactivity/impulsivity (t = -2.63; P = .008) and inattention (t = -2.34; P = .02) were associated with decreased functional connectivity within the default mode network. Some cross-modal correlations were purely phenotypic, such as that between axial diffusivity of the right superior longitudinal fasciculus and heritable aspects of the default mode network (phenotypic correlation, rho(p) = -0.12; P = .03). A genetic cross-modal correlation was seen between the ventral attention network and radial diffusivity of the right inferior fronto-occipital fasciculus (genetic correlation, rho(g) = -0.45, P = .02). CONCLUSIONS Analysis of data on multigenerational extended and nuclear families identified the features of structural and functional connectivity that are both significantly heritable and associated with ADHD. In addition, shared genetic factors account for some phenotypic correlations between functional and structural connections. Such work helps to prioritize the facets of the brain's connectivity for future genomic studies. C1 [Sudre, Gustavo; Choudhuri, Saadia; Szekely, Eszter; Bonner, Teighlor; Goduni, Elanda; Sharp, Wendy; Shaw, Philip] NHGRI, Sect Neurobehav Clin Res, Social & Behav Res Branch, Bldg 31,B1 B37, Bethesda, MD 20892 USA. RP Sudre, G (reprint author), NHGRI, Sect Neurobehav Clin Res, Social & Behav Res Branch, Bldg 31,B1 B37, Bethesda, MD 20892 USA. EM sudregp@mail.nih.gov FU intramural research program of the National Human Genome Research Institute; National Institute of Mental Health FX Funded by the intramural research program of the National Human Genome Research Institute and the National Institute of Mental Health. NR 62 TC 0 Z9 0 U1 4 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD JAN PY 2017 VL 74 IS 1 BP 76 EP 84 DI 10.1001/jamapsychiatry.2016.3072 PG 9 WC Psychiatry SC Psychiatry GA EH9UQ UT WOS:000392117300015 PM 27851842 ER PT J AU Stoddard, J Tseng, WL Kim, P Chen, G Yi, J Donahue, L Brotman, MA Towbin, KE Pine, DS Leibenluft, E AF Stoddard, Joel Tseng, Wan-Ling Kim, Pilyoung Chen, Gang Yi, Jennifer Donahue, Laura Brotman, Melissa A. Towbin, Kenneth E. Pine, Daniel S. Leibenluft, Ellen TI Association of Irritability and Anxiety With the Neural Mechanisms of Implicit Face Emotion Processing in Youths With Psychopathology SO JAMA PSYCHIATRY LA English DT Article ID SEVERE MOOD DYSREGULATION; MIXED-EFFECTS MODELS; BIPOLAR DISORDER; ATTENTION BIAS; FUNCTIONAL CONNECTIVITY; AMYGDALA RESPONSES; HEALTHY-VOLUNTEERS; THREAT; ADOLESCENTS; REACTIVITY AB IMPORTANCE Psychiatric comorbidity complicates clinical care and confounds efforts to elucidate the pathophysiology of commonly occurring symptoms in youths. To our knowledge, few studies have simultaneously assessed the effect of 2 continuously distributed traits on brain-behavior relationships in children with psychopathology. OBJECTIVE To determine shared and unique effects of 2 major dimensions of child psychopathology, irritability and anxiety, on neural responses to facial emotions during functional magnetic resonance imaging. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional functional magnetic resonance imaging study in a large, well-characterized clinical sample at a research clinic at the National Institute of Mental Health. The referred sample included youths ages 8 to 17 years, 93 youths with anxiety, disruptive mood dysregulation, and/or attention-deficit/hyperactivity disorders and 22 healthy youths. MAIN OUTCOMES AND MEASURES The child's irritability and anxiety were rated by both parent and child on the Affective Reactivity Index and Screen for Child Anxiety Related Disorders, respectively. Using functional magnetic resonance imaging, neural response was measured across the brain during gender labeling of varying intensities of angry, happy, or fearful face emotions. In mixed-effects analyses, the shared and unique effects of irritability and anxiety were tested on amygdala functional connectivity and activation to face emotions. RESULTS The mean (SD) age of participants was 13.2 (2.6) years; of the 115 included, 64 were male. Irritability and/or anxiety influenced amygdala connectivity to the prefrontal and temporal cortex. Specifically, irritability and anxiety jointly influenced left amygdala to left medial prefrontal cortex connectivity during face emotion viewing (F-4,F-888 = 9.20; P < .001 for mixed model term). During viewing of intensely angry faces, decreased connectivity was associated with high levels of both anxiety and irritability, whereas increased connectivity was associated with high levels of anxiety but low levels of irritability (Wald chi(2)(1) = 21.3; P < .001 for contrast). Irritability was associated with differences in neural response to face emotions in several areas (F-2,F-888 >= 13.45; all P < .001). This primarily occurred in the ventral visual areas, with a positive association to angry and happy faces relative to fearful faces. CONCLUSIONS AND RELEVANCE These data extend prior work conducted in youths with irritability or anxiety alone and suggest that research may miss important findings if the pathophysiology of irritability and anxiety are studied in isolation. Decreased amygdala-medial prefrontal cortex connectivity may mediate emotion dysregulation when very anxious and irritable youth process threat-related faces. Activation in the ventral visual circuitry suggests a mechanism through which signals of social approach (ie, happy and angry expressions) may capture attention in irritable youth. C1 [Stoddard, Joel] Univ Colorado, Dept Psychiat, Div Child & Adolescent Psychiat, Anshutz Med Campus, Aurora, CO USA. [Stoddard, Joel; Tseng, Wan-Ling; Yi, Jennifer; Donahue, Laura; Brotman, Melissa A.; Towbin, Kenneth E.; Leibenluft, Ellen] NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, NIH,US Dept HHS, Bethesda, MD 20892 USA. [Kim, Pilyoung] Univ Denver, Dept Psychol, Denver, CO 80208 USA. [Chen, Gang] NIMH, Sci & Stat Comp Core, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Yi, Jennifer] Univ North Carolina Chapel Hill, Dept Psychol & Neurosci, Chapel Hill, NC USA. [Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, Emot & Dev Branch, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Stoddard, J (reprint author), Univ Colorado, 13123 E 16th Ave,Box A036-B130, Aurora, CO 80045 USA. EM joel.stoddard@ucdenver.edu RI Brotman, Melissa/H-7409-2013 FU Intramural Research Program of the National Institute of Mental Health [02-M-0021, 00-M-0198, 01-M-0192] FX This research was supported by the Intramural Research Program of the National Institute of Mental Health, and it was conducted under protocols 02-M-0021 (ClinicalTrials.gov Identifier NCT00025935), 00-M-0198 (NCT00006177), and 01-M-0192 (NCT00018057). NR 42 TC 1 Z9 1 U1 11 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD JAN PY 2017 VL 74 IS 1 BP 95 EP 103 DI 10.1001/jamapsychiatry.2016.3282 PG 9 WC Psychiatry SC Psychiatry GA EH9UQ UT WOS:000392117300017 PM 27902832 ER PT J AU Bjornsson, ES Gu, JZ Kleiner, DE Chalasani, N Hayashi, PH Hoofnagle, JH AF Bjornsson, Einar S. Gu, Jiezhun Kleiner, David E. Chalasani, Naga Hayashi, Paul H. Hoofnagle, Jay H. CA DILIN Investigators TI Azathioprine and 6-Mercaptopurine-induced Liver Injury Clinical Features and Outcomes SO JOURNAL OF CLINICAL GASTROENTEROLOGY LA English DT Article DE hepatotoxicity; drug-induced liver injury; azathioprine; 6-mercaptopurine ID INFLAMMATORY-BOWEL-DISEASE; CAUSALITY ASSESSMENT; PORTAL-HYPERTENSION; UNITED-STATES; HEPATOTOXICITY; MERCAPTOPURINE; POPULATION; TRANSPLANTATION; HEPATITIS; PATIENT AB Objective: The objective of the study was to define the clinical, biochemical, and histologic features of liver injury from thiopurines. Background: Azathioprine (Aza) and 6-mercaptopurine (6-MP) can cause liver injury, but no large series exist. Methods: Clinical and laboratory data and 6-month outcomes of patients with thiopurine hepatotoxicity from the Drug-Induced Liver Injury Network Prospective Study were analyzed. Results: Twenty-two patients were identified, 12 due to Aza and 10 due to 6-MP, with a median age of 55 years; the majority were female (68%). Inflammatory bowel disease was the indication in 55%, and the median thiopurine dose was 150 (range, 25 to 300) mg daily. The median latency to onset was 75 (range, 3 to 2584) days. Injury first arose after a dose escalation in 59% of patients, the median latency after dose increase being 44 (range, 3 to 254) days. At onset, the median alanine aminotransferase level was 210 U/L, alkaline phosphatase was 151 U/L, and bilirubin was 7.4 mg/dL (peak, 13.4 mg/dL). There were no major differences between Aza and 6-MP cases, but anicteric cases typically had nonspecific symptoms and a hepatocellular pattern of enzyme elevations, whereas icteric cases experienced cholestatic hepatitis with modest enzyme elevations in a mixed pattern. One patient with preexisting cirrhosis required liver transplantation; all others resolved clinically. One patient still had moderate alkaline phosphatase elevations 2 years after onset. Conclusions: Nearly three-quarters of patients with thiopurine-induced liver injury present with self-limited, cholestatic hepatitis, typically within 3 months of starting or a dose increase. The prognosis is favorable except in patients with preexisting cirrhosis. C1 [Bjornsson, Einar S.; Hoofnagle, Jay H.] NIH, Liver Dis Res Branch, Div Digest Dis & Nutr, Bethesda, MD USA. [Bjornsson, Einar S.] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Bjornsson, Einar S.] Natl Univ Hosp Iceland, Reykjavik, Iceland. [Gu, Jiezhun] Duke Clin Res Inst, Durham, NC USA. [Kleiner, David E.] NCI, Lab Pathol, NIH, Indianapolis, IN USA. [Chalasani, Naga] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Hayashi, Paul H.] Univ N Carolina, Chapel Hill, NC USA. RP Hoofnagle, JH (reprint author), Liver Dis Res Branch, Room 655,Democracy 2,6707 Democracy Blvd, Bethesda, MD 20892 USA. EM HoofnagleJ@extra.niddk.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [1UO1DK065201, 1UO1DK065193, 1UO1DKO65184, 1UO1DK065211, 1UO1DK065238, 1UO1DK06F5176]; Intramural Research Program of the National Cancer Institute; Intramural Research Program of the NIDDK, NIH FX Supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under the following cooperative agreements: 1UO1DK065201, 1UO1DK065193, 1UO1DKO65184, 1UO1DK065211, 1UO1DK065238, and 1UO1DK06F5176. This research was supported in part by the Intramural Research Programs of the National Cancer Institute and NIDDK, NIH. NR 39 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 0192-0790 EI 1539-2031 J9 J CLIN GASTROENTEROL JI J. Clin. Gastroenterol. PD JAN PY 2017 VL 51 IS 1 BP 63 EP 69 DI 10.1097/MCG.0000000000000568 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EH6FJ UT WOS:000391867900011 PM 27648552 ER PT J AU Davis, RJ Silvin, C Allen, CT AF Davis, Ruth J. Silvin, Christopher Allen, Clint T. TI Avoiding phagocytosis-related artifact in myeloid derived suppressor cell T-lymphocyte suppression assays SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Review DE Myeloid-derived suppressor cells; MDSC; T-cell suppression assay; Phagocytosis; Artifact; CD3/28 microbeads ID TUMOR-GROWTH; CANCER; MICROENVIRONMENT; PROLIFERATION; IMMUNITY; HEAD AB Myeloid-derived suppressor cells (MDSCs) have garnered much attention in recent years as a potential target for altering the immunosuppressive tumor microenvironment in a variety of solid tumor types. The ability to accurately assess the immunosuppressive capacity of MDSCs is fundamental to the development of therapeutic approaches aimed at disabling these immunosuppressive functions. In this article we provide evidence that the use of CD3/28 coated microbeads leads to artefactual T-lymphocyte suppression due to sequestration of beads by MDSCs isolated from the spleens of wild-type mice bearing subcutaneous syngeneic, carcinogen-induced oral cavity carcinomas. Mechanisms of this finding may include early MDSC death and acquisition of phagocytic capacity. These artefactual findings were avoided by eliminating the use of microbeads and instead using plate bound CD3/28 antibody as the T-lymphocyte stimulus. We propose model-specific validation of microbead-based MDSC assays, or use of an alternative stimulation approach such as plate bound CD3/28 antibodies. (C) 2016 Elsevier B.V. All rights reserved. C1 [Davis, Ruth J.; Silvin, Christopher; Allen, Clint T.] Natl Inst Deafness & Other Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD USA. [Allen, Clint T.] Johns Hopkins Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD USA. RP Allen, CT (reprint author), NIH, Bldg 10,Room 7N240C, Bethesda, MD 20892 USA. EM clint.allen@nih.gov OI Davis, Ruth/0000-0001-9592-932X FU National Institute on Deafness and Other Communication Disorders intramural project [DC000087-01]; Johns Hopkins Specialized Program of Research Excellence (SPORE) Head and Neck Cancer Pilot Award FX This work was supported by National Institute on Deafness and Other Communication Disorders intramural project number DC000087-01 and by a Johns Hopkins Specialized Program of Research Excellence (SPORE) Head and Neck Cancer Pilot Award. We thank Drs. Jim Hodge, Nicole Schmitt and Zhong Chen for their critical reviews of this manuscript. NR 19 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 EI 1872-7905 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD JAN PY 2017 VL 440 BP 12 EP 18 DI 10.1016/j.jim.2016.11.006 PG 7 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA EH8TK UT WOS:000392045000002 PM 27856191 ER PT J AU Noro, R Ishigame, T Walsh, N Shiraishi, K Robles, AI Ryan, BM Schetter, AJ Bowman, ED Welsh, JA Seike, M Gemma, A Skaug, V Mollerup, S Haugen, A Yokota, J Kohno, T Harris, CC AF Noro, Rintaro Ishigame, Teruhide Walsh, Naomi Shiraishi, Kouya Robles, Ana I. Ryan, Brid M. Schetter, Aaron J. Bowman, Elise D. Welsh, Judith A. Seike, Masahiro Gemma, Akihiko Skaug, Vidar Mollerup, Steen Haugen, Aage Yokota, Jun Kohno, Takashi Harris, Curtis C. TI A Two-Gene Prognostic Classifier for Early-Stage Lung Squamous Cell Carcinoma in Multiple Large-Scale and Geographically Diverse Cohorts SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Lung squamous cell carcinoma; Prognostic classifier; Biomarker; Microarray; Gene expression ID GENE-EXPRESSION; CANCER CELLS; ADENOCARCINOMA; SIGNATURES; ACTININ-4; SURVIVAL; SMOKING; ACTN4; DUSP6; COPD AB Introduction: There are no validated molecular methods that prospectively identify patients with surgically resected lung squamous cell carcinoma (SCC) at high risk for recurrence. By focusing on the expression of genes with known functions in development of lung SCC and prognosis, we sought to develop a robust prognostic classifier of early stage lung SCC. Methods: The expression of 253 genes selected by literature search was evaluated in microarrays from 107 stage I/II tumors. Associations with survival were evaluated by Cox regression and Kaplan-Meier survival analyses in two independent cohorts of 121 and 91 patients with SCC, respectively. A classifier score based on multivariable Cox regression was derived and exam fined in six additional publicly available data sets of stage I/II lung SCC expression profiles (n = 358). The prognostic value of this classifier was evaluated in meta analysis of patients with stage I/II (n = 479) and stage I (n = 326) lung SCC. Results: Dual specificity phosphatase 6 gene (DUSP6) and actinin alpha 4 gene (ACTN4) were associated with prognostic outcome in two independent patient cohorts. Their expression values were utilized to develop a classifier that identified patients with stage I/II lung SCC at high risk for recurrence (hazard ratio [HR] = 4.7, p = 0.018) or cancer-specific mortality (HR = 3.5, p = 0.016). This classifier also identified patients at high risk for recurrence (HR = 2.7, p = 0.008) or death (HR = 2.2, p = 0.001) in publicly available data sets of stage I/II and in meta analysis of stage I patients. Conclusions: We have established and validated a prognostic classifier to inform clinical management of patients with lung SCC after surgical resection. Published by Elsevier Inc. on behalf of International Association for the Study of Lung Cancer. C1 [Noro, Rintaro; Ishigame, Teruhide; Walsh, Naomi; Robles, Ana I.; Ryan, Brid M.; Schetter, Aaron J.; Bowman, Elise D.; Welsh, Judith A.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. [Walsh, Naomi] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. [Shiraishi, Kouya; Kohno, Takashi] Natl Canc Ctr, Res Inst, Div Genome Biol, Tokyo 104, Japan. [Seike, Masahiro; Gemma, Akihiko] Nippon Med Sch, Grad Sch Med, Dept Pulm Med & Oncol, Tokyo, Japan. [Skaug, Vidar; Mollerup, Steen; Haugen, Aage] Natl Inst Occupat Hlth, Dept Chem & Biol Working Environm, Oslo, Norway. [Yokota, Jun] Inst Predict & Personalized Med Canc, Genom & Epigen Canc Predict Program, Barcelona, Spain. RP Harris, CC (reprint author), 37 Convent Dr,Rm 3068A,MSC 4258, Bethesda, MD 20892 USA. EM curtis_harris@nih.gov FU Intramural Research Program of the National Cancer Institute, National Institutes of Health; Department of Defense Congressionally Directed Medical Research Program [PR093793]; Health Research Board [CPFP/2012/2]; Norwegian Cancer Society; National Cancer Center Research and Development Fund [26A-1] FX This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, the Department of Defense Congressionally Directed Medical Research Program (Grant PR093793), the Health Research Board [CPFP/2012/2] (NW), the Norwegian Cancer Society, and the National Cancer Center Research and Development Fund (26A-1: NCC Biobank). The authors thank Ms. Yoko Shimada, Koji Tsuta, and Shun-ichi Watanabe for sample preparation. NR 48 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 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD JAN PY 2017 VL 12 IS 1 BP 65 EP 76 DI 10.1016/j.jtho.2016.08.141 PG 12 WC Oncology; Respiratory System SC Oncology; Respiratory System GA EH1IP UT WOS:000391518500008 PM 27613525 ER PT J AU Dominical, V Samsel, L Mccoy, JP AF Dominical, Venina Samsel, Leigh Mccoy, J. Philip, Jr. TI Masks in imaging flow cytometry SO METHODS LA English DT Article DE Imaging flow cytometry; Mask; Features; Data analysis; ImageStream ID DAMAGE; CELLS AB Data analysis in imaging flow cytometry incorporates elements of flow cytometry together with other aspects of morphological analysis of images. A crucial early step in this analysis is the creation of a mask to distinguish the portion of the image upon which further examination of specified features can be performed. Default masks are provided by the manufacturer of the imaging flow cytometer but additional custom masks can be created by the individual user for specific applications. Flawed or inaccurate masks can have a substantial negative impact on the overall analysis of a sample, thus great care must be taken to ensure the accuracy of masks. Here we discuss various types of masks and cite examples of their use. Furthermore we provide our insight for how to approach selecting and assessing the optimal mask for a specific analysis. Published by Elsevier Inc. C1 [Dominical, Venina; Samsel, Leigh; Mccoy, J. Philip, Jr.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Mccoy, JP (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM mccoyj@nhlbi.nih.gov FU Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, United States FX This work was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, United States. NR 18 TC 0 Z9 0 U1 4 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD JAN 1 PY 2017 VL 112 BP 9 EP 17 DI 10.1016/j.ymeth.2016.07.013 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EH6RK UT WOS:000391901400003 PM 27461256 ER PT J AU Hoogerheide, DP Gurnev, PA Rostovtseva, TK Bezrukov, SM AF Hoogerheide, David P. Gurnev, Philip A. Rostovtseva, Tatiana K. Bezrukov, Sergey M. TI Mechanism of alpha-synuclein translocation through a VDAC nanopore revealed by energy landscape modeling of escape time distributions SO NANOSCALE LA English DT Article ID DEPENDENT ANION CHANNEL; SOLID-STATE NANOPORE; POLYMER TRANSLOCATION; PARKINSONS-DISEASE; DNA TRANSLOCATION; 3 DECADES; MEMBRANE; HEMOLYSIN; PORE; MITOCHONDRIA AB We probe the energy landscape governing the passage of alpha-synuclein, a natural "diblock copolymer"-like polypeptide, through a nanoscale pore. alpha-Synuclein is an intrinsically disordered neuronal protein associated with Parkinson's pathology. The motion of this electrically heterogeneous polymer in the beta-barrel voltage-dependent anion channel (VDAC) of the mitochondrial outer membrane strongly depends on the properties of both the charged and uncharged regions of the alpha-synuclein polymer. We model this motion in two ways. First, a simple Markov model accounts for the transitions of the channel between the states of different occupancy by alpha-synuclein. Second, the detailed energy landscape of this motion can be accounted for using a drift-diffusion framework that incorporates the alpha-synuclein binding energy and the free energy cost of its confinement in the VDAC pore. The models directly predict the probability of alpha-synuclein translocation across the mitochondrial outer membrane, with immediate implications for the physiological role of alpha-synuclein in regulation of mitochondrial bioenergetics. Time-resolved measurements of the electrical properties of VDAC occupied by alpha-synuclein reveal distinct effects of the motion of the junction separating the differently charged regions of the polymer. C1 [Hoogerheide, David P.] NIST, Ctr Neutron Res, Gaithersburg, MD 20899 USA. [Gurnev, Philip A.; Rostovtseva, Tatiana K.; Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Transport, NIH, Bethesda, MD 20892 USA. RP Hoogerheide, DP (reprint author), NIST, Ctr Neutron Res, Gaithersburg, MD 20899 USA.; Bezrukov, SM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Transport, NIH, Bethesda, MD 20892 USA. EM david.hoogerheide@nist.gov; bezrukos@mail.nih.gov FU National Science Foundation [ACI-1053575]; NSF at the Pittsburgh Supercomputing Center (PSC) [ACI-1445606]; NIH/NIST Research Associateship Program through the National Academies of Sciences; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH FX This work used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation grant number ACI-1053575. Specifically, it used the Darter Cray XC30 system and the Bridges system, which is supported by NSF award number ACI-1445606, at the Pittsburgh Supercomputing Center (PSC). D. P. H. acknowledges support from the NIH/NIST Research Associateship Program through the National Academies of Sciences. P. A. G., T. K. R., and S. M. B. were supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. Certain commercial materials, equipment, and instruments are identified in this work to describe the experimental procedure as completely as possible. In no case does such an identification imply a recommendation or endorsement by NIST, nor does it imply that the materials, equipment, or instrument identified are necessarily the best available for the purpose. NR 52 TC 0 Z9 0 U1 3 U2 3 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2040-3364 EI 2040-3372 J9 NANOSCALE JI Nanoscale PY 2017 VL 9 IS 1 BP 183 EP 192 DI 10.1039/c6nr08145b PG 10 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA EH4KE UT WOS:000391739300024 PM 27905618 ER PT J AU Williamson, PR Jarvis, JN Panackal, AA Fisher, MC Molloy, SF Loyse, A Harrison, TS AF Williamson, Peter R. Jarvis, Joseph N. Panackal, Anil A. Fisher, Matthew C. Molloy, Sile F. Loyse, Angela Harrison, Thomas S. TI Cryptococcal meningitis: epidemiology, immunology, diagnosis and therapy SO NATURE REVIEWS NEUROLOGY LA English DT Review ID RECONSTITUTION INFLAMMATORY SYNDROME; HIV-INFECTED PATIENTS; HIGH-DOSE FLUCONAZOLE; RANDOMIZED CONTROLLED-TRIAL; PULMONARY ALVEOLAR PROTEINOSIS; ORGAN TRANSPLANT RECIPIENTS; AMPHOTERICIN-B DEOXYCHOLATE; RESOURCE-LIMITED SETTINGS; ANTIRETROVIRAL THERAPY; CEREBROSPINAL-FLUID AB HIV-associated cryptococcal meningitis is by far the most common cause of adult meningitis in many areas of the world that have high HIV seroprevalence. In most areas in Sub-Saharan Africa, the incidence of cryptococcal meningitis is not decreasing despite availability of antiretroviral therapy, because of issues of adherence and retention in HIV care. In addition, cryptococcal meningitis in HIV-seronegative individuals is a substantial problem: the risk of cryptococcal infection is increased in transplant recipients and other individuals with defects in cell-mediated immunity, and cryptococcosis is also reported in the apparently immunocompetent. Despite therapy, mortality rates in these groups are high. Over the past 5 years, advances have been made in rapid point-of-care diagnosis and early detection of cryptococcal antigen in the blood. These advances have enabled development of screening and pre-emptive treatment strategies aimed at preventing the development of clinical infection in patients with late-stage HIV infection. Progress in optimizing antifungal combinations has been aided by evaluation of the clearance rate of infection by using serial quantitative cultures of cerebrospinal fluid (CSF). Measurement and management of raised CSF pressure, a common complication, is a vital component of care. In addition, we now better understand protective immune responses in HIV-associated cases, immunogenetic predisposition to infection, and the role of immune-mediated pathology in patients with non-HIV associated infection and in the context of HIV-associated immune reconstitution reactions. C1 [Williamson, Peter R.; Panackal, Anil A.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Jarvis, Joseph N.] Botswana Univ Penn Partnership, POB AC157AC, Gaborone, Botswana. [Fisher, Matthew C.] Imperial Coll Sch Publ Hlth, Dept Infect Dis Epidemiol, St Marys Campus,Norfolk Pl, London W2 1PG, England. [Molloy, Sile F.; Loyse, Angela; Harrison, Thomas S.] St Georges Univ London, Inst Infect & Immun, Cranmer Terrace, London SW17 ORE, England. RP Harrison, TS (reprint author), St Georges Univ London, Inst Infect & Immun, Cranmer Terrace, London SW17 ORE, England. EM tharriso@sgul.ac.uk FU Gilead Sciences FX P.W. has a CRADA (cooperative research and development agreement) with Matinas BioPharma regarding an oral amphotericin formulation. J.J. has received an Investigator Award (to institution) from Gilead Sciences. T.H. has received an Investigator Award (to institution) from Gilead Sciences and has received a donation of cryptococcosis test kits for research purposes from Immuno-Mycologics, received honoraria from Pfizer, and is on the advisory board for Viamet. NR 144 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 1759-4758 EI 1759-4766 J9 NAT REV NEUROL JI Nat. Rev. Neurol. PD JAN PY 2017 VL 13 IS 1 BP 13 EP 24 DI 10.1038/nrneurol.2016.167 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA EH8SM UT WOS:000392042600005 PM 27886201 ER PT J AU Frankl, J Piaggi, P Foley, JE Krakoff, J Votruba, SB AF Frankl, Joseph Piaggi, Paolo Foley, James E. Krakoff, Jonathan Votruba, Susanne B. TI In Vitro Lipolysis is Associated with Whole-Body Lipid Oxidation and Weight Gain in Humans SO OBESITY LA English DT Article ID FAT-CELL LIPOLYSIS; ENERGY-EXPENDITURE; CARBOHYDRATE OXIDATION; RESPIRATORY CHAMBER; INSULIN-RESISTANCE; DETERMINANTS; OBESITY; DIET; ADIPOCYTES; PREDICTORS AB Objective: To assess the association of adipocyte size with cellular lipolysis and between cellular lipolysis and whole-body lipid oxidation. This study also assessed the association between adipocyte size and cellular lipolysis with weight and fat mass gain. Methods: Subjects had assessment of percent body fat (% fat) and adipose tissue biopsy for in vitro lipolysis (n = 325), and a subset of subjects had measurement of whole-body lipid oxidation (n = 112). A subset of subjects (n = 243) returned for repeated measurements of body weight and composition (mean follow-up 8.2 +/- 5.5 years). Results: In vitro lipolysis (r = 0.47, P < 0.0001) and adipocyte size (r = 0.49, P < 0.0001) were strongly associated with % fat. In vitro lipolysis (P = 0.04) but not adipocyte size (P = 0.44) was associated with whole-body fat oxidation. Adipocyte size was not associated with rate of percent weight gain (P = 0.20) but was negatively associated with rate of percent fat mass gain (P = 0.01). In vitro lipolysis was negatively associated with rate of percent weight gain (P = 0.02) and had a marginal negative association with rate of percent fat mass gain (P = 0.08). Conclusions: These results indicate inherent characteristics of adipocytes, including size and lipolytic activity, may be important determinants of whole-body lipid oxidation and subsequent weight gain. C1 [Frankl, Joseph] Natl Inst Diabet & Digest & Kidney Dis, Obes & Diabet Clin Res Sect, NIH, Phoenix, AZ USA. [Frankl, Joseph; Piaggi, Paolo; Foley, James E.; Krakoff, Jonathan; Votruba, Susanne B.] Univ Arizona, Coll Med, Tucson, AZ USA. [Foley, James E.] Novartis Pharmaceut, World Wide Med Affairs, E Hanover, NJ USA. RP Frankl, J (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Obes & Diabet Clin Res Sect, NIH, Phoenix, AZ USA.; Frankl, J (reprint author), Univ Arizona, Coll Med, Tucson, AZ USA. EM jfrankl@email.arizona.edu OI Frankl, Joseph/0000-0002-0156-3150 FU Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. NR 30 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD JAN PY 2017 VL 25 IS 1 BP 207 EP 214 DI 10.1002/oby.21670 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA EG7GU UT WOS:000391215200026 PM 27868388 ER PT J AU Bernardi, LA Carnethon, MR de Chavez, PJ Ikhena, DE Neff, LM Baird, DD Marsh, EE AF Bernardi, Lia A. Carnethon, Mercedes R. de Chavez, Peter J. Ikhena, Deborah E. Neff, Lisa M. Baird, Donna D. Marsh, Erica E. TI Relationship Between Obesity and Anti-Mullerian Hormone in Reproductive-Aged African American Women SO OBESITY LA English DT Article ID POLYCYSTIC-OVARY-SYNDROME; IN-VITRO FERTILIZATION; BODY-MASS INDEX; ANTIMULLERIAN HORMONE; GENE-EXPRESSION; RESERVE; OVERWEIGHT; WEIGHT; PREGNANCY; COHORT AB Objective: To determine whether there is an association between obesity and anti-Mullerian hormone (AMH) among reproductive-aged African American women (AAW). Methods: From the women participating in an ongoing National Institute of Environmental Health Sciences study, 1,654 AAW aged 23 to 35 were included in this study. Anthropometric measurements, personal health information, and serum AMH and adipokine levels were analyzed. Results: The median body mass index (BMI) was 32.4 kg/m(2), and the median AMH was 3.18 ng/mL. Participants with obesity had AMH concentrations that were 23.7% lower than those with a BMI <= 25 kg/m(2) (2.9 ng/mL vs. 3.8 ng/mL). In multivariable linear regression models, current BMI (beta = -0.015; 95% CI -0.021 to -0.009), BMI at age 18 (beta = -0.016; 95% CI -0.024 to -0.008), heaviest reported lifetime weight (beta = -0.002; 95% CI -0.003 to -0.001), and leptin (beta = -0.016; 95% CI -0.025 to -0.007) were inversely associated with AMH. There was no significant association between adiponectin and AMH. AMH was significantly lower (mean log = 0.91, SE = 0.11) in participants with obesity at age 18 and at enrollment when compared with those who were underweight or normal weight at age 18 but had obesity at enrollment (mean log = 1.16, SE = 0.12). Conclusions: In reproductive-aged AAW there is a significant association between obesity and AMH, suggesting that excess adiposity may compromise ovarian reserve. Effects of obesity on AMH may be cumulative. C1 [Bernardi, Lia A.; Ikhena, Deborah E.; Marsh, Erica E.] Northwestern Univ, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Feinberg Sch Med, Chicago, IL 60611 USA. [Carnethon, Mercedes R.; de Chavez, Peter J.] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Neff, Lisa M.] Northwestern Univ, Dept Med, Div Endocrinol Metab & Mol Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Baird, Donna D.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Marsh, EE (reprint author), Northwestern Univ, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Feinberg Sch Med, Chicago, IL 60611 USA. EM erica-marsh@northwestern.edu RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 FU Woman's Board of Northwestern Memorial Hospital Grant; National Institutes of Health NICHD [P01HD57877, R21 HD077479-01]; NIH [K12HD050121]; RWJF Harold Amos Medical Faculty Development Award; Friends of Prentice Women's Health Research Award; Evergreen Invitational Women's Health Grants Initiative; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences; American Recovery and Reinvestment Act FX The Woman's Board of Northwestern Memorial Hospital Grant (to LAB), the National Institutes of Health NICHD (Grants P01HD57877 and R21 HD077479-01) (to EEM), NIH K12HD050121 (to EEM), RWJF Harold Amos Medical Faculty Development Award (to EEM), the Friends of Prentice Women's Health Research Award (to EEM), the Evergreen Invitational Women's Health Grants Initiative (to EEM), and in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences along with funds allocated for health research by the American Recovery and Reinvestment Act (to DDB). NR 39 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD JAN PY 2017 VL 25 IS 1 BP 229 EP 235 DI 10.1002/oby.21681 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA EG7GU UT WOS:000391215200029 PM 27925445 ER PT J AU Facco, FL Parker, CB Reddy, UM Silver, RM Koch, MA Louis, JM Basner, RC Chung, JH Nhan-Chang, CL Pien, GW Redline, S Grobman, WA Wing, DA Simhan, HN Haas, DM Mercer, BM Parry, S Mobley, D Hunter, S Saade, GR Schubert, FP Zee, PC AF Facco, Francesca L. Parker, Corette B. Reddy, Uma M. Silver, Robert M. Koch, Matthew A. Louis, Judette M. Basner, Robert C. Chung, Judith H. Nhan-Chang, Chia-Ling Pien, Grace W. Redline, Susan Grobman, William A. Wing, Deborah A. Simhan, Hyagriv N. Haas, David M. Mercer, Brian M. Parry, Samuel Mobley, Daniel Hunter, Shannon Saade, George R. Schubert, Frank P. Zee, Phyllis C. TI Association Between Sleep-Disordered Breathing and Hypertensive Disorders of Pregnancy and Gestational Diabetes Mellitus SO OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 35th Annual Scientific Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine (SMFM) CY FEB 02-07, 2015 CL San Diego, CA SP Soc Maternal Fetal Med ID POSITIVE AIRWAY PRESSURE; NASAL CPAP; PORTABLE MONITORS; BLOOD-PRESSURE; RISK-FACTORS; APNEA; PREECLAMPSIA; TRIAL; DIAGNOSIS; COMPLICATIONS AB OBJECTIVE: To estimate whether sleep-disordered breathing during pregnancy is a risk factor for the development of hypertensive disorders of pregnancy and gestational diabetes mellitus (GDM). METHODS: In this prospective cohort study, nulliparous women underwent in-home sleep-disordered breathing assessments in early (6-15 weeks of gestation) and midpregnancy (22-31 weeks of gestation). Participants and health care providers were blinded to the sleep test results. An apnea-hypopnea index of 5 or greater was used to define sleep-disordered breathing. Exposure-response relationships were examined, grouping participants into four apnea-hypopnea index groups: 0, greater than 0 to less than 5, 5 to less than 15, and 15 or greater. The study was powered to test the primary hypothesis that sleep-disordered breathing occurring in pregnancy is associated with an increased incidence of preeclampsia. Secondary outcomes were rates of hypertensive disorders of pregnancy, defined as preeclampsia and antepartum gestational hypertension, and GDM. Crude and adjusted odds ratios and 95% confidence intervals (CIs) were calculated from univariate and multivariate logistic regression models. RESULTS: Three thousand seven hundred five women were enrolled. Apnea-hypopnea index data were available for 3,132 (84.5%) and 2,474 (66.8%) women in early and midpregnancy, respectively. The corresponding prevalence of sleep-disordered breathing was 3.6% and 8.3%. The prevalence of preeclampsia was 6.0%, hypertensive disorders of pregnancy 13.1%, and GDM 4.1%. In early and midpregnancy the adjusted odds ratios for preeclampsia when sleep-disordered breathing was present were 1.94 (95% CI 1.07-3.51) and 1.95 (95% CI 1.18-3.23), respectively; hypertensive disorders of pregnancy 1.46 (95% CI 0.91-2.32) and 1.73 (95% CI 1.192.52); and GDM 3.47 (95% CI 1.95-6.19) and 2.79 (95% CI 1.63-4.77). Increasing exposure-response relationships were observed between apnea-hypopnea index and both hypertensive disorders and GDM. CONCLUSION: There is an independent association between sleep-disordered breathing and preeclampsia, hypertensive disorders of pregnancy, and GDM. C1 Univ Pittsburgh, Pittsburgh, PA USA. Univ Penn, Philadelphia, PA 19104 USA. RTI Int, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. Univ Utah, Salt Lake City, UT USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Columbia Univ, New York, NY USA. Univ Calif Irvine, Irvine, CA USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Harvard Med Sch, Boston, MA USA. Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. Northwestern Univ, Chicago, IL 60611 USA. Indiana Univ, Bloomington, IN USA. Univ Texas Med Branch, Galveston, TX 77555 USA. RP Facco, FL (reprint author), Magee Womens Hosp, 300 Halket St,Room 2233, Pittsburgh, PA 15213 USA. EM faccof@upmc.edu FU Jazz; Eisai; Philips; Technogel FX Dr. Zee has served as a consultant for Aptalis, Merck, EISAI, Philips, Vanda, and Pernix. She has received research support (grants to Northwestern University) from Jazz, Eisai, Philips, and Technogel. She also owns stock in Teva. The other authors did not report any potential conflicts of interest. NR 42 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 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JAN PY 2017 VL 129 IS 1 BP 31 EP 41 DI 10.1097/AOG.0000000000001805 PG 11 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EH7KO UT WOS:000391951900005 PM 27926645 ER PT J AU Joseph, KS Lisonkova, S Muraca, GM Razaz, N Sabr, Y Mehrabadi, A Schisterman, EF AF Joseph, K. S. Lisonkova, Sarka Muraca, Giulia M. Razaz, Neda Sabr, Yasser Mehrabadi, Azar Schisterman, Enrique F. TI Factors Underlying the Temporal Increase in Maternal Mortality in the United States SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID PREGNANCY-RELATED MORTALITY; TRENDS AB OBJECTIVE: To identify the factors underlying the recent increase in maternal mortality ratios (maternal deaths per 100,000 live births) in the United States. METHODS: We carried out a retrospective study with data on maternal deaths and live births in the United States from 1993 to 2014 obtained from the birth and death files of the Centers for Disease Control and Prevention. Underlying causes of death were examined between 1999 and 2014 using International Classification of Diseases, 10th Revision (ICD-10) codes. Poisson regression was used to estimate maternal mortality rate ratios (RRs) and 95% confidence intervals (CIs) after adjusting for the introduction of a separate pregnancy question and the standard pregnancy checkbox on death certificates and adoption of ICD-10. RESULTS: Maternal mortality ratios increased from 7.55 in 1993, to 9.88 in 1999, and to 21.5 per 100,000 live births in 2014 (RR 2014 compared with 1993 2.84, 95% CI 2.49-3.24; RR 2014 compared with 1999 2.17, 95% CI 1.93-2.45). The increase in maternal deaths from 1999 to 2014 was mainly the result of increases in maternal deaths associated with two new ICD-10 codes (O26.8, ie, primarily renal disease; and O99, ie, other maternal diseases classifiable elsewhere); exclusion of such deaths abolished the increase in mortality (RR 1.09, 95% CI 0.94-1.27). Regression adjustment for improvements in surveillance also abolished the temporal increase in maternal mortality ratios (adjusted maternal mortality ratios 7.55 in 1993, 8.00 per 100,000 live births in 2013; adjusted RR 2013 compared with 1993 1.06, 95% CI 0.90-1.25). CONCLUSION: Recent increases in maternal mortality ratios in the United States are likely an artifact of improvements in surveillance and highlight past under-estimation of maternal death. Complete ascertainment of maternal death in populations remains a challenge even in countries with good systems for civil registration and vital statistics. C1 Univ British Columbia, Dept Obstet & Gynaecol, Vancouver, BC, Canada. Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC, Canada. Womens & Childrens Hosp, Vancouver, BC, Canada. Hlth Ctr British Columbia, Vancouver, BC, Canada. King Saud Univ, Coll Med, Dept Obstet & Gynaecol, Riyadh, Saudi Arabia. McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD USA. RP Joseph, KS (reprint author), Womens Hosp British Columbia, Dept Obstet & Gynaecol, Room C403,4500 Oak St, Vancouver, BC V6H 3N1, Canada. EM kjoseph@cw.bc.ca OI Schisterman, Enrique/0000-0003-3757-641X FU Vanier Canada Graduate Scholarship; Canadian Institutes of Health Research (CIHR) [MAH-15445]; British Columbia Children's Hospital Research Institute FX Ms. Muraca is the recipient of a Vanier Canada Graduate Scholarship and is also supported by a Canadian Institutes of Health Research (CIHR) grant on severe maternal morbidity (MAH-15445). Dr. Joseph is supported by the British Columbia Children's Hospital Research Institute and holds a CIHR Chair in maternal, fetal, and infant health services research (APR-126338). 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 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JAN PY 2017 VL 129 IS 1 BP 91 EP 100 DI 10.1097/AOG.0000000000001810 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EH7KO UT WOS:000391951900012 PM 27926651 ER PT J AU Brouwer, M Schinasi, L Freeman, LEB Baldi, I Lebailly, P Ferro, G Nordby, KC Schuz, J Leon, ME Kromhout, H AF Brouwer, Maartje Schinasi, Leah Freeman, Laura E. Beane Baldi, Isabelle Lebailly, Pierre Ferro, Gilles Nordby, Karl-Christian Schuz, Joachim Leon, Maria E. Kromhout, Hans TI Assessment of occupational exposure to pesticides in a pooled analysis of agricultural cohorts within the AGRICOH consortium: authors' response SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Letter C1 [Brouwer, Maartje; Kromhout, Hans] Univ Utrecht, IRAS, Div Environm Epidemiol, POB 80-178, NL-3584 TD Utrecht, Netherlands. [Schinasi, Leah; Ferro, Gilles; Schuz, Joachim; Leon, Maria E.] IARC, Sect Environm & Radiat, Lyon, France. [Freeman, Laura E. Beane] NCI, Occupat & Environm Epidemiol Branch, Bethesda, MD 20892 USA. [Baldi, Isabelle] Univ Bordeaux, ISPED, Lab Sante Travail Environm, Bordeaux, France. [Baldi, Isabelle] INSERM, Epidemiol Biostat, Bordeaux, France. [Baldi, Isabelle] CHU Bordeaux, Serv Med Travail, Bordeaux, France. [Lebailly, Pierre] INSERM, Canc & Prevent, Caen, France. [Lebailly, Pierre] Univ Caen Basse Normandie, Canc & Prevent, Caen, France. [Lebailly, Pierre] Ctr Lutte Canc Francois Baclesse, Caen, France. [Nordby, Karl-Christian] Natl Inst Occupat Hlth STAMI, Dept Occupat Med & Epidemiol, Oslo, Norway. RP Kromhout, H (reprint author), Univ Utrecht, IRAS, Div Environm Epidemiol, POB 80-178, NL-3584 TD Utrecht, Netherlands. EM h.kromhout@uu.nl RI Beane Freeman, Laura/C-4468-2015 OI Beane Freeman, Laura/0000-0003-1294-4124 NR 6 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 1351-0711 EI 1470-7926 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD JAN PY 2017 VL 74 IS 1 BP 82 EP 82 DI 10.1136/oemed-2016-104110 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EH0OH UT WOS:000391463000015 PM 27852645 ER PT J AU Michaliszyn, SF Sjaarda, LA Scifres, C Simhan, H Arslanian, SA AF Michaliszyn, Sara F. Sjaarda, Lindsey A. Scifres, Christina Simhan, Hyagriv Arslanian, Silva A. TI Maternal excess gestational weight gain and infant waist circumference: a 2-y observational study SO PEDIATRIC RESEARCH LA English DT Article ID FORMULA-FED INFANTS; BODY-MASS INDEX; ADIPOSITY; GROWTH; BMI; CHILDHOOD; OBESITY; RISK; ASSOCIATIONS; OVERWEIGHT AB BACKGROUND: The purpose of this study was to examine the effects of gestational weight gain (GWG) and infant feeding practices on infant growth parameters in infants from 6 to 24 mo of age. METHODS: Forty mother infant pairs were recruited after delivery and followed up to 24 mo postpartum. GWG was calculated as prepregnancy weight subtracted from weight at delivery. Infant weight velocity was calculated as the change in weight between consecutive visits divided by the intervening time. Infant feeding practices were measured by interview and infant growth and waist circumference by standard anthropometry. RESULTS: Infants born to mothers with excess GWG were heavier at birth (3,521 91 vs. 3,196 +/- 97 g, P = 0.02) and had an average 2.16 +/- 1.1 cm (P = 0.03) larger waist circumference throughout the 24 mo compared with infants born to mothers with appropriate GWG. Waist circumference increased by 0.12 and 2.0 cm for every 1 unit increase in GWG and infant birth weight. CONCLUSION: Infants born to women who exceeded the Institute of Medicine (IOM)-recommended guidelines for GWG were heavier at birth and had a significantly higher waist circumference up to 2 y of age. Strategies to control maternal excess GWG and thus the outcome on infant birth weight and waist circumference should be pursued. C1 [Michaliszyn, Sara F.] Youngstown State Univ, Human Performance & Exercise Sci, Youngstown, OH 44555 USA. [Sjaarda, Lindsey A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. [Scifres, Christina] Univ Oklahoma, Coll Med, Norman, OK 73019 USA. [Simhan, Hyagriv] Univ Pittsburgh, Sch Med, Div Maternal Fetal Med, Pittsburgh, PA USA. [Arslanian, Silva A.] Childrens Hosp Pittsburgh, Div Weight Management & Wellness, Pittsburgh, PA 15213 USA. [Arslanian, Silva A.] Childrens Hosp Pittsburgh, Div Pediat Endocrinol Metab & Diabet Mellitus, Pittsburgh, PA 15213 USA. RP Michaliszyn, SF (reprint author), Youngstown State Univ, Human Performance & Exercise Sci, Youngstown, OH 44555 USA. EM sbmichaliszyn@ysu.edu OI Michaliszyn, Sara/0000-0002-1176-9187 FU Thrasher Research Fund FX This project was supported by Thrasher Research Fund. NR 23 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 0031-3998 EI 1530-0447 J9 PEDIATR RES JI Pediatr. Res. PD JAN PY 2017 VL 81 IS 1 BP 63 EP 67 DI 10.1038/pr.2016.174 PN 1 PG 5 WC Pediatrics SC Pediatrics GA EH6TM UT WOS:000391906800010 PM 27632776 ER PT J AU Dripps, IJ Wang, Q Neubig, RR Rice, KC Traynor, JR Jutkiewicz, EM AF Dripps, Isaac J. Wang, Qin Neubig, Richard R. Rice, Kenner C. Traynor, John R. Jutkiewicz, Emily M. TI The role of regulator of G protein signaling 4 in delta-opioid receptor-mediated behaviors SO PSYCHOPHARMACOLOGY LA English DT Article DE Delta opioid receptor; Regulator of G protein signaling 4; Mice; Antinociception; Antidepressant; Convulsion ID TAIL-SUSPENSION TEST; DIFFERENTIAL MODULATION; AGONIST SNC80; MICE; RATS; ANTIDEPRESSANTS; ANTINOCICEPTION; INTERNALIZATION; CONVULSIONS; DEPRESSION AB Rationale Regulator of G protein signaling (RGS) proteins act as negative modulators of G protein signaling. RGS4 has been shown to negatively modulate G protein signaling mediated by the delta opioid receptor (DOPr) in vitro. However, the role of RGS4 in modulating DOPr-mediated behaviors in vivo has not been elucidated. The aim of this study was to compare the ability of the DOPr agonist SNC80 to induce DOPr-mediated antinociception, antihyperalgesia, antidepressant-like effects, and convulsions in wild-type and RGS4 knockout mice. Antinociception was assessed in the acetic acid stretch assay. Antihyperalgesia was measured in a nitroglycerin-induced thermal hyperalgesia assay. Antidepressant-like effects were evaluated in the forced swim and tail suspension tests. Mice were also observed for convulsive activity post-SNC80 treatment. SNC80-induced phosphorylation of MAP kinase in striatal tissue from RGS4 wild-type and knockout mice was quantified by Western blot. DOPr number from forebrain tissue was measured using [H-3]DPDPE saturation binding. Elimination of RGS4 potentiated SNC80-induced antinociception and antihyperalgesia. SNC80-induced antidepressant-like effects were potentiated in RGS4 knockout mice in the forced swim test but not in the tail suspension test. Additionally, RGS4 knockout did not alter SNC80-induced convulsions. SNC80-induced phosphorylation of MAP kinase was potentiated in striatum from RGS4 knockout mice. Loss of RGS4 did not affect total DOPr number. Overall, these findings demonstrate that reduction of RGS4 functionally may increase the therapeutic index of SNC80. These results provide the first evidence of differential regulation of DOPr-mediated behaviors by RGS proteins and G protein signaling pathways. C1 [Dripps, Isaac J.; Wang, Qin; Traynor, John R.; Jutkiewicz, Emily M.] Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA. [Neubig, Richard R.] Michigan State Univ, Dept Pharmacol & Toxicol, E Lansing, MI 48824 USA. [Rice, Kenner C.] NIDA, Drug Design & Synth Sect, Mol Targets & Medicat Discovery Branch, Rockville, MD USA. RP Jutkiewicz, EM (reprint author), Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA. EM ejutkiew@umich.edu FU PhRMA Foundation; University of Michigan Medical School; National Institute on Drug Abuse [DA 035316]; Intramural Research Program of the National Institute of Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; NIH [DA RO1 023252] FX Part of this work was funded by a PhRMA Foundation Research Starter Grant awarded to EMJ and funds from the University of Michigan Medical School. She has consulted for Trevena, Inc., in 2011-2012 with compensation. JRT has no conflicts and is supported by the National Institute on Drug Abuse grant DA 035316. This study was also supported in part by the Intramural Research Program of the National Institute of Alcohol Abuse and Alcoholism and by the National Institute on Drug Abuse (KCR). RRN is founder and owner of Argessin LLC which holds a license for small-molecule RGS inhibitors and is supported by NIH DA RO1 023252. 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 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JAN PY 2017 VL 234 IS 1 BP 29 EP 39 DI 10.1007/s00213-016-4432-5 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EG9EP UT WOS:000391361500004 PM 27624599 ER PT J AU Yoshimoto, R Kaida, D Furuno, M Burroughs, AM Noma, S Suzuki, H Kawamura, Y Hayashizaki, Y Mayeda, A Yoshida, M AF Yoshimoto, Rei Kaida, Daisuke Furuno, Masaaki Burroughs, A. Maxwell Noma, Shohei Suzuki, Harukazu Kawamura, Yumi Hayashizaki, Yoshihide Mayeda, Akila Yoshida, Minoru TI Global analysis of pre-mRNA subcellular localization following splicing inhibition by spliceostatin A SO RNA LA English DT Article DE pre-mRNA splicing; spliceostatin A; RNA-seq; pre-mRNA nuclear retention ID ANTITUMOR SUBSTANCES; NUCLEAR RETENTION; PHYSICOCHEMICAL PROPERTIES; GENE-EXPRESSION; PLADIENOLIDES; FR901464; SEQUENCE; CULTURE; YEAST; SF3B AB Spliceostatin A (SSA) is a methyl ketal derivative of FR901464, a potent antitumor compound isolated from a culture broth of Pseudomonas sp. no. 2663. These compounds selectively bind to the essential spliceosome component SF3b, a subcomplex of the U2 snRNP, to inhibit pre-mRNA splicing. However, the mechanism of SSA's antitumor activity is unknown. It is noteworthy that SSA causes accumulation of a truncated form of the CDK inhibitor protein p27 translated from CDKN1B premRNA, which is involved in SSA-induced cell-cycle arrest. However, it is still unclear whether pre-mRNAs are uniformly exported from the nucleus following SSA treatment. We performed RNA-seq analysis on nuclear and cytoplasmic fractions of SSA-treated cells. Our statistical analyses showed that intron retention is the major consequence of SSA treatment, and a small number of intron-containing pre-mRNAs leak into the cytoplasm. Using a series of reporter plasmids to investigate the roles of intronic sequences in the pre-mRNA leakage, we showed that the strength of the 5' splice site affects pre-mRNA leakage. Additionally, we found that the level of pre-mRNA leakage is related to transcript length. These results suggest that the strength of the 5' splice site and the length of the transcripts are determinants of the pre-mRNA leakage induced by SF3b inhibitors. C1 [Yoshimoto, Rei; Kaida, Daisuke; Kawamura, Yumi; Yoshida, Minoru] RIKEN, Chem Genet Lab, Wako, Saitama 3510198, Japan. [Yoshimoto, Rei; Mayeda, Akila] Fujita Hlth Univ, Inst Comprehens Med Sci, Div Gene Express Mech, Kutsukake Cho, Toyoake, Aichi 4701192, Japan. [Kaida, Daisuke] Toyama Univ, Frontier Res Core Life Sci, Toyama, Toyama 9300194, Japan. [Kaida, Daisuke] Toyama Univ, Grad Sch Med & Pharmaceut Sci, Toyama, Toyama 9300194, Japan. [Furuno, Masaaki; Burroughs, A. Maxwell; Noma, Shohei; Suzuki, Harukazu] RIKEN, Ctr Life Sci Technol, Div Genom Technol, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan. [Burroughs, A. Maxwell] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Hayashizaki, Yoshihide] RIKEN, Prevent Med & Diag Innovat Program PMI, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan. [Yoshida, Minoru] Japan Sci & Technol Corp, CREST Res Project, Kawaguchi, Saitama 3320012, Japan. RP Kaida, D; Yoshida, M (reprint author), RIKEN, Chem Genet Lab, Wako, Saitama 3510198, Japan.; Kaida, D (reprint author), Toyama Univ, Frontier Res Core Life Sci, Toyama, Toyama 9300194, Japan.; Kaida, D (reprint author), Toyama Univ, Grad Sch Med & Pharmaceut Sci, Toyama, Toyama 9300194, Japan.; Yoshida, M (reprint author), Japan Sci & Technol Corp, CREST Res Project, Kawaguchi, Saitama 3320012, Japan. EM kaida@med.u-toyama.ac.jp; yoshidam@riken.jp RI Hayashizaki, Yoshihide/N-6590-2015 FU Ministry of Education, Culture, Sports, Science and Technology of Japan; Japan Science and Technology Corporation, the CREST Research Project; Hori Information Science Promotion Foundation FX This work was supported in part by Grants-in-Aid for Scientific Research (S) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (M.Y.), the Japan Science and Technology Corporation, the CREST Research Project (M.Y.), and the Hori Information Science Promotion Foundation (R.Y.). We also thank Dr. Yuko Kimura and Dr. Shinichi Nakagawa for discussions and careful reading of the manuscript. NR 47 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 JAN PY 2017 VL 23 IS 1 BP 47 EP 57 DI 10.1261/rna.058065.116 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EH3QP UT WOS:000391687100006 PM 27754875 ER PT J AU Mead, B Logan, A Berry, M Leadbeater, W Scheven, BA AF Mead, Ben Logan, Ann Berry, Martin Leadbeater, Wendy Scheven, Ben A. TI Concise Review: Dental Pulp Stem Cells: A Novel Cell Therapy for Retinal and Central Nervous System Repair SO STEM CELLS LA English DT Review DE Dental pulp stem cells; mesenchymal stem cells; nerve repair; neural regeneration; retinal ganglion cells; CNS; glaucoma; optic nerve ID EXFOLIATED DECIDUOUS TEETH; FUNCTIONALLY ACTIVE NEURONS; RAT SPINAL-CORD; IN-VITRO; AXON REGENERATION; GANGLION-CELLS; BONE-MARROW; PROMOTE; DIFFERENTIATION; TRANSPLANTATION AB Dental pulp stem cells (DPSC) are neural crest-derived ecto-mesenchymal stem cells that can relatively easily and non-invasively be isolated from the dental pulp of extracted postnatal and adult teeth. Accumulating evidence suggests that DPSC have great promise as a cellular therapy for central nervous system (CNS) and retinal injury and disease. The mode of action by which DPSC confer therapeutic benefit may comprise multiple pathways, in particular, paracrine-mediated processes which involve a wide array of secreted trophic factors and is increasingly regarded as the principal predominant mechanism. In this concise review, we present the current evidence for the use of DPSC to repair CNS damage, including recent findings on retinal ganglion cell neuroprotection and regeneration in optic nerve injury and glaucoma. C1 [Mead, Ben; Scheven, Ben A.] Univ Birmingham, Coll Med & Dent Sci, Sch Dent, Oral Biol, Birmingham, W Midlands, England. [Mead, Ben; Logan, Ann; Berry, Martin; Leadbeater, Wendy] Univ Birmingham, Sch Clin & Expt Med, Neurotrauma & Neurobiol Res Grp, Birmingham, W Midlands, England. [Mead, Ben] NEI, Sect Retinal Gangl Cell Biol, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Scheven, BA (reprint author), Univ Birmingham, Coll Med & Dent Sci, Sch Dent, 5 Mill Pool, Birmingham B5 7EG, W Midlands, England. EM b.a.scheven@bham.ac.uk FU Rosetrees Trust; BBSRC [BB/F017553/1] FX This work was supported by The Rosetrees Trust and BBSRC (BB/F017553/1). NR 47 TC 0 Z9 0 U1 7 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD JAN PY 2017 VL 35 IS 1 BP 61 EP 67 DI 10.1002/stem.2398 PG 7 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA EH7QD UT WOS:000391966700009 PM 27273755 ER PT J AU Jarolim, P Claggett, BL Conrad, MJ Carpenter, MA Ivanova, A Bostom, AG Kusek, JW Hunsicker, LG Jacques, PF Gravens-Mueller, L Finn, P Solomon, SD Weiner, DE Levey, AS Pfeffer, MA AF Jarolim, Petr Claggett, Brian L. Conrad, Michael J. Carpenter, Myra A. Ivanova, Anastasia Bostom, Andrew G. Kusek, John W. Hunsicker, Lawrence G. Jacques, Paul F. Gravens-Mueller, Lisa Finn, Peter Solomon, Scott D. Weiner, Daniel E. Levey, Andrew S. Pfeffer, Marc A. TI B-Type Natriuretic Peptide and Cardiac Troponin I Are Associated With Adverse Outcomes in Stable Kidney Transplant Recipients SO TRANSPLANTATION LA English DT Article ID HIGH-SENSITIVITY TROPONIN; CORONARY-HEART-DISEASE; DIABETES-MELLITUS; PREDICTIVE-VALUE; DIAGNOSTIC PERFORMANCE; 99TH PERCENTILE; FOLIC-ACID; T LEVELS; ASSAY; POPULATION AB Background. Approximately 200 000 kidney transplant recipients are living in the United States; they are at increased risk for cardiovascular and other adverse outcomes. Biomarkers predicting these outcomes are needed. Using specimens collected during the Folic Acid for Vascular Outcome Reduction in Transplantation trial, we determined whether plasma levels of B-type natriuretic peptide (BNP) and cardiac troponin I are associated with adverse outcomes in stable kidney transplant recipients. Methods. Five hundred ten subjects were selected randomly from the 4110 Folic Acid for Vascular Outcome Reduction in Transplantation participants. This cohort was then enriched for all additional subjects with adverse outcomes (death, dialysis-dependent kidney failure (DDKF), and cardiovascular outcomes) for a total of 1131 participants studied. Quartiles of BNP and high-sensitivity cardiac troponin I (hs-cTnI) were included in adjusted models. Combinations of normal and elevated hs-cTnI (>26.2 ng/L) and BNP (>100 pg/mL) were also studied. Results. Median concentrations (interquartile ranges) were 5.6 (3.3-10.5) ng/L for hs-cTnI and 39 (15, 94) pg/mL for BNP. Hazard ratios for each adverse outcome were higher with higher quartiles of BNP after adjustment and remained statistically significant after adding hs-cTnI to the model. The highest quartile hazard ratio for DDKF was 2.47 (95% confidence interval [95% CI], 1.21-5.05). Simultaneous elevations of BNP and hs-cTnI over clinical cutoffs were strongly associated with adverse outcomes with hazard ratios 8.8 (95% CI, 3.4-23.1) for DDKF and 6.3 (95% CI, 2.7-15.0) for cardiovascular outcomes. Conclusions. Higher BNP is associated with mortality and cardiovascular and kidney outcomes in stable kidney transplant recipients. Elevated BNP and hs-cTnI identify candidates for targeted risk reduction. C1 [Jarolim, Petr; Conrad, Michael J.] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA USA. [Claggett, Brian L.; Finn, Peter; Solomon, Scott D.; Pfeffer, Marc A.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA USA. [Carpenter, Myra A.; Ivanova, Anastasia; Gravens-Mueller, Lisa] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Bostom, Andrew G.] Rhode Isl Hosp, Div Nephrol, Providence, RI USA. [Kusek, John W.] NIDDK, Bethesda, MD 20892 USA. [Hunsicker, Lawrence G.] Univ Iowa, Iowa City, IA USA. [Jacques, Paul F.] USDA, Jean Mayer Human Nutr Res Ctr Aging, Boston, MA USA. [Weiner, Daniel E.; Levey, Andrew S.] Tufts Med Ctr, Boston, MA USA. RP Jarolim, P (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM pjarolim@partners.org FU National Institute of Diabetes and Digestive and Kidney Diseases [U01 DK61700-01]; Office of Dietary Supplements, National Institutes of Health, Department of Health and Human Services FX The FAVORIT study was supported by cooperative agreement U01 DK61700-01 from the National Institute of Diabetes and Digestive and Kidney Diseases and additional financial support from the Office of Dietary Supplements, National Institutes of Health, Department of Health and Human Services. Vitamins were provided by Pamlab, Inc. BNP and high sensitivity troponin I reagents were provided by Abbott Diagnostics. NR 35 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 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JAN PY 2017 VL 101 IS 1 BP 182 EP 190 DI 10.1097/TP.0000000000001080 PG 9 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA EH7MQ UT WOS:000391957500039 PM 26910333 ER PT J AU Simon, AE Boss, EF Zelaya, CE Hoffman, HJ AF Simon, Alan E. Boss, Emily F. Zelaya, Carla E. Hoffman, Howard J. TI Racial and Ethnic Differences in Receipt of Pressure Equalization Tubes Among US Children, 2014 SO ACADEMIC PEDIATRICS LA English DT Article DE disparities; grommets; pressure-equalizing tubes; tympanostomy tubes; ventilation tubes ID PNEUMOCOCCAL CONJUGATE VACCINE; ACUTE OTITIS-MEDIA; TYMPANOSTOMY TUBES; UNITED-STATES; EFFICACY AB OBJECTIVE: Pressure equalization tube (PET) placement (also referred to as tympanostomy tube placement) is among the most common ambulatory surgical procedures performed on US children. More than 20 years ago, differences according to race/ethnicity in the national prevalence of having had PETs placed were documented. Whether these differences persist is unknown. METHODS: We used data from the 2014 National Health Interview Survey to examine the percentage of children 0 to 17 years of age who have ever undergone PET placement. Unadjusted logistic regression with predictive margins was used to assess the relationship between having received PETs and race/ethnicity, as well as other clinical, socioeconomic, and geographic factors. Multivariable logistic regression was used to determine whether other factors could account for any observed differences according to race/ethnicity. RESULTS: Overall, 8.9% of children 0 to 17 years of age had undergone PET surgery. By race/ethnicity, 12.6% of non-Hispanic white children received PETs, which was significantly greater than the 4.8% of non-Hispanic black, 4.4% of Hispanic, and 5.6% of non-Hispanic other/multiple race children who had this surgery (P < .001 for all comparisons). In multivariable analysis, the adjusted prevalence for non Hispanic white children (10.8%) was greater than for non Hispanic black (5.4%) and Hispanic (5.8%) children (P < .001 for both comparisons). CONCLUSIONS: Nearly 9% of US children have had PETs placed. Non-Hispanic white children still have a greater prevalence of PET placement compared with non-Hispanic black and Hispanic children. These differences could not be fully explained by other demographic, clinical, socioeconomic, or geographic differences between racial/ethnic groups. C1 [Simon, Alan E.; Zelaya, Carla E.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Boss, Emily F.] Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21205 USA. [Hoffman, Howard J.] Natl Inst Deafness & Other Commun Disorders, Epidemiol & Stat Program, NIH, Bethesda, MD USA. RP Simon, AE (reprint author), Natl Ctr Hlth Stat, 3311 Toledo Rd,Rm 6122, Hyattsville, MD 20782 USA. EM aes360@hotmail.com FU National Institute on Deafness and Other Communication Disorders, United States Department of Health and Human Services; Agency for Healthcare Research and Quality [1K08 HS22932-01]; Johns Hopkins Clinician Scientist Award; American Society of Pediatric Otolaryngology Career Development Award FX Financial Disclosure: No funding or research support was received specifically for this research or for preparation of this report. The National Institute on Deafness and Other Communication Disorders, United States Department of Health and Human Services funded the supplement to the NHIS upon which this research project was based. E.F.B. is supported by the Agency for Healthcare Research and Quality Grant 1K08 HS22932-01, the Johns Hopkins Clinician Scientist Award, and the American Society of Pediatric Otolaryngology Career Development Award. No sponsor had any role in study design, analysis, or interpretation of the data, writing of the report, or the decision to submit the article for publication. The findings and conclusions in this report are those of the authors and do not necessarily represent the official positions of the Centers for Disease Control and Prevention, the National Institute on Deafness and Other Communication Disorders, or the Agency for Healthcare Research and Quality. NR 32 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 1876-2859 EI 1876-2867 J9 ACAD PEDIATR JI Acad. Pediatr. PD JAN-FEB PY 2017 VL 17 IS 1 BP 88 EP 94 PG 7 WC Pediatrics SC Pediatrics GA EG9AJ UT WOS:000391349100013 PM 27422495 ER PT J AU Levine, M Violet, PC AF Levine, Mark Violet, Pierre-Christian TI Breaking down, starting up: can a vitamin C-enriched gelatin supplement before exercise increase collagen synthesis? SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Editorial Material ID CULTURED HUMAN-FIBROBLASTS; LIPID-PEROXIDATION; METABOLIC SYNDROME; HYDROGEN-PEROXIDE; ENZYMATIC HYDROXYLATION; GENE-EXPRESSION; ASCORBIC-ACID; CELLS; STIMULATION; MODULATION C1 [Levine, Mark; Violet, Pierre-Christian] NIDDK, Mol & Clin Nutr Sect, NIH, Bethesda, MD 20892 USA. RP Levine, M (reprint author), NIDDK, Mol & Clin Nutr Sect, NIH, Bethesda, MD 20892 USA. EM markl@mail.nih.gov NR 27 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JAN PY 2017 VL 105 IS 1 BP 5 EP 7 DI 10.3945/ajcn.116.148312 PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EG8YU UT WOS:000391344400003 PM 28003207 ER PT J AU Kant, AK Graubard, BI AF Kant, Ashima K. Graubard, Barry I. TI A prospective study of water intake and subsequent risk of all-cause mortality in a national cohort SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE all-cause mortality; beverages; fluid; food moisture; NHANES; plain water; prospective cohort; water intake ID COFFEE CONSUMPTION; DIETARY DIVERSITY; TEA CONSUMPTION; SEX-DIFFERENCES; FLUID INTAKE; PLAIN-WATER; METAANALYSIS; HEALTH; POPULATION; BEVERAGES AB Background: Water, an essential nutrient, is believed to be related to a variety of health outcomes. Published studies have examined the association of fluid or beverage intake with risk of mortality from coronary diseases, diabetes, or cancer, but few studies have examined the association of total water intake with all-cause mortality. Objective: We examined prospective risk of mortality from all causes in relation to intakes of total water and each of the 3 water sources. Design: We used public-domain, mortality-linked water intake data from the NHANES conducted in 1988-1994 and 1999-2004 for this prospective cohort study (n = 12,660 women and 12,050 men; aged >= 25 y). Mortality follow-up was completed through 31 December 2011. We used sex-specific Cox proportional hazards regression methods that were appropriate for complex surveys to examine the independent associations of plain water, beverage water, water in foods, and total water with multiple covariate adjusted risk of mortality from all causes. Results: Over a median of 11.4 y of follow-up, 3504 men and 3032 women died of any cause in this cohort. In men, neither total water intake nor each of the individual water source variables (plain water, water in beverages, and water in foods) was independently related with risk of all-cause mortality. In women, risk of mortality increased slightly in the highest quartile of total or plain water intake but did not approach the Bonferroni-corrected level of significance of P < 0.002. Conclusions: There was no survival advantage in association with higher total or plain water intake in men or women in this national cohort. The slight increase in risk of mortality noted in women with higher total and plain water intakes may be spurious and requires further investigation. C1 [Kant, Ashima K.] CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Flushing, NY 11367 USA. [Graubard, Barry I.] NCI, Div Canc Epidemiol & Genet, Biostat Branch, NIH, Bethesda, MD 20892 USA. RP Kant, AK (reprint author), CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Flushing, NY 11367 USA. EM ashima.kant@qc.cuny.edu FU intramural research program of the Department of Health and Human Services, National Cahcer Institute, NIH FX Supported in part by the intramural research program of the Department of Health and Human Services, National Cahcer Institute, NIH (BIG). NR 40 TC 0 Z9 0 U1 4 U2 4 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JAN PY 2017 VL 105 IS 1 BP 212 EP 220 DI 10.3945/ajcn.116.143826 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EG8YU UT WOS:000391344400026 PM 27903521 ER PT J AU Yetley, EA MacFarlane, AJ Greene-Finestone, LS Garza, C Ard, JD Atkinson, SA Bier, DM Carriquiry, AL Harlan, WR Hattis, D King, JC Krewski, D O'Connor, DL Prentice, RL Rodricks, JV Wells, GA AF Yetley, Elizabeth A. MacFarlane, Amanda J. Greene-Finestone, Linda S. Garza, Cutberto Ard, Jamy D. Atkinson, Stephanie A. Bier, Dennis M. Carriquiry, Alicia L. Harlan, William R. Hattis, Dale King, Janet C. Krewski, Daniel O'Connor, Deborah L. Prentice, Ross L. Rodricks, Joseph V. Wells, George A. TI Options for basing Dietary Reference Intakes (DRIs) on chronic disease endpoints: report from a joint US-/Canadian-sponsored working group SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE Dietary Reference Intakes; chronic disease; intake response; evidentiary challenges; evidence assessments ID PREVENTION TRIAL SELECT; SYSTEMATIC REVIEWS; MENDELIAN RANDOMIZATION; BLOOD-PRESSURE; CARDIOVASCULAR-DISEASE; RECOVERY BIOMARKERS; CANCER PREVENTION; VITAMIN-D; METHODOLOGICAL QUALITY; 25-HYDROXYVITAMIN D AB Dietary Reference Intakes (DRIs) are used in Canada and the United States in planning and assessing diets of apparently healthy individuals and population groups. The approaches used to establish DRIs on the basis of classical nutrient deficiencies and/or toxicities have worked well. However, it has proved to be more challenging to base DRI values on chronic disease endpoints; deviations from the traditional framework were often required, and in some cases, DRI values were not established for intakes that affected chronic disease outcomes despite evidence that supported a relation. The increasing proportions of elderly citizens, the growing prevalence of chronic diseases, and the persistently high prevalence of overweight and obesity, which predispose to chronic disease, highlight the importance of understanding the impact of nutrition on chronic disease prevention and control. A multidisciplinary working group sponsored by the Canadian and US government DRI steering committees met from November 2014 to April 2016 to identify options for addressing key scientific challenges encountered in the use of chronic disease endpoints to establish reference values. The working group focused on 3 key questions: 1) What are the important evidentiary challenges for selecting and using chronic disease endpoints in future DRI reviews, 2) what intake-response models can future DRI committees consider when using chronic disease endpoints, and 3) what are the arguments for and against continuing to include chronic disease endpoints in future DRI reviews? This report outlines the range of options identified by the working group for answering these key questions, as well as the strengths and weaknesses of each option. C1 [Yetley, Elizabeth A.] NIH, Off Dietary Supplements, Bldg 10, Bethesda, MD 20892 USA. [MacFarlane, Amanda J.; Greene-Finestone, Linda S.] Hlth Canada, Bur Nutr Sci, Ottawa, ON, Canada. [Garza, Cutberto] Boston Coll, Chestnut Hill, MA 02167 USA. [Garza, Cutberto] George Washington Univ, Sch Publ Hlth, Milken Inst, Dept Global Hlth, Washington, DC USA. [Garza, Cutberto] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Ard, Jamy D.] Wake Forest Univ, Wake Forest Sch Med, Winston Salem, NC 27109 USA. [Atkinson, Stephanie A.] McMaster Univ, Dept Pediat, Hamilton, ON, Canada. [Bier, Dennis M.] Baylor Coll Med, Childrens Nutr Res Ctr, Houston, TX 77030 USA. [Carriquiry, Alicia L.] Iowa State Univ, Dept Stat, Ames, IA USA. [Harlan, William R.] NIH, Off Director, Bldg 10, Bethesda, MD 20892 USA. [Hattis, Dale] Clark Univ, George Perkins Marsh Inst, Worcester, MA 01610 USA. [King, Janet C.] Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA. [King, Janet C.] Univ Calif Berkeley, Dept Nutr Sci, Berkeley, CA 94720 USA. [King, Janet C.] Univ Calif Davis, Dept Nutr, Davis, CA 95616 USA. [Krewski, Daniel] Univ Ottawa, McLaughlin Ctr Populat Hlth Risk Assessment, Ottawa, ON, Canada. [O'Connor, Deborah L.] Univ Toronto, Dept Nutr Sci, Toronto, ON M5S 1A1, Canada. [O'Connor, Deborah L.] Hosp Sick Children, Toronto, ON, Canada. [Prentice, Ross L.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Prentice, Ross L.] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Rodricks, Joseph V.] Ramboll Environ Int Corp, Arlington, VA USA. [Wells, George A.] Univ Ottawa, Inst Heart, Dept Epidemiol & Community Med, Ottawa, ON, Canada. RP MacFarlane, AJ (reprint author), Hlth Canada, Bur Nutr Sci, Ottawa, ON, Canada. EM amanda.macfarlane@hc-sc.gc.ca FU Bureau of Nutritional Sciences, Health Canada; Office of Nutrition Policy and Promotion, Health Canada; Social Determinants and Science Integration Directorate, Public Health Agency of Canada; Office of Dietary Supplements, NIH; Agricultural Research Service, USDA; National Heart, Lung, and Blood Institute, NIH; Center for Food Safety and Applied Nutrition, US Food and Drug Administration; National Center for Chronic Disease Prevention and Health Promotion, US CDC FX Supported by the Bureau of Nutritional Sciences, Health Canada; Office of Nutrition Policy and Promotion, Health Canada; the Social Determinants and Science Integration Directorate, Public Health Agency of Canada; the Office of Dietary Supplements, NIH; the Agricultural Research Service, USDA; the National Heart, Lung, and Blood Institute, NIH; the Center for Food Safety and Applied Nutrition, US Food and Drug Administration; and the National Center for Chronic Disease Prevention and Health Promotion, US CDC. This is a free access article, distributed under terms (http://www.nutrition.org/publications/guidelines-and-policies/license that permit unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. NR 105 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JAN PY 2017 VL 105 IS 1 BP 249S EP 285S DI 10.3945/ajcn.116.139097 PG 37 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EG8YU UT WOS:000391344400032 PM 27927637 ER PT J AU Nicolae, A Ganapathi, KA Pham, THT Xi, LQ Torres-Cabala, CA Nanaji, NM Zha, HD Fan, Z Irwin, S Pittaluga, S Raffeld, M Jaffe, ES AF Nicolae, Alina Ganapathi, Karthik A. Trinh Hoc-Tran Pham Xi, Liqiang Torres-Cabala, Carlos A. Nanaji, Nahid M. Zha, Hongbin D. Fan, Zhen Irwin, Sybil Pittaluga, Stefania Raffeld, Mark Jaffe, Elaine S. TI EBV-negative Aggressive NK-cell Leukemia/Lymphoma Clinical, Pathologic, and Genetic Features SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE aggressive NK leukemia/lymphoma; Epstein-Barr virus; JAK/STAT pathway; epidemiology; NK cells ID GRANULAR LYMPHOCYTE LEUKEMIA; OF-THE-LITERATURE; NASAL TYPE; LYMPHOPROLIFERATIVE DISORDERS; LYMPHOMA/LEUKEMIA; MUTATIONS; LYMPHOMAS; MOLECULE; SITES; PTPN2 AB Aggressive natural killer cell leukemia (ANKL) is a systemic NK-cell neoplasm, almost always associated with Epstein-Barr virus (EBV). Rare cases of EBV-negative ANKL have been described, and some reports suggested more indolent behavior. We report the clinicopathologic, immunophenotypic, and molecular characteristics of 7 EBV-negative ANKL. All patients were adults, with a median age of 63 years (range 22 to 83 y) and an M:F ratio of 2.5:1. Five patients were White, 1 Black, and 1 Asian. All patients presented acutely, with fever (6/7), cytopenias (6/7), and splenomegaly (4/7). Four patients had lymphadenopathy, 4 had extranodal disease. Bone marrow involvement was present in 5, with hemophagocytosis in 3. Peripheral blood was involved in 5 with the neoplastic cells containing prominent azurophilic granules. By immunohistochemistry and/or flow cytometry, the tumor cells lacked surface CD3 and were positive for CD56 (7/7), CD2 (5/5), CD8 (3/7), CD30 (4/5), and granzyme-B (6/6). They were negative for CD4, CD5, beta F1, TCR gamma, LMP1, and EBV-encoded RNA. Polymerase chain reaction for TCRG clonality was polyclonal. Mutational analysis revealed missense mutations in the STAT3 gene in both cases studied. Median survival was 8 weeks from the onset of disease. One patient received allogeneic bone marrow transplant and is alive with no disease (follow-up 15 mo). EBV-negative ANKL exists but is rare. It tends to occur in older patients and is indistinguishable clinically and pathologically from EBV-positive ANKL, with a similar fulminant clinical course. The high prevalence of Asian patients seen with EBV-positive disease seems less evident with EBV-negative cases. C1 [Nicolae, Alina; Ganapathi, Karthik A.; Trinh Hoc-Tran Pham; Xi, Liqiang; Pittaluga, Stefania; Raffeld, Mark; Jaffe, Elaine S.] NCI, Pathol Lab, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Nanaji, Nahid M.] Maryland Healthcare Syst, Dept Vet Affairs, Baltimore, MD USA. [Fan, Zhen] Univ Maryland, St Joseph Med Ctr, Dept Pathol, Towson, MD USA. [Torres-Cabala, Carlos A.] UT MD Anderson Canc Ctr, Dept Pathol, Houston, TX USA. [Torres-Cabala, Carlos A.] UT MD Anderson Canc Ctr, Dept Dermatol, Houston, TX USA. [Zha, Hongbin D.] Kaiser Permanente, Los Angeles, CA USA. [Irwin, Sybil] Wayne Mem Hosp, Commonwealth Med Coll, Scranton, PA USA. [Nicolae, Alina] Univ Bern, Inst Pathol, Murtenstr 31, CH-3010 Bern, Switzerland. RP Jaffe, ES (reprint author), NCI, NIH, 10 Ctr Dr,Bldg 10,Room 3S235, Bethesda, MD 20892 USA. EM elainejaffe@nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX Supported by the intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. NR 28 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 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD JAN PY 2017 VL 41 IS 1 BP 67 EP 74 DI 10.1097/PAS.0000000000000735 PG 8 WC Pathology; Surgery SC Pathology; Surgery GA EH0BL UT WOS:000391427300008 PM 27631517 ER PT J AU Inker, LA Coresh, J Sang, Y Hsu, CY Foster, MC Eckfeldt, JH Karger, AB Nelson, RG Liu, X Sarnak, M Appel, LJ Grams, M Xie, DW Kimmel, PL Feldman, H Ramachandran, V Levey, AS AF Inker, Lesley A. Coresh, Josef Sang, Yingying Hsu, Chi-Yuan Foster, Meredith C. Eckfeldt, John H. Karger, Amy B. Nelson, Robert G. Liu, Xun Sarnak, Mark Appel, Lawrence J. Grams, Morgan Xie, Dawei Kimmel, Paul L. Feldman, Harold Ramachandran, Vasan Levey, Andrew S. CA CKD Biomarkers Consortium TI Filtration Markers as Predictors of ESRD and Mortality: Individual Participant Data Meta-Analysis SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID SERUM CYSTATIN-C; CHRONIC KIDNEY-DISEASE; COLLABORATIVE METAANALYSIS; POPULATION COHORTS; CARDIOVASCULAR MORTALITY; GENERAL-POPULATION; HIGHER ALBUMINURIA; ALL-CAUSE; RISK; CREATININE AB Background and objectives Serum beta-trace protein (BTP) and beta-2 microglobulin (B2M) are associated with risk of ESRD and death in the general population and in populations at high risk for these outcomes (GP/HR) and those with CKD, but results differ among studies. Design, setting, participants, & measurements We performed an individual patient-level meta-analysis including three GP/HR studies (n=17,903 participants) and three CKD studies (n=5415). We compared associations, risk prediction, and improvement in reclassification of eGFR using BTP (eGFR(BTP)) and B2M (eGFR(B2M)) alone and the average (eGFR(avg)) of eGFR(BTP), eGFR(B2M), creatinine (eGFR(cr)), and cystatin C (eGFR(cys)), to eGFR(cr), eGFR(cys), and their combination (eGFR(cr-cys)) for ESRD (2075 events) and death (7275 events). Results Mean (SD) follow up times for ESRD and mortality for GP/HR and CKD studies were 13 (4), 6.2 (3.2), 14 (5), and 7.5 (3.9) years, respectively. Compared with eGFR(cr), eGFR(BTP) and eGFR(B2M) improved risk associations and modestly improved prediction for ESRD and death even after adjustment for established risk factors. eGFRavg provided the most consistent improvement in associations and prediction across both outcomes and populations. Assessment of heterogeneity did not yield clinically relevant differences. For ESRD, addition of albuminuria substantially attenuated the improvement in risk prediction and risk classification with novel filtration markers. For mortality, addition of albuminuria did not affect the improvement in risk prediction with the use of novel markers, but lessened improvement in risk classification, especially for the CKD cohort. Conclusions These markers do not provide substantial additional prognostic information to eGFRcr and albuminuria, but may be appropriate in circumstances where eGFR(cr) is not accurate or albuminuria is not available. Educational efforts to increase measurement of albuminuria in clinical practice may be more cost-effective than measurement of BTP and B2M for improving prognostic information. C1 [Inker, Lesley A.; Foster, Meredith C.; Liu, Xun; Sarnak, Mark; Levey, Andrew S.] Tufts Med Ctr, William B Schwartz Div Nephrol, 800 Washington St,Box 391, Boston, MA 02111 USA. [Coresh, Josef; Sang, Yingying; Appel, Lawrence J.; Grams, Morgan] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Hsu, Chi-Yuan] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Eckfeldt, John H.; Karger, Amy B.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Nelson, Robert G.] NIDDKD, NIH, Phoenix, AZ USA. [Xie, Dawei; Feldman, Harold] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kimmel, Paul L.] NIDDKD, NIH, Bethesda, MD USA. [Ramachandran, Vasan] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Inker, LA (reprint author), Tufts Med Ctr, Div Nephrol, 800 Washington St,Box 391, Boston, MA 02111 USA. EM Linker@tuftsmedicalcenter.org FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01DK85649, U01DK085673, U01DK085660, U01DK085688, U01DK085651, U01DK085689]; Intramural Research Program of the NIDDK; National Heart, Lung and Blood Institute [T32 HL007024]; NIDDK [U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902]; Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award National Institutes of Health (NIH)/National Center for Advancing Translational Sciences (NCATS) [UL1TR000003]; Johns Hopkins University [UL1 TR-000424]; University of Maryland General Clinical Research Center (GCRC) [M01 RR-16500]; Clinical and Translational Science Collaborative of Cleveland; National Center for Advancing Translational Sciences component of the NIH [UL1TR000439]; NIH roadmap for Medical Research; Michigan Institute for Clinical and Health Research [UL1TR000433]; University of Illinois at Chicago Center for Clinical and Translational Science (CTSA) [UL1RR029879]; Tulane University Translational Research in Hypertension and Renal Biology [P30GM103337]; Kaiser Permanente NIH/National Center for Research Resources (NCRR) University of California- San Francisco Clinical and Translational Science Institute (UCSF CTSI) [UL1RR024131]; National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; NIH/NIDDK [R01DK089174] FX The CKD Biomarkers Consortium is funded by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants U01DK85649, U01DK085673, U01DK085660, U01DK085688, U01DK085651, and U01DK085689, and by the Intramural Research Program of the NIDDK. M.C.F. was supported in part by National Heart, Lung and Blood Institute grant T32 HL007024. Funding for the Chronic Renal Insufficiency Cohort (CRIC) Study was obtained under a cooperative agreement from the NIDDK (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902). In addition, this work was supported in part by the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award National Institutes of Health (NIH)/National Center for Advancing Translational Sciences (NCATS) UL1TR000003, Johns Hopkins University UL1 TR-000424, University of Maryland General Clinical Research Center (GCRC) M01 RR-16500, Clinical and Translational Science Collaborative of Cleveland, UL1TR000439 from the National Center for Advancing Translational Sciences component of the NIH and the NIH roadmap for Medical Research, Michigan Institute for Clinical and Health Research UL1TR000433, University of Illinois at Chicago Center for Clinical and Translational Science (CTSA) UL1RR029879, Tulane University Translational Research in Hypertension and Renal Biology P30GM103337, Kaiser Permanente NIH/National Center for Research Resources (NCRR) University of California- San Francisco Clinical and Translational Science Institute (UCSF CTSI) UL1RR024131. The ARIC Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Funding for cystatin C measurements were supported by NIH/NIDDK grant R01DK089174 to Dr. Elizabeth Selvin. NR 23 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 JAN PY 2017 VL 12 IS 1 BP 69 EP 78 DI 10.2215/CJN.03660316 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA EG9YD UT WOS:000391416700011 PM 28062677 ER PT J AU Wanchoo, R Abudayyeh, A Doshi, M Edeani, A Glezerman, IG Monga, D Rosner, M Jhaveri, KD AF Wanchoo, Rimda Abudayyeh, Ala Doshi, Mona Edeani, Amaka Glezerman, Ilya G. Monga, Divya Rosner, Mitchell Jhaveri, Kenar D. TI Renal Toxicities of Novel Agents Used for Treatment of Multiple Myeloma SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Review ID ACUTE KIDNEY INJURY; ACUTE INTERSTITIAL NEPHRITIS; LOW-DOSE DEXAMETHASONE; LENALIDOMIDE PLUS DEXAMETHASONE; TUBEROUS SCLEROSIS COMPLEX; STEM-CELL TRANSPLANTATION; PLACEBO-CONTROLLED TRIAL; KIR ANTIBODY IPH2101; BRAF V600E MUTATION; THROMBOTIC MICROANGIOPATHY AB Survival for patients with multiple myeloma has significantly improved in the last decade in large part due to the development of proteasome inhibitors and immunomodulatory drugs. These next generation agents with novel mechanisms of action as well as targeted therapies are being used both in the preclinical and clinical settings for patients with myeloma. These agents include monoclonal antibodies, deacetylase inhibitors, kinase inhibitors, agents affecting various signaling pathways, immune check point inhibitors, and other targeted therapies. In some cases, off target effects of these therapies can lead to unanticipated effects on the kidney, that can range from electrolyte disorders to AKI. In this review, we discuss the nephrotoxicities of novel agents currently in practice as well as in development for the treatment of myeloma. C1 [Wanchoo, Rimda; Jhaveri, Kenar D.] Hofstra Northwell Sch Med, Div Nephrol, 100 Community Dr, Great Neck, NY 11021 USA. [Abudayyeh, Ala] Univ Texas MD Anderson Canc Ctr, Div Internal Med, Houston, TX 77030 USA. [Doshi, Mona] Wayne State Univ, Sch Med, Div Nephrol, Detroit, MI USA. [Edeani, Amaka] Natl Inst Diabet Digest & Kidney Dis, Kidney Dis Branch, NIH, Bethesda, MD USA. [Glezerman, Ilya G.] Mem Sloan Kettering Canc Ctr, Dept Med, Renal Serv, 1275 York Ave, New York, NY 10021 USA. [Glezerman, Ilya G.] Weill Cornell Med Ctr, New York, NY USA. [Monga, Divya] Univ Mississippi, Med Ctr, Div Nephrol, Jackson, MS 39216 USA. [Rosner, Mitchell] Univ Virginia Hlth Syst, Dept Med, Div Nephrol, Charlottesville, VA USA. RP Jhaveri, KD (reprint author), Hofstra Northwell Sch Med, Div Nephrol, 100 Community Dr, Great Neck, NY 11021 USA. EM kjhaveri@northwell.edu FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; National Institute of Health (Bethesda, MD)/National Cancer Institute (Bethesda, MD) Cancer Center Support Grant [P30 CA008748] FX A.E.'s work is supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. A.A., M.D., A.E., I.G.G., D.M., M.R., and K.D.J. are members of the American Society of Nephrology Onconephrology Forum. R.W. is an expert member of Cancer and Kidney International Network (CKIN) and K.D.J. is part of the governing body of CKIN. I.G.G. was funded in part through the National Institute of Health (Bethesda, MD)/National Cancer Institute (Bethesda, MD) Cancer Center Support Grant P30 CA008748; I.G.G. owns Pfizer Inc. stock and served on the Advisory Board for Astra Zeneca Inc. NR 130 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 JAN PY 2017 VL 12 IS 1 BP 176 EP 189 DI 10.2215/CJN.06100616 PG 14 WC Urology & Nephrology SC Urology & Nephrology GA EG9YD UT WOS:000391416700022 PM 27654928 ER PT J AU Eaker, S Abraham, E Allickson, J Brieva, TA Baksh, D Heathman, TRJ Mistry, B Zhang, N AF Eaker, Shannon Abraham, Eytan Allickson, Julie Brieva, Thomas A. Baksh, Dolores Heathman, Thomas R. J. Mistry, Biren Zhang, Nan TI Bioreactors for cell therapies: Current status and future advances SO CYTOTHERAPY LA English DT Article DE allogeneic; autologous; bioreactor; cell culture; cell therapy; scale-out; scale-up; stem cell; tissue engineering ID CHO-CELLS; CULTURE; MICROCARRIER; TECHNOLOGIES; SENESCENCE; BIOPROCESS; EXPANSION; GROWTH AB The use of bioreactors in cell therapy applications is on the rise, as clinical trials and commercialization of cell therapy based products are moving to the forefront of treatment opportunities. This review focuses on the considerations and benefits of using bioreactors for cell therapy manufacturing, with an emphasis on autologous versus allogenic, scalability, tissue engineering, automation and comparability and consistency in the final product. Evaluation and choice of the right bioreactor for any given process and indication is paramount when moving into scalable platforms and processes that can support the cell therapy industry's needs. C1 [Eaker, Shannon; Baksh, Dolores] GE Cell Therapy Technol, 100 Results Way, Marlborough, MA 01752 USA. [Abraham, Eytan] Lonza Walkersville Inc, Walkersville, MD USA. [Allickson, Julie] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Brieva, Thomas A.; Mistry, Biren] Celgene Cellular Therapeut, Warren, NJ USA. [Heathman, Thomas R. J.] PCT, Allendale, NJ USA. [Zhang, Nan] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Eaker, S (reprint author), GE Cell Therapy Technol, 100 Results Way, Marlborough, MA 01752 USA. EM shannon.eaker@ge.com NR 30 TC 0 Z9 0 U1 12 U2 12 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD JAN PY 2017 VL 19 IS 1 BP 9 EP 18 DI 10.1016/j.jcyt.2016.09.011 PG 10 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA EG8ZN UT WOS:000391346500002 ER PT J AU DiGiovanna, JJ AF DiGiovanna, John J. TI Basic Science Insights into Clinical Puzzles Preface SO DERMATOLOGIC CLINICS LA English DT Editorial Material C1 [DiGiovanna, John J.] NCI, DNA Repair Sect, Dermatol Branch, Ctr Canc Res,NIH, Bldg 37 Room 4002, Bethesda, MD 20892 USA. RP DiGiovanna, JJ (reprint author), NCI, DNA Repair Sect, Dermatol Branch, Ctr Canc Res,NIH, Bldg 37 Room 4002, Bethesda, MD 20892 USA. EM jdg@nih.gov NR 0 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 0733-8635 EI 1558-0520 J9 DERMATOL CLIN JI Dermatol. Clin. PD JAN PY 2017 VL 35 IS 1 BP IX EP X DI 10.1016/j.det.2016.10.001 PG 2 WC Dermatology SC Dermatology GA EG8YH UT WOS:000391342700001 PM 27890242 ER PT J AU Dimitrova, D Freeman, AF AF Dimitrova, Dimana Freeman, Alexandra F. TI Current Status of Dedicator of Cytokinesis-Associated Immunodeficiency DOCK8 and DOCK2 SO DERMATOLOGIC CLINICS LA English DT Article DE Immunodeficiency; Dedicator of cytokinesis 8; Dedicator of cytokinesis 2; Atopic dermatitis; Cutaneous viral infection; Malignancy ID HYPER-IGE SYNDROME; STEM-CELL TRANSPLANTATION; DOCK8-DEFICIENT PATIENTS; HOMOZYGOUS DELETIONS; IMMUNE-DEFICIENCY; ATOPIC-DERMATITIS; LUNG-CANCER; MUTATIONS; IDENTIFICATION; PHENOTYPE AB DOCK8 deficiency is an autosomal recessive combined immunodeficiency disease associated with elevated IgE, atopy, recurrent sinopulmonary and cutaneous viral infections, and malignancy. The DOCK8 protein is critical for cytoskeletal organization, and deficiency impairs dendritic cell transmigration, T-cell survival, and NK cell cytotoxicity. Early hematopoietic stem cell transplantation is gaining prominence as a definitive treatment given the potential for severe complications and mortality in this disease. Recently, DOCK2 deficiency has been identified in several patients with early-onset invasive bacterial and viral infections. C1 [Dimitrova, Dimana] NCI, Expt Transplantat & Immunol Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. [Freeman, Alexandra F.] NIAID, Lab Clin Infect Dis, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. RP Freeman, AF (reprint author), NIAID, Lab Clin Infect Dis, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM freemaal@mail.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 58 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 0733-8635 EI 1558-0520 J9 DERMATOL CLIN JI Dermatol. Clin. PD JAN PY 2017 VL 35 IS 1 BP 11 EP + DI 10.1016/j.det.2016.07.002 PG 10 WC Dermatology SC Dermatology GA EG8YH UT WOS:000391342700003 PM 27890234 ER PT J AU Shwin, KW Lee, CCR Goldbach-Mansky, R AF Shwin, Kyawt Win Lee, Chyi-Chia Richard Goldbach-Mansky, Raphaela TI Dermatologic Manifestations of Monogenic Autoinflammatory Diseases SO DERMATOLOGIC CLINICS LA English DT Article DE Autoinflammatory disorders; IL-1; Type I interferon; Immune dysregulation; Neutrophilic dermatoses; urticaria; Panniculitis ID FAMILIAL MEDITERRANEAN FEVER; CONGENITAL DYSERYTHROPOIETIC ANEMIA; RECURRENT MULTIFOCAL OSTEOMYELITIS; MACROPHAGE ACTIVATION SYNDROME; JUVENILE IDIOPATHIC ARTHRITIS; AICARDI-GOUTIERES SYNDROME; OF-FUNCTION MUTATION; INTERLEUKIN-10 RECEPTOR; HYPERIMMUNOGLOBULINEMIA-D; CUTANEOUS MANIFESTATIONS AB Autoinflammatory disorders are sterile inflammatory conditions characterized by episodes of early-onset fever, rash, and disease-specific patterns of organ inflammation. Gain-of-function mutations in innate danger-sensing pathways, including the inflammasomes and the nucleic acid sensing pathways, play critical roles in the pathogenesis of IL-1 and Type-I IFN-mediated disorders and point to an important role of excessive proinflammatory cytokine signaling, including interleukin (IL)-1 b, Type-I interferons, IL-18, TNF and others in causing the organ specific immune dysregulation. The article discusses the concept of targeting proinflammatory cytokines and their signaling pathways with cytokine blocking treatments that have been life changing for some patients. C1 [Shwin, Kyawt Win] Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, Translat Autoinflammatory Dis Studies, Rheumatol Fellowship Program, NIH, Bldg 10,Room 6D-52,10 Ctr Dr, Bethesda, MD 20892 USA. [Shwin, Kyawt Win] UT Southwestern Med Ctr, North Texas Hlth Care Syst, Dallas VA Med Ctr, Div Rheumat Dis, 4500 S Lancaster Rd, Dallas, TX 75216 USA. [Lee, Chyi-Chia Richard] NCI, Dermatopathol Sect, Pathol Lab, Ctr Canc Res,NIH, Bldg 10,Room 2S235J,9000 Rockville Pike, Bethesda, MD 20892 USA. [Goldbach-Mansky, Raphaela] NIAID, Translat Autoinflammatory Dis Studies, NIH, Bldg 10,Room 6D-47B,10 Ctr Dr, Bethesda, MD 20892 USA. RP Goldbach-Mansky, R (reprint author), NIAID, Translat Autoinflammatory Dis Studies, NIH, Bldg 10,Room 6D-47B,10 Ctr Dr, Bethesda, MD 20892 USA. EM goldbacr@mail.nih.gov FU SOBI; Novartis; Regeneron; Eli Lilly; Intramural Research Program of the NIH; NIAID; NIAMS; NCI FX R. Goldbach-Mansky received study support from SOBI, Novartis, Regeneron and Eli Lilly. The authors are supported by the Intramural Research Program of the NIH, NIAID, NIAMS, and NCI. NR 75 TC 0 Z9 0 U1 4 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0733-8635 EI 1558-0520 J9 DERMATOL CLIN JI Dermatol. Clin. PD JAN PY 2017 VL 35 IS 1 BP 21 EP + DI 10.1016/j.det.2016.07.005 PG 19 WC Dermatology SC Dermatology GA EG8YH UT WOS:000391342700004 PM 27890235 ER PT J AU Nathan, N Keppler-Noreuil, KM Biesecker, LG Moss, J Darling, TN AF Nathan, Neera Keppler-Noreuil, Kim M. Biesecker, Leslie G. Moss, Joel Darling, Thomas N. TI Mosaic Disorders of the PI3K/PTEN/AKT/TSC/mTORC1 Signaling Pathway SO DERMATOLOGIC CLINICS LA English DT Article DE Mosaicism; mTORC1; PIK3CA-related overgrowth spectrum; Proteus syndrome; Tuberous sclerosis complex; PTEN hamartoma tumor syndrome; Next-generation sequencing; Sirolimus ID TUBEROUS SCLEROSIS COMPLEX; GENOTYPE-PHENOTYPE CORRELATIONS; PIK3CA-RELATED OVERGROWTH SPECTRUM; WELL-DEFINED PHENOTYPES; PROTEUS-SYNDROME; EPIDERMAL NEVUS; COWDEN-SYNDROME; TUMOR-SUPPRESSOR; PTEN HAMARTOMA; SUBEPENDYMAL NODULES AB Somatic mutations in genes of the PI3K/PTEN/AKT/TSC/mTORC1 signaling pathway cause segmental overgrowth, hamartomas, and malignant tumors. Mosaicism for activating mutations in AKT1 or PIK3CA cause Proteus syndrome and PIK3CA-Related Overgrowth Spectrum, respectively. Postzygotic mutations in PTEN or TSC1/TSC2 cause mosaic forms of PTEN hamartoma tumor syndrome or tuberous sclerosis complex, respectively. Distinct features observed in these mosaic conditions in part reflect differences in embryological timing or tissue type harboring the mutant cells. Deep sequencing of affected tissue is useful for diagnosis. Drugs targeting mTORC1 or other points along this signaling pathway are in clinical trials to treat these disorders. C1 [Nathan, Neera; Darling, Thomas N.] Uniformed Serv Univ Hlth Sci, Dept Dermatol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. [Keppler-Noreuil, Kim M.; Biesecker, Leslie G.] NHGRI, Med Genom & Metab Genet Branch, NIH, Bldg 49,Room 4A56,49 Convent Dr, Bethesda, MD 20892 USA. [Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10,Room 6D05,10 Ctr Dr, Bethesda, MD 20892 USA. RP Darling, TN (reprint author), Uniformed Serv Univ Hlth Sci, Dept Dermatol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM thomas.darling@usuhs.edu OI Darling, Thomas/0000-0002-5161-1974 FU Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute; Intramural Research Program of the National Human Genome Research Institute; National Institutes of Health [R01 AR062080]; Doris Duke Charitable Foundation Clinical Research Mentorship grant [2014088] FX Dr J. Moss was supported by the Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute. Dr L.G. Biesecker and Dr K.M. Keppler-Noreuil were supported by the Intramural Research Program of the National Human Genome Research Institute. Dr T.N. Darling was supported by National Institutes of Health R01 AR062080. This research was also made possible through a Doris Duke Charitable Foundation Clinical Research Mentorship grant (#2014088). NR 84 TC 0 Z9 0 U1 5 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0733-8635 EI 1558-0520 J9 DERMATOL CLIN JI Dermatol. Clin. PD JAN PY 2017 VL 35 IS 1 BP 51 EP + DI 10.1016/j.det.2016.07.001 PG 11 WC Dermatology SC Dermatology GA EG8YH UT WOS:000391342700006 PM 27890237 ER PT J AU Brant, SR Okou, DT Simpson, CL Cutler, DJ Haritunians, T Bradfield, JP Chopra, P Prince, J Begum, F Kumar, A Huang, CR Venkateswaran, S Datta, LW Wei, Z Thomas, K Herrinton, LJ Klapproth, JMA Quiros, AJ Seminerio, J Liu, ZQ Alexander, JS Baldassano, RN Dudley-Brown, S Cross, RK Dassopoulos, T Denson, LA Dhere, TA Dryden, GW Hanson, JS Hou, JK Hussain, SZ Hyams, JS Isaacs, KL Kader, H Kappelman, MD Katz, J Kellermayer, R Kirschner, BS Kuemmerle, JF Kwon, JH Lazarev, M Li, E Mack, D Mannon, P Moulton, DE Newberry, RD Osuntokun, BO Patel, AS Saeed, SA Targan, SR Valentine, JF Wang, MH Zonca, M Rioux, JD Duerr, RH Silverberg, MS Cho, JH Hakonarson, H Zwick, ME McGovern, DPB Kugathasan, S AF Brant, Steven R. Okou, David T. Simpson, Claire L. Cutler, David J. Haritunians, Talin Bradfield, Jonathan P. Chopra, Pankaj Prince, Jarod Begum, Ferdouse Kumar, Archana Huang, Chengrui Venkateswaran, Suresh Datta, Lisa W. Wei, Zhi Thomas, Kelly Herrinton, Lisa J. Klapproth, Jan-Micheal A. Quiros, Antonio J. Seminerio, Jenifer Liu, Zhenqiu Alexander, Jonathan S. Baldassano, Robert N. Dudley-Brown, Sharon Cross, Raymond K. Dassopoulos, Themistocles Denson, Lee A. Dhere, Tanvi A. Dryden, Gerald W. Hanson, John S. Hou, Jason K. Hussain, Sunny Z. Hyams, Jeffrey S. Isaacs, Kim L. Kader, Howard Kappelman, Michael D. Katz, Jeffry Kellermayer, Richard Kirschner, Barbara S. Kuemmerle, John F. Kwon, John H. Lazarev, Mark Li, Ellen Mack, David Mannon, Peter Moulton, Dedrick E. Newberry, Rodney D. Osuntokun, Bankole O. Patel, Ashish S. Saeed, Shehzad A. Targan, Stephan R. Valentine, John F. Wang, Ming-Hsi Zonca, Martin Rioux, John D. Duerr, Richard H. Silverberg, Mark S. Cho, Judy H. Hakonarson, Hakon Zwick, Michael E. McGovern, Dermot P. B. Kugathasan, Subra TI Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease SO GASTROENTEROLOGY LA English DT Article DE SNP; Genetic Analysis; Risk Factor; Trans-Ethnic ID CROHNS-DISEASE; ULCERATIVE-COLITIS; IMMUNOCHIP ANALYSIS; RISK; VARIANTS; KOREANS; GENES AB BACKGROUND & AIMS: The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn's disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities. METHODS: We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database). Single-nucleotide polymorphisms (SNPs) associated at P < 5.0 x 10(-8) in meta-analysis with a nominal evidence (P < .05) in each scan were considered to have genome-wide significance. RESULTS: We detected SNPs at HLA-DRB1, and African-specific SNPs at ZNF649 and LSAMP, with associations of genome-wide significance for UC. We detected SNPs at USP25 with associations of genome-wide significance for IBD. No associations of genome-wide significance were detected for CD. In addition, 9 genes previously associated with IBD contained SNPs with significant evidence for replication (P < 1.6 x 10(-6)): ADCY3, CXCR6, HLA-DRB1 to HLA-DQA1 (genome-wide significance on conditioning), IL12B, PTGER4, and TNC for IBD; IL23R, PTGER4, and SNX20 (in strong linkage disequilibrium with NOD2) for CD; and KCNQ2 (near TNFRSF6B) for UC. Several of these genes, such as TNC (near TNFSF15), CXCR6, and genes associated with IBD at the HLA locus, contained SNPs with unique association patterns with African-specific alleles. CONCLUSIONS: We performed a genome-wide association study of African Americans with IBD and identified loci associated with UC in only this population; we also replicated IBD, CD, and UC loci identified in European populations. The detection of variants associated with IBD risk in only people of African descent demonstrates the importance of studying the genetics of IBD and other complex diseases in populations beyond those of European ancestry. C1 [Brant, Steven R.; Datta, Lisa W.] Johns Hopkins Univ, Sch Med, Meyerhoff Inflammatory Bowel Dis Ctr, Dept Med, Baltimore, MD USA. [Brant, Steven R.; Begum, Ferdouse] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Okou, David T.; Prince, Jarod; Venkateswaran, Suresh] Emory Univ, Dept Pediat, Sch Med, Atlanta, GA 30322 USA. [Simpson, Claire L.] Univ Tennessee Hlth Sci Ctr, Dept Genet Genom & Informat, Memphis, TN USA. [Simpson, Claire L.] NHGRI, Computat & Stat Genom Branch, NIH, Baltimore, MD USA. [Cutler, David J.] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA. [Haritunians, Talin; Liu, Zhenqiu; McGovern, Dermot P. B.] Cedars Sinai Med Ctr, F Widjaja Fdn Inflammatory Bowel, Los Angeles, CA 90048 USA. [Haritunians, Talin; Liu, Zhenqiu; Targan, Stephan R.; McGovern, Dermot P. B.] Cedars Sinai Med Ctr, Immunobiol Res Inst, Los Angeles, CA 90048 USA. Childrens Hosp Philadelphia, Abramson Res Ctr, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Bradfield, Jonathan P.; Wei, Zhi] Kaiser Permanente, Oakland, CA USA. [Herrinton, Lisa J.] Univ Penn, Philadelphia, PA 19104 USA. [Klapproth, Jan-Micheal A.] Med Univ South Carolina, Dept Pediat, Pediat Ctr Inflammatory Bowel Disorders, Summerville, SC USA. [Quiros, Antonio J.] Med Univ South Carolina, Ctr Digest Dis, Dept Gastroenterol, Summerville, SC USA. [Seminerio, Jenifer] Louisiana State Univ, Hlth Sci Ctr, Dept Mol & Cellular Physiol, Shreveport, LA 71105 USA. [Alexander, Jonathan S.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Baldassano, Robert N.] Johns Hopkins Univ, Dept Med, Sch Med, Baltimore, MD USA. [Dudley-Brown, Sharon] Sch Nursing, Baltimore, MD USA. [Dudley-Brown, Sharon] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Cross, Raymond K.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Dassopoulos, Themistocles] Cincinnati Childrens Hosp Med Ctr, Div Gastroenterol Hepatol & Nutr, Cincinnati, OH 45229 USA. [Denson, Lee A.] Emory Univ, Sch Med, Dept Med, Atlanta, GA USA. [Dhere, Tanvi A.] Univ Louisville, Dept Med, Louisville, KY 40292 USA. [Dryden, Gerald W.] Charlotte Gastroenterol & Hepatol, Charlotte, NC USA. [Hanson, John S.] Michael E DeBakey VA Med Ctr, Vet Affairs Hlth Serv Res & Dev Serv, Ctr Innovat Qual Effectiveness & Safety, Dept Med,Baylor Coll Med, Houston, TX USA. [Hou, Jason K.] Willis Knighton Phys Network, Dept Pediat, Shreveport, LA USA. [Hussain, Sunny Z.] Connecticut Childrens Med Ctr, Hartford, CT USA. [Hyams, Jeffrey S.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Isaacs, Kim L.] Univ Maryland, Dept Pediat, Sch Med, Baltimore, MD USA. [Kader, Howard] Univ N Carolina, Dept Pediat, Chapel Hill, NC USA. [Kappelman, Michael D.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Katz, Jeffry] Texas Childrens Hosp, Baylor Coll Med, Sect Pediat Gastroenterol, Houston, TX 77030 USA. [Kellermayer, Richard] Univ Chicago, Comer Childrens Hosp, Dept Pediat, Chicago, IL 60637 USA. [Kirschner, Barbara S.] Virginia Commonwealth Univ, Med Coll Virginia Campus, Med & Physiol & Biophys, Richmond, VA USA. [Kuemmerle, John F.] Univ Texas Southwestern Med Ctr, Dept Internal Med, Dallas, TX USA. [Kwon, John H.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD USA. [Lazarev, Mark] SUNY Stony Brook, Sch Med, Dept Med, Stony Brook, NY 11794 USA. [Li, Ellen] Univ Ottawa, Dept Pediat, Ottawa, ON, Canada. [Mack, David] Childrens Hosp Eastern Ontario, Ottawa, ON, Canada. [Mack, David] Univ Alabama Birmingham, Dept Med, Birmingham, AL USA. [Mannon, Peter] Vanderbilt Childrens Hosp, Nashville, TN USA. [Moulton, Dedrick E.] Washington Univ, Dept Internal Med, Sch Med, St Louis, MO USA. [Newberry, Rodney D.] Cook Childrens Med Ctr, Dept Pediat, Ft Worth, TX USA. [Osuntokun, Bankole O.] Univ Texas Southwestern Med Ctr, Dept Pediat, Dallas, TX USA. [Patel, Ashish S.] Univ Utah, Hlth Sci, Salt Lake City, UT USA. [Valentine, John F.] Mayo Clin, Div Gastroenterol & Hepatol, Jacksonville, FL USA. [Wang, Ming-Hsi] Henry Ford Hlth Syst, Dept Internal Med, Detroit, MI USA. [Zonca, Martin] Univ Montreal, Dept Med, Montreal, PQ, Canada. [Rioux, John D.] Montreal Heart Inst, Res Ctr, Montreal, PQ, Canada. [Rioux, John D.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Duerr, Richard H.] Univ Pittsburgh, Clin & Translat Sci Inst, Sch Med, Pittsburgh, PA USA. [Silverberg, Mark S.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA USA. [Cho, Judy H.] Univ Toronto, Mt Sinai Hosp, Zane Cohen Ctr Digest Dis, Dept Med, Toronto, ON, Canada. Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, Med & Genet, New York, NY USA. RP Kugathasan, S (reprint author), Emory Univ, Sch Med, Dept Pediat, Hlth Sci Res Bldg,1760 Haygood Dr, Atlanta, GA 30322 USA.; Kugathasan, S (reprint author), Emory Univ, Sch Med, Dept Human Genet, Div Pediat Gastroenterol, Hlth Sci Res Bldg,1760 Haygood Dr, Atlanta, GA 30322 USA. EM skugath@emory.edu RI Rioux, John/A-9599-2015 OI Rioux, John/0000-0001-7560-8326 FU National Institutes of Health (NIH) [DK062431, DK087694, DK062413, DK046763-19, AI067068, U54DE023789-01, DK062429, DK062422, DK062420, DK062432, DK062423]; Harvey M. and Lynn P. Meyerhoff Inflammatory Bowel Disease Center; Morton Hyatt Family; Buford and Linda Lewis family; Joshua L and Lisa Z Greer Endowed Chair; European Union [305479]; Leona M. and Harry B. Helmsley Charitable Trust; National Human Genome Research Institute (NIH); National Institute on Aging [U01AG009740, RC2AG036495, RC4AG039029] FX The National Institutes of Health (NIH) Grants DK062431 (S.R.B.), DK087694 (S.K.), DK062413 (D.P.B.M and K.T), DK046763-19, AI067068 and U54DE023789-01 (D.P.B.M.), DK062429, DK062422 (J.H.C.), DK062420 (R.H.D.), DK062432 (J.D.R.), and DK062423 (M.S.S.) supported this study. S.K. was supported by the endowed professorship from Marcus foundation; S.R.B. was supported by grant from Harvey M. and Lynn P. Meyerhoff Inflammatory Bowel Disease Center, the Morton Hyatt Family, the Buford and Linda Lewis family; D.P.B.M. was supported by the Joshua L and Lisa Z Greer Endowed Chair, grant 305479 from the European Union, and The Leona M. and Harry B. Helmsley Charitable Trust; C.L.S was supported in part by the intramural research program of the National Human Genome Research Institute (NIH). The Health and Retirement Study genetic data is sponsored by the National Institute on Aging (grant numbers U01AG009740, RC2AG036495, and RC4AG039029) and was conducted by the University of Michigan. NR 31 TC 1 Z9 1 U1 4 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD JAN PY 2017 VL 152 IS 1 BP 206 EP + DI 10.1053/j.gastro.2016.09.032 PG 14 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EG3PC UT WOS:000390956200042 PM 27693347 ER PT J AU Zhang, F Sodroski, C Cha, H Li, QS Liang, TJ AF Zhang, Fang Sodroski, Catherine Cha, Helen Li, Qisheng Liang, T. Jake TI Infection of Hepatocytes With HCV Increases Cell Surface Levels of Heparan Sulfate Proteoglycans, Uptake of Cholesterol and Lipoprotein, and Virus Entry by Up-regulating SMAD6 and SMAD7 SO GASTROENTEROLOGY LA English DT Article DE I-SMAD; Viral Entry; BMP; CTBP1 ID HEPATITIS-C-VIRUS; TGF-BETA; SCAVENGER RECEPTOR; HOST FACTORS; LIFE-CYCLE; IDENTIFICATION; BINDING; IRON; REPLICATION; ACTIVATION AB BACKGROUND & AIMS: The signaling molecule and transcriptional regulator SMAD6, which inhibits the transforming growth factor b signaling pathway, is required for infection of hepatocytes by hepatitis C virus (HCV). We investigated the mechanisms by which SMAD6 and another inhibitory SMAD (SMAD7) promote HCV infection in human hepatoma cells and hepatocytes. METHODS: We infected Huh7 and Huh7.5.1 cells and primary human hepatocytes with Japanese fulminant hepatitis-1 (JFH1) HCV cell culture system (HCVcc). We then measured HCV binding, intracellular levels of HCV RNA, and expression of target genes. We examined HCV entry in HepG2/microRNA (miR) 122/CD81 cells, which support entry and replication of HCV, were transfected these cells with small interfering RNAs targeting inhibitory SMADs to analyze gene expression profiles. Uptake of labeled low-density lipoprotein (LDL) and cholesterol was measured. Cell surface proteins were quantified by flow cytometry. We obtained liver biopsy samples from 69 patients with chronic HCV infection and 19 uninfected individuals (controls) and measured levels of syndecan 1 (SDC1), SMAD7, and SMAD6 messenger RNAs (mRNAs). RESULTS: Small interfering RNA knockdown of SMAD6 blocked the binding and infection of hepatoma cell lines and primary human hepatocytes by HCV, whereas SMAD6 overexpression increased HCV infection. We found levels of mRNAs encoding heparan sulfate proteoglycans (HSPGs), particularly SDC1 mRNA, and cell surface levels of heparan sulfate to be reduced in cells after SMAD6 knockdown. SMAD6 knockdown also reduced transcription of genes encoding lipoprotein and cholesterol uptake receptors, including the LDL receptor (LDLR), the very LDLR, and the scavenger receptor class B member 1 in hepatocytes; knockdown of SMAD6 also inhibited cell uptake of cholesterol and lipoprotein. Overexpression of SMAD6 increased the expression of these genes. Similar effects were observed with knockdown and overexpression of SMAD7. In addition, HCV infection of cells increased the expression of SMAD6, which required the activity of nuclear factor-kB, but not transforming growth factor beta. Liver tissues from patients with chronic HCV infection had significantly higher levels of SMAD6, SMAD7, and HSPG mRNAs than controls. CONCLUSIONS: In studies of hepatoma cell lines and primary human hepatocytes, we found that infection with HCV leads to activation of nuclear factor-kappa B, resulting in increased expression of SMAD6 and SMAD7. Up-regulation of SMAD6 and SMAD7 induces the expression of HSPGs, such as SDC1, as well as LDLR, very LDLR, and the scavenger receptor class B member 1, which promote HCV entry and propagation, as well as cellular uptake of cholesterol and lipoprotein. C1 [Zhang, Fang; Sodroski, Catherine; Cha, Helen; Li, Qisheng; Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bldg 10,Room 9B16,10 Ctr Dr, Bethesda, MD 20892 USA. RP Li, QS; Liang, TJ (reprint author), NIDDK, Liver Dis Branch, NIH, Bldg 10,Room 9B16,10 Ctr Dr, Bethesda, MD 20892 USA. EM liqisheng@niddk.nih.gov; jakel@bdg10.niddk.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 53 TC 1 Z9 1 U1 2 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD JAN PY 2017 VL 152 IS 1 BP 257 EP + DI 10.1053/j.gastro.2016.09.033 PG 21 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EG3PC UT WOS:000390956200046 PM 27693511 ER PT J AU Kantoff, PW Gulley, JL Pico-Navarro, C AF Kantoff, Philip W. Gulley, James L. Pico-Navarro, Cesar TI Revised Overall Survival Analysis of a Phase II, Randomized, Double-Blind, Controlled Study of PROSTVAC in Men With Metastatic Castration-Resistant Prostate Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 [Kantoff, Philip W.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Gulley, James L.] NCI, Bethesda, MD 20892 USA. [Pico-Navarro, Cesar] Bavarian Nord, Redwood City, CA USA. RP Kantoff, PW (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 1 PY 2017 VL 35 IS 1 BP 124 EP + DI 10.1200/JCO.2016.69.7748 PG 4 WC Oncology SC Oncology GA EG9LV UT WOS:000391381300026 PM 27646950 ER PT J AU Taieb, D Patronas, NJ Pacak, K AF Taieb, David Patronas, Nicholas J. Pacak, Karel TI Ga-68-DOTATATE PET/CT Versus MRI: Why the Comparison of Ga-68-DOTATATE PET/CT to an Appropriate MRI Protocol Is Essential REPLY SO JOURNAL OF NUCLEAR MEDICINE LA English DT Letter C1 [Taieb, David; Patronas, Nicholas J.; Pacak, Karel] NIH, CRC, Room 1E-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), NIH, CRC, Room 1E-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU Intramural NIH HHS [ZIA HD008735-15] NR 5 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD JAN PY 2017 VL 58 IS 1 BP 185 EP 185 DI 10.2967/jnumed.116.180109 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EG8YM UT WOS:000391343400042 PM 27493265 ER PT J AU Resnik, DB Konecny, B Kissling, GE AF Resnik, David B. Konecny, Brandon Kissling, Grace E. TI Conflict of Interest and Funding Disclosure Policies of Environmental, Occupational, and Public Health Journals SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID PEER-REVIEWED JOURNALS; BIOMEDICAL-RESEARCH; SCIENCE; SPONSORSHIP; OUTCOMES; QUALITY; IMPACT; BIAS AB Objective: The aim of this study was to analyze conflict of interest (COI) and funding disclosure policies of 224 journals listed in Journal Citation Reports as focusing on environmental, occupational, or public health research. Methods: A survey of journal policies and content analysis. Results: About 96.0% of the policies required COI disclosure, 92.4% required funding disclosure, 75.9% defined COIs, 69.6% provided examples of COIs, 68.8% addressed nonfinancial COIs, 33.9% applied to editors and reviewers, 32.1% required discussion of the role of the funding source, and 1.8% included enforcement mechanisms. Policies were significantly associated with journal impact factor and publisher. Conclusion: Although a high percentage of journals in our sample have COI policies that provide substantial guidance to authors, there is a room for improvement. Journals that have not done so should consider developing enforcement mechanisms and applying COI policies to editors and reviewers. C1 [Resnik, David B.] NIEHS, Eth Off, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Konecny, Brandon] North Carolina Cent Univ, Durham, NC USA. [Kissling, Grace E.] NIEHS, Biostat & Computat Biol Branch, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, Alexander Dr,POB 12233,Mail Drop E1-06, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU Intramural Research Program of the NIEHS/NIH FX Funding for this study was provided by Intramural Research Program of the NIEHS/NIH. 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 1076-2752 EI 1536-5948 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD JAN PY 2017 VL 59 IS 1 BP 28 EP 33 DI 10.1097/JOM.0000000000000910 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EG5ZI UT WOS:000391123100007 PM 28045794 ER PT J AU Hsu, CY Xie, DW Waikar, SS Bonventre, JV Zhang, XM Sabbisetti, V Mifflin, TE Coresh, J Diamantidis, CJ He, J Lora, CM Miller, ER Nelson, RG Ojo, AO Rahman, M Schelling, JR Wilson, FP Kimmel, PL Feldman, HI Vasan, RS Liu, KD AF Hsu, Chi-yuan Xie, Dawei Waikar, Sushrut S. Bonventre, Joseph V. Zhang, Xiaoming Sabbisetti, Venkata Mifflin, Theodore E. Coresh, Josef Diamantidis, Clarissa J. He, Jiang Lora, Claudia M. Miller, Edgar R. Nelson, Robert G. Ojo, Akinlolu O. Rahman, Mahboob Schelling, Jeffrey R. Wilson, Francis P. Kimmel, Paul L. Feldman, Harold I. Vasan, Ramachandran S. Liu, Kathleen D. CA CRIC Study Investigators CKD Biomarkers Consortium TI Urine biomarkers of tubular injury do not improve on the clinical model predicting chronic kidney disease progression SO KIDNEY INTERNATIONAL LA English DT Article DE chronic kidney disease; microalbuminuria; proteinuria ID GELATINASE-ASSOCIATED LIPOCALIN; RENAL-INSUFFICIENCY COHORT; GLOMERULAR-FILTRATION-RATE; TYPE-1 DIABETIC-PATIENTS; ACID-BINDING PROTEIN; BASE-LINE CHARACTERISTICS; TNF RECEPTORS 1; PROXIMAL TUBULE; RISK PREDICTION; MOLECULE-1 KIM-1 AB Few investigations have evaluated the incremental usefulness of tubular injury biomarkers for improved prediction of chronic kidney disease (CKD) progression. As such, we measured urinary kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, N-acetyl-ss-D-glucosaminidase and liver fatty acid binding protein under highly standardized conditions among 2466 enrollees of the prospective Chronic Renal Insufficiency Cohort Study. During 9433 person-years of follow-up, there were 581 cases of CKD progression defined as incident end-stage renal disease or halving of the estimated glomerular filtration rate. Levels of the urine injury biomarkers, normalized for urine creatinine, were strongly associated with CKD progression in unadjusted Cox proportional hazard models with hazard ratios in the range of 7 to 13 comparing the highest with the lowest quintiles. However, after controlling for the serum creatinine-based estimated glomerular filtration rate and urinary albumin/creatinine ratio, none of the normalized biomarkers was independently associated with CKD progression. None of the biomarkers improved on the high (0.89) C-statistic for the base clinical model. Thus, among patients with CKD, risk prediction with a clinical model that includes the serum creatinine-based estimated glomerular filtration rate and the Urinary albumin/creatinine ratio is not improved on with the addition of renal tubular injury biomarkers. C1 [Hsu, Chi-yuan; Liu, Kathleen D.] Univ Calif San Francisco, San Francisco, CA USA. [Hsu, Chi-yuan] Kaiser Permanente Northern Calif, Oakland, CA USA. [Xie, Dawei; Zhang, Xiaoming; Mifflin, Theodore E.; Feldman, Harold I.] Univ Penn, Philadelphia, PA USA. [Waikar, Sushrut S.; Bonventre, Joseph V.; Sabbisetti, Venkata] Brigham & Womens Hosp, Boston, MA USA. [Coresh, Josef; Miller, Edgar R.] Johns Hopkins Univ, Baltimore, MD USA. [Diamantidis, Clarissa J.] Duke Univ, Durham, NC USA. [He, Jiang] Tulane Univ, New Orleans, LA USA. [Lora, Claudia M.] Univ Illinois, Chicago, IL USA. [Nelson, Robert G.] NIDDK, Phoenix, AZ USA. [Ojo, Akinlolu O.] Univ Michigan, Ann Arbor, MI USA. [Rahman, Mahboob; Schelling, Jeffrey R.] Case Western Reserve Univ, Cleveland, OH USA. [Wilson, Francis P.] Yale Univ, New Haven, CT USA. [Kimmel, Paul L.] NIDDK, Bethesda, MD 20892 USA. [Vasan, Ramachandran S.] Boston Univ, Boston, MA USA. RP Hsu, CY (reprint author), Univ Calif San Francisco, Div Nephrol, 533 Parnassus Ave,U-400 Box 0532, San Francisco, CA 94143 USA. EM hsuchi@medicine.ucsf.edu FU CKD Biomarkers Consortium; Chronic Kidney Disease Biomarkers Consortium - NIDDK [U01DK85649, U01DK085673, U01DK085660, U01DK085688, U01DK085651, U01DK085689]; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Diabetes and Digestive and Kidney Diseases [U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902]; Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award [NIH/NCATS UL1TR000003]; Johns Hopkins University [UL1 TR-000424]; University of Maryland [GCRC M01 RR-16500]; Clinical and Translational Science Collaborative of Cleveland; National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health [UL1TR000439]; NIH roadmap for Medical Research; Michigan Institute for Clinical and Health Research (MICHR) [UL1TR000433]; University of Illinois at Chicago [CTSA UL1RR029879]; Tulane University Translational Research in Hypertension and Renal Biology [P30GM103337]; Kaiser Permanente NIH/NCRR UCSF-CTSI [UL1 RR-024131] FX This study was carried out under the auspices of the CKD Biomarkers Consortium, which was established in 2008 by the National Institute of Diabetes and Digestive and Kidney Diseases to advance the field of CKD biomarker discovery and validation (http://grants.nih.gov/grants/guide/rfa-files/RFA-DK-08-015.html). This work was supported by the Chronic Kidney Disease Biomarkers Consortium funded by NIDDK U01DK85649, U01DK085673, U01DK085660, U01DK085688, U01DK085651, and U01DK085689 and by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. Funding for the CRIC Study was obtained under a cooperative agreement from National Institute of Diabetes and Digestive and Kidney Diseases (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902). In addition, this work was supported in part by the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award NIH/NCATS UL1TR000003, Johns Hopkins University UL1 TR-000424, University of Maryland GCRC M01 RR-16500, Clinical and Translational Science Collaborative of Cleveland, UL1TR000439 from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health and NIH roadmap for Medical Research, Michigan Institute for Clinical and Health Research (MICHR) UL1TR000433, University of Illinois at Chicago CTSA UL1RR029879, Tulane University Translational Research in Hypertension and Renal Biology P30GM103337, and Kaiser Permanente NIH/NCRR UCSF-CTSI UL1 RR-024131. NR 69 TC 1 Z9 1 U1 9 U2 9 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 JAN PY 2017 VL 91 IS 1 BP 196 EP 203 DI 10.1016/j.kint.2016.09.003 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA EG6NH UT WOS:000391162700023 PM 28029431 ER PT J AU Osafo, C Adu, D Mims, MM Parekh, R AF Osafo, Charlotte Adu, Dwomoa Mims, Marva Moxey Parekh, Rulan TI Counterfeit and substandard drugs in Sub-Saharan Africa may pose a major hurdle to H3Africa's initiative to study genetics of kidney disease progression Reply SO KIDNEY INTERNATIONAL LA English DT Letter C1 [Osafo, Charlotte; Adu, Dwomoa] Univ Ghana, Coll Hlth Sci, Sch Med & Dent, Dept Med & Therapeut, Accra, Ghana. [Mims, Marva Moxey] NIDDK, NIH, Bethesda, MD 20892 USA. [Parekh, Rulan] Univ Toronto, Hosp Sick Children, Univ Hlth Network, Dept Pediat, Toronto, ON, Canada. [Parekh, Rulan] Univ Toronto, Hosp Sick Children, Univ Hlth Network, Dept Med, Toronto, ON, Canada. RP Osafo, C (reprint author), Univ Ghana, Coll Hlth Sci, Sch Med & Dent, Dept Med & Therapeut, Accra, Ghana. EM ceyosafo@gmail.com NR 2 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 JAN PY 2017 VL 91 IS 1 BP 253 EP 253 DI 10.1016/j.kint.2016.09.025 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA EG6NH UT WOS:000391162700030 PM 28003085 ER PT J AU Larmour, S Chow, K Kellman, P Thompson, RB AF Larmour, Sarah Chow, Kelvin Kellman, Peter Thompson, Richard B. TI Characterization of T-1 bias in skeletal muscle from fat in MOLLI and SASHA pulse sequences: Quantitative fat-fraction imaging with T-1 mapping SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE T-1 map; SASHA; MOLLI; fat fraction; fat; bSSFP ID INVERSION-RECOVERY MOLLI; MAGNETIC-RESONANCE; T1 VALUES; HEART; MRI; QUANTIFICATION; PRECISION; ACCURACY AB PurposeTo characterize the effects of fat on commonly used T-1 mapping sequences and evaluate a new method of quantitative fat fraction (FF) imaging for low fractions based on the modulation of T-1 values by the fat pool. MethodsBloch equation simulations and phantom and in vivo (skeletal muscle) experiments were used to characterize the response of the modified Look-Locker inversion recovery (MOLLI) and saturation recovery single-shot acquisition (SASHA) T-1 mapping sequences to fat-water systems with known FFs (0%-10%) at 1.5T. FFs were measured with single voxel spectroscopy and Dixon imaging methods. A new T-1-based FF imaging method was evaluated using Monte Carlo simulations and phantom and in vivo experiments. ResultsSASHA and MOLLI had similar T-1 dependence on FF, with characteristic under- or overestimation of T-1 values as a function of off-resonance frequency (30-70 ms variation in native T-1 per 1% FF). FF maps generated from the SASHA method yielded a low variability of 0.25% for a signal-to-noise ratio of 150:1 in the nonsaturation image, with good agreement with spectroscopy and a performance that is superior to that of Dixon methods at low FFs. ConclusionFat results in negative or positive shifts in native tissue T-1 measured with MOLLI and SASHA over a narrow range of off-resonance frequencies; T-1 shifts from fat can be used to accurately quantify FF. Magn Reson Med 77:237-249, 2017. (c) 2016 Wiley Periodicals, Inc. C1 [Larmour, Sarah; Chow, Kelvin; Thompson, Richard B.] Univ Alberta, Biomed Engn, Edmonton, AB, Canada. [Kellman, Peter] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Thompson, RB (reprint author), Univ Alberta, Dept Biomed Engn, Res Transit Facil 1082, Edmonton, AB T6G 2V2, Canada. EM richard.thompson@ualberta.ca NR 28 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD JAN PY 2017 VL 77 IS 1 BP 237 EP 249 DI 10.1002/mrm.26113 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EG4UI UT WOS:000391038800025 PM 26860524 ER PT J AU Inati, SJ Naegele, JD Zwart, NR Roopchansingh, V Lizak, MJ Hansen, DC Liu, CY Atkinson, D Kellman, P Kozerke, S Xue, H Campbell-Washburn, AE Sorensen, TS Hansen, MS AF Inati, Souheil J. Naegele, Joseph D. Zwart, Nicholas R. Roopchansingh, Vinai Lizak, Martin J. Hansen, David C. Liu, Chia-Ying Atkinson, David Kellman, Peter Kozerke, Sebastian Xue, Hui Campbell-Washburn, Adrienne E. Sorensen, Thomas S. Hansen, Michael S. TI ISMRM Raw data format: A proposed standard for MRI raw datasets SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE magnetic resonance imaging; image reconstruction; open source; raw data format AB PurposeThis work proposes the ISMRM Raw Data format as a common MR raw data format, which promotes algorithm and data sharing. MethodsA file format consisting of a flexible header and tagged frames of k-space data was designed. Application Programming Interfaces were implemented in C/C++, MATLAB, and Python. Converters for Bruker, General Electric, Philips, and Siemens proprietary file formats were implemented in C++. Raw data were collected using magnetic resonance imaging scanners from four vendors, converted to ISMRM Raw Data format, and reconstructed using software implemented in three programming languages (C++, MATLAB, Python). ResultsImages were obtained by reconstructing the raw data from all vendors. The source code, raw data, and images comprising this work are shared online, serving as an example of an image reconstruction project following a paradigm of reproducible research. ConclusionThe proposed raw data format solves a practical problem for the magnetic resonance imaging community. It may serve as a foundation for reproducible research and collaborations. The ISMRM Raw Data format is a completely open and community-driven format, and the scientific community is invited (including commercial vendors) to participate either as users or developers. Magn Reson Med 77:411-421, 2017. (c) 2016 Wiley Periodicals, Inc. C1 [Inati, Souheil J.; Naegele, Joseph D.; Roopchansingh, Vinai] NIMH, NIH, Bethesda, MD 20892 USA. [Zwart, Nicholas R.] Barrow Neurol Inst, Keller Ctr Imaging Innovat, Phoenix, AZ 85013 USA. [Lizak, Martin J.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Hansen, David C.] Aarhus Univ Hosp, Dept Oncol, Aarhus, Denmark. [Liu, Chia-Ying] NIH, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Atkinson, David] UCL, Ctr Med Image Comp, London, England. [Kellman, Peter; Xue, Hui; Campbell-Washburn, Adrienne E.; Hansen, Michael S.] NHLBI, NIH, NIH Bldg 10-B1D405,10 Ctr Dr, Bethesda, MD 20892 USA. [Kozerke, Sebastian] Univ Zurich, Inst Biomed Engn, Zurich, Switzerland. [Kozerke, Sebastian] Swiss Fed Inst Technol, Zurich, Switzerland. [Sorensen, Thomas S.] Aarhus Univ, Dept Clin Med, Aarhus, Denmark. RP Hansen, MS (reprint author), NHLBI, NIH, NIH Bldg 10-B1D405,10 Ctr Dr, Bethesda, MD 20892 USA. EM michael.hansen@nih.gov RI Atkinson, David/C-2270-2008; OI Atkinson, David/0000-0003-1124-6666; Sorensen, Thomas Sangild/0000-0002-8482-7667 FU NIH; NHLBI; NIMH; NINDS FX Grant sponsors: Intramural Research Program of the NIH, NHLBI, NIMH, NINDS. NR 11 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD JAN PY 2017 VL 77 IS 1 BP 411 EP 421 DI 10.1002/mrm.26089 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EG4UI UT WOS:000391038800041 PM 26822475 ER PT J AU Bertocchi, C Wang, Y Ravasio, A Hara, Y Wu, Y Sailov, T Baird, MA Davidson, MW Zaidel-Bar, R Toyama, Y Ladoux, B Mege, RM Kanchanawoneu, P AF Bertocchi, Cristina Wang, Yilin Ravasio, Andrea Hara, Yusuke Wu, Yao Sailov, Talgat Baird, Michelle A. Davidson, Michael W. Zaidel-Bar, Ronen Toyama, Yusuke Ladoux, Benoit Mege, Rene-Marc Kanchanawoneu, Pakorn TI Nanoscale architecture of cadherin-based cell adhesions SO NATURE CELL BIOLOGY LA English DT Article ID ALPHA-CATENIN; ADHERENS JUNCTIONS; VINCULIN BINDING; BETA-CATENIN; ACTIN; MICROSCOPY; TENSION; DYNAMICS; COMPLEX; TALIN AB Multicellularity in animals requires dynamic maintenance of cell-cell contacts. Intercellularly ligated cadherins recruit numerous proteins to form supramolecular complexes that connect with the actin cytoskeleton and support force transmission. However, the molecular organization within such structures remains unknown. Here we mapped protein organization in cadherin-based adhesions by super-resolution microscopy, revealing a multi -compartment nanoscale architecture, with the plasma -membrane-proximal cadherin-catenin compartment segregated from the actin cytoskeletal compartment, bridged by an interface zone containing vinculin. Vinculin position is determined by alpha-catenin, and following activation, vinculin can extend similar to 30 nm to bridge the cadherin-catenin and actin compartments, while modulating the nanoscale positions of the actin regulators zyxin and VASP. Vinculin conformational activation requires tension and tyrosine phosphorylation, regulated by Abl kinase and PTP1B phosphatase. Such modular architecture provides a structural framework for mechanical and biochemical signal integration by vinculin, which may differentially engage cadherin-catenin complexes with the actomyosin machinery to regulate cell adhesions. C1 [Bertocchi, Cristina; Wang, Yilin; Ravasio, Andrea; Hara, Yusuke; Wu, Yao; Sailov, Talgat; Zaidel-Bar, Ronen; Toyama, Yusuke; Ladoux, Benoit; Kanchanawoneu, Pakorn] Mechanobiol Inst, Singapore 117411, Singapore. [Baird, Michelle A.; Davidson, Michael W.] Florida State Univ, Natl High Magnet Field Lab, Tallahassee, FL 32310 USA. [Davidson, Michael W.] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA. [Zaidel-Bar, Ronen; Kanchanawoneu, Pakorn] Natl Univ Singapore, Dept Biomed Engn, Singapore 117583, Singapore. [Toyama, Yusuke] Natl Univ Singapore, Dept Biol Sci, Singapore 117543, Singapore. [Toyama, Yusuke] Natl Univ Singapore, Temasek Life Sci Lab, Singapore 117604, Singapore. [Ladoux, Benoit; Mege, Rene-Marc] Univ Paris Diderot, Inst Jacques Monod, CNRS UMR 7592, Paris, France. [Wang, Yilin] South Univ Sci & Technol, Dept Biol, Shenzhen 518055, Peoples R China. [Sailov, Talgat] Nanyang Technol Univ, Singapore Ctr Environm Life Sci Engn, Singapore 637551, Singapore. [Baird, Michelle A.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Kanchanawoneu, P (reprint author), Mechanobiol Inst, Singapore 117411, Singapore.; Kanchanawoneu, P (reprint author), Natl Univ Singapore, Dept Biomed Engn, Singapore 117583, Singapore. EM biekp@nus.edu.sg RI Toyama, Yusuke/H-8023-2012; OI Toyama, Yusuke/0000-0003-3230-1062; Mege, Rene-Marc/0000-0001-8128-5543; Hara, Yusuke/0000-0002-2005-7704 FU Singapore National Research Foundation Fellowship [NRF-NRFF-2011-04, NRF-RF2009-RF001-074, NRF2012NRF-CRP001-084]; Mechanobiology Institute; National University of Singapore Startup Grants; Singapore Ministry of Education Tier 2 grant [MOE2015-T2-1-116]; European Research Council under the European Union's Seventh Framework Programme (FP7)/ERC [617233]; Institut Universitaire de France; USPC-NUS; CNRS; Human Frontier Science Program [RGP0040/2012]; Agence Nationale de la Recherche [ANR 2010 Blan1515] FX We thank C. Ajo-Franklin (Lawrence Berkeley National Laboratory), G. Shtengel and H. Hess (Howard Hughes Medical Institute, Janelia Research Campus) for generous help with super-resolution microscopy instrumentation and analysis. We thank H. Chen (Protein Expression Facility, Mechanobiology Institute, Singapore) for generation of mutant constructs, H. T. Ong and A. Sathe (Mechanobiology Institute) for assistance with FRET analysis, C. Zhang (Mechanobiology Institute) for assistance with 3D graphical model, and J. Yan (National University of Singapore) for critical reading of the manuscript. P.K., C.B., Y.Wang, A.R., T.S. and R.Z.-B. are supported by Singapore National Research Foundation Fellowship awarded to P.K. (NRF-NRFF-2011-04), R.Z.-B. (NRF-RF2009-RF001-074), and Competitive Research Programme (NRF2012NRF-CRP001-084) to P.K. and R.Z.-B. Y.T. is supported by Mechanobiology Institute and National University of Singapore Startup Grants, and a Singapore Ministry of Education Tier 2 grant (MOE2015-T2-1-116). B.L. is supported by the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013/ERC grant agreement no. 617233), the Mechanobiology Institute, and the Institut Universitaire de France, and USPC-NUS funding. B.L. and R.-M.M. are also supported by CNRS, the Human Frontier Science Program (grant RGP0040/2012) and Agence Nationale de la Recherche (ANR 2010 Blan1515). NR 51 TC 1 Z9 1 U1 16 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 EI 1476-4679 J9 NAT CELL BIOL JI Nat. Cell Biol. PD JAN PY 2017 VL 19 IS 1 BP 28 EP 37 DI 10.1038/ncb3456 PG 10 WC Cell Biology SC Cell Biology GA EG9AI UT WOS:000391349000006 PM 27992406 ER PT J AU Gattinoni, L Speiser, DE Lichterfeld, M Bonini, C AF Gattinoni, Luca Speiser, Daniel E. Lichterfeld, Mathias Bonini, Chiara TI T memory stem cells in health and disease SO NATURE MEDICINE LA English DT Review ID CHIMERIC ANTIGEN RECEPTOR; SUPERIOR ANTITUMOR IMMUNITY; CHRONIC VIRAL-INFECTION; VERSUS-HOST-DISEASE; ADOPTIVE IMMUNOTHERAPY; BONE-MARROW; IN-VIVO; B-CELL; ANTIRETROVIRAL THERAPY; LINEAGE RELATIONSHIP AB T memory stem (TscM) cells are a rare subset of memory lymphocytes endowed with the stem cell like ability to self-renew and the multipotent capacity to reconstitute the entire spectrum of memory and effector T cell subsets. Cumulative evidence in mice, nonhuman primates and humans indicates that Tscm cells are minimally differentiated cells at the apex of the hierarchical system of memory T lymphocytes. Here we describe emerging findings demonstrating that Tscm cells, owing to their extreme longevity and robust potential for immune reconstitution, are central players in many physiological and pathological human processes. We also discuss how Tscm cell stemness could be leveraged therapeutically to enhance the efficacy of vaccines and adoptive T cell therapies for cancer and infectious diseases or, conversely, how it could be disrupted to treat Tscm cell driven and sustained diseases, such as autoimmunity, adult T cell leukemia and HIV-1. C1 [Gattinoni, Luca] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Speiser, Daniel E.] Univ Lausanne Hosp, Ludwig Canc Res, Dept Oncol, Lausanne, Switzerland. [Lichterfeld, Mathias] Harvard Med Sch, Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Bonini, Chiara] Ist Sci San Raffaele, Div Immunol Transplantat & Infect Dis, Expt Hematol Unit, Leukemia Unit, Milan, Italy. [Bonini, Chiara] Univ Vita Salute San Raffaele, Hematol Dept, Milan, Italy. RP Gattinoni, L (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.; Speiser, DE (reprint author), Univ Lausanne Hosp, Ludwig Canc Res, Dept Oncol, Lausanne, Switzerland.; Lichterfeld, M (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA.; Bonini, C (reprint author), Ist Sci San Raffaele, Div Immunol Transplantat & Infect Dis, Expt Hematol Unit, Leukemia Unit, Milan, Italy.; Bonini, C (reprint author), Univ Vita Salute San Raffaele, Hematol Dept, Milan, Italy. EM gattinol@mail.nih.gov; doc@dspeiser.ch; mlichterfeld@mgh.harvard.edu; bonini.chiara@hsr.it RI Gattinoni, Luca/A-2281-2008 OI Gattinoni, Luca/0000-0003-2239-3282 FU Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research [ZIABC011480]; US National Institutes of Health (NIH) Bench-to-Bedside Award; NIH [AI098487, AI106468, AI114235, AI117841, AI120008, AI124776]; Cancer Research Institute; Ludwig Cancer Research; Swiss Cancer League [3507-08-2014]; Swiss National Science Foundation [320030_152856, CRSII3_160708]; SwissTransMed [KIP 18]; Italian Association for Cancer Research; SUPERSIST (EU-FP7 project) FX This work was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research (ZIABC011480), the 2014 US National Institutes of Health (NIH) Bench-to-Bedside Award, (to L.G.) NIH grants AI098487, AI106468, AI114235, AI117841, AI120008, AI124776 (to M.L.), the Cancer Research Institute (N.Y.), the Ludwig Cancer Research (N.Y.), the Swiss Cancer League (3507-08-2014), the Swiss National Science Foundation (320030_152856, CRSII3_160708), the SwissTransMed (KIP 18) (to D.E.S.), the Italian Association for Cancer Research and the SUPERSIST (EU-FP7 project) (to C.B.). NR 158 TC 0 Z9 0 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD JAN PY 2017 VL 23 IS 1 BP 18 EP 27 DI 10.1038/nm.4241 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA EH3CN UT WOS:000391646800010 PM 28060797 ER PT J AU Huang, BH Faucette, AN Pawlitz, MD Pei, B Goyert, JW Zhou, JZ El-Hage, NG Deng, J Lin, J Yao, FY Dewar, RS Jassal, JS Sandberg, ML Dai, J Cols, M Shen, C Polin, LA Nichols, RA Jones, TB Bluth, MH Puder, KS Gonik, B Nayak, NR Puscheck, E Wei, WZ Cerutti, A Colonna, M Chen, K AF Huang, Bihui Faucette, Azure N. Pawlitz, Michael D. Pei, Bo Goyert, Joshua W. Zhou, Jordan Zheng El-Hage, Nadim G. Deng, Jie Lin, Jason Yao, Fayi Dewar, Robert S., III Jassal, Japnam S. Sandberg, Maxwell L. Dai, Jing Cols, Montserrat Shen, Cong Polin, Lisa A. Nichols, Ronald A. Jones, Theodore B. Bluth, Martin H. Puder, Karoline S. Gonik, Bernard Nayak, Nihar R. Puscheck, Elizabeth Wei, Wei-Zen Cerutti, Andrea Colonna, Marco Chen, Kang TI Interleukin-33-induced expression of PIBF1 by decidual B cells protects against preterm labor SO NATURE MEDICINE LA English DT Article ID INDUCED BLOCKING FACTOR; REGULATORY T-CELLS; PROGESTERONE; PREGNANCY; MICE; LIPOPOLYSACCHARIDE; PREECLAMPSIA; AUTOIMMUNE; BIRTH; RESISTANCE AB Preterm birth (PTB) is a leading cause of neonatal death worldwide(1). Intrauterine and systemic infection and inflammation cause 30-40% of spontaneous preterm labor (PTL)(2), which precedes PTB. Although antibody production is a major immune defense mechanism against infection, and B cell dysfunction has been implicated in pregnancy complications associated with PTL3,4, the functions of B cells in pregnancy are not well known(5-8). We found that choriodecidua of women undergoing spontaneous PTL harbored functionally altered B cell populations. B cell-deficient mice were markedly more susceptible than wild-type (WT) mice to PTL after inflammation, but B cells conferred interleukin (IL)-10-independent protection against PTL. B cell deficiency in mice resulted in a lower uterine level of active progesterone-induced blocking factor 1 (PIBF1), and therapeutic administration of PIBF1 mitigated PTL and uterine inflammation in B cell-deficient mice. B cells are a significant producer of PIBF1 in human choriodecidua and mouse uterus in late gestation. PIBF1 expression by B cells is induced by the mucosal alarmin IL-33 (ref. 9). Human PTL was associated with diminished expression of the alpha-chain of IL-33 receptor on choriodecidual B cells and a lower level of active PIBF1 in late gestation choriodecidua. These results define a vital regulatory cascade involving IL-33, decidual B cells and PIBF1 in safeguarding term pregnancy and suggest new therapeutic approaches based on IL-33 and PIBF1 to prevent human PTL. C1 [Huang, Bihui; Faucette, Azure N.; Pawlitz, Michael D.; Pei, Bo; Goyert, Joshua W.; Zhou, Jordan Zheng; El-Hage, Nadim G.; Lin, Jason; Yao, Fayi; Dewar, Robert S., III; Jassal, Japnam S.; Dai, Jing; Nichols, Ronald A.; Jones, Theodore B.; Puder, Karoline S.; Gonik, Bernard; Nayak, Nihar R.; Puscheck, Elizabeth; Chen, Kang] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48202 USA. [Sandberg, Maxwell L.] Yale Sch Med, Dept Obstet Gynecol & Reprod Sci, New Haven, CT USA. [Cols, Montserrat; Shen, Cong] Union Coll, Leadership Med Program, Schenectady, NY 12308 USA. [Polin, Lisa A.; Wei, Wei-Zen; Chen, Kang] Mem Sloan Kettering Canc Ctr, Program Immunol, 1275 York Ave, New York, NY 10021 USA. [Polin, Lisa A.; Chen, Kang] Wayne State Univ, Dept Oncol, Detroit, MI 48202 USA. [Nichols, Ronald A.; Jones, Theodore B.] Beaumont Dearborn Hosp, Dept Obstet & Gynecol Med Ed, Dearborn, MI USA. [Bluth, Martin H.] Wayne State Univ, Dept Pathol, Detroit, MI 48202 USA. [Cerutti, Andrea] Catalan Inst Res & Adv Studies, Barcelona Biomed Res Pk, Barcelona, Spain. [Cerutti, Andrea] Inst Hosp Mar Invest Med, Program Inflammatory & Cardiovasc Disorders, Barcelona, Spain. [Cerutti, Andrea] Icahn Sch Med Mt Sinai, Inst Immunol, New York, NY 10029 USA. [Cerutti, Andrea; Colonna, Marco; Chen, Kang] NIAID, Mucosal Immunol Studies Team, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Faucette, Azure N.; Colonna, Marco] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA. [Faucette, Azure N.] CUNY, Kingsborough Community Coll, Dept Biol, Brooklyn, NY USA. RP Chen, K (reprint author), Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48202 USA.; Chen, K (reprint author), Mem Sloan Kettering Canc Ctr, Program Immunol, 1275 York Ave, New York, NY 10021 USA.; Chen, K (reprint author), Wayne State Univ, Dept Oncol, Detroit, MI 48202 USA.; Chen, K (reprint author), NIAID, Mucosal Immunol Studies Team, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kang@wayne.edu FU Burroughs Wellcome Fund; US National Institutes of Health [U01AI95776, R21AI122256, P30CA22453]; American Congress of Obstetricians and Gynecologists; Wayne State University (Perinatal Initiative); Wayne State University Office of the Vice President for Research FX We thank the European Conditional Mouse Mutagenesis Program and Barry Rosen (Wellcome Trust Sanger Institute) for mouse 1133 targeting vectors, the NIAID Mucosal Immunology Studies Team (MIST) mouse core for generating the Il33-/- lacZ reporter mice, and M. Treadwell (University of Michigan at Ann Arbor) and X. Xu (Bristol-Myers Squibb) for discussion of the manuscript. This study was supported by grants from the Burroughs Wellcome Fund (Preterm Birth Initiative), US National Institutes of Health (U01AI95776 MIST Young Investigator Award, R21AI122256, P30CA22453), American Congress of Obstetricians and Gynecologists and Wayne State University (Perinatal Initiative) (to K.C.). A.N.F. was partially supported by a fellowship from the Wayne State University Office of the Vice President for Research. NR 40 TC 0 Z9 0 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD JAN PY 2017 VL 23 IS 1 BP 128 EP 135 DI 10.1038/nm.4244 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA EH3CN UT WOS:000391646800022 PM 27918564 ER PT J AU Navid, F Colbert, RA AF Navid, Fatemeh Colbert, Robert A. TI Causes and consequences of endoplasmic reticulum stress in rheumatic disease SO NATURE REVIEWS RHEUMATOLOGY LA English DT Review ID UNFOLDED-PROTEIN-RESPONSE; TUMOR-NECROSIS-FACTOR; SYSTEMIC-LUPUS-ERYTHEMATOSUS; IDIOPATHIC INFLAMMATORY MYOPATHIES; TRANSCRIPTION FACTOR XBP-1; THIOREDOXIN-INTERACTING PROTEIN; PLASMA-CELL DIFFERENTIATION; INDUCIBLE GENE-EXPRESSION; C/EBP HOMOLOGOUS PROTEIN; GENOME-WIDE ASSOCIATION AB Rheumatic diseases represent a heterogeneous group of inflammatory conditions, many of which involve chronic activation of both innate and adaptive immune responses by multiple genetic and environmental factors. These immune responses involve the secretion of excessive amounts of cytokines and other signalling mediators by activated immune cells. The endoplasmic reticulum (ER) is the cellular organelle that directs the folding, processing and trafficking of membrane-bound and secreted proteins, including many key components of the immune response. Maintaining homeostasis in the ER is critical to cell function and survival. Consequently, elaborate mechanisms have evolved to sense and respond to ER stress through three main signalling pathways that together comprise the unfolded protein response (UPR). Activation of the UPR can rapidly resolve the accumulation of misfolded proteins, direct permanent changes in the size and function of cells during differentiation, and critically influence the immune response and inflammation. Recognition of the importance of ER stress and UPR signalling pathways in normal and dysregulated immune responses has greatly increased in the past few years. This Review discusses several settings in which ER stress contributes to the pathogenesis of rheumatic diseases and considers some of the therapeutic opportunities that these discoveries provide. C1 [Navid, Fatemeh; Colbert, Robert A.] Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, Pediat Translat Res Branch, NIH, Bldg 10,Room 12N248B,10 Ctr Dr, Bethesda, MD 20892 USA. RP Colbert, RA (reprint author), Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, Pediat Translat Res Branch, NIH, Bldg 10,Room 12N248B,10 Ctr Dr, Bethesda, MD 20892 USA. EM colbertr@mail.nih.gov FU NIH; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Intramural Research Program [ZO1-AR-041184] FX The research of R.A.C. and F.N. is supported by the NIH and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Intramural Research Program grant ZO1-AR-041184. NR 237 TC 0 Z9 0 U1 6 U2 6 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 JAN PY 2017 VL 13 IS 1 BP 25 EP 40 DI 10.1038/nrrheum.2016.192 PG 16 WC Rheumatology SC Rheumatology GA EG8YR UT WOS:000391344100006 PM 27904144 ER PT J AU Lobanov, AV Heaphy, SM Turanov, AA Gerashchenko, MV Pucciarelli, S Devaraj, RR Xie, F Petyuk, VA Smith, RD Klobutcher, LA Atkins, JF Miceli, C Hatfield, DL Baranov, PV Gladyshev, VN AF Lobanov, Alexei V. Heaphy, Stephen M. Turanov, Anton A. Gerashchenko, Maxim V. Pucciarelli, Sandra Devaraj, Raghul R. Xie, Fang Petyuk, Vladislav A. Smith, Richard D. Klobutcher, Lawrence A. Atkins, John F. Miceli, Cristina Hatfield, Dolph L. Baranov, Pavel V. Gladyshev, Vadim N. TI Position-dependent termination and widespread obligatory frameshifting in Euplotes translation SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID CILIATE; DNA; SLIPPAGE; SCALE; YEAST; GENE; RNAS AB The ribosome can change its reading frame during translation in a process known as programmed ribosomal frameshifting. These rare events are supported by complex mRNA signals. However, we found that the ciliates Euplotes crassus and Euplotes focardii exhibit widespread frameshifting at stop codons. 47 different codons preceding stop signals resulted in either +1 or +2 frameshifts, and +1 frameshifting at AAA was the most frequent. The frameshifts showed unusual plasticity and rapid evolution, and had little influence on translation rates. The proximity of a stop codon to the 3' mRNA end, rather than its occurrence or sequence context, appeared to designate termination. Thus, a 'stop codon' is not a sufficient signal for translation termination, and the default function of stop codons in Euplotes is frameshifting, whereas termination is specific to certain mRNA positions and probably requires additional factors. C1 [Lobanov, Alexei V.; Turanov, Anton A.; Gerashchenko, Maxim V.; Gladyshev, Vadim N.] Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA. [Lobanov, Alexei V.; Turanov, Anton A.; Gerashchenko, Maxim V.; Gladyshev, Vadim N.] Harvard Med Sch, Boston, MA 02115 USA. [Heaphy, Stephen M.; Atkins, John F.; Baranov, Pavel V.] Univ Coll Cork, Sch Biochem & Cell Biol, Cork, Ireland. [Pucciarelli, Sandra; Devaraj, Raghul R.; Miceli, Cristina] Univ Camerino, Sch Biosci & Vet Med, Camerino, Italy. [Xie, Fang; Petyuk, Vladislav A.; Smith, Richard D.] Pacific Northwest Natl Lab, Biol Sci Div, Richland, WA USA. [Klobutcher, Lawrence A.] Univ Connecticut, Ctr Hlth, Dept Mol Biol & Biophys, Farmington, CT USA. [Hatfield, Dolph L.] NIH, Mol Biol Selenium Sect, Mouse Canc Genet Program, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. RP Gladyshev, VN (reprint author), Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA.; Gladyshev, VN (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Baranov, PV (reprint author), Univ Coll Cork, Sch Biochem & Cell Biol, Cork, Ireland. EM p.baranov@ucc.ie; vgladyshev@rics.bwh.harvard.edu RI Smith, Richard/J-3664-2012; OI Smith, Richard/0000-0002-2381-2349; Devaraj, Raghul Rajan/0000-0001-8319-0513; Atkins, John/0000-0001-7933-0165 FU NIH [GM061603, GM065402, GM103493]; Wellcome Trust [094423]; Science Foundation Ireland [12/IA/1335]; W.R. Wiley Environmental Molecular Science Laboratory - DOE at Pacific Northwest National Laboratory; DOE [DE-AC05-76RLO-1830]; Italian PNRA; COST action [BM1102] FX Supported by NIH GM061603 and GM065402 to V.N.G. S.M.H. and P.V.B. are supported by the grants from Wellcome Trust (094423) and Science Foundation Ireland (12/IA/1335). Portions of this research were also supported by NIH GM103493 and the W.R. Wiley Environmental Molecular Science Laboratory (sponsored by DOE and located at Pacific Northwest National Laboratory). Pacific Northwest National Laboratory is operated by the Battelle Memorial Institute under the DOE contract DE-AC05-76RLO-1830. C.M. acknowledges the Italian PNRA and the COST action BM1102 for supporting a part of this work. NR 24 TC 2 Z9 2 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD JAN PY 2017 VL 24 IS 1 BP 61 EP 68 DI 10.1038/nsmb.3330 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA EG9AN UT WOS:000391349500013 PM 27870834 ER PT S AU Garmire, LX Gliske, S Nguyen, QC Chen, JH Nemati, S Van Horn, JD Moore, JH Shreffler, C Dunn, M AF Garmire, Lana X. Gliske, Stephen Nguyen, Quynh C. Chen, Jonathan H. Nemati, Shamim Van Horn, John D. Moore, Jason H. Shreffler, Carol Dunn, Michelle BE Altman, RB Dunker, AK Hunter, L Ritchie, MD Murray, T Klein, TE TI THE TRAINING OF NEXT GENERATION DATA SCIENTISTS IN BIOMEDICINE SO PACIFIC SYMPOSIUM ON BIOCOMPUTING 2017 SE Biocomputing Series LA English DT Proceedings Paper CT 22nd Pacific Symposium on Biocomputing (PSB) CY JAN 04-08, 2017 CL HI ID BIG DATA; HEALTH AB With the booming of new technologies, biomedical science has transformed into digitalized, data intensive science. Massive amount of data need to be analyzed and interpreted, demand a complete pipeline to train next generation data scientists. To meet this need, the trans-institutional Big Data to Knowledge (BD2K) Initiative has been implemented since 2014, complementing other NIH institutional efforts. In this report, we give an overview the BD2K K01 mentored scientist career awards, which have demonstrated early success. We address the specific trainings needed in representative data science areas, in order to make the next generation of data scientists in biomedicine. C1 [Garmire, Lana X.] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96813 USA. [Gliske, Stephen] Univ Michigan, Dept Neurol, Ann Arbor, MI 48109 USA. [Nguyen, Quynh C.] Univ Utah, Dept Hlth Kinesiol & Recreat, Salt Lake City, UT 84112 USA. [Chen, Jonathan H.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Nemati, Shamim] Emory Univ, Dept Biomed Informat, Atlanta, GA 30322 USA. [Van Horn, John D.] Univ Southern Calif, Mark & Mary Stevens Neuroimaging & Informat Inst, Los Angeles, CA 90032 USA. [Moore, Jason H.] Univ Penn, Inst Biomed Informat, Philadelphia, PA 19104 USA. [Shreffler, Carol] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. [Dunn, Michelle] Natl Inst Hlth, Office Associate Director Data Sci ADDA, Bethesda, MD 20892 USA. RP Garmire, LX (reprint author), Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96813 USA. EM LGarmire@Hawaii.edu NR 15 TC 0 Z9 0 U1 4 U2 4 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA PO BOX 128 FARRER RD, SINGAPORE 9128, SINGAPORE SN 2335-6936 BN 978-981-3207-81-3; 978-981-3207-80-6 J9 BIOCOMPUTING PY 2017 BP 640 EP 645 PG 6 WC Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA BG7FY UT WOS:000391254200059 ER PT J AU Melvin, AJ Montepiedra, G Aaron, L Meyer, WA Spiegel, HM Borkowsky, W Abzug, MJ Best, BM Crain, MJ Borum, PR Graham, B Anthony, P Shin, K Siberry, GK AF Melvin, Ann J. Montepiedra, Grace Aaron, Lisa Meyer, William A., III Spiegel, Hans M. Borkowsky, William Abzug, Mark J. Best, Brookie M. Crain, Marilyn J. Borum, Peggy R. Graham, Bobbie Anthony, Patricia Shin, Katherine Siberry, George K. CA P1063 Study Team TI Safety and Efficacy of Atorvastatin in Human Immunodeficiency Virus-infected Children, Adolescents and Young Adults With Hyperlipidemia SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE HIV; children; atorvastatin ID C-REACTIVE PROTEIN; INTIMA-MEDIA THICKNESS; CARDIOVASCULAR RISK-FACTORS; ACTIVE ANTIRETROVIRAL THERAPY; ACUTE MYOCARDIAL-INFARCTION; CORONARY-ARTERY-DISEASE; PLACEBO-CONTROLLED TRIAL; LIPID-LOWERING THERAPY; STATIN THERAPY; HIV-INFECTION AB Background: Human immunodeficiency virus (HIV)-infected children receiving antiretroviral therapy (ART) have increased prevalence of hyperlipidemia and risk factors for cardiovascular disease. No studies have investigated the efficacy and safety of statins in this population. Methods: HIV-infected youth 10 to <24 years of age on stable ART with low-density lipoprotein cholesterol (LDL-C) >= 130 mg/dL for >= 6 months initiated atorvastatin 10 mg once daily. Atorvastatin was increased to 20 mg if LDL-C efficacy criteria (LDL-C <110 mg/dL or decreased >= 30% from baseline) were not met at week 4. Primary outcomes were safety and efficacy. Results: Twenty-eight youth initiated atorvastatin; 7 were 10-15 years and 21 were 15-24 years. Mean baseline LDL-C was 161 mg/dL (standard deviation 19 mg/dL). Efficacy criteria were met at week 4 by 17 of 27 (63%) participants. Atorvastatin was increased to 20 mg in 10 participants. Mean LDL-C decreased from baseline by 30% (90% confidence interval: 26%, 35%) at week 4, 28% (90% confidence interval: 23%, 33%) at week 24 and 26% (90% confidence interval: 20%, 33%) at week 48. LDL-C was less than 110 mg/dL in 44% at week 4, 42% at week 12 and 46% at weeks 24 and 48. Total cholesterol, non high-density lipoprotein (non-HDL)-C and apolipoprotein B decreased significantly, but IL-6 and high-sensitivity C-reactive protein did not. Two participants in the younger age group discontinued study for toxicities possibly related to atorvastatin. Conclusions: Atorvastatin lowered total cholesterol, LDL-C, non HDL-C and apolipoprotein B in HIV-infected youth with ART-associated hyperlipidemia. Atorvastatin could be considered for HIV-infected children with hyperlipidemia, but safety monitoring is important particularly in younger children. C1 [Melvin, Ann J.] Univ Washington, Dept Pediat, Div Pediat Infect Dis, Seattle, WA 98195 USA. [Melvin, Ann J.] Seattle Childrens Res Inst, Seattle, WA USA. [Montepiedra, Grace; Aaron, Lisa] Harvard Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA USA. [Meyer, William A., III] Quest Diagnost, Baltimore, MD USA. [Spiegel, Hans M.] HJF DAIDS, Bethesda, MD USA. [Borkowsky, William] NYU, Dept Pediat, Sch Med, New York, NY 10016 USA. [Abzug, Mark J.] Univ Colorado, Sch Med, Dept Pediat Infect Dis, Aurora, CO USA. [Abzug, Mark J.] Childrens Hosp Colorado, Aurora, CO USA. [Best, Brookie M.] Univ Calif San Diego, UC San Diego Skaggs Sch Pharm & Pharmaceut Sci, San Diego, CA 92103 USA. [Best, Brookie M.] Univ Calif San Diego, Sch Med, San Diego, CA 92103 USA. [Crain, Marilyn J.] Univ Alabama Birmingham, Dept Pediat & Microbiol, Birmingham Pediat Infect Dis, Birmingham, AL USA. [Borum, Peggy R.] Univ Florida, Dept Food Sci & Human Nutr, Gainesville, FL 32611 USA. [Graham, Bobbie] Frontier Sci Inc, Buffalo, NY USA. [Anthony, Patricia] Univ Southenr Calif, Maternal Child Adolescent Virol Res Lab, Los Angeles, CA USA. [Shin, Katherine] NIAID, Pharmaceut Affairs Branch Div AIDS, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, NIH, Bethesda, MD USA. RP Melvin, AJ (reprint author), Seattle Childrens Hosp, Div Pediat Infect Dis, MA 7-226,4800 Sandpoint Way NE, Seattle, WA 98105 USA. EM ann.melvin@seattlechildrens.org FU Pfizer, Inc. FX Atorvastatin (Lipitor) for this study was provided by Pfizer, Inc. We gratefully acknowledge the contributions of the site investigators and site staff who conducted the P1063 study: Texas Children's Hospital: Chivon McMullen-Jackson, RN, BSN, CCRP; Norma Cooper, RN, BSN, MS; Mary Paul, MD, William Shearer, MD, PhD; Lurie Children's Hospital of Chicago: Ruth Williams, RN; Lynn Heald, PNP; Margaret Ann Sanders, MPH; Ram Yogev, MD; University of Miami Pediatric Perinatal HIV/AIDS: Charles D. Mitchell, MD; Gwendolyn B. Scott, MD; Monica Stone, MD; Patricia Bryan, RN, BS, MPH; Metropolitan Hospital: Mahrukh Bamji, MD; Santa Paul, MD; Boston Medical Center Pediatric HIV Program: Ellen R. Cooper, MD; Diana Clarke, PharmD; Deb McLaud, RN; C. Moloney, RN, PNP, MEd; New York University: Nagamah Deygoo, MS; Siham Akleh, RN; Aditya Kaul, MD; Sulachni Chandwani, MD; University of South Florida-Tampa: Carina A. Rodriguez, MD; Patricia J. Emmanuel, MD; Denise Casey, RN; Elizabeth Enriquez-Bruce, MD; University of Colorado School of Medicine and Children's Hospital Colorado: Suzanne Paul, BSN, MSN, FNP-C; Hannah Bernath, MPH; Jason Child, PharmD; Jenna Wallace, MSW, CCRP; Tulane University: Margarita Silio, MD; Thomas Alchediak, MD; Russell Van Dyke, MD; Bronx-Lebanon Hospital: Mary Elizabeth Vachon, MPH; Ana Maria Emeh, MD; Murli Udharam Purswani, MD; St Jude's Children's Hospital: Nehali Patel, MD; Sandra Boyd, PNP; Thomas Wride, MS; Aditya Gaur, MD. NR 81 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 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD JAN PY 2017 VL 36 IS 1 BP 53 EP 60 DI 10.1097/INF.0000000000001352 PG 8 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA EG7TU UT WOS:000391259900015 PM 27749649 ER PT J AU Mattingly, AS Unsal, AB Purdy, JB Gharib, AM Rupert, A Kovacs, JA McAreavey, D Hazra, R Abd-Elmoniem, KZ Hadigan, C AF Mattingly, Aviva S. Unsal, Aylin B. Purdy, Julia B. Gharib, Ahmed M. Rupert, Adam Kovacs, Joseph A. McAreavey, Dorothea Hazra, Rohan Abd-Elmoniem, Khaled Z. Hadigan, Colleen TI T-cell Activation and E-selectin Are Associated With Coronary Plaque in HIV-infected Young Adults SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE perinatal HIV; coronary plaque; E-selectin; cardiovascular disease; immune activation ID COMPUTED-TOMOGRAPHY; CT ANGIOGRAPHY; DISEASE; COHORT; RISK; ATHEROSCLEROSIS; PROGRESSION; MARKERS AB We evaluated immune activation and coronary artery plaque in young adults with human immunodeficiency virus acquired in early life (n = 31). Coronary plaque was positively associated with lipids, immune activation marker %CD8+CD38+DR+ and E-selectin, a marker of endothelial inflammation. Immune activation and endothelial inflammation may drive coronary plaque formation during the early stages of atherosclerosis in the context of chronic human immunodeficiency virus. C1 [Mattingly, Aviva S.; Unsal, Aylin B.; Hadigan, Colleen] NIAID, Immunoregulat Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Purdy, Julia B.; Kovacs, Joseph A.; McAreavey, Dorothea] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Gharib, Ahmed M.; Abd-Elmoniem, Khaled Z.] NIDDK, Biomed & Metab Imaging Branch, Bethesda, MD 20892 USA. [Rupert, Adam] Canc Res Leidos Biomed Res Inc, AIDS Monitoring Labs, Frederick Natl Lab, Frederick, MD USA. [Hazra, Rohan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Hadigan, C (reprint author), NIAID, Immunoregulat Lab, NIH, 10 Ctr Dr,11C103, Bethesda, MD 20892 USA. EM hadiganc@niaid.nih.gov FU National Institutes of Health through National Institute of Allergy and Infectious Diseases Intramural Research Program; National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program; National Institutes of Health Clinical Center FX This study was supported by the National Institutes of Health through the National Institute of Allergy and Infectious Diseases Intramural Research Program, the National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program and The National Institutes of Health Clinical Center. 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 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD JAN PY 2017 VL 36 IS 1 BP 63 EP 65 DI 10.1097/INF.0000000000001354 PG 3 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA EG7TU UT WOS:000391259900017 PM 27749650 ER PT J AU Meyers, JL Brown, Q Grant, BF Hasin, D AF Meyers, J. L. Brown, Q. Grant, B. F. Hasin, D. TI Religiosity, race/ethnicity, and alcohol use behaviors in the United States SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Alcohol use; alcohol use disorder; NESARC; race; religiosity; spirituality ID NATIONAL EPIDEMIOLOGIC SURVEY; GENERAL-POPULATION SAMPLE; PSYCHIATRIC DIAGNOSTIC MODULES; INTERVIEW SCHEDULE AUDADIS; OLDER AFRICAN-AMERICANS; DSM-IV ALCOHOL; SUBSTANCE USE; USE-DISORDER; DRUG-USE; PSYCHOLOGICAL DISTRESS AB Background. Religiosity is a protective factor against many health problems, including alcohol use disorders (AUD). Studies suggest that religiosity has greater buffering effects on mental health problems among US Blacks and Hispanics than Whites. However, whether race/ethnic differences exist in the associations of religiosity, alcohol consumption and AUD is unclear. Method. Using 2004-2005 NESARC data (analytic n = 21 965), we examined the relationship of public religiosity (i.e. frequency of service attendance, religious social group size), and intrinsic religiosity (i.e. importance of religious/spiritual beliefs) to frequency of alcohol use and DSM-IV AUD in non-Hispanic (NH) Blacks, Hispanics and NH Whites, and whether associations differed by self-identified race/ethnicity. Results. Only public religiosity was related to AUD. Frequency of religious service attendance was inversely associated with AUD (NH Whites beta: -0.103, p < 0.001; NH Blacks beta: -0.115, p < 0.001; Hispanics beta: -0.096, p < 0.001). This association was more robust for NH Blacks as compared with NH Whites and Hispanics (interaction beta: 0.025, p < 0.001). Among NH Whites, higher intrinsic religiosity was inversely associated with alcohol use frequency (beta: -0.143, p < 0.001). These effects were more robust among NH Whites (interaction (beta: 0.072, p < 0.033) than for NH Blacks (beta: -0.080, p > 0.05) or Hispanics (beta: -0.002, p > 0.05). Conclusions. US adults reporting greater public religiosity were at lower risk for AUD. Public religiosity may be particularly important among NH Blacks, while intrinsic religiosity may be particularly important among NH Whites, and among Hispanics who frequently attend religious services. Findings may be explained by variation in drinking-related norms observed among these groups generally, and in the context of specific religious institutions. C1 [Meyers, J. L.] Suny Downstate Med Ctr, Dept Psychiat & Behav Sci, Brooklyn, NY USA. [Brown, Q.; Hasin, D.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Grant, B. F.] NIAAA, Lab Epidemiol & Biometry, Bethesda, MD USA. [Hasin, D.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. [Hasin, D.] New York State Psychiat Inst & Hosp, New York, NY USA. RP Meyers, JL (reprint author), Suny Downstate Med Ctr, Dept Psychiat, Henri Begleiter Neurodynam Lab, 450 Clarkson Ave,Box 1203, Brooklyn, NY 11203 USA. EM jacquelyn.meyers@downstate.edu FU National Institutes of Health [1K01DA037914, U01AA018111]; New York State Psychiatric Institute [T32DA031099] FX This research was funded by National Institutes of Health grants 1K01DA037914 (Meyers), U01AA018111 (Hasin), the New York State Psychiatric Institute (Hasin), and T32DA031099 (Brown, PI Hasin). NR 82 TC 0 Z9 0 U1 5 U2 5 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 JAN PY 2017 VL 47 IS 1 BP 103 EP 114 DI 10.1017/S0033291716001975 PG 12 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA EG8PJ UT WOS:000391318900010 PM 27667499 ER PT J AU Gavrila, A Hasselgren, PO Glasgow, A Doyle, AN Lee, AJ Fox, P Gautam, S Hennessey, JV Kolodny, GM Cypess, AM AF Gavrila, Alina Hasselgren, Per-Olof Glasgow, Allison Doyle, Ashley N. Lee, Alice J. Fox, Peter Gautam, Shiva Hennessey, James V. Kolodny, Gerald M. Cypess, Aaron M. TI Variable Cold-Induced Brown Adipose Tissue Response to Thyroid Hormone Status SO THYROID LA English DT Article DE brown adipose tissue; thyroid hormone; hypothyroidism; thyrotoxicosis; thermogenesis ID NONSHIVERING THERMOGENESIS; METABOLISM; HUMANS; ACTIVATION; MECHANISMS; OBESITY; MUSCLE; ADULTS; MICE; FAT AB Background: In addition to its role in adaptive thermogenesis, brown adipose tissue (BAT) may protect from weight gain, insulin resistance/diabetes, and metabolic syndrome. Prior studies have shown contradictory results regarding the influence of thyroid hormone (TH) levels on BAT volume and activity. The aim of this pilot study was to gain further insights regarding the effect of TH treatment on BAT function in adult humans by evaluating the BAT mass and activity prospectively in six patients, first in the hypothyroid and then in the thyrotoxic phase. Methods: The study subjects underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) scanning after cold exposure to measure BAT mass and activity while undergoing treatment for differentiated thyroid cancer, first while hypothyroid following TH withdrawal at the time of the radioactive iodine treatment and then three to six months after starting TH suppressive treatment when they were iatrogenically thyrotoxic. Thermogenic and metabolic parameters were measured in both phases. Results: All study subjects had detectable BAT under cold stimulation in both the hypothyroid and thyrotoxic state. The majority but not all (4/6) subjects showed an increase in detectable BAT volume and activity under cold stimulation between the hypothyroid and thyrotoxic phase (total BAT volume: 72.0+/-21.0 vs. 87.7+/-16.5mL, p = 0.25; total BAT activity 158.1+/-72.8 vs. 189.0+/-55.5 SUV*g/mL, p = 0.34). Importantly, circulating triiodothyronine was a stronger predictor of energy expenditure changes compared with cold-induced BAT activity. Conclusions: Iatrogenic hypothyroidism lasting two to four weeks does not prevent cold-induced BAT activation, while the use of TH to induce thyrotoxicosis does not consistently increase cold-induced BAT activity. It remains to be determined which physiological factors besides TH play a role in regulating BAT function. Keywords: brown adipose tissue, thyroid hormone, hypothyroidism, thyrotoxicosis, thermogenesis C1 [Gavrila, Alina; Gautam, Shiva; Hennessey, James V.; Cypess, Aaron M.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Hasselgren, Per-Olof] Beth Israel Deaconess Med Ctr, Dept Surg, 330 Brookline Ave, Boston, MA 02215 USA. [Glasgow, Allison; Doyle, Ashley N.; Lee, Alice J.] Beth Israel Deaconess Med Ctr, Harvard Catalyst Clin Res Ctr, Boston, MA 02215 USA. [Kolodny, Gerald M.] Beth Israel Deaconess Med Ctr, Dept Radiol, 330 Brookline Ave, Boston, MA 02215 USA. [Fox, Peter; Cypess, Aaron M.] Harvard Med Sch, Joslin Diabet Ctr, Div Res, Sect Integrat Physiol & Metab, Boston, MA USA. [Cypess, Aaron M.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. RP Cypess, AM (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA.; Gavrila, A (reprint author), Beth Israel Deaconess Med Ctr, Div Endocrinol & Metab, 330 Brookline Ave GZ6, Boston, MA 02215 USA. EM agavrila@bidmc.harvard.edu; aaron.cypess@nih.gov FU Harvard Catalyst Clinical Research Center (HCCRC); National Institutes of Health (NIH) [K23 DK081604]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Center for Research Resources (NCRR) [UL1RR025758, UL1TR000170, UL1TR001102]; National Center for Advancing Translational Science; Harvard University and its affiliated academic healthcare centers FX This work was supported by the 2012 Harvard Catalyst Clinical Research Center (HCCRC) Resources and Services Funding Award; the 2013 Harvard Catalyst Clinical Research Center (HCCRC) Laboratory Support and Genotyping Award; National Institutes of Health (NIH) grants K23 DK081604, the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); and the Clinical Translational Science Awards UL1RR025758, UL1TR000170 and UL1TR001102 to Harvard University and its affiliated academic healthcare centers from the National Center for Research Resources (NCRR) and the National Center for Advancing Translational Science and financial contributions from Harvard University and its affiliated academic healthcare centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health. NR 32 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD JAN PY 2017 VL 27 IS 1 BP 1 EP 10 DI 10.1089/thy.2015.0646 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG9RV UT WOS:000391398100001 PM 27750020 ER PT J AU Machado-Vieira, R Luckenbaugh, DA Ballard, ED Henter, ID Tohen, M Suppes, T Zarate, CA AF Machado-Vieira, Rodrigo Luckenbaugh, David A. Ballard, Elizabeth D. Henter, Ioline D. Tohen, Mauricio Suppes, Trisha Zarate, Carlos A., Jr. TI Increased Activity or Energy as a Primary Criterion for the Diagnosis of Bipolar Mania in DSM-5: Findings From the STEP-BD Study SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID TREATMENT ENHANCEMENT PROGRAM; WEEKLY SYMPTOMATIC STATUS; II-DISORDER; NATURAL-HISTORY; INDIVIDUALS; HYPOMANIA AB Objective: DSM-5 describes "a distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased activity or energy" as a primary criterion for mania. Thus, increased energy or activity is now considered a core symptom of manic and hypomanic episodes. Using data from the Systematic Treatment Enhancement Program for Bipolar Disorder study, the authors analyzed point prevalence data obtained at the initial visit to assess the diagnostic validity of this new DSM-5 criterion. The study hypothesis was that the DSM-5 criterion would alter the prevalence of mania and/or hypomania. Method: The authors compared prevalence, clinical characteristics, validators, and outcome in patients meeting the DSM-5 criteria (i.e., DSM-IV criteria plus the DSM-5 criterion of increased activity or energy) and those who did not meet the new DSM-5 criterion (i.e., who only met DSM-IV criteria). Results: All 4,360 participants met DSM-IV criteria for bipolar disorder, and 310 met DSM-IV criteria for a manic or hypo manic episode. When the new DSM-5 criterion of increased activity or energy was added as a coprimary symptom, the prevalence of mania and hypomania was reduced. Although minor differences were noted in clinical and concurrent validators, no changes were observed in longitudinal outcomes. Conclusions: The findings confirm that including increased activity or energy as part of DSM-5 criterion A decreases the prevalence of manic and hypomanic episodes but does not affect longitudinal clinical outcomes. C1 [Zarate, Carlos A., Jr.] NIMH, Sect Neurobiol & Treatment Mood Disorders, Bethesda, MD 20892 USA. Univ New Mexico, Hlth Sci Ctr, Dept Psychiat & Behav Sci, Albuquerque, NM 87131 USA. VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA. RP Zarate, CA (reprint author), NIMH, Sect Neurobiol & Treatment Mood Disorders, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov FU Intramural Research Program at NIMH; Elan Pharma; NIH; Pathway Genomics; Stanley Medical Research Institute; Sunovion; VA Cooperative Studies Program FX The authors gratefully acknowledge the support and funding of the Intramural Research Program at NIMH, and they thank the 7SE research unit and staff for their support.; Dr. Tohen has received honoraria from or consulted for Abbott, Alkermes, Allergan, AstraZeneca, Bristol-Myers Squibb, Elan, Eli Lilly, Forest, Geodon Richter, GlaxoSmithKline, Johnson & Johnson, Lundbeck, Merck, Minerva, Otsuka, Pamlab, Roche, Sunovion, Teva, Wiley Publishing, and Wyeth. Dr. Suppes has received research support from Elan Pharma, NIH, Pathway Genomics, Stanley Medical Research Institute, Sunovion, and the VA Cooperative Studies Program; she has served as a consultant for Lundbeck, Merck, and Sunovion, has participated in CME activities for Medscape Education, Global Medical Education, and CMEology, and has received royalties from Jones & Bartlett and UpToDate. Dr. Zarate is listed as a co-inventor on a patent for the use of ketamine and its metabolites in the treatment of major depression. The other authors report no financial relationships with commercial interests. NR 24 TC 2 Z9 2 U1 2 U2 2 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JAN PY 2017 VL 174 IS 1 BP 70 EP 76 DI 10.1176/appi.ajp.2016.15091132 PG 7 WC Psychiatry SC Psychiatry GA EG4BB UT WOS:000390987300013 PM 27523498 ER PT J AU Blanco, C Wall, MM Okuda, M Wang, S Iza, M Olfson, M AF Blanco, Carlos Wall, Melanie M. Okuda, Mayumi Wang, Shuai Iza, Miren Olfson, Mark TI Distinguishing Between Physiological Dependence and Substance Use Disorder: Response to Ruan et al. SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Letter ID OPIOID-USE DISORDER; DRUG-USE DISORDERS; PREVALENCE; ALCOHOL; PAIN C1 [Blanco, Carlos] NIDA, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. New York State Psychiat Inst & Hosp, Dept Psychiat, New York, NY 10032 USA. Columbia Univ, New York, NY USA. Fdn Jimenez Diaz, Dept Psychiat, Madrid, Spain. RP Blanco, C (reprint author), NIDA, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 U1 1 U2 1 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JAN PY 2017 VL 174 IS 1 BP 79 EP 80 DI 10.1176/appi.ajp.2016.16070836r PG 2 WC Psychiatry SC Psychiatry GA EG4BB UT WOS:000390987300017 PM 28040995 ER PT J AU Papadakis, GZ Sadowski, SM Bagci, U Millo, C AF Papadakis, Georgios Z. Sadowski, Samira M. Bagci, Ulas Millo, Corina TI Application of Ga-68-DOTA-TATEPET/CT in metastatic neuroendocrine tumor of gastrointestinal origin SO ANNALS OF GASTROENTEROLOGY LA English DT Editorial Material ID PET/CT C1 NIH, Warren Grant Magnuson Clin Ctr CC, Bldg 10, Bethesda, MD 20892 USA. [Sadowski, Samira M.] NCI, NIH, Endocrine Oncol Branch, Bethesda, MD 20892 USA. [Sadowski, Samira M.] Univ Hosp Geneva, Endocrine & Thorac Surg, Geneva, Switzerland. [Bagci, Ulas] Univ Cent Florida, Ctr Res Comp Vis, Elect & Comp Sci Dept, Orlando, FL 32816 USA. [Millo, Corina] NIH, Ctr Clin, PET Dept, Bethesda, MD 20892 USA. [Papadakis, Georgios Z.] Warren Grant Magnuson Clin Ctr, Radiol & Imaging Sci, Bethesda, MD USA. RP Papadakis, GZ (reprint author), NIH, Dept Radiol & Imaging Sci, Warrant Grant Magnuson Clin Ctr, 10 Ctr Dr,Room 1C370, Bethesda, MD 20892 USA. EM papadakisg@cc.nih.gov NR 3 TC 0 Z9 0 U1 0 U2 0 PU HELLENIC SOC GASTROENTEROLOGY PI ATHENS PA DEMOKRATIAS AVE 67, ATHENS, 15451, GREECE SN 1108-7471 EI 1792-7463 J9 ANN GASTROENTEROL JI Ann. Gastroenterol. PY 2017 VL 30 IS 1 BP 130 EP 130 DI 10.20524/aog.2016.0082s PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EG2NH UT WOS:000390879900021 PM 28042252 ER PT J AU Nish, SA Zens, KD Kratchmarov, R Lin, WHW Adams, WC Chen, YH Yen, B Rothman, NJ Bhandoola, A Xue, HH Farber, DL Reiner, SL AF Nish, Simone A. Zens, Kyra D. Kratchmarov, Radomir Lin, Wen-Hsuan W. Adams, William C. Chen, Yen-Hua Yen, Bonnie Rothman, Nyanza J. Bhandoola, Avinash Xue, Hai-Hui Farber, Donna L. Reiner, Steven L. TI CD4(+) T cell effector commitment coupled to self-renewal by asymmetric cell divisions SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID ACUTE VIRAL-INFECTION; FOLLICULAR HELPER; MEMORY CELLS; B-CELL; TRANSCRIPTION FACTOR; IMMUNE-RESPONSES; LEISHMANIA-MAJOR; DNA METHYLATION; DIFFERENTIATION; NAIVE AB Upon infection, an activated CD4(+) T cell produces terminally differentiated effector cells and renews itself for continued defense. In this study, we show that differentiation and self-renewal arise as opposing outcomes of sibling CD4(+) T cells. After influenza challenge, antigen-specific cells underwent several divisions in draining lymph nodes ( LN; DLNs) while maintaining expression of TCF1. After four or five divisions, some cells silenced, whereas some cells maintained TCF1 expression. TCF1silenced cells were T helper 1-like effectors and concentrated in the lungs. Cells from earliest divisions were memory-like and concentrated in nondraining LN. TCF1-expressing cells from later divisions in the DLN could self-renew, clonally yielding a TCF1-silenced daughter cell as well as a sibling cell maintaining TCF1 expression. Some TCF1-expressing cells in DLNs acquired an alternative, follicular helper-like fate. Modeled differentiation experiments in vitro suggested that unequal PI3K/mechanistic target of rapamycin signaling drives intraclonal cell fate heterogeneity. Asymmetric division enables self-renewal to be coupled to production of differentiated CD4(+) effector T cells during clonal selection. C1 [Nish, Simone A.; Kratchmarov, Radomir; Lin, Wen-Hsuan W.; Adams, William C.; Chen, Yen-Hua; Yen, Bonnie; Rothman, Nyanza J.; Reiner, Steven L.] Columbia Univ, Dept Microbiol & Immunol, Coll Phys & Surg, New York, NY 10032 USA. [Nish, Simone A.; Kratchmarov, Radomir; Lin, Wen-Hsuan W.; Adams, William C.; Chen, Yen-Hua; Yen, Bonnie; Rothman, Nyanza J.; Reiner, Steven L.] Columbia Univ, Dept Pediat, Coll Phys & Surg, New York, NY 10032 USA. [Zens, Kyra D.; Farber, Donna L.] Columbia Univ, Med Ctr, Columbia Ctr Translat Immunol, New York, NY 10032 USA. [Zens, Kyra D.; Farber, Donna L.] Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY 10032 USA. [Zens, Kyra D.; Farber, Donna L.] Columbia Univ, Med Ctr, Dept Surg, New York, NY 10032 USA. [Bhandoola, Avinash] NCI, T Cell Biol & Dev Unit, Lab Genome Integr, Ctr Canc Res, Bethesda, MD 20892 USA. [Xue, Hai-Hui] Univ Iowa, Carver Coll Med, Dept Microbiol, Iowa City, IA 52242 USA. RP Reiner, SL (reprint author), Columbia Univ, Dept Microbiol & Immunol, Coll Phys & Surg, New York, NY 10032 USA.; Reiner, SL (reprint author), Columbia Univ, Dept Pediat, Coll Phys & Surg, New York, NY 10032 USA. EM sr2978@cumc.columbia.edu FU National Institutes of Health [AI061699, AI113365, AI076458, AI112579, AI115149, AI119160, AI121080]; U.S. Department of Veterans Affairs Merit Review Award [I01 BX002903] FX This study was supported by National Institutes of Health grants (AI061699, AI113365, and AI076458 to S.L. Reiner and AI112579, AI115149, AI119160, and AI121080 to H.-H. Xue) and the U.S. Department of Veterans Affairs Merit Review Award (I01 BX002903 to H.-H. Xue). NR 51 TC 1 Z9 1 U1 1 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD JAN PY 2017 VL 214 IS 1 BP 39 EP 47 DI 10.1084/jem.20161046 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EG5ZN UT WOS:000391123600005 PM 27923906 ER PT J AU Wang, Q Kieffer-Kwon, KR Oliveira, TY Mayer, CT Yao, KH Pai, J Cao, Z Dose, M Casellas, R Jankovic, M Nussenzweig, MC Robbiani, DF AF Wang, Qiao Kieffer-Kwon, Kyong-Rim Oliveira, Thiago Y. Mayer, Christian T. Yao, Kaihui Pai, Joy Cao, Zhen Dose, Marei Casellas, Rafael Jankovic, Mila Nussenzweig, Michel C. Robbiani, Davide F. TI The cell cycle restricts activation-induced cytidine deaminase activity to early G1 SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID CLASS-SWITCH RECOMBINATION; URACIL-DNA GLYCOSYLASE; SOMATIC HYPERMUTATION; GENOMIC INSTABILITY; B-CELLS; SUPER-ENHANCERS; NUCLEAR IMPORT; TARGETS AID; TRANSCRIPTION; MECHANISMS AB Activation-induced cytidine deaminase (AID) converts cytosine into uracil to initiate somatic hypermutation (SHM) and class switch recombination (CSR) of antibody genes. In addition, this enzyme produces DNA lesions at off-target sites that lead to mutations and chromosome translocations. However, AID is mostly cytoplasmic, and how and exactly when it accesses nuclear DNA remains enigmatic. Here, we show that AID is transiently in spatial contact with genomic DNA from the time the nuclear membrane breaks down in prometaphase until early G1, when it is actively exported into the cytoplasm. Consistent with this observation, the immunoglobulin (Igh) gene deamination as measured by uracil accumulation occurs primarily in early G1 after chromosomes decondense. Altering the timing of cell cycle-regulated AID nuclear residence increases DNA damage at off-target sites. Thus, the cell cycle-controlled breakdown and reassembly of the nuclear membrane and the restoration of transcription after mitosis constitute an essential time window for AID-induced deamination, and provide a novel DNA damage mechanism restricted to early G1. C1 [Wang, Qiao; Oliveira, Thiago Y.; Mayer, Christian T.; Yao, Kaihui; Pai, Joy; Jankovic, Mila; Nussenzweig, Michel C.; Robbiani, Davide F.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. [Kieffer-Kwon, Kyong-Rim; Dose, Marei; Casellas, Rafael] NIAMSD, Genom & Immun, NIH, Bethesda, MD 20892 USA. [Kieffer-Kwon, Kyong-Rim; Dose, Marei; Casellas, Rafael] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Cao, Zhen] Weill Cornell Med Coll, New York, NY 10065 USA. [Cao, Zhen] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. RP Wang, Q; Nussenzweig, MC; Robbiani, DF (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 qiaoqiaolang@gmail.com; nussen@rockefeller.edu; drobbiani@rockefeller.edu OI Oliveira, Thiago/0000-0002-2654-0879 FU National Institutes of Health [AI112602, AI037526, AI072529] FX This work was supported in part by National Institutes of Health grants AI112602 (to D.F. Robbiani), and AI037526 and AI072529 (to M.C. Nussenzweig). M.C. Nussenzweig is an HHMI Investigator. NR 36 TC 0 Z9 0 U1 2 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD JAN PY 2017 VL 214 IS 1 BP 49 EP 58 DI 10.1084/jem.20161649 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EG5ZN UT WOS:000391123600006 PM 27998928 ER PT J AU Abolhassani, H Edwards, ESJ Ikinciogullari, A Jing, HE Borte, S Buggert, M Du, LK Matsuda-Lennikov, M Romano, R Caridha, R Bade, S Zhang, Y Frederiksen, J Fang, MY Bal, SK Haskologlu, S Dogu, F Tacyildiz, N Matthews, HF McElwee, JJ Gostick, E Price, DA Palendira, U Aghamohammadi, A Boisson, B Rezaei, N Karlsson, AC Lenardo, MJ Casanova, JL Hammarstrom, L Tangye, SG Su, HC Pan-Hammarstrom, Q AF Abolhassani, Hassan Edwards, Emily S. J. Ikinciogullari, Aydan Jing, Huie Borte, Stephan Buggert, Marcus Du, Likun Matsuda-Lennikov, Mami Romano, Rosa Caridha, Rozina Bade, Sangeeta Zhang, Yu Frederiksen, Juliet Fang, Mingyan Bal, Sevgi Kostel Haskologlu, Sule Dogu, Figen Tacyildiz, Nurdan Matthews, Helen F. McElwee, Joshua J. Gostick, Emma Price, David A. Palendira, Umaimainthan Aghamohammadi, Asghar Boisson, Bertrand Rezaei, Nima Karlsson, Annika C. Lenardo, Michael J. Casanova, Jean-Laurent Hammarstrom, Lennart Tangye, Stuart G. Su, Helen C. Pan-Hammarstrom, Qiang TI Combined immunodeficiency and Epstein-Barr virus-induced B cell malignancy in humans with inherited CD70 deficiency SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID COMMON VARIABLE IMMUNODEFICIENCY; T-CELL; CD27/CD70 INTERACTION; ADAPTIVE RESPONSES; CD27 DEFICIENCY; IN-VIVO; INFECTION; NK; GENERATION; DISEASE AB In this study, we describe four patients from two unrelated families of different ethnicities with a primary immunodeficiency, predominantly manifesting as susceptibility to Epstein-Barr virus (EBV)-related diseases. Three patients presented with EBV-associated Hodgkin's lymphoma and hypogammaglobulinemia; one also had severe varicella infection. The fourth had viral encephalitis during infancy. Homozygous frameshift or in-frame deletions in CD70 in these patients abolished either CD70 surface expression or binding to its cognate receptor CD27. Blood lymphocyte numbers were normal, but the proportions of memory B cells and EBV-specific effector memory CD8(+) T cells were reduced. Furthermore, although T cell proliferation was normal, in vitro-generated EBV-specific cytotoxic T cell activity was reduced because of CD70 deficiency. This reflected impaired activation by, rather than effects during killing of, EBV-transformed B cells. Notably, expression of 2B4 and NKG2D, receptors implicated in controlling EBV infection, on memory CD8(+) T cells from CD70-deficient individuals was reduced, consistent with their impaired killing of EBV-infected cells. Thus, autosomal recessive CD70 deficiency is a novel cause of combined immunodeficiency and EBV-associated diseases, reminiscent of inherited CD27 deficiency. Overall, human CD70-CD27 interactions therefore play a nonredundant role in T and B cell-mediated immunity, especially for protection against EBV and humoral immunity. C1 [Abolhassani, Hassan; Du, Likun; Romano, Rosa; Caridha, Rozina; Fang, Mingyan; Hammarstrom, Lennart; Pan-Hammarstrom, Qiang] Karolinska Univ, Huddinge Hosp, Karolinska Inst, Div Clin Immunol,Dept Lab Med, SE-1418 Stockholm, Sweden. [Buggert, Marcus; Karlsson, Annika C.] Karolinska Univ, Huddinge Hosp, Karolinska Inst, Div Clin Microbiol,Dept Lab Med, SE-1418 Stockholm, Sweden. [Abolhassani, Hassan; Aghamohammadi, Asghar; Rezaei, Nima] Univ Tehran Med Sci, Res Ctr Immunodeficiencies, Childrens Med Ctr, Tehran 14149, Iran. [Edwards, Emily S. J.; Tangye, Stuart G.] Garvan Inst Med Res, Div Immunol, Darlinghurst, NSW 2010, Australia. [Edwards, Emily S. J.; Tangye, Stuart G.] Univ New South Wales, St Vincents Clin Sch, Fac Med, Darlinghurst, NSW 2010, Australia. [Ikinciogullari, Aydan; Bal, Sevgi Kostel; Haskologlu, Sule; Dogu, Figen] Ankara Univ, Sch Med, Dept Pediat Immunol & Allergy, TR-06100 Dikimevi Ankara, Turkey. [Tacyildiz, Nurdan] Ankara Univ, Sch Med, Dept Pediat Hematol & Oncol, TR-06100 Dikimevi Ankara, Turkey. [Jing, Huie; Bade, Sangeeta; Zhang, Yu; Matthews, Helen F.; Su, Helen C.] NIAID, Lab Host Def, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Jing, Huie; Matsuda-Lennikov, Mami; Bade, Sangeeta; Zhang, Yu; Matthews, Helen F.; Lenardo, Michael J.; Su, Helen C.] NIAID, Clin Genom Program, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Matsuda-Lennikov, Mami] NIAID, Lab Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Price, David A.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Borte, Stephan] Hosp St Georg Leipzig, ImmunoDeficiency Ctr Leipzig, D-04129 Leipzig, Germany. [Buggert, Marcus] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA. [Frederiksen, Juliet] Tech Univ Denmark, Dept Syst Biol, DK-2800 Lyngby, Denmark. [McElwee, Joshua J.] Merck & Co Inc, Merck Res Labs, Boston, MA 02115 USA. [Gostick, Emma; Price, David A.] Cardiff Univ, Sch Med, Div Infect & Immun, Cardiff CF14 4XN, S Glam, Wales. [Palendira, Umaimainthan] Univ Sydney, Centenary Inst, Newtown, NSW 2042, Australia. [Aghamohammadi, Asghar; Rezaei, Nima] Univ Sci Educ & Res Network, Primary Immunodeficiency Dis Network, Tehran 14149, Iran. [Boisson, Bertrand; Casanova, Jean-Laurent] Rockefeller Univ, St Giles Lab Human Genet Infect Dis, New York, NY 10065 USA. [Boisson, Bertrand; Casanova, Jean-Laurent] Necker Hosp Sick Children, INSERM, Lab Human Genet Infect Dis, U 1163, F-75015 Paris, France. [Casanova, Jean-Laurent] Necker Hosp Sick Children, Pediat Hematol Immunol Unit, F-75015 Paris, France. [Boisson, Bertrand; Casanova, Jean-Laurent] Paris Descartes Univ, Imagine Inst, F-75015 Paris, France. [Casanova, Jean-Laurent] Howard Hughes Med Inst, New York, NY 10065 USA. RP Pan-Hammarstrom, Q (reprint author), Karolinska Univ, Huddinge Hosp, Karolinska Inst, Div Clin Immunol,Dept Lab Med, SE-1418 Stockholm, Sweden.; Tangye, SG (reprint author), Garvan Inst Med Res, Div Immunol, Darlinghurst, NSW 2010, Australia.; Tangye, SG (reprint author), Univ New South Wales, St Vincents Clin Sch, Fac Med, Darlinghurst, NSW 2010, Australia.; Su, HC (reprint author), NIAID, Lab Host Def, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Su, HC (reprint author), NIAID, Clin Genom Program, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM tangye@garvan.org.au; hsu@niaid.nih.gov; Qiang.Pan-Hammarstrom@ki.se RI Fang, Mingyan/B-8505-2017; OI Buggert, Marcus/0000-0003-0633-1719 FU Swedish Research Council; Swedish Cancer Society; Swedish Childhood Cancer Foundation; Susan and John Freeman Cancer Research Grant from Cancer Council NSW (Australia) [RG16-11]; Intramural Research Program of National Institute of Allergy and Infectious Diseases, National Institutes of Health; Institut National de la Sante et de la Recherche Medicale; University Paris Descartes; French National Research Agency under the Investments for the Future program [ANR-10-IAHU-01]; Rockefeller University; St. Giles Foundation; National Health and Medical Research Council of Australia [1042925]; Fulbright Senior Scholarship FX This study was supported by the Swedish Research Council (grant to L. Hammarstrom and Q. Pan-Hammarstrom), the Swedish Cancer Society (grant to Q. Pan-Hammarstrom), the Swedish Childhood Cancer Foundation (grant to Q. Pan-Hammarstrom), the Susan and John Freeman Cancer Research Grant from Cancer Council NSW (Australia; grant RG16-11), and the Intramural Research Program of National Institute of Allergy and Infectious Diseases, National Institutes of Health. The laboratory of Human Genetics of Infectious Diseases is supported by grants from Institut National de la Sante et de la Recherche Medicale, University Paris Descartes, the French National Research Agency under the Investments for the Future program (grant no ANR-10-IAHU-01), the Rockefeller University, and the St. Giles Foundation. D.A. Price is a Wellcome Trust Senior Investigator. S.G. Tangye is a recipient of a Principal Research Fellowship from the National Health and Medical Research Council of Australia (grant 1042925) and a Fulbright Senior Scholarship. NR 54 TC 1 Z9 1 U1 3 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD JAN PY 2017 VL 214 IS 1 BP 91 EP 106 DI 10.1084/jem.20160849 PG 16 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EG5ZN UT WOS:000391123600009 PM 28011864 ER PT J AU Vaidyanathan, B Chaudhry, A Yewdell, WT Angeletti, D Yen, WF Wheatley, AK Bradfield, CA McDermott, AB Yewdell, JW Rudensky, AY Chaudhuri, J AF Vaidyanathan, Bharat Chaudhry, Ashutosh Yewdell, William T. Angeletti, Davide Yen, Wei-Feng Wheatley, Adam K. Bradfield, Christopher A. McDermott, Adrian B. Yewdell, Jonathan W. Rudensky, Alexander Y. Chaudhuri, Jayanta TI The aryl hydrocarbon receptor controls cell-fate decisions in B cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID CLASS-SWITCH RECOMBINATION; CYTIDINE DEAMINASE AID; MEMORY B; IMMUNE-SYSTEM; H5N1 VACCINATION; PLASMA-CELLS; DIFFERENTIATION; RESPONSES; ROLES; DNA AB Generation of cellular heterogeneity is an essential feature of the adaptive immune system. This is best exemplified during humoral immune response when an expanding B cell clone assumes multiple cell fates, including class-switched B cells, antibody- secreting plasma cells, and memory B cells. Although each cell type is essential for immunity, their generation must be exquisitely controlled because a class-switched B cell cannot revert back to the parent isotype, and a terminally differentiated plasma cell cannot contribute to the memory pool. In this study, we show that an environmental sensor, the aryl hydrocarbon receptor (AhR) is highly induced upon B cell activation and serves a critical role in regulating activation-induced cell fate outcomes. We find that AhR negatively regulates class-switch recombination ex vivo by altering activation-induced cytidine deaminase expression. We further demonstrate that AhR suppresses class switching in vivo after influenza virus infection and immunization with model antigens. In addition, by regulating Blimp-1 expression via Bach2, AhR represses differentiation of B cells into plasmablasts ex vivo and antibody-secreting plasma cells in vivo. These experiments suggest that AhR serves as a molecular rheostat in B cells to brake the effector response, possibly to facilitate optimal recall responses. Thus, AhR might represent a novel molecular target for manipulation of B cell responses during vaccination. C1 [Vaidyanathan, Bharat; Chaudhry, Ashutosh; Yewdell, William T.; Yen, Wei-Feng; Rudensky, Alexander Y.; Chaudhuri, Jayanta] Mem Sloan Kettering Canc Ctr, Immunol Program, Ludwig Ctr, New York, NY 10065 USA. [Rudensky, Alexander Y.] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, Ludwig Ctr, New York, NY 10065 USA. [Vaidyanathan, Bharat; Rudensky, Alexander Y.; Chaudhuri, Jayanta] Weill Cornell Grad Sch Med Sci, Immunol & Microbial Pathogenesis Program, New York, NY 10065 USA. [Yen, Wei-Feng] Weill Cornell Grad Sch Med Sci, Biochem Cellular & Mol Biol Program, New York, NY 10065 USA. [Angeletti, Davide; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20814 USA. [Wheatley, Adam K.; McDermott, Adrian B.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Bradfield, Christopher A.] Univ Wisconsin, McArdle Lab Canc Res, Madison, WI 53792 USA. RP Chaudhuri, J (reprint author), Mem Sloan Kettering Canc Ctr, Immunol Program, Ludwig Ctr, New York, NY 10065 USA.; Chaudhuri, J (reprint author), Weill Cornell Grad Sch Med Sci, Immunol & Microbial Pathogenesis Program, New York, NY 10065 USA. EM chaudhuj@mskcc.org OI Chaudhry, Ashutosh/0000-0003-3379-5236; Angeletti, Davide/0000-0002-5256-1972 FU National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) [1R01AI072194, 1R01AI124186]; Starr Cancer Research Foundation [I7-A767]; Ludwig Center at Memorial Sloan Kettering Cancer Center; Hilton-Ludwig Cancer Prevention Initiative (Conrad N. Hilton Foundation); Howard Hughes Medical Institute; NIH/National Cancer Institute Cancer Center Support Grant [P30 CA008748]; Division of Intramural Research, NIAID, NIH; Intramural Research Program of the Vaccine Research Center, NIAID, NIH; NIH [R37-ES005703]; Hilton-Ludwig Cancer Prevention Initiative (Ludgwig Cancer Research) FX This work was supported by grants from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH; 1RO1AI072194 and 1RO1AI124186) and the Starr Cancer Research Foundation (I7-A767) to J. Chaudhuri, grants from the Ludwig Center at Memorial Sloan Kettering Cancer Center, the Hilton-Ludwig Cancer Prevention Initiative (Conrad N. Hilton Foundation and Ludgwig Cancer Research), and the Howard Hughes Medical Institute to A.Y. Rudensky, an NIH/National Cancer Institute Cancer Center Support Grant (P30 CA008748) to A.Y. Rudensky and J. Chaudhuri, a grant from the Division of Intramural Research, NIAID, NIH to J.W. Yewdell and A.B. McDermott, a grant from the Intramural Research Program of the Vaccine Research Center, NIAID, NIH to A.B. McDermott, and a grant from the NIH (R37-ES005703) to C.A. Bradfield. NR 40 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 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD JAN PY 2017 VL 214 IS 1 BP 197 EP 208 DI 10.1084/jem.20160789 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EG5ZN UT WOS:000391123600015 PM 28011866 ER PT J AU Cremer, M Maza, M Alfaro, K Velado, MM Felix, J Castle, PE Kim, J Gage, JC AF Cremer, Miriam Maza, Mauricio Alfaro, Karla Velado, Mario Morales Felix, Juan Castle, Philip E. Kim, Jane Gage, Julia C. TI Scale-Up of an Human Papillomavirus Testing Implementation Program in El Salvador SO JOURNAL OF LOWER GENITAL TRACT DISEASE LA English DT Article DE cervical cancer; human papillomavirus; screening and care of human papillomavirus ID LOW-RESOURCE SETTINGS; CERVICAL-CANCER PREVENTION; COST-EFFECTIVENESS; SELF-COLLECTION; TRIAL; ACCEPTABILITY; WOMEN AB Objective: The Cervical Cancer Prevention in El Salvador is a demonstration project to introduce a lower-cost human papillomavirus (HPV)-DNA test into a public sector project. Started in October 2012, The Cervical Cancer Prevention in El Salvador consists of 3 phases and will ultimately screen 30,000 women. Results of phase 2 of the project are presented. The objective of this project was to compare colposcopy and non-colposcopy-based management for HPV-positive women. Material and Methods: In phase 2, a total of 8,050 women, aged 30 to 49 years, were screened; 6,761 provided both self-and provider-collected specimens and 1,289 provided only provider-testing specimens. HPV results from self-collected specimens were not used in clinical management decisions. Women with provider-collected HPV-positive results were treated based on the strategy assigned to their community; the strategy was colposcopy management (CM) or screen-and-treat (ST) management if they were cryotherapy eligible or colposcopy if not eligible. Outcomes were assessed 6 months after screening. Results: Overall, 489 (12.3%) of 3,963 women receiving CM and 465 (11.4%) of 4,087 women receiving ST tested HPV positive. In the CM cohort, 216 (44.2%) of 489 completed their intervention (203 treated, 11 diagnosed negative, 2 pregnant). In the ST cohort, 411 (88.4%) of 465 completed their intervention (407 treated, 2 diagnosed negative, 1 pregnant). Overall agreement between HPV test results from self-collected and provider-collected specimens was 93.7%, with a. value of 0.70 (95% CI = 0.68-0.73). Conclusions: Human papillomavirus testing with ST management resulted in an approximately twice completion rate compared with CM management. Agreement between self-and provider-based sampling was good and might be used to extend screening to women in areas that are more difficult to reach. C1 [Cremer, Miriam] Cleveland Clin, Lerner Coll Med, Obstet Gynecol & Womens Hlth Inst, 9500 Euclid Ave, Cleveland, OH 44106 USA. [Cremer, Miriam; Maza, Mauricio; Alfaro, Karla] Basic Hlth Int, San Salvador, El Salvador. [Velado, Mario Morales] Minist Hlth, Natl Unit Control & Prevent Canc, San Salvador, El Salvador. [Felix, Juan; Gage, Julia C.] Univ Southern Calif, Dept Pathol, Los Angeles, CA 90089 USA. [Castle, Philip E.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Castle, Philip E.] Albert Einstein Coll Med, Bronx, NY USA. Global Coalit Cerv Canc, Arlington, VA USA. [Kim, Jane] Harvard TH Chan Sch Publ Hlth, Ctr Hlth Decis Sci, Boston, MA USA. RP Cremer, M (reprint author), Cleveland Clin, Lerner Coll Med, Obstet Gynecol & Womens Hlth Inst, 9500 Euclid Ave, Cleveland, OH 44106 USA. EM bhisubmissions@gmail.com FU Einhorn Family Charitable Trust; Union for International Cancer Control FX The authors thank the Einhorn Family Charitable Trust and the Union for International Cancer Control for their support of this project. NR 20 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 1089-2591 EI 1526-0976 J9 J LOW GENIT TRACT DI JI J. Low. Genit. Tract. Dis. PD JAN PY 2017 VL 21 IS 1 BP 26 EP 32 DI 10.1097/LGT.0000000000000280 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EG3MG UT WOS:000390948200009 PM 27922905 ER PT J AU Wiggins, JL Brotman, MA Adleman, NE Kim, P Wambach, CG Reynolds, RC Chen, G Towbin, K Pine, DS Leibenluft, E AF Wiggins, Jillian Lee Brotman, Melissa A. Adleman, Nancy E. Kim, Pilyoung Wambach, Caroline G. Reynolds, Richard C. Chen, Gang Towbin, Kenneth Pine, Daniel S. Leibenluft, Ellen TI Neural Markers in Pediatric Bipolar Disorder and Familial Risk for Bipolar Disorder SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE bipolar; brain; adolescence; risk; endophenotype ID MAJOR DEPRESSIVE DISORDER; FACIAL EMOTION; CHILDREN; YOUTH; ENDOPHENOTYPES; SCHIZOPHRENIA; UNIPOLAR; DEFICITS; FMRI AB Objective: Bipolar disorder (BD) is highly heritable. Neuroimaging studies comparing unaffected youth at high familial risk for BD (i.e., those with a first-degree relative with the disorder; termed "high-risk" [HR]) to "low-risk" (LR) youth (i.e., those without a first-degree relative with BD) and to patients with BD may help identify potential brain-based markers associated with risk (i.e., regions where BR+BD not equal LR), resilience (HR not equal BD+LR), or illness (BD not equal HR+LR). Method: During functional magnetic resonance imaging (fMRI), 99 youths (i.e., adolescents and young adults) aged 9.8 to 24.8 years (36 BD, 22 HR, 41 LR) performed a task probing face emotion labeling, previously shown to be impaired behaviorally in youth with BD and HR youth. Results: We found three patterns of results. Candidate risk endophenotypes (i.e., where BD and HR shared deficits) included dysfunction in higher-order face processing regions (e.g., middle temporal gyrus, dorsolateral prefrontal cortex). Candidate resilience markers and disorder sequelae (where HR and BD, respectively, show unique alterations relative to the other two groups) included different patterns of neural responses across other regions mediating face processing (e.g., fusiform), executive function (e.g., inferior frontal gyrus), and social cognition (e.g., default network, superior temporal sulcus, temporoparietal junction). Conclusion: If replicated in longitudinal studies and with additional populations, neural patterns suggesting risk endophenotypes could be used to identify individuals at risk for BD who may benefit from prevention measures. Moreover, information about risk and resilience markers could be used to develop novel treatments that recruit neural markers of resilience and attenuate neural patterns associated with risk. C1 [Wiggins, Jillian Lee; Brotman, Melissa A.; Adleman, Nancy E.; Kim, Pilyoung; Wambach, Caroline G.; Towbin, Kenneth; Pine, Daniel S.; Leibenluft, Ellen] NIMH, Emot & Dev Branch, NIH, Bethesda, MD 20892 USA. [Wiggins, Jillian Lee] San Diego State Univ, San Diego, CA 92182 USA. [Wiggins, Jillian Lee] San Diego State Univ Univ Calif San Diego Joint D, San Diego, CA USA. [Adleman, Nancy E.] Catholic Univ Amer, Washington, DC 20064 USA. [Kim, Pilyoung] Univ Denver, Denver, CO 80208 USA. [Reynolds, Richard C.; Chen, Gang] NIMH, Sci & Stat Comp Core, NIH, Bethesda, MD USA. RP Wiggins, JL (reprint author), 6363 Alvarado Court,Suite 103,MC 1863, San Diego, CA 92120 USA. EM jillian.wiggins@sdsu.edu RI Brotman, Melissa/H-7409-2013 FU Intramural Research Program of the National Institute of Mental Health (NIMH)/the National Institutes of Health (NIH) [02-M-0021, 00-M-0198] FX This research was supported by the Intramural Research Program of the National Institute of Mental Health (NIMH)/the National Institutes of Health (NIH), conducted under NIH Clinical Study Protocols 02-M-0021 (ClinicalTrials.gov ID: NCT00025935) and 00-M-0198 (NCT00006177). Authors are U.S. federal government employees (NIMH IRP). NR 29 TC 0 Z9 0 U1 12 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD JAN PY 2017 VL 56 IS 1 BP 67 EP 78 DI 10.1016/j.jaac.2016.10.009 PG 12 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA EG3WE UT WOS:000390974600010 PM 27993231 ER PT J AU AlGhatrif, M Wang, MY Fedorova, OV Bagrov, AY Lakatta, EG AF AlGhatrif, Majd Wang, Mingyi Fedorova, Olga V. Bagrov, Alexei Y. Lakatta, Edward G. TI The Pressure of Aging SO MEDICAL CLINICS OF NORTH AMERICA LA English DT Article DE Hemodynamics; Aging; Arterial wall remodeling; Age-dependent salt-sensitive hypertension; Pulse wave velocity; Arterial fibrosis; Angiotensin II; Marinobufagenin ID SMOOTH-MUSCLE-CELLS; ENDOGENOUS CARDIOTONIC STEROIDS; SALT-SENSITIVE HYPERTENSION; DIETARY-SODIUM RESTRICTION; CHRONIC-RENAL-FAILURE; PULSE-WAVE VELOCITY; BLOOD-PRESSURE; ANGIOTENSIN-II; ARTERIAL STIFFNESS; VASCULAR-DISEASE AB Significant hemodynamic changes ensue with aging, leading to an evergrowing epidemic of hypertension. Alterations in central arterial properties play a major role in these hemodynamic changes. These alterations are characterized by an initial decline in aortic distensibility and an increase of diastolic blood pressure, followed by a sharp increase in pulse wave velocity (PWV), and an increase in pulse pressure (PP) beyond the sixth decade. However, the trajectories of PWV and PP diverge with advancing age. There is an increased prevalence of salt-sensitive hypertension with advancing age that is, in part, mediated by marinobufagenin, an endogenous sodium pump ligand. C1 [AlGhatrif, Majd; Wang, Mingyi; Fedorova, Olga V.; Bagrov, Alexei Y.; Lakatta, Edward G.] NIA, NIH, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. [AlGhatrif, Majd] Johns Hopkins Sch Med, Johns Hopkins Bayview Med Ctr, Dept Med, Baltimore, MD USA. RP Lakatta, EG (reprint author), Biomed Res Ctr, Cardiovasc Sci Lab, 251 Bayview Blvd,Suite 100,Room 09B116, Baltimore, MD 21224 USA. EM LakattaE@grc.nia.nih.gov FU Intramural NIH HHS [Z01 AG000235-01] NR 107 TC 1 Z9 1 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0025-7125 EI 1557-9859 J9 MED CLIN N AM JI Med. Clin. N. Am. PD JAN PY 2017 VL 101 IS 1 BP 81 EP + DI 10.1016/j.mcna.2016.08.006 PG 22 WC Medicine, General & Internal SC General & Internal Medicine GA EG3UQ UT WOS:000390970600010 PM 27884238 ER PT J AU Joo, HS Otto, M AF Joo, Hwang-Soo Otto, Michael TI Toxin-mediated gene regulatory mechanism in Staphylococcus aureus SO MICROBIAL CELL LA English DT Article DE Staphylococcus aureus; phenol-soluble modulins; toxin; gene regulation; GntR; YtrA AB The dangerous human pathogen Staphylococcus aureus relies heavily on toxins to cause disease, but toxin production can put a strong burden on the bacteria's energy balance. Thus, controlling the synthesis of proteins solely needed in times of toxin production represents a way for the bacteria to avoid wasting energy. One hypothetical manner to accomplish this sort of regulation is by gene regulatory functions of the toxins themselves. There have been several reports about gene regulation by toxins in S. aureus, but these were never verified on the molecular level. In our study published in MBio [Joo et al., 7(5). pii: e01579-16], we show that phenol-soluble modulins (PSMs), important peptide toxins of S. aureus, release a repressor from the promoter of the operon encoding the toxin export system, thereby enabling toxin secretion. This study describes the first molecular regulatory mechanism exerted by an S. aureus toxin, setting a paradigmatic example of how S. aureus toxins may influence cell functions to adjust them to times of toxin production. C1 [Joo, Hwang-Soo; Otto, Michael] NIAID, NIH, Bacteriol Lab, Bethesda, MD 20814 USA. RP Otto, M (reprint author), NIAID, NIH, Bacteriol Lab, Bethesda, MD 20814 USA. EM MOtto@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health FX This study was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health. NR 0 TC 0 Z9 0 U1 4 U2 4 PU SHARED SCIENCE PUBLISHERS OG PI GRAZ PA AM BLUMENHAG 25-4, GRAZ, 8010, AUSTRIA SN 2311-2638 J9 MICROB CELL JI Microb. Cell PD JAN PY 2017 VL 4 IS 1 BP 29 EP 31 DI 10.15698/mic2017.01.553 PG 3 WC Cell Biology SC Cell Biology GA EG5WL UT WOS:000391115400004 ER PT J AU Patriat, R Reynolds, RC Birn, RM AF Patriat, Remi Reynolds, Richard C. Birn, Rasmus M. TI An improved model of motion-related signal changes in fMRI SO NEUROIMAGE LA English DT Article DE Motion; Correction; Rs-fMRI; Methods ID FUNCTIONAL CONNECTIVITY MRI; RESTING-STATE FMRI; TIME-SERIES; NOISE; BOLD AB Head motion is a significant source of noise in the estimation of functional connectivity from resting state functional MRI (rs-fMRI). Current strategies to reduce this noise include image realignment, censoring time points corrupted by motion, and including motion realignment parameters and their derivatives as additional nuisance regressors in the general linear model. However, this nuisance regression approach assumes that the motion-induced signal changes are linearly related to the estimated realignment parameters, which is not always the case. In this study we develop an improved model of motion-related signal changes, where nuisance regressors are formed by first rotating and translating a single brain volume according to the estimated motion, re-registering the data, and then performing a principal components analysis (PCA) on the resultant time series of both moved and re-registered data. We show that these "Motion Simulated (MotSim)" regressors account for significantly greater fraction of variance, result in higher temporal signal-to-noise, and lead to functional connectivity estimates that are less affected by motion compared to the most common current approach of using the realignment parameters and their derivatives as nuisance regressors. This improvement should lead to more accurate estimates of functional connectivity, particularly in populations where motion is prevalent, such as patients and young children. (C) 2016 Published by Elsevier Inc. C1 [Patriat, Remi; Birn, Rasmus M.] Univ Wisconsin, Dept Med Phys, 1530 Med Sci Ctr, Madison, WI 53706 USA. [Birn, Rasmus M.] Univ Wisconsin, Dept Psychiat, 6001 Res Pk Blvd, Madison, WI 53719 USA. [Reynolds, Richard C.] NIMH, Sci & Stat Comp Core, NIH, Bethesda, MD 20892 USA. RP Birn, RM (reprint author), Univ Wisconsin, Dept Psychiat, 6001 Res Pk Blvd, Madison, WI 53719 USA. EM rbirn@wisc.edu FU NIH [RC1MH090912, R21MH101526, P50MH100031]; Wisconsin Alumni Research Foundation; Health Emotions Research Institute FX This work was funded by NIH grants RC1MH090912, R21MH101526, P50MH100031 the Wisconsin Alumni Research Foundation, and the Health Emotions Research Institute. We thank Timothy B. Meier, Veena B. Nair, Rebecca D. Ray, Ricardo Pizarro and Jie Song for assistance with data collection. The authors do not report any conflict of interest of any kind. NR 17 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 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD JAN 1 PY 2017 VL 144 BP 74 EP 82 DI 10.1016/j.neuroimage.2016.08.051 PN A PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EG3ZI UT WOS:000390982800006 PM 27570108 ER PT J AU Karageorgiadis, AS Lyssikatos, C Belyavskaya, E Papadakis, GZ Patronas, NJ Lodish, MB Stratakis, CA AF Karageorgiadis, Alexander S. Lyssikatos, Charalampos Belyavskaya, Elena Papadakis, Georgios Z. Patronas, Nicholas J. Lodish, Maya B. Stratakis, Constantine A. TI Poor Growth With Presence of a Pituitary Lesion in an 11-year-old Boy SO PEDIATRICS IN REVIEW LA English DT Editorial Material ID PROLACTINOMA C1 [Karageorgiadis, Alexander S.; Lyssikatos, Charalampos; Belyavskaya, Elena; Lodish, Maya B.; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Karageorgiadis, Alexander S.] Georgetown Univ Hosp, Dept Pediat, Washington, DC 20007 USA. [Papadakis, Georgios Z.; Patronas, Nicholas J.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Karageorgiadis, AS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, NIH, Bethesda, MD 20892 USA.; Karageorgiadis, AS (reprint author), Georgetown Univ Hosp, Dept Pediat, Washington, DC 20007 USA. NR 8 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 0191-9601 EI 1526-3347 J9 PEDIATR REV JI Pediatr. Rev. PD JAN PY 2017 VL 38 IS 1 BP 44 EP + PG 4 WC Pediatrics SC Pediatrics GA EG6ER UT WOS:000391137800007 PM 28044033 ER PT J AU Theodore, WH AF Theodore, William H. TI Presurgical Focus Localization in Epilepsy: PET and SPECT SO SEMINARS IN NUCLEAR MEDICINE LA English DT Review ID TEMPORAL-LOBE EPILEPSY; POSITRON-EMISSION-TOMOGRAPHY; COMPLEX PARTIAL SEIZURES; 5-HT1A RECEPTOR-BINDING; TUBEROUS SCLEROSIS COMPLEX; CEREBRAL GLUCOSE-METABOLISM; SEROTONIN 1A RECEPTORS; MU-OPIATE RECEPTORS; LONG-TERM OUTCOMES; FDG-PET AB Positron emission tomography (PET) and single photon emission computed tomography (SPECT) can be used to assist localization of seizure foci in patients with drug-resistant epilepsy. Both should be interpreted in the context of clinical, electrographic, and magnetic resonance imaging data. PET has wider research applications, particularity when used with ligands for neurotransmitter receptors or inflammatory processes. (C) 2017 Published by Elsevier Inc. C1 [Theodore, William H.] Natl Inst Neurol Disorders & Stroke, NIH Bldg 10,Room 7D-43, Bethesda, MD 20892 USA. RP Theodore, WH (reprint author), Natl Inst Neurol Disorders & Stroke, NIH Bldg 10,Room 7D-43, Bethesda, MD 20892 USA. EM theodorw@ninds.nih.gov NR 118 TC 0 Z9 0 U1 3 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0001-2998 EI 1558-4623 J9 SEMIN NUCL MED JI Semin. Nucl. Med. PD JAN PY 2017 VL 47 IS 1 BP 44 EP 53 DI 10.1053/j.semnuclmed.2016.09.008 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EG6NZ UT WOS:000391164500006 PM 27987556 ER PT J AU Power, JD Schlaggar, BL AF Power, Jonathan D. Schlaggar, Bradley L. TI Neural plasticity across the lifespan SO WILEY INTERDISCIPLINARY REVIEWS-DEVELOPMENTAL BIOLOGY LA English DT Article ID CRITICAL-PERIOD PLASTICITY; VISUAL-CORTEX; SOMATOSENSORY CORTEX; STRIATE CORTEX; RECEPTIVE-FIELDS; KITTENS; REORGANIZATION; MONKEYS; AREAS; MAP AB An essential feature of the brain is its capacity to change. Neuroscientists use the term plasticity' to describe the malleability of neuronal connectivity and circuitry. How does plasticity work? A review of current data suggests that plasticity encompasses many distinct phenomena, some of which operate across most or all of the lifespan, and others that operate exclusively in early development. This essay surveys some of the key concepts related to neural plasticity, beginning with how current patterns of neural activity (e.g., as you read this essay) come to impact future patterns of activity (e.g., your memory of this essay), and then extending this framework backward into more development-specific mechanisms of plasticity. WIREs Dev Biol 2017, 6:e216. doi: 10.1002/wdev.216 For further resources related to this article, please visit the . C1 [Power, Jonathan D.] NIMH, Bethesda, MD 20892 USA. [Schlaggar, Bradley L.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. RP Power, JD (reprint author), NIMH, Bethesda, MD 20892 USA. EM jonathan.power@nih.gov FU National Institutes of Health [F30-MH940322] FX Preparation of this article was made possible in part by a grant from the National Institutes of Health (F30-MH940322) to JDP. NR 34 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1759-7684 EI 1759-7692 J9 WIRES DEV BIOL JI Wiley Interdiscip. Rev.-Dev. Biol. PD JAN-FEB PY 2017 VL 6 IS 1 AR UNSP e216 DI 10.1002/wdev.216 PG 9 WC Developmental Biology SC Developmental Biology GA EG4TN UT WOS:000391036700001 ER PT J AU Bauler, TJ Starr, T Nagy, TA Sridhar, S Scott, D Winkler, CW Steele-Mortimer, O Detweiler, CS Peterson, KE AF Bauler, Timothy J. Starr, Tregei Nagy, Toni A. Sridhar, Sushmita Scott, Dana Winkler, Clayton W. Steele-Mortimer, Olivia Detweiler, Corrella S. Peterson, Karin E. TI Salmonella Meningitis Associated with Monocyte Infiltration in Mice SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID ENTERICA SEROVAR TYPHIMURIUM; BLOOD-BRAIN-BARRIER; BACTERIAL-MENINGITIS; INFECTION; RESISTANCE; INFANTS; NRAMP1; COMPLICATIONS; TRANSLOCATION; ENTERITIDIS AB In the current study, we examined the ability of Salmonella enterica serovar Typhimurium to infect the central nervous system and cause meningitis following the natural route of infection in mice. C57BL/6J mice are extremely susceptible to systemic infection by Salmonella Typhimurium because of loss-of-function mutations in Nramp1 (SLC11A1), a phagosomal membrane protein that controls iron export from vacuoles and inhibits Salmonella growth in macrophages. Therefore, we assessed the ability of Salmonella to disseminate to the central nervous system (CNS) after oral infection in C57BL/6J mice expressing either wild-type (resistant) or mutant (susceptible) alleles of Nramp1. In both strains, oral infection resulted in focal meningitis and ventriculitis with recruitment of inflammatory monocytes to the CNS. In susceptible Nramp1(-/-) mice, there was a direct correlation between bacteremia and the number of bacteria in the brain, which was not observed in resistant Nramp1(+/+) mice. A small percentage of Nramp1(+/+) mice developed severe ataxia, which was associated with high bacterial loads in the CNS as well as clear histopathology of necrotizing vasculitis and hemorrhage in the brain. Thus, Nramp1 is not essential for Salmonella entry into the CNS or neuroinflammation, but may influence the mechanisms of CNS entry as well as the severity of meningitis. C1 [Bauler, Timothy J.; Starr, Tregei; Sridhar, Sushmita; Steele-Mortimer, Olivia] NIAID, Bacteriol Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [Winkler, Clayton W.] NIAID, Lab Persistent Viral Dis, Rocky Mt Labs, NIH, Hamilton, MT USA. [Scott, Dana] NIAID, Rocky Mt Vet Branch, Rocky Mt Labs, NIH, Hamilton, MT USA. [Nagy, Toni A.; Detweiler, Corrella S.] Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA. [Bauler, Timothy J.] Western Michigan Univ, Homer Stryker MD Sch Med, Dept Biomed Sci, Kalamazoo, MI 49008 USA. RP Peterson, KE (reprint author), Rocky Mt Labs, Persistent Viral Dis Lab, 903 S 4th St, Hamilton, MT 59840 USA. EM petersonka@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases Intramural Program; NIH [R01AI095395] FX Supported in part by the National Institute of Allergy and Infectious Diseases Intramural Program and in part by NIH grant R01AI095395. NR 28 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 0002-9440 EI 1525-2191 J9 AM J PATHOL JI Am. J. Pathol. PD JAN PY 2017 VL 187 IS 1 BP 187 EP 199 DI 10.1016/j.ajpath.2016.09.002 PG 13 WC Pathology SC Pathology GA EG1YC UT WOS:000390829300019 PM 27955815 ER PT J AU Al Hazzouri, AZ Elfassy, T Sidney, S Jacobs, D Stable, EJP Yaffe, K AF Al Hazzouri, Adina Zeki Elfassy, Tali Sidney, Stephen Jacobs, David Stable, Eliseo J. Perez Yaffe, Kristine TI Sustained Economic Hardship and Cognitive Function: The Coronary Artery Risk Development in Young Adults Study SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID SOCIOECONOMIC POSITION; EDUCATIONAL-ATTAINMENT; MIDDLE-AGE; HEALTH; LIFE; INCOME; INEQUALITY; TRAJECTORIES; POPULATION; LIFECOURSE AB Introduction: The relationship between low income and worse health outcomes is evident, yet its association with cognitive outcomes is less explored. Most studies have measured income at one time and none have examined how sustained exposure to low income influences cognition in a relatively young cohort. This study examined the effect of sustained poverty and perceived financial difficulty on cognitive function in midlife. Methods: Income data were collected six times between 1985 and 2010 for 3,383 adults from the Coronary Artery Risk Development in Young Adults prospective cohort study. Sustained poverty was defined by the percentage of time participants' household income was <200% of the federal poverty level-"never" in poverty, "0< to <1/3," " >= 1/3 to <100%" or " all-time." In 2010, at a mean age of 50 years, participants underwent a cognitive battery. Data were analyzed in 2015. Results: In demographic-adjusted linear regression models, individuals with all-time poverty performed significantly worse than individuals never in poverty: 0.92 points worse on verbal memory (z-score, -0.28; 95% CI=-0.43, -0.13), 11.60 points worse on processing speed (z-score, -0.72; 95% CI=- 0.85, -0.58), and 3.50 points worse on executive function (z-score, -0.32; 95% CI=-0.47, -0.17). Similar results were observed with perceived financial difficulty. Findings were robust when restricted to highly educated participants, suggesting little evidence for reverse causation. Conclusions: Cumulative exposure to low income over 2 decades was strongly associated with worse cognitive function of a relatively young cohort. Poverty and perceived hardship may be important contributors to premature aging among disadvantaged populations. (C) 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved. C1 [Al Hazzouri, Adina Zeki; Elfassy, Tali] Univ Miami, Dept Publ Hlth Sci, Div Epidemiol & Populat Hlth Sci, Miami, FL 33136 USA. [Sidney, Stephen] Kaiser Permanente, Div Res, Oakland, CA USA. [Jacobs, David] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Stable, Eliseo J. Perez] Natl Inst Minor Hlth & Hlth Dispar, Bethesda, MD USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. RP Al Hazzouri, AZ (reprint author), Univ Miami, Dept Publ Hlth Sci, Div Epidemiol & Populat Hlth Sci, Miami, FL 33136 USA. EM axz122@miami.edu FU NIH, National Institute on Aging (NIA) [K01AG047273]; NIH/NIA [k24AG031155]; T32 training grant from NIH, National Heart, Lung, and Blood Institute (NHLBI), "Behavioral Medicine Approaches to Cardiovascular Disease" [HL 007426]; University of California at San Francisco Center for Aging in Diverse Communities under "Resource Centers for Minority Aging Research program of the National Institute on Aging" [P30-AG15272]; NHLBI [HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268-201300028C, HHSN268201300029C, HHSN26820-0900041C, AG0005]; Intramural Research Program of NIA; NIA [AG0005] FX Dr. Zeki Al Hazzouri was supported by a grant from NIH, National Institute on Aging (NIA) (K01AG047273). Dr. Yaffe was supported by a grant from the NIH/NIA (k24AG031155). Tali Elfassy was supported by a T32 training grant from NIH, National Heart, Lung, and Blood Institute (NHLBI), "Behavioral Medicine Approaches to Cardiovascular Disease," (HL 007426). Funding for this study was supported in part by the University of California at San Francisco Center for Aging in Diverse Communities (P30-AG15272) under the "Resource Centers for Minority Aging Research program of the National Institute on Aging." The Coronary Artery Risk Development in Young Adults Study is supported by contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268-201300028C, HHSN268201300029C, and HHSN26820-0900041C from NHLBI, the Intramural Research Program of NIA, and an intra-agency agreement between NIA and NHLBI (AG0005). NR 41 TC 0 Z9 0 U1 7 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD JAN PY 2017 VL 52 IS 1 BP 1 EP 9 DI 10.1016/j.amepre.2016.08.009 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA EF9RM UT WOS:000390667400005 ER PT J AU James, P Hart, JE Banay, RF Laden, F Signorello, LB AF James, Peter Hart, Jaime E. Banay, Rachel F. Laden, Francine Signorello, Lisa B. TI Built Environment and Depression in Low-Income African Americans and Whites SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID EMERGENCY-DEPARTMENT VISITS; SOUTHERN COMMUNITY COHORT; PHYSICAL-ACTIVITY; AIR-POLLUTION; MENTAL-HEALTH; CES-D; CARDIOVASCULAR-DISEASE; SOCIOECONOMIC-STATUS; CANCER-PATIENTS; UNITED-STATES AB Introduction: Urban environments are associated with a higher risk of adverse mental health outcomes; however, it is unclear which specific components of the urban environment drive these associations. Methods: Using data collected in 2002-2009 from 73,225 low-income, racially diverse individuals across the Southeastern U.S., analyses evaluated the cross-sectional relationship between a walkability index and depression. Walkability was calculated from population density, street connectivity, and destination count in the 1,200-meter area around participants' homes, and depression was measured using the Center for Epidemiologic Studies Depression Scale for depression symptomatology and questionnaire responses regarding doctor-diagnosed depression and antidepressant use. Data were analyzed in 2015. Results: Participants living in neighborhoods with the highest walkability index had 6% higher odds of moderate or greater depression symptoms (score >= 15, 95% CI=0.99, 1.14), 28% higher odds of doctor-diagnosed depression (95% CI=1.20, 1.36), and 16% higher odds of current antidepressant use (95% CI=1.08, 1.25), compared with those in the lowest walkability index. Higher walkability was associated with higher odds of depression symptoms in the most deprived neighborhoods only, whereas walkability was associated with lower odds of depression symptoms in the least deprived neighborhoods. Conclusions: Living in a more walkable neighborhood was associated with modestly higher levels of doctor-diagnosed depression and antidepressant use, and walkability was associated with greater depression symptoms in neighborhoods with higher deprivation. Although dense urban environments may provide opportunities for physical activity, they may also increase exposure to noise, air pollution, and social stressors that could increase levels of depression. (C) 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved. C1 [James, Peter; Laden, Francine; Signorello, Lisa B.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, 401 Pk Dr,3rd Floor West, Boston, MA 02215 USA. [James, Peter; Hart, Jaime E.; Banay, Rachel F.; Laden, Francine] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [James, Peter; Hart, Jaime E.; Laden, Francine] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [James, Peter; Hart, Jaime E.; Laden, Francine] Harvard Med Sch, Boston, MA USA. [Signorello, Lisa B.] NCI, Canc Prevent Fellowship Program, Rockville, MD USA. RP James, P (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, 401 Pk Dr,3rd Floor West, Boston, MA 02215 USA. EM pjames@hsph.harvard.edu FU Harvard National Heart, Lung, and Blood Institute Cardiovascular Epidemiology Training Grant [T32 HL 098048]; Harvard National Institute of Environmental Health Sciences Environmental Epidemiology Training Grant [T32 ES 07069, R01 CA092447] FX The research conducted for this manuscript was supported by the Harvard National Heart, Lung, and Blood Institute Cardiovascular Epidemiology Training Grant T32 HL 098048, Harvard National Institute of Environmental Health Sciences Environmental Epidemiology Training Grant T32 ES 07069, and R01 CA092447 (Southern Community Cohort Study). NR 67 TC 0 Z9 0 U1 16 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD JAN PY 2017 VL 52 IS 1 BP 74 EP 84 DI 10.1016/j.amepre.2016.08.022 PG 11 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA EF9RM UT WOS:000390667400013 PM 27720338 ER PT J AU Stevens, J Pratt, C Boyington, J Nelson, C Truesdale, KP Ward, DS Lytle, L Sherwood, NE Robinson, TN Moore, S Barkin, S Cheung, YK Murray, DM AF Stevens, June Pratt, Charlotte Boyington, Josephine Nelson, Cheryl Truesdale, Kimberly P. Ward, Dianne S. Lytle, Leslie Sherwood, Nancy E. Robinson, Thomas N. Moore, Shirley Barkin, Shari Cheung, Ying Kuen Murray, David M. TI Multilevel Interventions Targeting Obesity: Research Recommendations for Vulnerable Populations SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID REGRESSION DISCONTINUITY DESIGNS; RANDOMIZED-TRIAL SMART; BEHAVIOR-CHANGE INTERVENTIONS; MULTIPHASE OPTIMIZATION STRATEGY; NEW-YORK-CITY; CHILDHOOD OBESITY; CAUSAL-INFERENCE; UNITED-STATES; FORMATIVE RESEARCH; PHYSICAL-ACTIVITY AB Introduction: The origins of obesity are complex and multifaceted. To be successful, an intervention aiming to prevent or treat obesity may need to address multiple layers of biological, social, and environmental influences. Methods: NIH recognizes the importance of identifying effective strategies to combat obesity, particularly in high-risk and disadvantaged populations with heightened susceptibility to obesity and subsequent metabolic sequelae. To move this work forward, the National Heart, Lung, and Blood Institute, in collaboration with the NIH Office of Behavioral and Social Science Research and NIH Office of Disease Prevention convened a working group to inform research on multilevel obesity interventions in vulnerable populations. The working group reviewed relevant aspects of intervention planning, recruitment, retention, implementation, evaluation, and analysis, and then made recommendations. Results: Recruitment and retention techniques used in multilevel research must be culturally appropriate and suited to both individuals and organizations. Adequate time and resources for preliminary work are essential. Collaborative projects can benefit from complementary areas of expertise and shared investigations rigorously pretesting specific aspects of approaches. Study designs need to accommodate the social and environmental levels under study, and include appropriate attention given to statistical power. Projects should monitor implementation in the multiple venues and include a priori estimation of the magnitude of change expected within and across levels. Conclusions: The complexity and challenges of delivering interventions at several levels of the social - ecologic model require careful planning and implementation, but hold promise for successful reduction of obesity in vulnerable populations. (C) 2016 Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Stevens, June; Truesdale, Kimberly P.; Ward, Dianne S.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Nutr, Chapel Hill, NC 27599 USA. [Stevens, June; Truesdale, Kimberly P.; Ward, Dianne S.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Stevens, June] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Pratt, Charlotte; Boyington, Josephine; Nelson, Cheryl] NHLBI, Div Cardiovasc Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Lytle, Leslie] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Hlth Behav, Chapel Hill, NC USA. [Sherwood, Nancy E.] HealthPartners Inst Educ & Res, Bloomington, MN USA. [Robinson, Thomas N.] Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA. [Robinson, Thomas N.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Moore, Shirley] Case Western Reserve Univ, Frances Payne Bolton Sch, Cleveland, OH 44106 USA. [Barkin, Shari] Vanderbilt Univ, Ctr Med, Dept Pediat, Nashville, TN 37232 USA. [Cheung, Ying Kuen] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY USA. [Murray, David M.] NIH, Div Program Coordinat Planning & Strateg Initiat, Bldg 10, Bethesda, MD 20892 USA. RP Stevens, J (reprint author), Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Nutr, Chapel Hill, NC 27599 USA. EM june_stevens@unc.edu FU National Heart, Lung, and Blood Institute (NHLBI); NIH Offices of Disease Prevention and Behavioral and Social Science Research FX On September 15-16, 2015, the working group meeting was supported by the National Heart, Lung, and Blood Institute (NHLBI), and the NIH Offices of Disease Prevention and Behavioral and Social Science Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH or NHLBI. NR 108 TC 0 Z9 0 U1 20 U2 20 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD JAN PY 2017 VL 52 IS 1 BP 115 EP 124 DI 10.1016/j.amepre.2016.09.011 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA EF9RM UT WOS:000390667400018 PM 28340973 ER PT J AU Lago, T Davis, A Grillon, C Ernst, M AF Lago, Tiffany Davis, Andrew Grillon, Christian Ernst, Monique TI Striatum on the anxiety map: Small detours into adolescence SO BRAIN RESEARCH LA English DT Review DE Dopamine; Attention bias; Learning; Conditioning; Prediction error; Motivation ID INTRINSIC FUNCTIONAL CONNECTIVITY; NATIONAL-COMORBIDITY-SURVEY; RISKY DECISION-MAKING; AGE-RELATED-CHANGES; MOTIVATED BEHAVIOR; PSYCHIATRIC-DISORDERS; NUCLEUS-ACCUMBENS; VENTRAL STRIATUM; DORSAL STRIATUM; BASAL GANGLIA AB Adolescence is the most sensitive period for the development of pathological anxiety. Moreover, specific neural changes associated with the striatum might be related to adolescent vulnerability to anxiety. Up to now, the study of anxiety has primarily focused on the amygdala, bed nucleus of the stria terminalis (BNST), hippocampus and ventromedial prefrontal cortex (vmPFC), while the striatum has typically not been considered as part of the anxiety system. This review proposes the addition of the striatum, a complex, multi-component structure, to the anxiety network by underscoring two lines of research. First, the co-occurrence of the adolescent striatal development with the peak vulnerability of adolescents to anxiety disorders might potentially reflect a causal relationship. Second, the recognition of the role of the striatum in fundamental behavioral processes that do affect anxiety supports the putative importance of the striatum in anxiety. These behavioral processes include (1) attention, (2) conditioning/prediction error, and (3) motivation. This review proposes a simplistic schematic representation of the anxiety circuitry that includes the striatum, and aims to promote further work in this direction, as the role of the striatum in shaping an anxiety phenotype during adolescence could have critical implications for understanding and preventing the peak onset of anxiety disorders during this period. This article is part of a Special Issue entitled SI: Adolescent plasticity. Published by Elsevier B.V. C1 [Lago, Tiffany; Davis, Andrew; Grillon, Christian; Ernst, Monique] NIMH, NIH, SNFA, 15K North Dr, Bethesda, MD 20892 USA. RP Ernst, M (reprint author), NIMH, NIH, SNFA, 15K North Dr, Bethesda, MD 20892 USA. EM tiffany.lago@nih.gov; andrew.jo.davis@gmail.com; grillonc@mail.nih.gov; ernstm@mail.nih.gov FU Intramural Research Program of the National Institute of Mental Health [ZIAMH002798, NCT00026559: Protocol ID 01-M-0185] FX The authors report no conflicts of interest. Financial support of this study was provided by the Intramural Research Program of the National Institute of Mental Health, ZIAMH002798 (ClinicalTrial.gov Identifier: NCT00026559: Protocol ID 01-M-0185). NR 129 TC 0 Z9 0 U1 12 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD JAN 1 PY 2017 VL 1654 SI SI BP 177 EP 184 DI 10.1016/j.brainres.2016.06.006 PN B PG 8 WC Neurosciences SC Neurosciences & Neurology GA EG0SD UT WOS:000390741600011 PM 27276526 ER PT J AU Fabbri, E Chia, CW Spencer, RG Fishbein, KW Reiter, DA Cameron, D Zane, AC Moore, ZA Gonzalez-Freire, M Zoli, M Studenski, SA Kalyani, RR Egan, JM Ferrucci, L AF Fabbri, Elisa Chia, Chee W. Spencer, Richard G. Fishbein, Kenneth W. Reiter, David A. Cameron, Donnie Zane, Ariel C. Moore, Zenobia A. Gonzalez-Freire, Marta Zoli, Marco Studenski, Stephanie A. Kalyani, Rita R. Egan, Josephine M. Ferrucci, Luigi TI Insulin Resistance Is Associated With Reduced Mitochondrial Oxidative Capacity Measured by P-31-Magnetic Resonance Spectroscopy in Participants Without Diabetes From the Baltimore Longitudinal Study of Aging SO DIABETES LA English DT Article ID GRAPHICAL USER-INTERFACE; SKELETAL-MUSCLE; WEIGHT-LOSS; GLUCOSE; QUANTITATION; SENSITIVITY; DYSFUNCTION; MELLITUS; PACKAGE; MRUI AB Whether individuals with insulin resistance (IR) but without criteria for diabetes exhibit reduced mitochondrial oxidative capacity is unclear; addressing this question could guide research for new therapeutics. We investigated 248 participants without diabetes from the Baltimore Longitudinal Study of Aging (BLSA) to determine whether impaired mitochondria! capacity is associated with pre-diabetes, IR, and duration and severity of hyperglycemia exposure. Mitochondrial capacity was assessed as the postexercise phosphocreatine recovery time constant (tau(PCR)) by P-31-magnetic resonance spectroscopy, with higher tau(PCR) values reflecting reduced capacity. Prediabetes was defined using the American Diabetes Association criteria from fasting and 2-h glucose measurements. IR and sensitivity were calculated using HOMA-IR and Matsuda indices. The duration and severity of hyperglycemia exposure were estimated as the number of years from prediabetes onset and the average oral glucose tolerance test (OGTT) 2-h glucose measurement over previous BLSA visits. Covariates included age, sex, body composition, physical activity, and other confounders. Higher likelihood of prediabetes, higher HOMA-IR, and lower Matsuda index were associated with longer tau(PCR). Among 205 participants with previous OGTT data, greater severity and longer duration of hyperglycemia were independently associated with longer tau(PCR). In conclusion, in individuals without diabetes a more impaired mitochondrial capacity is associated with greater IR and a higher likelihood of prediabetes. C1 [Fabbri, Elisa; Cameron, Donnie; Zane, Ariel C.; Moore, Zenobia A.; Gonzalez-Freire, Marta; Studenski, Stephanie A.; Ferrucci, Luigi] NIA, Longitudinal Study Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Fabbri, Elisa; Zoli, Marco] Univ Bologna, Dept Med & Surg Sci, Bologna, Italy. [Chia, Chee W.; Spencer, Richard G.; Fishbein, Kenneth W.; Reiter, David A.; Egan, Josephine M.] NIA, Lab Clin Invest, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Kalyani, Rita R.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. RP Ferrucci, L (reprint author), NIA, Longitudinal Study Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. EM ferruccilu@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute on Aging FX This research was supported entirely by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. Data for these analyses were obtained from the Baltimore Longitudinal Study of Aging, a study performed by the National Institute on Aging (03-AG-0325). NR 25 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 JAN PY 2017 VL 66 IS 1 BP 170 EP 176 DI 10.2337/db16-0754 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG2AA UT WOS:000390834300021 PM 27737951 ER PT J AU Vijayakumar, P Nelson, RG Hanson, RL Knowler, WC Sinha, M AF Vijayakumar, Pavithra Nelson, Robert G. Hanson, Robert L. Knowler, William C. Sinha, Madhumita TI HbA(1c) and the Prediction of Type 2 Diabetes in Children and Adults SO DIABETES CARE LA English DT Article ID PLASMA-GLUCOSE CONCENTRATIONS; HEMOGLOBIN A1C; PIMA-INDIANS; RISK-FACTORS; YOUTH; SEARCH; ADOLESCENTS; POPULATION; PREVALENCE; DISEASE AB OBJECTIVE Long-term data validating glycated hemoglobin (HbA(1c)) in assessing the risk of type 2 diabetes in children are limited. HbA(1c), fasting plasma glucose (FPG), and 2-h post-load plasma glucose (2hPG) concentrations were measured in a longitudinal study of American Indians to determine their utility in predicting incident diabetes, all of which is thought to be type 2 in this population. RESEARCH DESIGN AND METHODS Incident diabetes (FPG >= 126 mg/dL [7.0 mmol/L], 2hPG >= 200 mg/dL [11.1 mmol/L], HbA(1c) >= 6.5% [8 mmol/mol], or clinical diagnosis) was determined in 2,095 children without diabetes ages 10-19 years monitored through age 39, and in 2,005 adults ages 20-39 monitored through age 59. Areas under the receiver operating characteristic (ROC) curve for HbA(1c), FPG, and 2hPG in predicting diabetes within 10 years were compared. RESULTS During long-term follow-up of children and adolescents who did not initially have diabetes, the incidence rate of subsequent diabetes was fourfold (in boys) as high and more than sevenfold (in girls) as high in those with HbA(1c) >= 5.7% as in those with HbA(1c) <= 5.3%-greater rate ratios than experienced by adults in the same HbA(1c) categories. Analyses of ROCs revealed no significant differences between HbA(1c), FPG, and 2hPG in sensitivity and specificity for identifying children and adolescents who later developed diabetes. CONCLUSIONS HbA(1c) is a useful predictor of diabetes risk in children and can be used to identify prediabetes in children with other type 2 diabetes risk factors with the same predictive value as FPG and 2hPG. C1 [Vijayakumar, Pavithra; Nelson, Robert G.; Hanson, Robert L.; Knowler, William C.; Sinha, Madhumita] NIDDK, Diabet Epidemiol & Clin Res Sect, NIH, Phoenix, AZ 85016 USA. RP Sinha, M (reprint author), NIDDK, Diabet Epidemiol & Clin Res Sect, NIH, Phoenix, AZ 85016 USA. EM madhumita.sinha@nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 23 TC 0 Z9 0 U1 7 U2 7 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD JAN PY 2017 VL 40 IS 1 BP 16 EP 21 DI 10.2337/dc16-1358 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG2BA UT WOS:000390846100006 PM 27810987 ER PT J AU Grau-Perez, M Kuo, CC Spratlen, M Thayer, KA Mendez, MA Hamman, RF Dabelea, D Adgate, JL Knowler, WC Bell, RA Miller, FW Liese, AD Zhang, CB Douillet, C Drobna, Z Mayer-Davis, EJ Styblo, M Navas-Acien, A AF Grau-Perez, Maria Kuo, Chin-Chi Spratlen, Miranda Thayer, Kristina A. Mendez, Michelle A. Hamman, Richard F. Dabelea, Dana Adgate, John L. Knowler, William C. Bell, Ronny A. Miller, Frederick W. Liese, Angela D. Zhang, Chongben Douillet, Christelle Drobna, Zuzana Mayer-Davis, Elizabeth J. Styblo, Miroslav Navas-Acien, Ana TI The Association of Arsenic Exposure and Metabolism With Type 1 and Type 2 Diabetes in Youth: The SEARCH Case-Control Study SO DIABETES CARE LA English DT Article ID METHYLATION CAPACITY; TRIVALENT ARSENICALS; FOLIC-ACID; BANGLADESH; COHORT; MEXICO; RISK; PREVALENCE; CHIHUAHUA; AMERICAN AB OBJECTIVE Little is known about arsenic and diabetes in youth. We examined the association of arsenic with type 1 and type 2 diabetes in the SEARCH for Diabetes in Youth Case-Control (SEARCH-CC) study. Because one-carbon metabolism can influence arsenic metabolism, we also evaluated the potential interaction of folate and vitamin B12 with arsenic metabolism on the odds of diabetes. RESEARCH DESIGN AND METHODS Six hundred eighty-eight participants <22 years of age (429 with type 1 diabetes, 85 with type 2 diabetes, and 174 control participants) were evaluated. Arsenic species (inorganic arsenic [iAs], monomethylated arsenic [MMA], dimethylated arsenic [DMA]), and one-carbon metabolism biomarkers (folate and vitamin B12) were measured in plasma. We used the sum of iAs, MMA, and DMA (Sigma As) and the individual species as biomarkers of arsenic concentrations and the relative proportions of the species over their sum (iAs%, MMA%, DMA%) as biomarkers of arsenic metabolism. RESULTS Median Sigma As, iAs%, MMA%, and DMA% were 83.1 ng/L, 63.4%, 10.3%, and 25.2%, respectively. Sigma As was not associated with either type of diabetes. The fully adjusted odds ratios (95% CI), rescaled to compare a difference in levels corresponding to the interquartile range of iAs%, MMA%, and DMA%, were 0.68 (0.50-0.91), 1.33 (1.02-1.74), and 1.28 (1.01-1.63), respectively, for type 1 diabetes and 0.82 (0.48-1.39), 1.09 (0.65-1.82), and 1.17 (0.77-1.77), respectively, for type 2 diabetes. In interaction analysis, the odds ratio of type 1 diabetes by MMA% was 1.80 (1.25-2.58) and 0.98 (0.70-1.38) for participants with plasma folate levels above and below the median (P for interaction = 0.02), respectively. CONCLUSIONS Low iAs% versus high MMA% and DMA% was associated with a higher odds of type 1 diabetes, with a potential interaction by folate levels. These data support further research on the role of arsenic metabolismin type 1 diabetes, including the interplay with one-carbon metabolism biomarkers. C1 [Grau-Perez, Maria; Kuo, Chin-Chi; Spratlen, Miranda; Navas-Acien, Ana] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. [Grau-Perez, Maria; Navas-Acien, Ana] Columbia Univ, Dept Environm Hlth Sci, Mailman Sch Publ Hlth, New York, NY 10027 USA. [Kuo, Chin-Chi; Navas-Acien, Ana] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Kuo, Chin-Chi; Navas-Acien, Ana] Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. [Kuo, Chin-Chi] China Med Univ Hosp, Kidney Inst, Taichung, Taiwan. [Kuo, Chin-Chi] China Med Univ Hosp, Div Nephrol, Dept Internal Med, Taichung, Taiwan. [Kuo, Chin-Chi] China Med Univ, Coll Med, Taichung, Taiwan. [Thayer, Kristina A.] NIEHS, Div Natl Toxicol Program, Dept Hlth & Human Serv, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Mendez, Michelle A.; Zhang, Chongben; Douillet, Christelle; Drobna, Zuzana; Mayer-Davis, Elizabeth J.; Styblo, Miroslav] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Nutr, Chapel Hill, NC USA. [Hamman, Richard F.; Dabelea, Dana] Univ Colorado Denver, Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA. [Adgate, John L.] Univ Colorado Denver, Colorado Sch Publ Hlth, Dept Environm & Occupat Hlth, Aurora, CO USA. [Knowler, William C.] NIDDK, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ USA. [Bell, Ronny A.] Wake Forest Sch Med, Winston Salem, NC USA. [Miller, Frederick W.] NIEHS, NIH, Bethesda, MD USA. [Liese, Angela D.] Univ South Carolina, Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. [Drobna, Zuzana] North Carolina State Univ, Dept Biol Sci, Raleigh, NC 27695 USA. [Mayer-Davis, Elizabeth J.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Med, Chapel Hill, NC USA. RP Grau-Perez, M; Navas-Acien, A (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA.; Grau-Perez, M; Navas-Acien, A (reprint author), Columbia Univ, Dept Environm Hlth Sci, Mailman Sch Publ Hlth, New York, NY 10027 USA.; Navas-Acien, A (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA.; Navas-Acien, A (reprint author), Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. EM mgraupe1@jhu.edu; anavasa1@jhu.edu OI Miller, Frederick/0000-0003-2831-9593 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK059184, DK056350]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (Intramural Research Program of NIDDK); National Institute of Environmental Health Sciences (NIEHS) [R01-ES-021367, R01-ES-025216, P30-ES-010126, 5P42-ES-10349]; National Institute of Environmental Health Sciences (NIEHS) (Intramural Research Program of NIEHS) FX This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK059184, DK056350, and Intramural Research Program of NIDDK) and the National Institute of Environmental Health Sciences (NIEHS) (R01-ES-021367, R01-ES-025216, P30-ES-010126, 5P42-ES-10349, and Intramural Research Program of NIEHS). NR 37 TC 0 Z9 0 U1 13 U2 13 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 JAN PY 2017 VL 40 IS 1 BP 46 EP 53 DI 10.2337/dc16-0810 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG2BA UT WOS:000390846100010 PM 27810988 ER PT J AU Strollo, S Lionakis, MS Adjemian, J Steiner, CA Prevots, DR AF Strollo, Sara Lionakis, Michail S. Adjemian, Jennifer Steiner, Claudia A. Prevots, D. Rebecca TI Epidemiology of Hospitalizations Associated with Invasive Candidiasis, United States, 2002-2012 SO EMERGING INFECTIOUS DISEASES LA English DT Article ID BLOOD-STREAM INFECTIONS; NONCULTURE DIAGNOSTICS; CANDIDEMIA; CARE; SURVEILLANCE; COST AB Invasive candidiasis is a major nosocomial fungal disease in the United States associated with high rates of illness and death. We analyzed inpatient hospitalization records from the Healthcare Cost and Utilization Project to estimate incidence of invasive candidiasis associated hospitalizations in the United States. We extracted data for 33 states for 2002-2012 by using codes from the International Classification of Diseases, 9th Revision, Clinical Modification, for invasive candidiasis; we excluded neonatal cases. The overall age-adjusted average annual rate was 5.3 hospitalizations/100,000 population. Highest risk was for adults >= 65 years of age, particularly men. Median length of hospitalization was 21 days; 22% of patients died during hospitalization. Median unadjusted associated cost for inpatient care was $46,684. Age-adjusted annual rates decreased during 2005-2012 for men (annual change -3.9%) and women (annual change -4.5%) and across nearly all age groups. We report a high mortality rate and decreasing incidence of hospitalizations for this disease. C1 [Strollo, Sara; Lionakis, Michail S.; Adjemian, Jennifer; Prevots, D. Rebecca] NIH, Bldg 10, Bethesda, MD 20892 USA. [Adjemian, Jennifer] US PHS, Rockville, MD USA. [Steiner, Claudia A.] Agcy Healthcare Res & Qual, Rockville, MD USA. [Strollo, Sara] Amer Canc Soc, Atlanta, GA 30329 USA. RP Prevots, DR (reprint author), NIAID, Lab Clin Infect Dis, NIH, 8 West Dr,MSC 2665, Bethesda, MD 20892 USA. EM rprevots@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; Intramural Research Training Award fellow at the National Institutes of Health, Bethesda, MD FX This study was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.; At the time of this study, Ms. Strollo was Intramural Research Training Award fellow at the National Institutes of Health, Bethesda, MD. She is currently a research analyst at the American Cancer Society, Atlanta, GA. Her research interests are epidemiology and population health. NR 24 TC 0 Z9 0 U1 7 U2 7 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 JAN PY 2017 VL 23 IS 1 BP 7 EP 13 DI 10.3201/eid2301.161198 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EG2AV UT WOS:000390836400002 PM 27983497 ER PT J AU Cui, XZ Nolen, LD Sun, JF Booth, M Donaldson, L Quinn, CP Boyer, AE Hendricks, K Shadomy, S Bothma, P Judd, O McConnell, P Bower, WA Eichacker, PQ AF Cui, Xizhong Nolen, Leisha D. Sun, Junfeng Booth, Malcolm Donaldson, Lindsay Quinn, Conrad P. Boyer, Anne E. Hendricks, Katherine Shadomy, Sean Bothma, Pieter Judd, Owen McConnell, Paul Bower, William A. Eichacker, Peter Q. TI Analysis of Anthrax Immune Globulin Intravenous with Antimicrobial Treatment in Injection Drug Users, Scotland, 2009-2010 SO EMERGING INFECTIOUS DISEASES LA English DT Article ID INHALATION ANTHRAX; UNITED-STATES; LETHAL FACTOR; MANAGEMENT; INFECTION; SHOCK; CARE AB We studied anthrax immune globulin intravenous (AIG-IV) use from a 2009-2010 outbreak of Bacillus anthracis soft tissue infection in injection drug users in Scotland, UK, and we compared findings from 15 AIG-IV recipients with findings from 28 nonrecipients. Death rates did not differ significantly between recipients and nonrecipients (33% vs. 21%). However, whereas only 8 (27%) of 30 patients at low risk for death (admission sequential organ failure assessment score of 0-5) received AIG-IV, 7 (54%) of the 13 patients at high risk for death (sequential organ failure assessment score of 6-11) received treatment. AIG-IV recipients had surgery more often and, among survivors, had longer hospital stays than did nonrecipients. AIG-IV recipients were sicker than nonrecipients. This difference and the small number of higher risk patients confound assessment of AIG-IV effectiveness in this outbreak. C1 [Cui, Xizhong; Sun, Junfeng; Eichacker, Peter Q.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Nolen, Leisha D.; Quinn, Conrad P.; Boyer, Anne E.; Hendricks, Katherine; Shadomy, Sean; Bower, William A.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Booth, Malcolm; Donaldson, Lindsay] Glasgow Royal Infirm, Glasgow, Lanark, Scotland. [Bothma, Pieter] James Paget Univ Hosp, Norfolk, VA USA. [Judd, Owen] Royal Derby Hosp, Derby, England. [McConnell, Paul] Crosshouse Hosp, Kilmarnock, Scotland. RP Eichacker, PQ (reprint author), NIH, Dept Crit Care Med, Bldg 10,Rm 2C145, Bethesda, MD 20892 USA. EM peichacker@mail.nih.gov FU National Institutes of Health Intramural Research Program; Clinical Center; CDC FX The work was supported by the National Institutes of Health Intramural Research Program and the Clinical Center and by CDC. NR 27 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 JAN PY 2017 VL 23 IS 1 BP 56 EP 65 DI 10.3201/eid2301.160608 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EG2AV UT WOS:000390836400008 PM 27983504 ER PT J AU Priest, DH Nutman, TB AF Priest, David H. Nutman, Thomas. B. TI Loiasis in US Traveler Returning from Bioko Island, Equatorial Guinea, 2016 SO EMERGING INFECTIOUS DISEASES LA English DT Letter ID LOA-LOA INFECTION; TEMPORARY RESIDENTS AB The filarial parasite Loa loa overlaps geographically with Onchocera volvulus and Wuchereria bancrofti filariae in central Africa. Accurate information regarding this overlap is critical to elimination programs targeting O. volvulus and W. bancrofti. We describe a case of loiasis in a traveler returning from Bioko Island, Equatorial Guinea, a location heretofore unknown for L. loa transmission. C1 [Priest, David H.] Novant Hlth, Winston Salem, NC USA. [Nutman, Thomas. B.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Priest, DH (reprint author), 1381 Westgate Ctr Dr, Winston Salem, NC 27103 USA. EM dhpriest@novanthealth.org NR 10 TC 0 Z9 0 U1 1 U2 1 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 JAN PY 2017 VL 23 IS 1 BP 160 EP 162 DI 10.3201/eid2301.161427 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EG2AV UT WOS:000390836400036 PM 27983940 ER PT J AU Chiu, CY Jung, J Wang, YF Weeks, DE Wilson, AF Bailey-Wilson, JE Amos, CI Mills, JL Boehnke, M Xiong, MM Fan, RZ AF Chiu, Chi-Yang Jung, Jeesun Wang, Yifan Weeks, Daniel E. Wilson, Alexander F. Bailey-Wilson, Joan E. Amos, Christopher I. Mills, James L. Boehnke, Michael Xiong, Momiao Fan, Ruzong TI A comparison study of multivariate fixed models and Gene Association with Multiple Traits (GAMuT) for next-generation sequencing SO GENETIC EPIDEMIOLOGY LA English DT Article DE association mapping; common variants; complex traits; functional data analysis; multivariate analysis of variance (MANOVA); multivariate functional linear models (MFLM); quantitative trait loci; rare variants ID FUNCTIONAL LINEAR-MODELS; RARE-VARIANT ASSOCIATION; QUANTITATIVE TRAITS; COMPLEX DISEASES; LEVEL; PLEIOTROPY; METAANALYSIS; PHENOTYPES; NETWORK AB In this paper, extensive simulations are performed to compare two statistical methods to analyze multiple correlated quantitative phenotypes: (1) approximate F-distributed tests of multivariate functional linear models (MFLM) and additive models of multivariate analysis of variance (MANOVA), and (2) Gene Association with Multiple Traits (GAMuT) for association testing of high-dimensional genotype data. It is shown that approximate F-distributed tests of MFLM and MANOVA have higher power and are more appropriate for major gene association analysis (i.e., scenarios in which some genetic variants have relatively large effects on the phenotypes); GAMuT has higher power and is more appropriate for analyzing polygenic effects (i.e., effects from a large number of genetic variants each of which contributes a small amount to the phenotypes). MFLM and MANOVA are very flexible and can be used to perform association analysis for (i) rare variants, (ii) common variants, and (iii) a combination of rare and common variants. Although GAMuT was designed to analyze rare variants, it can be applied to analyze a combination of rare and common variants and it performs well when (1) the number of genetic variants is large and (2) each variant contributes a small amount to the phenotypes (i.e., polygenes). MFLM and MANOVA are fixed effect models that perform well for major gene association analysis. GAMuT can be viewed as an extension of sequence kernel association tests (SKAT). Both GAMuT and SKAT are more appropriate for analyzing polygenic effects and they perform well not only in the rare variant case, but also in the case of a combination of rare and common variants. Data analyses of European cohorts and the Trinity Students Study are presented to compare the performance of the two methods. C1 [Chiu, Chi-Yang; Fan, Ruzong] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, NIH, Bethesda, MD USA. [Jung, Jeesun] NIAAA, Lab Epidemiol & Biometry, NIH, Bethesda, MD USA. [Wang, Yifan] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Weeks, Daniel E.] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA. [Wilson, Alexander F.; Bailey-Wilson, Joan E.] NHGRI, Computat & Stat Genom Branch, NIH, Bethesda, MD 20892 USA. [Mills, James L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, NIH, Bethesda, MD USA. [Amos, Christopher I.] Geisel Sch Med Dartmouth, Dept Biomed Data Sci, Lebanon, NH USA. [Boehnke, Michael] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. [Xiong, Momiao] Univ Texas Houston, Ctr Human Genet, Houston, TX USA. RP Fan, RZ (reprint author), Georgetown Univ, Dept Biostat Bioinformat & Biomath, Med Ctr, 4000 Reservoir Rd NW,Bldg D-180, Washington, DC 20057 USA. EM rf740@georgetown.edu OI Weeks, Daniel/0000-0001-9410-7228 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; Intramural Research Program of the National Human Genome Research Institute; National Institutes of Health, Bethesda, MD FX Two anonymous reviewers and the editors, Dr. Shete and Dr. Cordell, provided very good and insightful comments for us to improve the manuscript. We greatly thank the European cohorts groups for letting us analyze the data and using them as examples. Dr. Heather M. Stringham and Dr. Tanya M. Teslovich kindly sent us the data of the European cohorts and patiently answered many questions about the cohorts, and we greatly appreciate their help. This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R.F., C.-Y.C., and J.L.M.), by the Intramural Research Program of the National Human Genome Research Institute (A.F.W. and J.E.B.-W.), National Institutes of Health, Bethesda, MD. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). NR 44 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD JAN PY 2017 VL 41 IS 1 BP 18 EP 34 DI 10.1002/gepi.22014 PG 17 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA EG1OE UT WOS:000390801300002 PM 27917525 ER PT J AU Fu, J Beaty, TH Scott, AF Hetmanski, J Parker, MM Wilson, JEB Marazita, ML Mangold, E Albacha-Hejazi, H Murray, JC Bureau, A Carey, J Cristiano, S Ruczinski, I Scharpf, RB AF Fu, Jack Beaty, Terri H. Scott, Alan F. Hetmanski, Jacqueline Parker, Margaret M. Wilson, Joan E. Bailey Marazita, Mary L. Mangold, Elisabeth Albacha-Hejazi, Hasan Murray, Jeffrey C. Bureau, Alexandre Carey, Jacob Cristiano, Stephen Ruczinski, Ingo Scharpf, Robert B. TI Whole exome association of rare deletions in multiplex oral cleft families SO GENETIC EPIDEMIOLOGY LA English DT Article DE copy number; multiplex families; oral clefts; rare variants; structural variants ID COPY-NUMBER VARIATION; VARIANT ASSOCIATION; COMPLEX TRAITS; SEQUENCING DATA; COMMON; RELATIVES; ALIGNMENT; SIBPAIR; ROBUST; RISK AB By sequencing the exomes of distantly related individuals in multiplex families, rare mutational and structural changes to coding DNA can be characterized and their relationship to disease risk can be assessed. Recently, several rare single nucleotide variants (SNVs) were associated with an increased risk of nonsyndromic oral cleft, highlighting the importance of rare sequence variants in oral clefts and illustrating the strength of family-based study designs. However, the extent to which rare deletions in coding regions of the genome occur and contribute to risk of nonsyndromic clefts is not well understood. To identify putative structural variants underlying risk, we developed a pipeline for rare hemizygous deletions in families from whole exome sequencing and statistical inference based on rare variant sharing. Among 56 multiplex families with 115 individuals, we identified 53 regions with one or more rare hemizygous deletions. We found 45 of the 53 regions contained rare deletions occurring in only one family member. Members of the same family shared a rare deletion in only eight regions. We also devised a scalable global test for enrichment of shared rare deletions. C1 [Fu, Jack; Cristiano, Stephen; Ruczinski, Ingo] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Beaty, Terri H.; Hetmanski, Jacqueline; Carey, Jacob] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Scott, Alan F.] Johns Hopkins Sch Med, Ctr Inherited Dis Res, Baltimore, MD USA. [Scott, Alan F.] Johns Hopkins Sch Med, Inst Med Genet, Baltimore, MD USA. [Parker, Margaret M.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Wilson, Joan E. Bailey] NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD USA. [Marazita, Mary L.] Univ Pittsburgh, Ctr Craniofacial & Dent Genet, Sch Dent Med, Dept Oral Biol, Pittsburgh, PA 15260 USA. [Mangold, Elisabeth] Univ Bonn, Inst Human Genet, Bonn, Germany. [Albacha-Hejazi, Hasan] Dr Hejazi Clin, Damascus, Syria. [Murray, Jeffrey C.] Univ Iowa, Sch Med, Dept Pediat, Iowa City, IA 52242 USA. [Bureau, Alexandre] Univ Laval, Ctr Rech, Inst Univ Sante Mentale Quebec, Quebec City, PQ, Canada. [Bureau, Alexandre] Univ Laval, Dept Med Sociale & Prevent, Quebec City, PQ, Canada. [Scharpf, Robert B.] Johns Hopkins Sch Med, Dept Oncol, 550 N Broadway,Suite 1101, Baltimore, MD 21205 USA. RP Scharpf, RB (reprint author), Johns Hopkins Sch Med, Dept Oncol, 550 N Broadway,Suite 1101, Baltimore, MD 21205 USA. EM rscharpf@jhu.edu FU National Institutes of Health [R01-DE-014581, U01-DE-018993, R01-DE-016148, P50-DE-016215, R03-DE-02579] FX Grant sponsor: National Institutes of Health; Grant number: R01-DE-014581, U01-DE-018993, R01-DE-016148, P50-DE-016215 and R03-DE-02579. NR 39 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD JAN PY 2017 VL 41 IS 1 BP 61 EP 69 DI 10.1002/gepi.22010 PG 9 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA EG1OE UT WOS:000390801300006 PM 27910131 ER PT J AU Grady, PA AF Grady, Patricia A. TI Advancing palliative and end-of-life science in cardiorespiratory populations: The contributions of nursing science SO HEART & LUNG LA English DT Article DE Nursing science; End-of-life care; Palliative care; Advanced heart failure; Advanced respiratory disease ID INTENSIVE-CARE-UNIT; ADVANCED HEART-FAILURE; OBSTRUCTIVE PULMONARY-DISEASE; DECISION-MAKING; FAMILY CONFERENCES; FUTURE-DIRECTION; RANDOMIZED-TRIAL; ADVANCED CANCER; HOSPICE CARE; COMMUNICATION AB Nursing science has a critical role to inform practice, promote health, and improve the lives of individuals across the lifespan who face the challenges of advanced cardiorespiratory disease. Since 1997, the National Institute of Nursing Research (NINR) has focused attention on the importance of palliative and end-of-life care for advanced heart failure and advanced pulmonary disease through the publication of multiple funding opportunity announcements and by supporting a cadre of nurse scientists that will continue to address new priorities and future directions for advancing palliative and end-of-life science in cardiorespiratory populations. Published by Elsevier Inc. C1 [Grady, Patricia A.] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Grady, PA (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM info@ninr.nih.gov NR 59 TC 0 Z9 0 U1 11 U2 11 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0147-9563 EI 1527-3288 J9 HEART LUNG JI Heart Lung PD JAN-FEB PY 2017 VL 46 IS 1 BP 3 EP 6 DI 10.1016/j.hrtlng.2016.07.009 PG 4 WC Cardiac & Cardiovascular Systems; Nursing; Respiratory System SC Cardiovascular System & Cardiology; Nursing; Respiratory System GA EG2AG UT WOS:000390834900002 PM 27612388 ER PT J AU Kleiner, DE AF Kleiner, David E. TI The histopathological evaluation of drug-induced liver injury SO HISTOPATHOLOGY LA English DT Review DE acute hepatitis; acute liver failure; cholestasis; hepatic necrosis; hepatotoxicity ID SINUSOIDAL OBSTRUCTION SYNDROME; AUTOIMMUNE HEPATITIS; CLINICAL ASSOCIATIONS; GEMTUZUMAB OZOGAMICIN; NUCLEOSIDE ANALOG; LACTIC-ACIDOSIS; HEPATOTOXICITY; THERAPY; PATIENT; DISEASE AB Drug-induced liver injury (DILI) presents unique challenges to the pathologist. It is not only an uncommon reason for liver biopsy, but the pathology of DILI is spread across the entire spectrum of hepatic injury patterns. It is important for the pathologist to suspect DILI when the histological changes are unusual or out of synchronicity with the patient's history. A systematic evaluation approach will yield the most information. It begins with the characterization of the general pattern of injury which, for most cases, will be found in a handful of necroinflammatory and cholestatic patterns. A careful assessment of the severity of injury across the various anatomic compartments will provide information on the probable natural history of the injury. Correlation of liver injury with the patient's medication history and clinical findings will help to narrow the differential diagnosis, particularly when it is recognized that most drugs have a limited range of histological findings and vary in their propensity to cause injury. This review provides an overview of the assessment of the liver biopsy and its use to confirm or exclude particular drugs as contributing to the patient's liver injury. C1 [Kleiner, David E.] NCI, Pathol Lab, Bldg 10, Bethesda, MD 20892 USA. RP Kleiner, DE (reprint author), NCI, Pathol Lab, Postmortem Sect, 10 Ctr Dr,Bldg 10,Room 2S235,MSC1500, Bethesda, MD 20892 USA. EM kleinerd@mail.nih.gov OI Kleiner, David/0000-0003-3442-4453 FU NIH, National Cancer Institute FX This review was supported by the Intramural Research Program of the NIH, National Cancer Institute. NR 62 TC 1 Z9 1 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0309-0167 EI 1365-2559 J9 HISTOPATHOLOGY JI Histopathology PD JAN PY 2017 VL 70 IS 1 BP 81 EP 93 DI 10.1111/his.13082 PG 13 WC Cell Biology; Pathology SC Cell Biology; Pathology GA EF9YQ UT WOS:000390687800008 PM 27960237 ER PT J AU Topaz, M Goss, F Blumenthal, K Lai, K Seger, DL Slight, SP Wickner, PG Robinson, GA Fung, KW McClure, RC Spiro, S Acker, WW Bates, DW Zhou, L AF Topaz, Maxim Goss, Foster Blumenthal, Kimberly Lai, Kenneth Seger, Diane L. Slight, Sarah P. Wickner, Paige G. Robinson, George A. Fung, Kin Wah McClure, Robert C. Spiro, Shelly Acker, Warren W. Bates, David W. Zhou, Li TI Towards improved drug allergy alerts: Multidisciplinary expert recommendations SO INTERNATIONAL JOURNAL OF MEDICAL INFORMATICS LA English DT Letter ID ORDER-ENTRY SYSTEM C1 [Topaz, Maxim; Lai, Kenneth; Seger, Diane L.; Slight, Sarah P.; Wickner, Paige G.; Acker, Warren W.; Bates, David W.; Zhou, Li] Brigham & Womens Hosp, Gen Internal Med & Primary Care, 75 Francis St, Boston, MA 02115 USA. [Topaz, Maxim; Blumenthal, Kimberly; Bates, David W.; Zhou, Li] Harvard Med Sch, Boston, MA USA. [Goss, Foster; Zhou, Li] Univ Colorado, Dept Emergency Med, Aurora, CO USA. [Blumenthal, Kimberly] Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Blumenthal, Kimberly] Massachusetts Gen Hosp, Dept Med, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Seger, Diane L.; Acker, Warren W.] Partners Healthcare Syst, Clin & Qual Anal, Wellesley, MA USA. [Slight, Sarah P.] Univ Durham, Sch Med Pharm & Hlth, Div Pharm, Durham, England. [Robinson, George A.] First Databank Inc, San Francisco, CA USA. [Fung, Kin Wah] NIH, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. [McClure, Robert C.] MD Partners Inc, Lafayette, CO USA. [Spiro, Shelly] Pharm HIT Collaborat, Alexandria, VA USA. RP Topaz, M (reprint author), 93 Worcester St,Wellesley Gateway,Suite 20301, Wellesley, MA 02481 USA. EM mtopaz80@gmail.com OI Acker, Warren/0000-0002-9338-8782 NR 9 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1386-5056 EI 1872-8243 J9 INT J MED INFORM JI Int. J. Med. Inform. PD JAN PY 2017 VL 97 BP 353 EP 355 DI 10.1016/j.ijmedinf.2016.10.006 PG 3 WC Computer Science, Information Systems; Health Care Sciences & Services; Medical Informatics SC Computer Science; Health Care Sciences & Services; Medical Informatics GA EF7BQ UT WOS:000390485500034 PM 27729200 ER PT J AU Ferland, CL O'Hayre, M Knosp, WM Fox, CH Horsford, DJ AF Ferland, C. L. O'Hayre, M. Knosp, W. M. Fox, C. H. Horsford, D. J. TI The NIH's Funding to US Dental Institutions from 2005 to 2014 SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE dental schools; dental research; dentistry; dental education; National Institute of Dental and Craniofacial Research; trends AB This study examines funding from the National Institutes of Health (NIH) to US dental institutions between 2005 and 2014 based on publicly available data from the NIH Research Portfolio Online Reporting Tools. Over the 10-y span, 56 US dental institutions received approximately $2.2 billion from 20 Institutes, Centers, and Offices at the NIH. The National Institute of Dental and Craniofacial Research (NIDCR) is the largest NIH supporter of dental institutions, having invested 70% of the NIH total, about $1.5 billion. The NIDCR is also the primary supporter of research training and career development, as it has invested $177 million, which represents 92% of the total NIH investment of $192 million. Over the past 10 y, about half of the NIDCR's extramural award dollars have gone to dental schools, while the NIH has invested about 1%. There has been an approximately 10% net decrease in extramural dollars awarded to dental institutions over the past decade; however, given the year-to-year variability in support to dental institutions, it is unclear if this net decline reflects a long-term trend. In addition, there was an overall reduction in the extramural dollars awarded by the NIDCR and by the NIH. For example, from 2005 to 2014, the total NIDCR budget for extramural research decreased by roughly 4%, which represents a decrease of $20 million to dental institutions. After adjusting for inflation, the decline in funding to dental institutions from the NIDCR and NIH was approximately 30%. Although the NIDCR and NIH continue to invest in dental institutions, if the current decline were to continue, it could negatively affect the research conducted at dental institutions. Therefore, we discuss opportunities for dental institutions to increase NIDCR and NIH support and improve their capacity for research, research training, and career development. C1 [Ferland, C. L.; Knosp, W. M.; Horsford, D. J.] Natl Inst Dent & Craniofacial Res, Off Sci Policy, 31 Ctr Dr, Bethesda, MD 20892 USA. [O'Hayre, M.] Natl Inst Dent & Craniofacial Res, Off Director, Bethesda, MD USA. [Fox, C. H.] Int & Amer Associat Dent Res, Alexandria, VA USA. RP Horsford, DJ (reprint author), Natl Inst Dent & Craniofacial Res, Off Sci Policy, 31 Ctr Dr, Bethesda, MD 20892 USA. EM Jonathan.Horsford@NIH.gov NR 9 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 EI 1544-0591 J9 J DENT RES JI J. Dent. Res. PD JAN PY 2017 VL 96 IS 1 BP 10 EP 16 DI 10.1177/0022034516680555 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA EF9SL UT WOS:000390670400003 PM 28033063 ER PT J AU Foster, BL Kuss, P Yadav, MC Kolli, TN Narisawa, S Lukashova, L Cory, E Sah, RL Somerman, MJ Millan, JL AF Foster, B. L. Kuss, P. Yadav, M. C. Kolli, T. N. Narisawa, S. Lukashova, L. Cory, E. Sah, R. L. Somerman, M. J. Millan, J. L. TI Conditional Alpl Ablation Phenocopies Dental Defects of Hypophosphatasia SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE bone biology; cementum; dentin; periodontal tissues/periodontium; mineralized tissue/development; tooth development ID ALKALINE-PHOSPHATASE GENE; ENZYME REPLACEMENT; INFANTILE HYPOPHOSPHATASIA; MURINE HYPOPHOSPHATASIA; ACELLULAR CEMENTUM; CRE RECOMBINASE; HOMEOBOX GENE; MICE; MODEL; EXPRESSION AB Loss-of-function mutations in ALPL result in hypophosphatasia (HPP), an inborn error of metabolism that causes defective skeletal and dental mineralization. ALPL encodes tissue-nonspecific alkaline phosphatase, an enzyme expressed in bone, teeth, liver, and kidney that hydrolyzes the mineralization inhibitor inorganic pyrophosphate. As Alpl-null mice die before weaning, we aimed to generate mouse models of late-onset HPP with extended life spans by engineering a floxed Alpl allele, allowing for conditional gene ablation (conditional knockout [cKO]) when crossed with Cre recombinase transgenic mice. The authors hypothesized that targeted deletion of Alpl in osteoblasts and selected dental cells (Col1a1-cKO) or deletion in chondrocytes, osteoblasts, and craniofacial mesenchyme (Prx1-cKO) would phenocopy skeletal and dental manifestations of late-onset HPP. Col1a1-cKO and Prx1-cKO mice were viable and fertile, and they did not manifest the epileptic seizures characteristic of the Alpl-/-model of severe infantile HPP. Both cKO models featured normal postnatal body weight but significant reduction as compared with wild type mice by 8 to 12 wk. Plasma alkaline phosphatase for both cKO models at 24 wk was reduced by approximately 75% as compared with controls. Radiography revealed profound skeletal defects in cKO mice, including rachitic changes, hypomineralized long bones, deformations, and signs of fractures. Microcomputed tomography confirmed quantitative differences in cortical and trabecular bone, including decreased cortical thickness and mineral density. Col1a1-cKO mice exhibited classic signs of HPP dentoalveolar disease, including short molar roots with thin dentin, lack of acellular cementum, and osteoid accumulation in alveolar bone. Prx1-cKO mice exhibited the same array of periodontal defects but featured less affected molar dentin. Both cKO models exhibited reduced alveolar bone height and 4-fold increased numbers of osteoclast-like cells versus wild type at 24 wk, consistent with HPP-associated periodontal disease. These novel models of late-onset HPP can inform on long-term skeletal and dental manifestations and will provide essential tools to further studies of etiopathologies and therapeutic interventions. C1 [Foster, B. L.; Kolli, T. N.] Ohio State Univ, Coll Dent, Div Biosci, Columbus, OH 43210 USA. [Kuss, P.; Yadav, M. C.; Narisawa, S.; Millan, J. L.] Sanford Burnham Prebys Med Discovery Inst, Sanford Childrens Hlth Res Ctr, La Jolla, CA USA. [Lukashova, L.] Hosp Special Surg, 535 E 70th St, New York, NY 10021 USA. [Cory, E.; Sah, R. L.] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. [Cory, E.; Sah, R. L.] Univ Calif San Diego, Ctr Musculoskeletal Res, La Jolla, CA 92093 USA. [Sah, R. L.] Univ Calif San Diego, Dept Orthopaed Surg, La Jolla, CA 92093 USA. [Somerman, M. J.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Millan, JL (reprint author), Sanford Burnham Prebys Med Discovery Inst, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM millan@sbpdiscovery.org FU National Institute of Dental and Craniofacial Research of the National Institutes of Health (NIH) [DE 12889]; Soft Bones, Inc.; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) / NIH [AR 066110]; German Research Foundation; National Institute of Aging / NIH [AG 007996]; NIAMS/NIH [AR 046121]; Intramural Research Program of NIAMS FX This research was supported by grant DE 12889 to J.L.M. from the National Institute of Dental and Craniofacial Research of the National Institutes of Health (NIH); a research grant to B.L.F. from Soft Bones, Inc.; grant AR 066110 to B.L.F. from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) / NIH; a fellowship to P.K. from the German Research Foundation; grant AG 007996 to R.L.S. from the National Institute of Aging / NIH; grant AR 046121 from NIAMS/NIH to the Hospital for Special Surgery; and the Intramural Research Program of NIAMS (M.J.S.). The authors thank Kenn Holmbeck (National Institute of Dental and Craniofacial Research) for assistance with micro-computed tomography analysis and Nasrin Kalantari Pour (NIAMS) for assistance with histology. The authors thank Diana Sandoval and the personnel at the Sanford Burnham Prebys Medical Discovery Institute animal facility for their assistance and careful animal husbandry. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 35 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 EI 1544-0591 J9 J DENT RES JI J. Dent. Res. PD JAN PY 2017 VL 96 IS 1 BP 81 EP 91 DI 10.1177/0022034516663633 PG 11 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA EF9SL UT WOS:000390670400012 PM 27582029 ER PT J AU Stewart, JG Esposito, EC Glenn, CR Gilman, SE Pridgen, B Gold, J Auerbach, RP AF Stewart, Jeremy G. Esposito, Erika C. Glenn, Catherine R. Gilman, Stephen E. Pridgen, Bryan Gold, Joseph Auerbach, Randy P. TI Adolescent self-injurers: Comparing non-ideators, suicide ideators, and suicide attempters SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Adolescence; Non-suicidal self-injury; Suicide attempts; Suicide ideation; Risky behavior engagement; Inpatients ID INJURIOUS THOUGHTS; YOUNG-ADULTS; BEHAVIOR; SAMPLE; IDEATION; RELIABILITY; IMPULSIVITY; PREVALENCE; SYMPTOMS; VALIDITY AB Adolescent non-suicidal self-injury (NSSI) and suicidality are serious health concerns; however, factors that contribute to the transition from NSSI to suicide ideation and suicide attempts are unclear. To address this gap, we investigated whether demographic characteristics, child maltreatment, and psychiatric factors are associated with the level suicidality among adolescents with a history of self-injury. Participants were three groups of adolescent inpatient self-injurers (n = 397, 317 female), aged 13-18 years (M = 15.44, SD = 1.36): (a) non-ideators (n = 96; no current suicide ideation and no lifetime suicide attempts), (b) suicide ideators (n = 149; current ideation and no lifetime attempts), and (c) suicide attempters (n = 152; current ideation and at least one lifetime attempt). Participants completed interviews assessing psychiatric diagnoses, suicidality, and NSSI characteristics, as well as questionnaires on childhood trauma, psychiatric symptoms, and risky behavior engagement. Depression severity was associated with greater odds being a suicide ideator (p < 0.001, OR = 1.04) and an attempter (p < 0.001, OR = 1.05) compared to a non-ideator. Suicide attempters used more NSSI methods and reported greater risky behavior engagement than non-ideators (p = 0.03, OR = 1.29 and p = 0.03, OR = 1.06, respectively) and ideators (p = 0.015, OR = 1.25 and p = 0.04, OR = 1.05, respectively); attempters used more severe NSSI methods (e.g., burning). Our results identify a wide range of risk markers for increasing lethality in a sample at high risk for suicide mortality; future research is needed to refine risk assessments for adolescent self-injurers and determine the clinical utility of using risk markers for screening and intervention. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Stewart, Jeremy G.; Esposito, Erika C.; Pridgen, Bryan; Gold, Joseph; Auerbach, Randy P.] Harvard Med Sch, Dept Psychiat, McLean Hosp, Ctr Depress Anxiety & Stress Res, Belmont, MA USA. [Glenn, Catherine R.] Univ Rochester, Dept Clin & Social Sci Psychol, Rochester, NY USA. [Gilman, Stephen E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, Rockville, MD USA. [Gilman, Stephen E.] Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. [Gilman, Stephen E.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Stewart, JG (reprint author), 115 Mill St,Mailstop 331,de Marneffe Bldg,Room 23, Belmont, MA 02478 USA. EM jstewart@mclean.harvard.edu FU NIMH [K23MH097786]; Klingenstein Third Generation Foundation Adolescent Depression Fellowship; Tommy Fuss Fund; Rolfe Fund; Simches Fund; Pope-Hintz Endowed Fellowship; McLean Hospital; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This study was partially supported through funding from the NIMH (K23MH097786), the Klingenstein Third Generation Foundation Adolescent Depression Fellowship, the Tommy Fuss Fund, the Rolfe Fund, and the Simches Fund awarded to Randy P. Auerbach.; Further support was provided by the Pope-Hintz Endowed Fellowship, awarded by McLean Hospital to Jeremy G. Stewart.; Finally, the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development supported Stephen E. Gilman. NR 50 TC 0 Z9 0 U1 10 U2 10 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 JAN PY 2017 VL 84 BP 105 EP 112 DI 10.1016/j.jpsychires.2016.09.031 PG 8 WC Psychiatry SC Psychiatry GA EG0OW UT WOS:000390733100014 PM 27716512 ER PT J AU Park, M Newman, LE Gold, PW Luckenbaugh, DA Yuan, P Machado-Vieira, R Zarate, CA AF Park, Minkyung Newman, Laura E. Gold, Philip W. Luckenbaugh, David A. Yuan, Peixiong Machado-Vieira, Rodrigo Zarate, Carlos A., Jr. TI Change in cytokine levels is not associated with rapid antidepressant response to ketamine in treatment-resistant depression SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Major depressive disorder; Bipolar disorder; Cytokine; Ketamine; Interleukin-6 (IL-6); Soluble tumor necrosis factor receptor 1 (sTNFR1) ID REUPTAKE INHIBITOR THERAPY; TUMOR-NECROSIS-FACTOR; TNF RECEPTORS 1; BIPOLAR DISORDER; MAJOR DEPRESSION; PLASMA-LEVELS; METAANALYSIS; SURGERY; DISEASE; SYSTEM AB Several pro-inflammatory cytokines have been implicated in depression and in antidepressant response. This exploratory analysis assessed: 1) the extent to which baseline cytokine levels predicted positive antidepressant response to ketamine; 2) whether ketamine responders experienced acute changes in cytokine levels not observed in non-responders; and 3) whether ketamine lowered levels of pro inflammatory cytokines, analogous to the impact of other antidepressants. Data from double-blind, placebo-controlled studies of patients with major depressive disorder (MDD) or bipolar disorder (BD) who received a single infusion of sub-anesthetic dose ketamine were used (N = 80). Plasma levels of the eight cytokines were measured at baseline and at 230 min, 1 day, and 3 days post-ketamine. A significant positive correlation was observed between sTNFR1 and severity of depression at baseline. Cytokine changes did not correlate with changes in mood nor predict mood changes associated with ketamine administration. Ketamine significantly increased IL-6 levels and significantly decreased sTNFR1 levels. IL-6 and TNF-cz levels were also significantly higher and sTNFR1 levels were significantly lower-in BD compared to MDD subjects. The functional significance of this difference is unknown. Changes in cytokine levels post-ketamine were not related to antidepressant response, suggesting they are not a primary mechanism involved in ketamine's acute antidepressant effects. Taken together, the results suggest that further study of cytokine levels is warranted to assess their potential role as a surrogate outcome in the rapid antidepressant response paradigm. Published by Elsevier Ltd. C1 [Park, Minkyung; Newman, Laura E.; Gold, Philip W.; Luckenbaugh, David A.; Yuan, Peixiong; Machado-Vieira, Rodrigo; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, 10 Ctr Dr,Room 7-5432, Bethesda, MD 20892 USA. RP Machado-Vieira, R (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, NIH, 10 Ctr Dr,Room 7-5432, Bethesda, MD 20892 USA. EM machadovieirar@mail.nih.gov FU Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) [NCT00088699, protocol 04-M-0222]; 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; NCT00088699, protocol 04-M-0222), by a NARSAD Independent Investigator Award to CAZ, and by a Brain and Behavior Mood Disorders Research Award to CAZ. The NIMH, NARSAD, and the Brain & 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 25 TC 1 Z9 1 U1 5 U2 5 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 JAN PY 2017 VL 84 BP 113 EP 118 DI 10.1016/j.jpsychires.2016.09.025 PG 6 WC Psychiatry SC Psychiatry GA EG0OW UT WOS:000390733100015 PM 27718369 ER PT J AU Blanco, C Compton, WM Saha, TD Goldstein, BI Ruan, WJ Huang, BJ Grant, BF AF Blanco, Carlos Compton, Wilson M. Saha, Tulshi D. Goldstein, Benjamin I. Ruan, W. June Huang, Boji Grant, Bridget F. TI Epidemiology of DSM-5 bipolar I disorder: Results from the National Epidemiologic Survey on Alcohol and Related Conditions - III SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Bipolar I disorder; Epidemiology; Prevalence; Comorbidity; Treatment ID BORDERLINE PERSONALITY-DISORDER; MENTAL-HEALTH SURVEY; COMORBIDITY SURVEY REPLICATION; TASK-FORCE RECOMMENDATIONS; SUBSTANCE USE DISORDERS; QUALITY-OF-LIFE; UNITED-STATES; MOOD DISORDERS; GENERAL-POPULATION; PSYCHIATRIC-DISORDERS AB Background: The objective of this study was to present 12-month and lifetime prevalence, correlates, comorbidity, treatment and disability of DSM-5 bipolar I disorder. Methods: Nationally representative U.S. adult sample (N = 36,309), the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions - III. Results: Prevalences of 12-month and lifetime DSM-5 bipolar I disorder were 1.5% and 2.1% and did not differ between men (1.6% and 2.2%) and women (1.5% and 2.0%). Prevalences of bipolar I disorder were greater among Native Americans, and lower among Blacks, Hispanics and Asians/Pacific Islanders than whites. Rates were also lower among younger than older individuals, those previously married than currently married and with lower education and income relative to higher education and income. Bipolar I disorder was more strongly related to borderline and schizotypal personality disorders (adjusted odds ratios (AORS) = 2.2-4.7)), than to anxiety disorders (AORs = 1.3-2.9), and substance use disorders (AORs = 1.3-2.1) overall and among men and women. Quality of life was lower among individuals with bipolar I disorder relative to those without the disorder. Treatment rates among individuals with bipolar I disorder were low in the total sample (46%, SE = 2.63), among men (36.7%, SE = 3.82) and among women (55.8%, SE = 3.32). Conclusions: Bipolar I disorder continues to be common disabling and highly comorbid disorder among men and women, contributing substantially to low quality of life and burden of disease in our society. (C) 2016 Published by Elsevier Ltd. C1 [Blanco, Carlos; Compton, Wilson M.] NIDA, Div Epidemiol Serv & Prevent Res, 6001 Execut Blvd, Rockville, MD 20852 USA. [Saha, Tulshi D.; Ruan, W. June; Huang, Boji; Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, 5635 Fishers Lane, Rockville, MD 20852 USA. [Goldstein, Benjamin I.] Sunnybrook Hlth Sci Ctr, 2075 Bayview Ave,Room FG 53, Toronto, ON M4N 3M5, Canada. RP Saha, TD (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, 5635 Fishers Lane, Rockville, MD 20852 USA. EM carlos.blanco2@nih.gov; wcompton@nida.nih.gov; sahatd@mail.nih.gov; benjamin.goldstein@sunnybrook.ca; ruanj@mail.nih.gov; huangbo@mail.nih.gov; bgrant@mail.nih.gov FU National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse FX This work was supported by the National Institute on Alcohol Abuse and Alcoholism (Intramural Program) and National Institute on Drug Abuse. NR 81 TC 1 Z9 1 U1 3 U2 3 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 JAN PY 2017 VL 84 BP 310 EP 317 DI 10.1016/j.jpsychires.2016.10.003 PG 8 WC Psychiatry SC Psychiatry GA EG0OW UT WOS:000390733100038 PM 27814503 ER PT J AU Chomba, E Carlo, WA Goudar, SS Jehan, I Tshefu, A Garces, A Parida, S Althabe, F McClure, EM Derman, RJ Goldenberg, RL Bose, C Krebs, NF Panigrahi, P Buekens, P Wallace, D Moore, J Koso-Thomas, M Wright, LL AF Chomba, Elwyn Carlo, Wally A. Goudar, Shivaprasad S. Jehan, Imtiaz Tshefu, Antoinette Garces, Ana Parida, Sailajandan Althabe, Fernando McClure, Elizabeth M. Derman, Richard J. Goldenberg, Robert L. Bose, Carl Krebs, Nancy F. Panigrahi, Pinaki Buekens, Pierre Wallace, Dennis Moore, Janet Koso-Thomas, Marion Wright, Linda L. CA First Breath Study Grp TI Effects of Essential Newborn Care Training on Fresh Stillbirths and Early Neonatal Deaths by Maternal Education SO NEONATOLOGY LA English DT Article DE Education; Neonatal mortality; Developing countries; Low and mid resource countries ID TRADITIONAL BIRTH ATTENDANTS; PERINATAL-MORTALITY; INFANT-MORTALITY; DETERMINANTS; COUNTRIES; SURVIVAL; DELIVERY; PAKISTAN; TRENDS; LEVEL AB Background: Infants of women with lower education levels are at higher risk for perinatal mortality. Objectives: We explored the impact of training birth attendants and pregnant women in the Essential Newborn Care (ENC) Program on fresh stillbirths (FSBs) and early (7-day) neonatal deaths (END) by maternal education level in developing countries. Methods: A train-the-trainer model was used with local instructors in rural communities in six countries (Argentina, Democratic Republic of the Congo, Guatemala, India, Pakistan, and Zambia). Data were collected using a pre-/post active baseline controlled study design. Results: A total of 57,643 infants/mothers were enrolled. The follow-up rate at 7 days of age was 99.2%. The risk for FSB and END was higher for mothers with 0-7 years of education than for those with years of education during both the pre- and postENC periods in unadjusted models and in models adjusted for confounding. The effect of ENC differed as a function of maternal education for FSB (interaction p =0.041) without evidence that the effect of ENC differed as a function of maternal education for END. The model-based estimate of FSB risk was reduced among mothers with 0-7 years of education (19.7/1,000 live births pre-ENC, Cl: 16.3, 23.0 vs. 12.2/1,000 live births post-ENC, CI: 16.3, 23.0, p < 0.001), but was not significantly different for mothers with >= 8 years of education, respectively. Conclusion: A low level of maternal education was associated with higher risk for FSB and END. ENC training was more effective in reducing FSB among mothers with low education levels. (C) 2016 S. Karger AG, Basel. C1 [Chomba, Elwyn; Carlo, Wally A.] Univ Alabama Birmingham, Birmingham, AL USA. [Chomba, Elwyn] Ctr Infect Dis Res Zambia, Lusaka, Zambia. [Chomba, Elwyn] Univ Teaching Hosp, Lusaka, Zambia. [Goudar, Shivaprasad S.] KLE Univ Jawaharlal Nehru Med Coll, Belgaum, India. [Jehan, Imtiaz] Aga Khan Univ, Karachi, Pakistan. [Tshefu, Antoinette] Kinshasa Sch Publ Hlth, Kinshasa, DEM REP CONGO. [Garces, Ana] Inst Nutr Cent Amer & Panama, Guatemala City, Guatemala. [Parida, Sailajandan] SCB Med Coll, Cuttack, Odisha, India. [Althabe, Fernando] Inst Clin Effect & Hlth Policy, Buenos Aires, DF, Argentina. [McClure, Elizabeth M.; Wallace, Dennis; Moore, Janet] RTI Int, Durham, NC USA. [Derman, Richard J.] Christiana Care Hlth Syst, Newark, DE USA. [Goldenberg, Robert L.] Columbia Univ, Sch Med, New York, NY USA. [Bose, Carl] Univ N Carolina, Chapel Hill, NC USA. [Krebs, Nancy F.] Univ Colorado, Hlth Sci Ctr, Denver, CO USA. [Panigrahi, Pinaki] Univ Nebraska Med Ctr, Omaha, NE USA. [Buekens, Pierre] Tulane Univ, Sch Publ Hlth & Trop Med, New Orleans, LA USA. [Koso-Thomas, Marion; Wright, Linda L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Carlo, WA (reprint author), Univ Alabama Birmingham, Div Neonatol, 1700 6th Ave South, Birmingham, AL 35233 USA. EM wcarlo@peds.uab.edu FU NICHD NIH HHS [U10 HD078438, U01 HD042372, U01 HD043464, U10 HD076457, U10 HD076474, U10 HD078437] NR 30 TC 0 Z9 0 U1 3 U2 3 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1661-7800 EI 1661-7819 J9 NEONATOLOGY JI Neonatology PY 2017 VL 111 IS 1 BP 61 EP 67 DI 10.1159/000447421 PG 7 WC Pediatrics SC Pediatrics GA EF8CB UT WOS:000390554700009 PM 27544512 ER PT J AU Dehner, LP Messinger, YH Williams, GM Stewart, DR Harney, LA Schultzh, KA Hill, DA AF Dehner, Louis P. Messinger, Yoav H. Williams, Gretchen M. Stewart, Douglas R. Harney, Laura A. Schultzh, Kris Ann Hill, D. Ashley TI Type I Pleuropulmonary Blastoma versus Congenital Pulmonary Airway Malformation Type IV SO NEONATOLOGY LA English DT Letter ID PATHOLOGY; REGISTRY C1 [Dehner, Louis P.] Washington Univ, Med Ctr, Lauren V Ackerman Lab Surg Pathol, St Louis, MO USA. [Dehner, Louis P.; Messinger, Yoav H.; Williams, Gretchen M.; Schultzh, Kris Ann] Childrens Hosp & Clin Minnesota, Int Pleuropulmonary Blastoma Registry, Minneapolis, MN USA. [Stewart, Douglas R.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Harney, Laura A.] WESTAT Corp, Rockville, MD USA. [Hill, D. Ashley] Childrens Natl Med Ctr, Dept Pathol, Washington, DC 20010 USA. RP Dehner, LP (reprint author), Washington Univ, Sch Med, Dept Pathol & Immunol, 660 S Euclid Ave,Campus Box 8118, St Louis, MO 63110 USA. EM dehner@path.wustl.edu NR 9 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1661-7800 EI 1661-7819 J9 NEONATOLOGY JI Neonatology PY 2017 VL 111 IS 1 BP 76 EP 76 DI 10.1159/000447992 PG 1 WC Pediatrics SC Pediatrics GA EF8CB UT WOS:000390554700011 PM 27562209 ER PT J AU Koskela, M Back, S Voikar, V Richie, CT Domanskyi, A Harvey, BK Airavaara, M AF Koskela, Maryna Back, Susanne Voikar, Vootele Richie, Christopher T. Domanskyi, Andrii Harvey, Brandon K. Airavaara, Mikko TI Update of neurotrophic factors in neurobiology of addiction and future directions SO NEUROBIOLOGY OF DISEASE LA English DT Review ID VENTRAL TEGMENTAL AREA; SPERMATOGONIAL STEM-CELLS; CATECHOLAMINERGIC NEURON SURVIVAL; MIDBRAIN DOPAMINERGIC-NEURONS; GENETICALLY-MODIFIED MICE; INBRED MOUSE STRAINS; IN-VIVO; SUBSTANTIA-NIGRA; ALCOHOL-CONSUMPTION; BDNF EXPRESSION AB Drug addiction is a chronic brain disease and drugs of abuse cause long lasting neuroadaptations. Addiction is characterized by the loss of control over drug use despite harmful consequences, and high rates of relapse even after long periods of abstinence. Neurotrophic factors (NTFs) are well known for their actions on neuronal survival in the peripheral nervous system. Moreover, NTFs have been shown to be involved in synaptic plasticity in the brain. Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) are two of the most studied NTFs and both of them have been reported to increase craving when administered into the mesocorticolimbic dopaminergic system after drug self-administration. Here we review recent data on BDNF and GDNF functions in addiction-related behavior and discuss them in relation to previous findings. Finally, we give an insight into how new technologies could aid in further elucidating the role of these factors in drug addiction. (C) 2016 Elsevier Inc. All rights reserved. C1 [Koskela, Maryna; Domanskyi, Andrii; Airavaara, Mikko] Univ Helsinki, Inst Biotechnol, Room 6028B,POB 56,Viikinkaari 5D, FIN-00014 Helsinki, Finland. [Voikar, Vootele] Univ Helsinki, Neurosci Ctr, POB 56, FIN-00014 Helsinki, Finland. [Back, Susanne; Richie, Christopher T.; Harvey, Brandon K.] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. RP Airavaara, M (reprint author), Univ Helsinki, Inst Biotechnol, Room 6028B,POB 56,Viikinkaari 5D, FIN-00014 Helsinki, Finland. EM mikko.airavaara@helsinki.fi OI Airavaara, Mikko/0000-0002-2026-1609; Voikar, Vootele/0000-0003-4201-8666 FU Academy of Finland; Finnish alcohol research foundation; Intramural Research Program, National Institute on Drug Abuse FX For funding MA, AD acknowledge Academy of Finland, MM, MA Finnish alcohol research foundation and SB, CTR, and BKH were supported by the Intramural Research Program, National Institute on Drug Abuse. NR 187 TC 0 Z9 0 U1 14 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 EI 1095-953X J9 NEUROBIOL DIS JI Neurobiol. Dis. PD JAN PY 2017 VL 97 SI SI BP 189 EP 200 DI 10.1016/j.nbd.2016.05.010 PN B PG 12 WC Neurosciences SC Neurosciences & Neurology GA EF8YS UT WOS:000390618500013 PM 27189755 ER PT J AU Thein, MS Igbineweka, NE Thein, SL AF Thein, Mya S. Igbineweka, Norris E. Thein, Swee Lay TI Sickle cell disease in the older adult SO PATHOLOGY LA English DT Review DE Sickle cell disease; older adults; vasculopathy; multi-organ damage ID ACUTE CHEST SYNDROME; QUALITY-OF-LIFE; PULMONARY-HYPERTENSION; RISK-FACTORS; ALPHA-THALASSEMIA; NITRIC-OXIDE; VENOUS THROMBOEMBOLISM; TRANSCRANIAL DOPPLER; HYDROXYUREA THERAPY; CLINICAL-COURSE AB Sickle cell disease (SCD) is an inherited haemoglobin disorder, associated with recurrent painful episodes, ongoing haemolytic anaemia and progressive multi-organ damage. Until the early 1990s, survival beyond the fourth decade for a patient with SCD was considered unusual and prompted case reports. Nowadays, in countries with developed health care systems, more than 90 percent of newborns with SCD survive into adulthood. Nevertheless, their life expectancy is still shortened by more than two decades compared to the general population. With an increasing life expectancy, SCD has now evolved into a debilitating disorder with substantial morbidity resulting from ongoing sickle cell vasculopathy and multi-organ damage. Limited data on health care issues of older adults with SCD poses multiple challenges to patients, their families and health care providers. In this review, we will address and discuss acute and chronic complications of SCD with a special focus on the older adult. C1 [Thein, Mya S.; Thein, Swee Lay] NHLBI, Sickle Cell Branch, NIH, Bldg 10,Room 6S241A,10 Ctr Dr, Bethesda, MD 20892 USA. [Igbineweka, Norris E.] Univ Sussex, Brighton & Sussex Med Sch, Dept Haematol, Brighton, E Sussex, England. RP Thein, SL (reprint author), NHLBI, Sickle Cell Branch, NIH, Bldg 10,Room 6S241A,10 Ctr Dr, Bethesda, MD 20892 USA. EM sl.thein@nih.gov NR 120 TC 0 Z9 0 U1 25 U2 25 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0031-3025 EI 1465-3931 J9 PATHOLOGY JI Pathology PD JAN PY 2017 VL 49 IS 1 BP 1 EP 9 DI 10.1016/j.pathol.2016.10.002 PG 9 WC Pathology SC Pathology GA EG1NC UT WOS:000390798500001 PM 27914684 ER PT J AU Moghanaki, D Turkbey, B Vapiwala, N Ehdaie, B Frank, SJ McLaughlin, PW Harisinghani, M AF Moghanaki, Drew Turkbey, Baris Vapiwala, Neha Ehdaie, Behfar Frank, Steven J. McLaughlin, Patrick W. Harisinghani, Mukesh TI Advances in Prostate Cancer Magnetic Resonance Imaging and Positron Emission Tomography-Computed Tomography for Staging and Radiotherapy Treatment Planning SO SEMINARS IN RADIATION ONCOLOGY LA English DT Article ID EXTERNAL-BEAM RADIATION; CLINICALLY LOCALIZED ADENOCARCINOMA; RADICAL RETROPUBIC PROSTATECTOMY; PERMANENT SOURCE BRACHYTHERAPY; PLANAR BONE-SCINTIGRAPHY; PATHOLOGICAL T3 DISEASE; DIFFUSION-WEIGHTED MRI; LYMPH-NODE METASTASES; PHASE-II TRIAL; ACTIVE SURVEILLANCE AB Conventional prostate cancer staging strategies have limited accuracy to define the location, grade, and burden of disease. Evaluations have historically relied upon prostate-specific antigen levels, digital rectal examinations, random systematic biopsies, computed tomography, pelvic lymphadenectomy, or (99m)technetium methylene diphosphonate bone scans. Today, risk stratification tools incorporate these data in a weighted format to guide management. However, the limitations and potential consequences of their uncertainties are well known. Inaccurate information may contribute to understaging and undertreatment, or overstaging and overtreatment. Meanwhile, advances in multiparametric magnetic resonance imaging (MRI), whole-body MRI, lymphotropic nanoparticle-enhanced MRI, and positron emission tomography are now available to improve the accuracy of risk stratification to facilitate more informed medical decisions. They also guide radiation oncologists to develop more accurate treatment plans. This review provides a primer to incorporate these advances into routine clinical workflow. Published by Elsevier Inc. C1 [Moghanaki, Drew] Hunter Holmes McGuire VA Med Ctr, Radiat Oncol Serv, Richmond, VA USA. [Moghanaki, Drew] Virginia Commonwealth Univ, Dept Radiat Oncol, Richmond, VA USA. [Turkbey, Baris] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Vapiwala, Neha] Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. [Ehdaie, Behfar] Mem Sloan Kettering Canc Ctr, Dept Surg, Urol Serv, New York, NY 10021 USA. [Frank, Steven J.] Univ Texas MD Anderson Canc Ctr, Div Radiat Oncol, Houston, TX 77030 USA. [McLaughlin, Patrick W.] Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. [Harisinghani, Mukesh] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. RP Moghanaki, D (reprint author), Hunter Holmes McGuire VA Med Ctr, Radiat Oncol Serv, 1201 Broad Rock Blvd, Richmond, VA 23249 USA. EM drew.moghanaki@gmail.com NR 76 TC 0 Z9 0 U1 2 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1053-4296 EI 1532-9461 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD JAN PY 2017 VL 27 IS 1 BP 21 EP 33 DI 10.1016/j.semradonc.2016.08.008 PG 13 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA EF9GU UT WOS:000390639500004 PM 27986208 ER PT J AU Dettmer, AM Wooddell, LJ Rosenberg, KL Kaburu, SSK Novak, MA Meyer, JS Suomi, SJ AF Dettmer, Amanda M. Wooddell, Lauren J. Rosenberg, Kendra L. Kaburu, Stefano S. K. Novak, Melinda A. Meyer, Jerrold S. Suomi, Stephen J. TI Associations between early life experience, chronic HPA axis activity, and adult social rank in rhesus monkeys SO SOCIAL NEUROSCIENCE LA English DT Article DE Early experience; social rank; cortisol; HPA axis; Macaca mulatta ID PITUITARY-ADRENOCORTICAL ACTIVITY; MACAQUES MACACA-MULATTA; SOCIOECONOMIC-STATUS; HAIR CORTISOL; SALIVARY CORTISOL; EARLY ADVERSITY; CYNOMOLGUS MONKEYS; REARING CONDITION; STRESS RESPONSES; BEHAVIOR AB Early life experience and socioeconomic status (SES) are well-established predictors of health outcomes in people. Both factors likely influence health outcomes via hypothalamic-pituitary-adrenal (HPA) axis regulation. However, it is unclear how early experience and HPA axis activity influence adult social status. We studied differentially reared female rhesus monkeys (Macaca mulatta, N=90) as models to test the hypothesis that chronic HPA axis activity assessed via hair cortisol concentrations (HCCs) mediated the relationship between early life experience and adult social rank. We found that mother-peer-reared (MPR) monkeys acquired higher social ranks than either of the two nursery-reared (NR) groups (peer-reared, PR, or surrogate-peer-reared, SPR monkeys) (=-0.07, t((89))=-2.16, p=0.034). We also found that MPR HCCs were lower during the juvenile period at 18months (F-(2,F-25)=3.49, p=0.047). Furthermore, for MPR but not NR monkeys, changes in HCCs from 18 to 24months (r((s))=-0.627, p=0.039) and adult HCCs (r((s))=-0.321, p=0.03) were negatively correlated with adult social rank. These findings suggest that chronic HPA axis regulation in juvenility, and perhaps in adulthood, may influence adult social status for primates that experience typical early rearing. However, early life adversity may result in dissociation between neuroendocrine stress regulation and adult social competence, which may be risk factors for adverse health outcomes. C1 [Dettmer, Amanda M.; Wooddell, Lauren J.; Suomi, Stephen J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Comparat Ethol, NIH, POB 529, Poolesville, MD 20837 USA. [Rosenberg, Kendra L.; Novak, Melinda A.; Meyer, Jerrold S.] Univ Massachusetts, Dept Psychol & Brain Sci, Amherst, MA 01003 USA. [Kaburu, Stefano S. K.] Univ Calif Davis, Sch Vet Med, Dept Populat Hlth & Reprod, Davis, CA 95616 USA. RP Dettmer, AM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Comparat Ethol, NIH, POB 529, Poolesville, MD 20837 USA. EM dettmera@mail.nih.gov FU Division of Intramural Research at the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health [OD011180] FX This work was supported by the Division of Intramural Research at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and by the National Institutes of Health [Grant number OD011180]. NR 77 TC 0 Z9 0 U1 9 U2 9 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1747-0919 EI 1747-0927 J9 SOC NEUROSCI-UK JI Soc. Neurosci. PY 2017 VL 12 IS 1 BP 92 EP 101 DI 10.1080/17470919.2016.1176952 PG 10 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA EG2CH UT WOS:000390849700009 PM 27063359 ER PT J AU Babic, B Patel, D Aufforth, R Assadipour, Y Sadowski, SM Quezado, M Nilubol, N Prodanov, T Pacak, K Kebebew, E AF Babic, Bruna Patel, Dhaval Aufforth, Rachel Assadipour, Yasmine Sadowski, Samira M. Quezado, Martha Nilubol, Naris Prodanov, Tamara Pacak, Karel Kebebew, Electron TI Pediatric patients with pheochromocytoma and paraganglioma should have routine preoperative genetic testing for common susceptibility genes in addition to imaging to detect extra-adrenal and metastatic tumors SO SURGERY LA English DT Article; Proceedings Paper CT 37th Annual Meeting of the American-Association-of-Endocrine-Surgeons CY APR 10-12, 2016 CL Baltimore, MD SP Amer Assoc Endocrine Surg ID HEREDITARY PHEOCHROMOCYTOMA; NEUROFIBROMATOSIS TYPE-1; MAX MUTATIONS; DIAGNOSIS; CHILDHOOD; CHILDREN; NECK; HEAD AB Background. Pediatric pheochromocytomas and paragangliomas are rare with limited data on the optimal management approach. The aim of this study was to determine the role of genetic testing and imaging to detect extra-adrenal and/or metastatic tumors in pediatric pheochromocytomas and paragangliomas. Methods. We performed a retrospective study of 55 patients diagnosed at <= 21 years of age with pheochromocytomas and paragangliomas with analysis of data on genetic testing and multimodal imaging. Results. Eighty percent of patients (n = 44/55) had a gemline mutation. The majority were found to have either VHL (38%) or SDHB (25 %) mutation. Pheochromocytoma was present in 67% (n = 37/55) of patients and was bilateral in 51 % (n = 19/37). The majority of patients with bilateral pheochromocytomas had VHL (79%). Abdominal paragangliomas was present in 22% (n = 12/55), head and neck paragangliomas in 11 % (n = 6/55), and thoracic paragangliomas in 2 of 55 patients. For paragangliomas, SDHx accounted for 72% (n = 13/18) of mutations. The rate of malignancy was 16% (n = 9/55), 56% of whom had SDHB mutations. In two-thirds of patients, functional imaging identified either extra-adrenal paragangliomas and/or metastatic disease. Conclusion. The majority of pediatric patients with pheochromocytomas and paragangliomas have detectable germline mutations. Therefore, we suggest strongly that all pediatric patients with pheochromocytomas and paragangliomas undergo genetic testing and imaging to detect extra-adrenal paragangliomas and metastatic disease to guide treatment and follow-up. C1 [Babic, Bruna; Patel, Dhaval; Aufforth, Rachel; Sadowski, Samira M.; Nilubol, Naris; Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. [Assadipour, Yasmine] George Washington Univ Hosp, Dept Surg, Washington, DC USA. [Sadowski, Samira M.] Univ Hosp Geneva, Thorac & Endocrine Surg, Geneva, Switzerland. [Quezado, Martha] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Prodanov, Tamara; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov OI Patel, Dhaval/0000-0002-5744-568X FU Intramural NIH HHS [Z99 CA999999, ZIA BC011275-05, ZIA BC011275-06, ZIA BC011275-07, ZIE BC011656-01, ZIE BC011656-02] NR 23 TC 1 Z9 1 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD JAN PY 2017 VL 161 IS 1 BP 220 EP 226 DI 10.1016/j.surg.2016.05.059 PG 7 WC Surgery SC Surgery GA EG2AR UT WOS:000390836000051 PM 27865588 ER PT J AU Assadipour, Y Sadowski, SM Alimchandani, M Quezado, M Steinberg, SM Nilubol, N Patel, D Prodanov, T Pacak, K Kebebew, E AF Assadipour, Yasmine Sadowski, Samira M. Alimchandani, Meghna Quezado, Martha Steinberg, Seth M. Nilubol, Naris Patel, Dhaval Prodanov, Tamara Pacak, Karel Kebebew, Electron TI SDHB mutation status and tumor size but not tumor grade are important predictors of clinical outcome in pheochromocytoma and abdominal paraganglioma SO SURGERY LA English DT Article ID METASTATIC PHEOCHROMOCYTOMA; MALIGNANT PHEOCHROMOCYTOMAS; EXPRESSION; SURVIVAL; BEHAVIOR; DISEASE; BENIGN; PASS AB Background. A staging/prognostic system has long been desired to better categorize pheochromocytoma/paraganglioma which can be very aggressive in the setting of SDHB mutations. Methods. A retrospective analysis was conducted of clinical characteristics and outcomes including results of genetic testing, tumor recurrence/metastasis, Ki67/MIB1% staining, and tumor mitotic index in patients with pheochromocytoma/paraganglioma. Results. Patients with SDHB mutation presented at younger age (33.0 years old vs 49.6 years old, P < .001), had increased local recurrence and distant metastases (47.6% vs 9.1 %, P < .001, and 56.3% vs 9.1 %, P < .001, respectively), and lesser median disease-free interval (89.8 months, 95% confidence interval 36.0-96.4 vs not reached, P < .001). SDHB mutation, greatest tumor diameter, and open operative resection were associated with a greater rate of local recurrence and distant metastases (P < .006 each). SDHB mutation and tumor diameter were independent risk factors for local recurrence (P <= .04 each) and metastases. Ki67 % and mitotic index were not associated with SDHB mutation (P >= .09 each), local recurrence (P = .48, P = .066, respectively), metastases (P >= .22 each), or disease-free interval (P >= .19 each). Conclusion. SDHB status and primary tumor size are more predictive of patient outcome than Ki67 % or mitotic index and should be part of any clinically relevant, prognostic scoring system. C1 [Assadipour, Yasmine] NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Assadipour, Yasmine] George Washington Univ Hosp, Dept Surg, Washington, DC USA. [Sadowski, Samira M.; Nilubol, Naris; Patel, Dhaval; Kebebew, Electron] NCI, Endocrine Oncol Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. [Sadowski, Samira M.] Univ Hosp Geneva, Thorac & Endocrine Surg, Geneva, Switzerland. [Alimchandani, Meghna; Quezado, Martha] NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Prodanov, Tamara; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol, NIH, Bethesda, MD USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov OI Patel, Dhaval/0000-0002-5744-568X FU intramural research programs of the Center for Cancer Research, National Cancer Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Supported by the intramural research programs of the Center for Cancer Research,National Cancer Institute, and Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 25 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 0039-6060 J9 SURGERY JI Surgery PD JAN PY 2017 VL 161 IS 1 BP 230 EP 237 DI 10.1016/j.surg.2016.05.050 PG 8 WC Surgery SC Surgery GA EG2AR UT WOS:000390836000054 PM 27839933 ER PT J AU Chen, KH Reese, EA Kim, HW Rapoport, SI Rao, JS AF Chen, Kevin H. Reese, Edmund A. Kim, Hyung-Wook Rapoport, Stanley I. Rao, Jagadeesh S. TI Disturbed Neurotransmitter Transporter Expression in Alzheimer's Disease Brain (Retraction of Vol 26, Pg 755, 2011) SO JOURNAL OF ALZHEIMERS DISEASE LA English DT Retraction C1 [Chen, Kevin H.; Reese, Edmund A.; Kim, Hyung-Wook; Rapoport, Stanley I.; Rao, Jagadeesh S.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Chen, KH (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 2 U2 2 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 1387-2877 EI 1875-8908 J9 J ALZHEIMERS DIS JI J. Alzheimers Dis. PY 2017 VL 55 IS 1 BP 445 EP 445 DI 10.3233/JAD-179001 PG 1 WC Neurosciences SC Neurosciences & Neurology GA EB8WI UT WOS:000387671600035 ER PT J AU Venkatesh, BA Nauffal, V Noda, C Fujii, T Yang, PC Bettencourt, J Ricketts, EP Murphy, M Leeper, NJ Moye, L Ebert, RF Muthupillai, R Bluemke, DA Perin, EC Hirsch, AT Lima, JAC AF Venkatesh, Bharath Ambale Nauffal, Victor Noda, Chikara Fujii, Tomoki Yang, Phillip C. Bettencourt, Judy Ricketts, Erin P. Murphy, Michael Leeper, Nicholas J. Moye, Lem Ebert, Ray F. Muthupillai, Raja Bluemke, David A. Perin, Emerson C. Hirsch, Alan T. Lima, Joao A. C. CA CCTRN TI Baseline assessment and comparison of arterial anatomy, hyperemic flow, and skeletal muscle perfusion in peripheral artery disease: The Cardiovascular Cell Therapy Research Network "Patients with Intermittent Claudication Injected with ALDH Bright Cells" (CCTRN PACE) study SO AMERICAN HEART JOURNAL LA English DT Article ID MAGNETIC-RESONANCE ANGIOGRAPHY; CONTRAST-ENHANCED MRI; INPUT FUNCTION; REPRODUCIBILITY; STRESS; IMPACT; RISK AB Background Peripheral artery disease (PAD) is important to public health as a major contributor to cardiovascular morbidity and mortality. Recent developments in magnetic resonance imaging (MRI) techniques permit improved assessment of PAD anatomy and physiology, and may serve as surrogate end points after proangiogenic therapies. Methods The PACE study is a randomized, double-blind, placebo-controlled clinical trial designed to assess the physiologic impact and potential clinical efficacy of autologous bone marrow-derived ALDH(br) stem cells. The primary MRI end points of the study are as follows: (1) total collateral count, (2) calf muscle plasma volume (a measure of capillary perfusion) by dynamic contrast-enhanced MRI, and (3) peak hyperemic popliteal flow by phase-contrast MRI (PC-MRI). Results The interreader and intrareader and test-retest results demonstrated good-to-excellent reproducibility ( interclass correlation coefficient range 0.61-0.98) for all magnetic resonance measures. The PAD participants (n = 82) had lower capillary perfusion measured by calf muscle plasma volume (3.8% vs 5.6%) and peak hyperemic popliteal flow (4.1 vs 13.5 mL/s) as compared with the healthy participants (n = 16), with a significant level of collateralization. Conclusions Reproducibility of the MRI primary end points in PACE was very good to excellent. The PAD participants exhibited decreased calf muscle capillary perfusion as well as arterial flow reserve when compared with healthy participants. The MRI tools used in PACE may advance PAD science by enabling accurate measurement of PAD microvascular anatomy and perfusion before and after stem cell or other PAD therapies. C1 [Venkatesh, Bharath Ambale; Nauffal, Victor; Noda, Chikara; Fujii, Tomoki; Ricketts, Erin P.; Lima, Joao A. C.] Johns Hopkins Univ, Baltimore, MD USA. [Yang, Phillip C.; Leeper, Nicholas J.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Bettencourt, Judy; Moye, Lem] Univ Texas Houston, Hlth Sci Ctr, Sch Publ Hlth, Houston, TX USA. [Murphy, Michael] Indiana Univ Sch Med, Bloomington, IN USA. [Ebert, Ray F.; Bluemke, David A.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Muthupillai, Raja; Perin, Emerson C.] Texas Heart Inst, Houston, TX 77025 USA. [Hirsch, Alan T.] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. RP Moye, L (reprint author), Univ Texas Houston, Sch Publ Hlth, 1200 Pressler E-1009, Houston, TX 77030 USA. EM lemmoye@msn.com FU National Institutes of Health (National Heart, Lung, and Blood Institute) [UM1HL087318] FX PACE funded by National Institutes of Health network grants (National Heart, Lung, and Blood Institute UM1HL087318). The views expressed in this manuscript by one of the authors (RFE) do not necessarily reflect those of the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the US Department of Health and Human Services NR 22 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD JAN PY 2017 VL 183 BP 24 EP 34 DI 10.1016/j.ahj.2016.09.013 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EF3XX UT WOS:000390259600004 PM 27979038 ER PT J AU Verma, AK Schulte, PJ Bittner, V Keteyian, SJ Fleg, JL Pina, IL Swank, AM Fitz-Gerald, M Ellis, SJ Kraus, WE Whellan, DJ O'Connor, CM Mentz, RJ AF Verma, Amanda K. Schulte, Phillip J. Bittner, Vera Keteyian, Steven J. Fleg, Jerome L. Pina, Ileana L. Swank, Ann M. Fitz-Gerald, Meredith Ellis, Stephen J. Kraus, William E. Whellan, David J. O'Connor, Christopher M. Mentz, Robert J. TI Socioeconomic and partner status in chronic heart failure: Relationship to exercise capacity, quality of life, and clinical outcomes SO AMERICAN HEART JOURNAL LA English DT Article ID TRIAL INVESTIGATING OUTCOMES; TRAINING HF-ACTION; EVENT-FREE SURVIVAL; MARITAL-STATUS; MORTALITY; DISEASE; RISK; ASSOCIATION; READMISSION; ADHERENCE AB Background Prognosis in patients with heart failure (HF) is commonly assessed based on clinical characteristics. The association between partner status and socioeconomic status (SES) and outcomes in chronic HF requires further study. Methods We performed a post hoc analysis of HF-ACTION, which randomized 2,331 HF patients with ejection fraction <= 35% to usual care +/- aerobic exercise training. We examined baseline quality of life and functional capacity and outcomes (all-cause mortality/hospitalization) by partner status and SES using adjusted Cox models and explored an interaction with exercise training. Outcomes were examined based on partner status, education level, annual income, and employment. Results Having a partner, education beyond high school, an income >$25,000, and being employed were associated with better baseline functional capacity and quality of life. Over a median follow-up of 2.5 years, higher education, higher income, being employed, and having a partner were associated with lower all-cause mortality/hospitalization. After multivariable adjustment, lower mortality was seen associated with having a partner (hazard ratio 0.91, 95% CI 0.81-1.03, P = .15) and more than a high school education (hazard ratio 0.91, CI 0.80-1.02, P = .12), although these associations were not statistically significant. There was no interaction between any of these variables and exercise training on outcomes (all P > .5). Conclusions Having a partner and higher SES were associated with greater functional capacity and quality of life at baseline but were not independent predictors of long-term clinical outcomes in patients with chronic HF. These findings provide information that may be considered as potential variables impacting outcomes. C1 [Verma, Amanda K.] Washington Univ, Sch Med, 660 South Euclid Ave, St Louis, MO 63110 USA. [Schulte, Phillip J.] Mayo Clin, Rochester, MN USA. [Bittner, Vera; Fitz-Gerald, Meredith] Univ Alabama Birmingham, Birmingham, AL USA. [Keteyian, Steven J.] Henry Ford Hosp, Detroit, MI 48202 USA. [Fleg, Jerome L.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Pina, Ileana L.] Montefiore Einstein Med Ctr, New York, NY USA. [Swank, Ann M.] Univ Louisville, Louisville, KY 40292 USA. [Ellis, Stephen J.; Kraus, William E.; O'Connor, Christopher M.; Mentz, Robert J.] Duke Univ, Med Ctr, Durham, NC USA. [Whellan, David J.] Jefferson Med Coll, Philadelphia, PA USA. RP Verma, AK (reprint author), Washington Univ, Sch Med, 660 South Euclid Ave, St Louis, MO 63110 USA. EM amanda.verma@wustl.edu FU National Heart, Lung, and Blood Institute [HL063747, HL093374]; National Institutes of Health [U10HL110312] FX This research was supported by Grants HL063747 and HL093374 from the National Heart, Lung, and Blood Institute. RJM receives research support from the National Institutes of Health (U10HL110312). NR 40 TC 0 Z9 0 U1 7 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD JAN PY 2017 VL 183 BP 54 EP 61 DI 10.1016/j.ahj.2016.10.007 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EF3XX UT WOS:000390259600008 PM 27979042 ER PT J AU Rahman, F Himali, JJ Yin, XY Beiser, AS Ellinor, PT Lubitz, SA Vasan, RS Magnani, JW McManus, DD Seshadri, S Benjamin, EJ AF Rahman, Faisal Himali, Jayandra J. Yin, Xiaoyan Beiser, Alexa S. Ellinor, Patrick T. Lubitz, Steven A. Vasan, Ramachandran S. Magnani, Jared W. McManus, David D. Seshadri, Sudha Benjamin, Emelia J. TI Serum brain-derived neurotrophic factor and risk of atrial fibrillation SO AMERICAN HEART JOURNAL LA English DT Article ID CORONARY-ARTERY-DISEASE; COMMUNITY-BASED COHORT; NECROSIS-FACTOR-ALPHA; MYOCARDIAL-INFARCTION; CADHERIN EXPRESSION; ENDOTHELIAL-CELLS; INFLAMMATION; PREVALENCE; PREDICTION; PREVENTS AB Background and objective Brain-derived neurotrophic factor (BDNF) is expressed by endothelial cells and can affect cardiovascular function. We examined if serum BDNF was associated with risk of incident atrial fibrillation (AF) in the Framingham Heart Study. Methods We studied individuals without an AF diagnosis at baseline from the Framingham original and offspring cohorts. We used age-and sex-adjusted, and multivariable-adjusted Cox proportional hazards regression models to examine the association of serum BDNF concentrations with 10-year risk of incident AF. Results We studied 3,457 participants (mean age 65 +/- 11 years, 58% women). During follow-up, 395 participants developed AF. In unadjusted analysis, higher mean serum BDNF concentration was associated with lower incidence of AF (hazard ratio 0.89 per SD, 95% CI 0.80-0.99). In multivariable-adjusted analyses, serum BDNF concentration was not significantly associated with incident AF (hazard ratio 0.98 per SD, 95% CI 0.88-1.09). Compared with the lowest quartile, BDNF levels in the other quartiles were not associated with risk of AF in multivariable-adjusted analyses. No interactions between sex or age with serum BDNF concentrations and risk of AF were found. Conclusions In our prospective, community-based sample, we did not find a statistically significant association of serum BDNF levels with risk of incident AF. C1 [Rahman, Faisal] Boston Univ, Med Ctr, Dept Med, Boston, MA USA. [Himali, Jayandra J.; Yin, Xiaoyan; Beiser, Alexa S.; Vasan, Ramachandran S.; McManus, David D.; Seshadri, Sudha; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Himali, Jayandra J.; Yin, Xiaoyan; Beiser, Alexa S.; Vasan, Ramachandran S.; McManus, David D.; Seshadri, Sudha; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Himali, Jayandra J.; Beiser, Alexa S.; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Himali, Jayandra J.; Yin, Xiaoyan; Beiser, Alexa S.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Yin, Xiaoyan; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Cardiovasc Med Prevent Med & Epidemiol, Boston, MA 02118 USA. [Ellinor, Patrick T.; Lubitz, Steven A.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Magnani, Jared W.] Univ Pittsburgh, Dept Med, UPMC Heart & Vasc Inst, Div Cardiol, Pittsburgh, PA USA. [McManus, David D.] Univ Massachusetts, Dept Med, Worcester, MA 01605 USA. [McManus, David D.] Univ Massachusetts, Dept Quantitat Hlth Sci, Worcester, MA 01605 USA. [McManus, David D.] Worcester Polytech Inst, Dept Biomed Engn, Worcester, MA 01609 USA. RP Benjamin, EJ (reprint author), Boston Univ, Framingham Heart Study, Sch Med, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA.; Benjamin, EJ (reprint author), Boston Univ, Framingham Heart Study, Sch Publ Hlth, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM emelia@bu.edu OI /0000-0003-1391-9481 FU National Institutes of Health [R03AG045075, K23HL114724, 6RO1NS17950, 2R01HL092577, 1R01HL128914, R01HL101056, 1P50HL120163, R01HL104156, K24HL105780, KL2RR031981, 5R01HL126911-02, 1R15HL121761-01A1, 1UH2TR000921-02]; Doris Duke Charitable Foundation [2015084, 2014105]; American Heart Association Award [13EIA14220013]; Evans Scholar Award from the Department of Medicine, Boston University School of Medicine; Fondation Leducg [14CVD01]; [HHSN268201500001I]; [N01-HC-25195] FX This work was supported by contracts HHSN268201500001I and N01-HC-25195 (Vasan) and National Institutes of Health Grants R03AG045075 (Magnani); K23HL114724 (Lubitz); 6RO1NS17950 (Seshadri); 2R01HL092577 and 1R01HL128914 (Ellinor and Benjamin); R01HL101056 and 1P50HL120163 (Benjamin); R01HL104156 and K24HL105780 (Ellinor); and KL2RR031981, 5R01HL126911-02, 1R15HL121761-01A1, and 1UH2TR000921-02 (McManus). This work was also supported by Grant 2015084 from the Doris Duke Charitable Foundation (Magnani), Grant 2014105 from the Doris Duke Charitable Foundation (Lubitz), American Heart Association Award 13EIA14220013 (Ellinor), Evans Scholar Award from the Department of Medicine, Boston University School of Medicine (Vasan), and the Fondation Leducg 14CVD01 (Ellinor). NR 38 TC 0 Z9 0 U1 3 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD JAN PY 2017 VL 183 BP 69 EP 73 DI 10.1016/j.ahj.2016.07.027 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EF3XX UT WOS:000390259600010 PM 27979044 ER PT J AU Marques, EA Figueiredo, P Harris, TB Wanderley, FA Carvalho, J AF Marques, Elisa A. Figueiredo, Pedro Harris, Tamara B. Wanderley, Flavia A. Carvalho, Joana TI Are resistance and aerobic exercise training equally effective at improving knee muscle strength and balance in older women? SO ARCHIVES OF GERONTOLOGY AND GERIATRICS LA English DT Article DE Muscle strength; Isokinetics; Postural control; Endurance training; Aging ID PHYSICAL FUNCTION; SKELETAL-MUSCLE; ADULTS; PERFORMANCE; MOBILITY; POWER; MASS; ADAPTATIONS; IMPROVEMENT; DISABILITY AB This study aimed to compare the magnitude of knee muscle strength and static and dynamic balance change in response to 8 months of progressive RE and AE training in healthy community-dwelling older women. A secondary aim was to assess the relationship between muscle strength and balance changes (up and go test (UGT), one-leg stance test, and center of pressure measures). This study was a secondary analysis of longitudinal data from a randomized controlled trial, a three-arm intervention study in older women (n = 71, mean age 69.0 y). The results suggest that both interventions elicited likely to almost certain improvements (using magnitude-based inference) in balance performance. Leg strength was improved after RE whereas it was unclear following AE. Improvements in strength were almost certainly moderate after RE and possibly trivial after AE, with very likely greater improvements following RE compared to AE. A large and significant negative correlation (r = -0.5; CI 90%: -0.7 to -0.2) was found between Delta UGT and change in both knee extension and knee flexion strength after 8-month RE. In conclusion, our results showed that both types of training improve balance, but RE was also effective at improving leg strength. In addition, improvements in both knee extension and flexion strength after RE appear to make an important contribution to meaningful improvements in static and dynamic balance. Published by Elsevier Ireland Ltd. C1 [Marques, Elisa A.; Harris, Tamara B.] NIA, Intramural Res Program, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Marques, Elisa A.; Figueiredo, Pedro] ISMAI, Univ Inst Maia, CIDESD, Res Ctr Sports Sci Hlth Sci & Human Dev, Maia, Portugal. [Figueiredo, Pedro] Univ Maryland, Dept Kinesiol, College Pk, MD 20742 USA. [Wanderley, Flavia A.] Alagoas State Univ Hlth Sci UNCISAL, Maceio, Brazil. [Carvalho, Joana] Univ Porto, Res Ctr Phys Act Hlth & Leisure, CIAFEL, Fac Sport, Oporto, Portugal. RP Marques, EA (reprint author), NIA, NIH, 7201 Wisconsin Ave,Gateway Bldg,Suite 2N212, Bethesda, MD 20892 USA. EM elisa.marques@nih.gov FU Portuguese Foundation of Science and Technology (FCT) [UID/DTP/00617/2013]; NIH, National Institute on Aging FX This research was funded by the Portuguese Foundation of Science and Technology (FCT) [grant UID/DTP/00617/2013]; and was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 37 TC 0 Z9 0 U1 16 U2 16 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-4943 EI 1872-6976 J9 ARCH GERONTOL GERIAT JI Arch. Gerontol. Geriatr. PD JAN-FEB PY 2017 VL 68 BP 106 EP 112 DI 10.1016/j.archger.2016.10.002 PG 7 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA EF6NR UT WOS:000390448300016 PM 27764726 ER PT J AU Balderston, NL Mathur, A Adu-Brimpong, J Hale, EA Ernst, M Grillon, C AF Balderston, Nicholas L. Mathur, Ambika Adu-Brimpong, Joel Hale, Elizabeth A. Ernst, Monique Grillon, Christian TI Effect of anxiety on behavioural pattern separation in humans SO COGNITION & EMOTION LA English DT Article DE Pattern separation; threat of shock; anxiety; startle; generalisation ID COMPLEMENTARY LEARNING-SYSTEMS; DENTATE GYRUS; EMOTIONAL INFORMATION; HIPPOCAMPAL DENTATE; DEPENDENT MEMORY; LONG-TERM; AMYGDALA; STARTLE; CA3; MOOD AB Behavioural pattern separation (BPS), the ability to distinguish among similar stimuli based on subtle physical differences, has been used to study the mechanism underlying stimulus generalisation. Fear overgeneralisation is often observed in individuals with posttraumatic stress disorder and other anxiety disorders. However, the relationship between anxiety and BPS remains unclear. The purpose of this study was to determine the effect of anxiety (threat of shock) on BPS, which was assessed across separate encoding and retrieval sessions. Images were encoded/retrieved during blocks of threat or safety in a 2x2 factorial design. During retrieval, participants indicated whether images were new, old, or altered. Better accuracy was observed for altered images encoded during periods of threat compared to safety, but only if those images were also retrieved during periods of safety. These results suggest that overgeneralisation in anxiety may be due to altered pattern separation. C1 [Balderston, Nicholas L.; Mathur, Ambika; Adu-Brimpong, Joel; Hale, Elizabeth A.; Ernst, Monique; Grillon, Christian] NIMH, Sect Neurobiol Fear & Anxiety, NIH, Bethesda, MD 20892 USA. RP Balderston, NL (reprint author), NIMH, Sect Neurobiol Fear & Anxiety, NIH, Bethesda, MD 20892 USA. EM nicholas.balderston@nih.gov OI Balderston, Nicholas/0000-0002-8565-1544 FU Intramural Research Program of the National Institute of Mental Health [MH002798, 01-M-0185] FX This research was supported by the Intramural Research Program of the National Institute of Mental Health [grant number MH002798] (Protocol 01-M-0185). NR 52 TC 1 Z9 1 U1 2 U2 2 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0269-9931 EI 1464-0600 J9 COGNITION EMOTION JI Cogn. Emot. PY 2017 VL 31 IS 2 BP 238 EP 248 DI 10.1080/02699931.2015.1096235 PG 11 WC Psychology, Experimental SC Psychology GA EF2OT UT WOS:000390164800003 PM 26480349 ER PT J AU Edelman, AB Cherala, G Li, H Pau, F Blithe, DL Jensen, JT AF Edelman, Alison B. Cherala, Ganesh Li, Hong Pau, Francis Blithe, Diana L. Jensen, Jeffrey T. TI Levonorgestrel butanoate intramuscular injection does not reliably suppress ovulation for 90 days in obese and normal-BMI women: a pilot study SO CONTRACEPTION LA English DT Article DE Contraceptive injection; Levonorgestrel butanoate; Pharmacokinetics; Obesity; Body weight; Contraception ID CONTRACEPTIVE EFFECTIVENESS; PROGRAM; ONSET; USERS AB Background: We performed a pilot evaluation of a new formulation of levonorgestrel butanoate (LB) designed to be a long-acting injectable (6 months) contraceptive to determine pharmacodynamic end points in normal-body mass index (BMI) and obese women. Study design: Obese (BMI >= 30 kg/m(2)) and normal-BMI, otherwise healthy, women received a single intramuscular injection of LB after ovulation was confirmed in a baseline cycle. The primary outcome was return of ovulation in days. Results: A total of 14 women enrolled and completed the study [normal BMI n=9, median BMI 22.7 kg/m(2) (range 19.4-25.8); obese n=5, median BMI 35.7 kg/m(2) (30.1-39.2)]. The first 6 subjects (normal BMI=4/9, obese BMI=2/5) received 40 mg of LB, and the remaining 8 received 20 mg. All women except one returned to ovulation prior to 6 months. Return to ovulation occurred earlier in the obese group; 3/5 obese and 0/9 normal BMI subjects returned to ovulation within 90 days (p=.03). No serious adverse events were reported during the study. Conclusion: Return to ovulation was earlier than 6 months in both BMI groups but more so in the obese BMI group. (C) 2016 Elsevier Inc. All rights reserved. C1 [Edelman, Alison B.; Cherala, Ganesh; Li, Hong; Jensen, Jeffrey T.] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. [Cherala, Ganesh] CONRAD, Arlington, VA USA. [Edelman, Alison B.; Pau, Francis; Jensen, Jeffrey T.] Oregon Natl Primate Res Ctr, Beaverton, OR USA. [Blithe, Diana L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Edelman, AB (reprint author), Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA.; Edelman, AB (reprint author), Oregon Natl Primate Res Ctr, Beaverton, OR USA. EM edelmana@ohsu.edu FU National Institute of Child Health and Human Development Contraception Clinical Trial Network [HHSN275200403378I]; National Institutes of Health (NIH); OHSU Oregon Clinical & Translational Research Institute [NIH NCRR 1 UL1 RR024120]; Endocrine Technologies Support Core at the Oregon National Primate Research Center [NIH P51 OD011092] FX Support for this research was from National Institute of Child Health and Human Development Contraception Clinical Trial Network HHSN275200403378I. The authors also acknowledge grant support from National Institutes of Health (NIH), the OHSU Oregon Clinical & Translational Research Institute (NIH NCRR 1 UL1 RR024120) and the Endocrine Technologies Support Core at the Oregon National Primate Research Center (NIH P51 OD011092). NR 9 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 0010-7824 EI 1879-0518 J9 CONTRACEPTION JI Contraception PD JAN PY 2017 VL 95 IS 1 BP 55 EP 58 DI 10.1016/j.contraception.2016.07.018 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EF1KB UT WOS:000390082600007 PM 27475035 ER PT J AU Shiels, MS Engels, EA AF Shiels, Meredith S. Engels, Eric A. TI Evolving epidemiology of HIV-associated malignancies SO CURRENT OPINION IN HIV AND AIDS LA English DT Review DE aging; cancer; epidemiology; HIV; immunosuppression; rates ID HUMAN-IMMUNODEFICIENCY-VIRUS; AIDS-DEFINING CANCERS; UNITED-STATES; ANTIRETROVIRAL THERAPY; LUNG-CANCER; HEPATOCELLULAR-CARCINOMA; HUMAN-PAPILLOMAVIRUS; INFECTED PERSONS; RISK-FACTORS; TIME TRENDS AB Purpose of review The purpose of this review is to describe the epidemiology of cancers that occur at an elevated rate among people with HIV infection in the current treatment era, including discussion of the cause of these cancers, as well as changes in cancer incidence and burden over time. Recent findings Rates of Kaposi sarcoma, non-Hodgkin lymphoma and cervical cancer have declined sharply in developed countries during the highly active antiretroviral therapy era, but remain elevated 800-fold, 10-fold and fourfold, respectively, compared with the general population. Most studies have reported significant increases in liver cancer rates and decreases in lung cancer over time. Although some studies have reported significant increases in anal cancer rates and declines in Hodgkin lymphoma rates, others have shown stable incidence. Declining mortality among HIV-infected individuals has resulted in the growth and aging of the HIV-infected population, causing an increase in the number of non-AIDS-defining cancers diagnosed each year in HIV-infected people. Summary The epidemiology of cancer among HIV-infected people has evolved since the beginning of the HIV epidemic with particularly marked changes since the introduction of modern treatment. Public health interventions aimed at prevention and early detection of cancer among HIV-infected people are needed. C1 [Shiels, Meredith S.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Shiels, MS (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,RM 6-E218, Bethesda, MD 20892 USA. EM shielsms@mail.nih.gov FU National Cancer Institute FX This work was funded by the Intramural Program of the National Cancer Institute. NR 48 TC 0 Z9 0 U1 9 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1746-630X EI 1746-6318 J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD JAN PY 2017 VL 12 IS 1 BP 6 EP 11 DI 10.1097/COH.0000000000000327 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EE8IL UT WOS:000389868800002 PM 27749369 ER PT J AU Goncalves, PH Ziegelbauer, J Uldrick, TS Yarchoan, R AF Goncalves, Priscila H. Ziegelbauer, Joseph Uldrick, Thomas S. Yarchoan, Robert TI Kaposi sarcoma herpesvirus-associated cancers and related diseases SO CURRENT OPINION IN HIV AND AIDS LA English DT Review DE human herpesvirus-8; Kaposi sarcoma; Kaposi sarcoma associated herpesvirus ID MULTICENTRIC CASTLEMAN-DISEASE; PRIMARY EFFUSION LYMPHOMA; PEGYLATED-LIPOSOMAL DOXORUBICIN; NF-KAPPA-B; INFLAMMATORY CYTOKINE SYNDROME; AIDS MALIGNANCY CONSORTIUM; HIV-INFECTED PATIENTS; PHASE-II TRIAL; ANTIRETROVIRAL THERAPY; ENDOTHELIAL-CELLS AB Purpose of review This review discusses the pathogenesis and recent advances in the management of Kaposi sarcoma herpesvirus (KSHV)-associated diseases. Recent findings KSHV, a gammaherpesvirus, causes several tumors and related diseases, including Kaposi sarcoma, a form of multicentric Castleman disease (KSHV-MCD), and primary effusion lymphoma. These most often develop in patients infected with human immunodeficiency virus (HIV). KSHV inflammatory cytokine syndrome (KICS) is a newly describe nd syndrome with high mortality that has inflammatory symptoms-like MCD butot the pathologic lymph node findings. KSHV-associated diseases are often associated with dysregulated human interleukin-6, and KSHV encodes a viral interleukin-6, both of which contribute to disease pathogenesis. Treatment of HIV is important in HIV-infected patients. Strategies to prevent KSHV infection may reduce the incidence of these tumors. Pomalidomide, an immunomodulatory agent, has activity in Kaposi sarcoma. Rituximab is active in KSHV-MCD but can cause Kaposi sarcoma exacerbation; rituximab plus liposomal doxorubicin is useful to treat KSHV-MCD patients with concurrent Kaposi sarcoma. Summary KSHV is the etiological agents of all forms of Kaposi sarcoma and several other diseases. Strategies employing immunomodulatory agents, cytokine inhibition, and targeting of KSHV-infected cells are areas of active research. C1 [Goncalves, Priscila H.; Ziegelbauer, Joseph; Uldrick, Thomas S.; Yarchoan, Robert] NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Yarchoan, R (reprint author), HIV & AIDS Malignancy Branch, 10 Ctr Dr,Bldg 10,Room 6N106,MSC 1868, Bethesda, MD 20892 USA. EM robert.yarchoan@nih.gov FU NIH, National Cancer Institute FX This work was supported by the Intramural Research Programme of the NIH, National Cancer Institute. NR 91 TC 0 Z9 0 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1746-630X EI 1746-6318 J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD JAN PY 2017 VL 12 IS 1 BP 47 EP 56 DI 10.1097/COH.0000000000000330 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EE8IL UT WOS:000389868800008 PM 27662501 ER PT J AU Suneja, G Coghill, A AF Suneja, Gita Coghill, Anna TI Cancer care disparities in people with HIV in the United States SO CURRENT OPINION IN HIV AND AIDS LA English DT Review DE AIDS-defining cancers; cancer outcomes; health services research; HIV-associated cancer; non-AIDS-defining cancers; treatment disparities ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; CELL LUNG-CANCER; AIDS-DEFINING CANCERS; INFECTED INDIVIDUALS; LIVER-TRANSPLANTATION; HODGKIN-LYMPHOMA; CLINICAL-TRIALS; SURVIVAL; CARCINOMA AB Purpose of review Cancer is a growing problem in the HIV population, in large part because of aging of HIV-infected people treated with antiretroviral therapy. Overall and cancer-specific survival is worse in HIV-infected cancer patients compared with uninfected patients. One potential reason for the observed survival deficit is differences in cancer treatment. Recent findings Recent population-based data suggest that HIV-infected cancer patients are less likely to receive cancer treatment compared with uninfected patients. This review describes these treatment disparities and their impact on patient outcomes, explores reasons for the disparity and highlights areas for future research. Summary Cancer is the leading cause of non-AIDS death in HIV-infected individuals. Understanding the underlying cancer treatment disparity between HIV-infected patients and their uninfected counterparts, and developing solutions to address the problem, is of great importance to improve cancer outcomes in this growing patient population. C1 [Suneja, Gita] Duke Univ, Dept Radiat Oncol, Duke Global Hlth Inst, Durham, NC USA. [Coghill, Anna] NCI, Bethesda, MD 20892 USA. RP Suneja, G (reprint author), Duke Univ, Duke Global Hlth Inst, Dept Radiat Oncol, DUMC, POB 3085, Durham, NC 27710 USA. EM gita.suneja@icloud.com FU National Cancer Institute; American Cancer Society; University of Pennsylvania FX The research work of the authors, some of which has been cited in this review article, was funded by intramural funds from the National Cancer Institute and American Cancer Society, as well as the University of Pennsylvania. NR 58 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 1746-630X EI 1746-6318 J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD JAN PY 2017 VL 12 IS 1 BP 63 EP 68 DI 10.1097/COH.0000000000000320 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EE8IL UT WOS:000389868800010 PM 27753654 ER PT J AU Little, RF AF Little, Richard F. TI Cancer clinical trials in persons with HIV infection SO CURRENT OPINION IN HIV AND AIDS LA English DT Review DE immunotherapy; pharmacokinetics; transplant ID MULTICENTRIC CASTLEMAN DISEASE; ANTIRETROVIRAL THERAPY; HODGKIN-LYMPHOMA; HERPESVIRUS; COMBINATION; OUTCOMES AB Purpose of review The era of modern HIV therapeutics is well underway. The cancer and infectious disease epidemiology of HIV disease has markedly altered as populations are availed to the benefits of antiretroviral therapy (ARV). The types of cancers occurring among those with HIV infection has broadened but the case burden in absolute numbers is very low relative to the background population. There are fewer incident cases of the AIDS-defining cancers (aggressive B-cell lymphomas, Kaposi's sarcoma, and cervical cancer). There is an increased risk for certain non-AIDS-defining cancers, but these occur somewhat sporadically relative to clinical trial enrollment. The changing epidemiology of cancer in HIV poses challenges as well as opportunities for participation of persons with HIV in cancer therapy clinical trials. Recent findings There are excellent examples of cancer trials that inform cancer therapy for patients with HIV infection. Examples include those from HIV-specific trials and from trials mainly focused on the background population that included patients with HIV infection. Summary Interpretation of clinical trials to guide therapy for those with HIV infection and cancer largely depends on data that does not include HIV-infected patients. The ability to extend clinical trial findings to populations not included in clinical trials remains problematic for a variety of populations, including those with HIV or AIDS. Careful prioritization of studies designed to bridge this gap is needed. However, there are published studies that serve as excellent examples bridging these gaps and the portfolio of cancer therapy trials underway will inform HIV and cancer better than at any time in the past. C1 [Little, Richard F.] NCI, Head Blood & AIDS Related Canc Therapeut, Clin Invest Branch, Div Canc Treatment & Diag,NIH, Bethesda, MD 20892 USA. RP Little, RF (reprint author), 9609 Med Ctr Dr,MSC 9737, Bethesda, MD 20892 USA. EM littler@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 15 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 1746-630X EI 1746-6318 J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD JAN PY 2017 VL 12 IS 1 BP 84 EP 88 DI 10.1097/COH.0000000000000321 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EE8IL UT WOS:000389868800013 PM 27559711 ER PT J AU Lightfoot, YL Kaplan, MJ AF Lightfoot, Yaima L. Kaplan, Mariana J. TI Disentangling the role of neutrophil extracellular traps in rheumatic diseases SO CURRENT OPINION IN RHEUMATOLOGY LA English DT Review DE glomerulonephritis; neutrophil extracellular traps; rheumatic diseases; systemic autoimmunity; thrombosis ID ANTIBODY-ASSOCIATED VASCULITIS; SMALL-VESSEL VASCULITIS; MICROSCOPIC POLYANGIITIS; NETTING NEUTROPHILS; INNATE IMMUNITY; LUPUS; MYELOPEROXIDASE; AUTOIMMUNITY; ARTHRITIS; CHROMATIN AB Purpose of reviewA breakdown of immune tolerance to self-antigens in a genetically predisposing background, precipitated by environmental triggers, contributes to the development of systemic autoimmune diseases. Renewed interest in the immunomodulatory capabilities of neutrophils in systemic autoimmunity has identified neutrophil extracellular trap (NET) formation as a distinguishing action of neutrophils in afflicted hosts.Recent findingsOxidation of nucleic acids and posttranslational modifications of proteins distinctly occur during NET formation and may promote enhanced immunogenicity. Various autoantibodies, immune complexes, and other inflammatory stimuli have been recently reported to promote NET formation in individuals with autoimmune diseases. Associations between level of NETosis and adverse outcomes in systemic autoimmune diseases, including thrombosis, adverse pregnancy outcomes, and renal disease, continue to be investigated.SummaryUnderstanding the putative pathogenic role and sequelae of NETosis in rheumatic diseases is a major focus of ongoing research efforts. Mechanisms elucidated by these discoveries may provide novel therapeutic targets to inhibit NET formation and/or promote the clearance of immunogenic NET material. C1 [Lightfoot, Yaima L.; Kaplan, Mariana J.] NIAMSD, System Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Kaplan, MJ (reprint author), Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, System Autoimmun Branch, NIH, 10 Ctr Dr,6D-47C, Bethesda, MD 20892 USA. EM mariana.kaplan@nih.gov FU NIAMS/NIH [ZIAAR041199] FX The work was supported by the Intramural Research Program at NIAMS/NIH (ZIAAR041199). NR 51 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 1040-8711 EI 1531-6963 J9 CURR OPIN RHEUMATOL JI Curr. Opin. Rheumatol. PD JAN PY 2017 VL 29 IS 1 BP 65 EP 70 DI 10.1097/BOR.0000000000000357 PG 6 WC Rheumatology SC Rheumatology GA EF3SD UT WOS:000390243800011 PM 27755122 ER PT J AU Puligilla, C Kelley, MW AF Puligilla, Chandrakala Kelley, Matthew W. TI Dual Role for Sox2 in Specification of Sensory Competence and Regulation of Atoh1 Function SO DEVELOPMENTAL NEUROBIOLOGY LA English DT Article DE Sox2; Atoh1; hair cell competence; hair cell induction; cell fate ID MAMMALIAN INNER-EAR; DEVELOPING NERVOUS-SYSTEM; HAIR-CELLS; IN-VIVO; ORGAN DEVELOPMENT; SUPPORTING CELLS; GENE-TRANSFER; COCHLEA; EXPRESSION; MATH1 AB The formation of inner ear sensory epithelia is believed to occur in two steps, initial specification of sensory competent (prosensory) regions followed by determination of specific cell-types, such as hair cells (HCs) and supporting cells. However, studies in which the HC determination factor Atoh1 was ectopically expressed in nonprosensory regions indicated that expression of Atoh1 alone is sufficient to induce HC formation suggesting that prosensory formation may not be a prerequisite for HC development. To test this hypothesis, interactions between Sox2 and Atoh1, which are required for prosensory and HC formation respectively, were examined. Forced expression of Atoh1 in nonprosensory cells resulted in transient expression of Sox2 prior to HC formation, suggesting that expression of Sox2 is required for formation of ectopic HCs. Moreover, Atoh1 overexpression failed to induce HC formation in Sox2 mutants, confirming that Sox2 is required for prosensory competence. To determine whether expression of Sox2 alone is sufficient to induce prosensory identity, Sox2 was transiently activated in a manner that mimicked endogenous expression. Following transient Sox2 activation, nonprosensory cells developed as HCs, a result that was never observed in response to persistent expression of Sox2. These results, suggest a dual role for Sox2 in inner ear formation. Initially, Sox2 is required to specify prosensory competence, but subsequent down-regulation of Sox2 must occur to allow Atoh1 expression, most likely through a direct interaction with the Atoh1 promoter. These results implicate Sox2-mediated changes in prosensory cells as an essential step in their ability to develop as HCs. (C) 2016 Wiley Periodicals, Inc. C1 [Puligilla, Chandrakala] Med Univ South Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA. [Kelley, Matthew W.] Natl Inst Deafness & Other Commun Disorders, Lab Cochlear Dev, NIH, Bethesda, MD 20982 USA. RP Puligilla, C (reprint author), Med Univ South Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA. EM puligill@musc.edu FU NIH [5R00-DC010220]; Intramural Program at NIDCD FX Contract grant sponsor: NIH; contract grant number: 5R00-DC010220.; Contract grant sponsor: Intramural Program at NIDCD. NR 42 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1932-8451 EI 1932-846X J9 DEV NEUROBIOL JI Dev. Neurobiol. PD JAN PY 2017 VL 77 IS 1 BP 3 EP 13 DI 10.1002/dneu.22401 PG 11 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA EF0IV UT WOS:000390010000001 PM 27203669 ER PT J AU Niehoff, N White, AJ McCullough, LE Steck, SE Beyea, J Mordukhovich, I Shen, J Neugut, AI Conway, K Santella, RM Gammon, MD AF Niehoff, Nicole White, Alexandra J. McCullough, Lauren E. Steck, Susan E. Beyea, Jan Mordukhovich, Irina Shen, Jing Neugut, Alfred I. Conway, Kathleen Santella, Regina M. Gammon, Marilie D. TI Polycyclic aromatic hydrocarbons and postmenopausal breast cancer: An evaluation of effect measure modification by body mass index and weight change SO ENVIRONMENTAL RESEARCH LA English DT Article DE Polycyclic aromatic hydrocarbons; Breast cancer; Obesity; Weight gain; Adducts ID ENVIRONMENTAL TOBACCO-SMOKE; NEW-YORK EXPOSURES; DNA-ADDUCTS; LONG-ISLAND; ACTIVE SMOKING; AIR-POLLUTION; CALIFORNIA TEACHERS; CIGARETTE-SMOKING; OXIDATIVE STRESS; PASSIVE SMOKING AB Background: Polycyclic aromatic hydrocarbons (PAHs) have been linked to breast cancer in many, but not all, previous studies. PAHs are lipophilic and stored in fat tissue, which we hypothesized may result in constant low dose exposure to these carcinogens. No previous studies have evaluated whether obesity modifies associations between multiple measures of PAHs and breast cancer incidence. Methods: This population-based study included 1,006 postmenopausal women with first primary in situ or invasive breast cancer and 990 age-frequency matched controls. To evaluate effect modification by obesity (adult body mass index (BMI, kg/m(2)) and weight change) on multiple PAH measures (the biomarker PAH-DNA adducts, and long-term sources active cigarette smoking, living with a smoking spouse, grilled/smoked meat intake, residential synthetic log burning, and vehicular traffic), interaction contrast ratios (ICRs) for the additive scale, and ratio of odds ratios (RORs) with log-likelihood ratio tests (LRT) for the multiplicative scale, were determined using unconditional logistic regression. Results: BMI modified the PAH-DNA adduct and postmenopausal breast cancer association on the additive (ICR: 0.49; 95% CI: 0.01, 0.96) and multiplicative (ROR: 1.56; 95% CI: 0.91, 2.68) scales. The odds ratio for detectable vs. non-detectable adducts was increased among women with BMI >= 25 (OR=1.34; 95% CI: 0.94, 1.92), but not in those with BMI < 25 (OR=0.86; 95% CI: 0.57, 1.28) (LRT p=0.1). For most other PAH measures, the pattern of modification by BMI/weight gain was similar, but estimates were imprecise. Conclusions: The association between PAH-DNA adducts and breast cancer incidence may be elevated among overweight/obese women. C1 [Niehoff, Nicole; Conway, Kathleen; Gammon, Marilie D.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. [White, Alexandra J.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [McCullough, Lauren E.] Emory Univ, Dept Epidemiol, Atlanta, GA 30322 USA. [Steck, Susan E.] Univ South Carolina, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. [Beyea, Jan] Dept Consulting Publ Interest CIPI, Lambertville, NJ USA. [Mordukhovich, Irina] Harvard Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Shen, Jing; Santella, Regina M.] Columbia Univ, Dept Environm Hlth Sci, New York, NY USA. [Neugut, Alfred I.] Columbia Univ, Dept Epidemiol, New York, NY USA. [Neugut, Alfred I.] Columbia Univ, Dept Med, New York, NY USA. RP Niehoff, N (reprint author), Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. EM nicolen@live.unc.edu FU National Cancer Institute and the National Institute of Environmental Health and Sciences [CA/ES66572, ES007018, ES009089, ES10126]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01-ES044005] FX This work was supported by the National Cancer Institute and the National Institute of Environmental Health and Sciences Grant nos. CA/ES66572, ES007018, ES009089 and ES10126; and in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (AJW) Grant no. Z01-ES044005. NR 85 TC 0 Z9 0 U1 17 U2 17 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD JAN PY 2017 VL 152 BP 17 EP 25 DI 10.1016/j.envres.2016.09.022 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA EE5YD UT WOS:000389684600004 PM 27741445 ER PT J AU Zijlema, W Cai, YT Doiron, D Mbatchou, S Fortier, I Gulliver, J de Hoogh, K Morley, D Hodgson, S Elliott, P Key, T Kongsgard, H Hveem, K Gaye, A Burton, P Hansell, A Stolk, R Rosmalen, J AF Zijlema, Wilma Cai, Yutong Doiron, Dany Mbatchou, Stephane Fortier, Isabel Gulliver, John de Hoogh, Kees Morley, David Hodgson, Susan Elliott, Paul Key, Timothy Kongsgard, Havard Hveem, Kristian Gaye, Amadou Burton, Paul Hansell, Anna Stolk, Ronald Rosmalen, Judith TI Road traffic noise, blood pressure and heart rate: Pooled analyses of harmonized data from 88,336 participants (vol 151, pg 804, 2016) SO ENVIRONMENTAL RESEARCH LA English DT Correction C1 [Zijlema, Wilma; Stolk, Ronald] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. [Zijlema, Wilma] Ctr Res Environm Epidemiol CREAL, ISGlobal, Barcelona, Spain. [Zijlema, Wilma] Univ Pompeu Fabra, Barcelona, Spain. [Zijlema, Wilma] CIBER Epidemiol & Salud Publ CIB ERESP, Madrid, Spain. [Cai, Yutong; Gulliver, John; de Hoogh, Kees; Morley, David; Hodgson, Susan; Elliott, Paul; Hansell, Anna] Imperial Coll London, MRC PHE Ctr Environm & Hlth, London, England. [Doiron, Dany; Mbatchou, Stephane; Fortier, Isabel] McGill Univ, Hlth Ctr RI MUHC, Res Inst, Montreal, PQ, Canada. [Doiron, Dany; de Hoogh, Kees] Swiss Trop & Publ Hlth Inst, Basel, Switzerland. [Doiron, Dany; de Hoogh, Kees] Univ Basel, Basel, Switzerland. [Key, Timothy] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford, England. [Kongsgard, Havard; Hveem, Kristian] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, Levanger, Norway. [Gaye, Amadou] NHGRI, Metab Cardiovasc & Inflammatory Dis Genom Branch, Bethesda, MD 20892 USA. [Burton, Paul] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Hansell, Anna] Imperial Coll Healthcare NHS Trust, London, England. [Rosmalen, Judith] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. [Rosmalen, Judith] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Groningen, Netherlands. RP Zijlema, W (reprint author), Ctr Res Environm Epidemiol CREAL, ISGlobal, Barcelona, Spain. EM wilma.zijlema@isglobal.org NR 1 TC 0 Z9 0 U1 3 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD JAN PY 2017 VL 152 BP 520 EP 520 DI 10.1016/j.envres.2016.10.025 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA EE5YD UT WOS:000389684600063 PM 27823774 ER PT J AU Schisterman, EF Perkins, NJ Mumford, SL Ahrens, KA Mitchell, EM AF Schisterman, Enrique F. Perkins, Neil J. Mumford, Sunni L. Ahrens, Katherine A. Mitchell, Emily M. TI Collinearity and Causal Diagrams A Lesson on the Importance of Model Specification SO EPIDEMIOLOGY LA English DT Article ID COLLIDER-STRATIFICATION BIAS; MENSTRUAL-CYCLE; EPIDEMIOLOGY; SELECTION; LEPTIN; WOMEN AB Background: Correlated data are ubiquitous in epidemiologic research, particularly in nutritional and environmental epidemiology where mixtures of factors are often studied. Our objectives are to demonstrate how highly correlated data arise in epidemiologic research and provide guidance, using a directed acyclic graph approach, on how to proceed analytically when faced with highly correlated data. Methods: We identified three fundamental structural scenarios in which high correlation between a given variable and the exposure can arise: intermediates, confounders, and colliders. For each of these scenarios, we evaluated the consequences of increasing correlation between the given variable and the exposure on the bias and variance for the total effect of the exposure on the outcome using unadjusted and adjusted models. We derived closed-form solutions for continuous outcomes using linear regression and empirically present our findings for binary outcomes using logistic regression. Results: For models properly specified, total effect estimates remained unbiased even when there was almost perfect correlation between the exposure and a given intermediate, confounder, or collider. In general, as the correlation increased, the variance of the parameter estimate for the exposure in the adjusted models increased, while in the unadjusted models, the variance increased to a lesser extent or decreased. Conclusion: Our findings highlight the importance of considering the causal framework under study when specifying regression models. Strategies that do not take into consideration the causal structure may lead to biased effect estimation for the original question of interest, even under high correlation. C1 [Schisterman, Enrique F.; Perkins, Neil J.; Mumford, Sunni L.; Ahrens, Katherine A.; Mitchell, Emily M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Bethesda, MD USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, 6710B Rockledge Dr MSC 7004, Bethesda, MD 20892 USA. EM schistee@mail.nih.gov OI Schisterman, Enrique/0000-0003-3757-641X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 22 TC 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 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD JAN PY 2017 VL 28 IS 1 BP 47 EP 53 DI 10.1097/EE.0000000000000554 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EF3VD UT WOS:000390252100016 PM 27676260 ER PT J AU Lum, KJ Sundaram, R Barr, DB Louis, TA Louis, GMB AF Lum, Kirsten J. Sundaram, Rajeshwari Barr, Dana B. Louis, Thomas A. Louis, Germaine M. Buck TI Perfluoroalkyl Chemicals, Menstrual Cycle Length, and Fecundity Findings from a Prospective Pregnancy Study SO EPIDEMIOLOGY LA English DT Article ID PERFLUORINATED CHEMICALS; PROSPECTIVE COHORT; SERUM COTININE; TIME; EXPOSURE; SUBFECUNDITY; SUBSTANCES; FERTILITY; CONTAMINANTS; ASSOCIATION AB Background: Perfluoroalkyl substances have been associated with changes in menstrual cycle characteristics and fecundity, when modeled separately. However, these outcomes are biologically related, and we evaluate their joint association with exposure to perfluoroalkyl substances. Methods: We recruited 501 couples from Michigan and Texas in 2005-2009 upon their discontinuing contraception and followed them until pregnancy or 12 months of trying. Female partners provided a serum sample on enrollment and completed daily journals on menstruation, intercourse, and pregnancy test results. We measured seven perfluoroalkyl substances in serum using liquid chromatography-tandem mass spectrometry. We assessed the association between perfluoroalkyl substances and menstrual cycle length using accelerated failure time models and between perfluoroalkyl substances and fecundity using a Bayesian joint modeling approach to incorporate cycle length. Results: Menstrual cycles were 3% longer comparing women in the second versus first tertile of perfluorodecanoate (PFDeA; acceleration factor [AF] = 1.03, 95% credible interval [CrI] = [1.00, 1.05]), but 2% shorter for women in the highest versus lowest tertile of perfluorooctanoic acid (PFOA; AF = 0.98, 95% CrI = [0.96, 1.00]). When accounting for cycle length, relevant covariates, and remaining perfluoroalkyl substances, the probability of pregnancy was lower for women in second versus first tertile of perfluorononanoate (PFNA; odds ratio [OR] = 0.6, 95% CrI = [0.4, 1.0]) although not when comparing the highest versus lowest (OR = 0.7, 95% CrI = [0.3, 1.1]) tertile. Conclusions: In this prospective cohort study, we observed associations between two perfluoroalkyl substances and menstrual cycle length changes, and between select perfluoroalkyl substances and diminished fecundity at some (but not all) concentrations. See video abstract at, http://links.lww.com/EDE/B136. C1 [Lum, Kirsten J.; Sundaram, Rajeshwari; Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Rockville, MD USA. [Lum, Kirsten J.; Louis, Thomas A.] Johns Hopkins Univ, Dept Biostat, Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Barr, Dana B.] Emory Univ, Rollins Sch Publ Hlth, Dept Environm Hlth, Atlanta, GA 30322 USA. RP Lum, KJ (reprint author), Univ Penn, Dept Biostat & Epidemiol, Perelman Sch Med, 423 Guardian Dr,208 Blockley Hall, Philadelphia, PA 19104 USA. EM KLum@upenn.edu FU NIH, Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [N01-HD-3-3355, N01-HD-3-3356, N01-HD-3-3358]; Intramural Research Training Award from the NICHD; National Institute of Environmental Health Sciences [2T32ES012871] FX This research was funded by the NIH, Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [Contracts: N01-HD-3-3355, N01-HD-3-3356, N01-HD-3-3358]. K.J.L. was supported by an Intramural Research Training Award from the NICHD and a training grant from the National Institute of Environmental Health Sciences [Training Grant 2T32ES012871]. NR 42 TC 0 Z9 0 U1 6 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD JAN PY 2017 VL 28 IS 1 BP 90 EP 98 DI 10.1097/EDE.0000000000000552 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EF3VD UT WOS:000390252100023 PM 27541842 ER PT J AU Liu, Q Rossouw, JE Roberts, MB Liu, SM Johnson, KC Shikany, JM Manson, JE Tinker, LF Eaton, CB AF Liu, Qing Rossouw, Jacques E. Roberts, Mary B. Liu, Simin Johnson, Karen C. Shikany, James M. Manson, JoAnn E. Tinker, Lesley F. Eaton, Charles B. TI Theoretical Effects of Substituting Butter with Margarine on Risk of Cardiovascular Disease SO EPIDEMIOLOGY LA English DT Review ID CORONARY-HEART-DISEASE; DIETARY-FAT INTAKE; POSTMENOPAUSAL WOMEN; PROSPECTIVE COHORT; BREAST-CANCER; SATURATED FAT; SERUM-LIPIDS; TOTAL-ENERGY; PROTEIN; ACIDS AB Background: Several recent articles have called into question the deleterious effects of high animal fat diets due to mixed results from epidemiologic studies and the lack of clinical trial evidence in meta-analyses of dietary intervention trials. We were interested in examining the theoretical effects of substituting plant-based fats from different types of margarine for animal-based fat from butter on the risk of atherosclerosis-related cardiovascular disease (CVD). Methods: We prospectively studied 71,410 women, aged 50-79 years, and evaluated their risk for clinical myocardial infarction (MI), total coronary heart disease (CHD), ischemic stroke, and atherosclerosis-related CVD with an average of 13.2 years of follow-up. Butter and margarine intakes were obtained at baseline and year 3 by means of a validated food frequency questionnaire. Cox proportional hazards regression using a cumulative average diet method was used to estimate the theoretical effect of substituting 1 teaspoon/day of three types of margarine for the same amount of butter. Results: Substituting butter or stick margarine with tub margarine was associated with lower risk of MI (HRs = 0.95 and 0.91). Subgroup analyses, which evaluated these substitutions among participants with a single source of spreadable fat, showed stronger associations for MI (HRs = 0.92 and 0.87). Outcomes of total CHD, ischemic stroke, and atherosclerosis-related CVD showed wide confidence intervals but the same trends as the MI results. Conclusions: This theoretical dietary substitution analysis suggests that substituting butter and stick margarine with tub margarine when spreadable fats are eaten may be associated with reduced risk of myocardial infarction. C1 [Liu, Qing; Liu, Simin; Eaton, Charles B.] Brown Univ, Sch Publ Hlth, Dept Epidemiol, Providence, RI 02912 USA. [Liu, Qing; Roberts, Mary B.; Eaton, Charles B.] Mem Hosp Rhode Isl, Ctr Primary Care & Prevent, 111 Brewster St, Pawtucket, RI 02860 USA. [Rossouw, Jacques E.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Liu, Simin] Brown Univ, Dept Med, Alpert Sch Med, Providence, RI 02912 USA. [Johnson, Karen C.] Univ Tennessee, Hlth Sci Ctr, Memphis, TN USA. [Shikany, James M.] Univ Alabama Birmingham, Sch Med, Div Prevent Med, Birmingham, AL 35233 USA. [Manson, JoAnn E.] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. [Tinker, Lesley F.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Eaton, Charles B.] Brown Univ, Dept Family Med, Alpert Med Sch, Providence, RI 02912 USA. RP Eaton, CB (reprint author), Mem Hosp Rhode Isl, Ctr Primary Care & Prevent, 111 Brewster St, Pawtucket, RI 02860 USA. EM cbeaton51@gmail.com FU National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C] FX The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. NR 37 TC 0 Z9 0 U1 16 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD JAN PY 2017 VL 28 IS 1 BP 145 EP 156 DI 10.1097/EDE.0000000000000557 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EF3VD UT WOS:000390252100030 PM 27648593 ER PT J AU Marusak, HA Calhoun, VD Brown, S Crespo, LM Sala-Hamrick, K Gotlib, IH Thomason, ME AF Marusak, Hilary A. Calhoun, Vince D. Brown, Suzanne Crespo, Laura M. Sala-Hamrick, Kelsey Gotlib, Ian H. Thomason, Moriah E. TI Dynamic functional connectivity of neurocognitive networks in children SO HUMAN BRAIN MAPPING LA English DT Article DE resting-state; brain development; intrinsic connectivity; fMRI; intrinsic activity; independent component analysis; state variability; default mode network; salience network; central executive network ID DEFAULT NETWORK; RESTING-STATE; BRAIN NETWORKS; FMRI; MODE; TASK; ARCHITECTURE; ADOLESCENCE; RELEVANCE; TRACKING AB The human brain is highly dynamic, supporting a remarkable range of cognitive abilities that emerge over the course of development. While flexible and dynamic coordination between neural systems is firmly established for children, our understanding of brain functional organization in early life has been built largely on the implicit assumption that functional connectivity (FC) is static. Understanding the nature of dynamic neural interactions during development is a critical issue for cognitive neuroscience, with implications for neurodevelopmental pathologies that involve anomalies in brain connectivity. In this work, FC dynamics of neurocognitive networks in a sample of 146 youth from varied sociodemographic backgrounds were delineated. Independent component analysis, sliding time window correlation, and k-means clustering were applied to resting-state fMRI data. Results revealed six dynamic FC states that re-occur over time and that complement, but significantly extend, measures of static FC. Moreover, the occurrence and amount of time spent in specific FC states are related to the content of self-generated thought during the scan. Additionally, some connections are more variable over time than are others, including those between inferior parietal lobe and precuneus. These regions contribute to multiple networks and likely play a role in adaptive processes in childhood. Age-related increases in temporal variability of FC among neurocognitive networks were also found. Taken together, these findings lay the groundwork for understanding how variation in the developing chronnectome is related to risk for neurodevelopmental disorders. Understanding how brain systems reconfigure with development should provide insight into the ontogeny of complex, flexible cognitive processes. Hum Brain Mapp 38:97-108, 2017. (c) 2016 Wiley Periodicals, Inc. C1 [Marusak, Hilary A.] Wayne State Univ, Dept Pharm Practice, 259 Mack Ave,Suite 2190, Detroit, MI 48202 USA. [Calhoun, Vince D.] Mind Res Network, Albuquerque, NM USA. [Calhoun, Vince D.] Univ New Mexico, Dept Elect & Comp Engn, Albuquerque, NM 87131 USA. [Brown, Suzanne] Wayne State Univ, Sch Social Work, Detroit, MI USA. [Crespo, Laura M.; Sala-Hamrick, Kelsey] Wayne State Univ, Dept Psychol, 71 W Warren Ave, Detroit, MI 48202 USA. [Gotlib, Ian H.] Stanford Univ, Dept Psychol, Stanford, CA USA. [Thomason, Moriah E.] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Thomason, Moriah E.] Wayne State Univ, Sch Med, Dept Pediat, Detroit, MI 48201 USA. [Thomason, Moriah E.] Wayne State Univ, Merrill Palmer Skillman Inst Child & Family Dev, Detroit, MI USA. RP Marusak, HA (reprint author), Wayne State Univ, Dept Pharm Practice, 259 Mack Ave,Suite 2190, Detroit, MI 48202 USA. EM hmarusak@med.wayne.edu FU Merrill Palmer Skillman Institute; Department of Pediatrics, Wayne State University School of Medicine; NARSAD Young Investigator Award; NIEHS [P30ES020957, R21ES026022]; NIGMS [P20GM103472, R01EB020407]; NSF [1539067]; American Cancer Society [129368-PF-16-057-01-PCSM]; NIMH [R21 MH074849] FX Contract grant sponsors: The Merrill Palmer Skillman Institute and the Department of Pediatrics, Wayne State University School of Medicine, a NARSAD Young Investigator Award (MET), NIEHS awards P30ES020957 and R21ES026022 (MET), NIGMS awards P20GM103472 and R01EB020407 (VDC), NSF grant #1539067 (VDC), American Cancer Society award 129368-PF-16-057-01-PCSM (HAM), and NIMH R21 MH074849 (IHG) NR 46 TC 0 Z9 0 U1 10 U2 10 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 JAN PY 2017 VL 38 IS 1 BP 97 EP 108 DI 10.1002/hbm.23346 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EF3XY UT WOS:000390259700008 PM 27534733 ER PT J AU de Jong, LW Vidal, JS Forsberg, LE Zijdenbos, AP Haight, T Sigurdsson, S Gudnason, V van Buchem, MA Launer, LJ AF de Jong, Laura W. Vidal, Jean-Sebastien Forsberg, Lars E. Zijdenbos, Alex P. Haight, Thaddeus Sigurdsson, Sigurdur Gudnason, Vilmundur van Buchem, Mark A. Launer, Lenore J. CA Alzheimer's Dis Neuroimaging TI Allometric scaling of brain regions to intra-cranial volume: An epidemiological MRI study SO HUMAN BRAIN MAPPING LA English DT Article DE MRI; allometry; intra-cranial volume; brain; cortex; striatum; white matter; thalamus; AGES-Reykjavik; ADNI; CARDIA ID CORTICAL SURFACE; CEREBRAL-CORTEX; SIZE; IMAGES; SHAPE; SEGMENTATION; ADJUSTMENT; REYKJAVIK; MAMMALS; AGE AB There is growing evidence that sub-structures of the brain scale allometrically to total brain size, that is, in a non-proportional and non-linear way. Here, scaling of different volumes of interest (VOI) to intra-cranial volume (ICV) was examined. It was assessed whether scaling was allometric or isometric and whether scaling coefficients significantly differed from each other. We also tested to what extent allometric scaling of VOI was introduced by the automated segmentation technique. Furthermore, reproducibility of allometric scaling was studied different age groups and study populations. Study samples included samples of cognitively healthy adults from the community-based Age Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik Study) (N=3,883), the Coronary Artery Risk Development in Young Adults Study (CARDIA) (N =709), and the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N=180). Data encompassed participants with different age, ethnicity, risk factor profile, and ICV and VOI obtained with different automated MRI segmentation techniques. Our analysis showed that (1) allometric scaling is a trait of all parts of the brain, (2) scaling of neo-cortical white matter, neo-cortical gray matter, and deep gray matter structures including the cerebellum are significantly different from each other, and (3) allometric scaling of brain structures cannot solely be explained by age-associated atrophy, sex, ethnicity, or a systematic bias from study-specific segmentation algorithm, but appears to be a true feature of brain geometry. Hum Brain Mapp 38:151-164, 2017. (c) 2016 Wiley Periodicals, Inc. C1 [de Jong, Laura W.; van Buchem, Mark A.] Leiden Univ, Dept Radiol, Med Ctr, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands. [Vidal, Jean-Sebastien] Broca Hosp, AP HP, Dept Geriatr, F-75013 Paris, France. [Vidal, Jean-Sebastien] Univ Paris 05, Sorbonne Paris 5, EA 4468, F-75006 Paris, France. [Forsberg, Lars E.] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Zijdenbos, Alex P.] Biospective Inc, Montreal, PQ, Canada. [Haight, Thaddeus; Launer, Lenore J.] NIA, Intramural Res Program, Bethesda, MD 20892 USA. [Sigurdsson, Sigurdur; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. RP de Jong, LW (reprint author), Leiden Univ, Dept Radiol, Med Ctr, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands. EM L.W.de_Jong@lumc.nl FU National Institutes of Health [N01-AG-1-2100]; National Institute on Aging Intramural Research Program; Hjartavernd (Icelandic Heart Association); Althingi (Icelandic Parliament); Netherlands Organisation for Health Research and Development (AGIKO) [92003536]; Dutch Genomics Initiative [NCHA 050-060-810] FX Contract grant sponsor: This work was supported by the National Institutes of Health (N01-AG-1-2100), National Institute on Aging Intramural Research Program, the Hjartavernd (Icelandic Heart Association), and the Althingi (Icelandic Parliament). Dr. de Jong is supported by the Netherlands Organisation for Health Research and Development (AGIKO grant number 92003536). Prof van Buchem is supported by an unrestricted grant from the Dutch Genomics Initiative (NCHA 050-060-810). Drs. Vidal, Zijdenbos, Gudnason and Launer, and Mr. Sigurdsson report no disclosures. NR 29 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 JAN PY 2017 VL 38 IS 1 BP 151 EP 164 DI 10.1002/hbm.23351 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EF3XY UT WOS:000390259700012 PM 27557999 ER PT J AU Mensah, GA Galis, ZS Fine, LJ Garcia, ME Levy, DF Gibbons, GH AF Mensah, George A. Galis, Zorina S. Fine, Lawrence J. Garcia, Melissa E. Levy, Daniel F. Gibbons, Gary H. TI Building on a Legacy of Hypertension Research: Charting Our Future Together SO HYPERTENSION LA English DT Review ID LEFT-VENTRICULAR HYPERTROPHY; GENOME-WIDE ASSOCIATION; INSTITUTE WORKING GROUP; BLOOD-PRESSURE CONTROL; NATIONAL HEART; INCIDENT HYPERTENSION; NOBEL LECTURE; LUNG; DISEASE; RISK C1 [Mensah, George A.; Galis, Zorina S.; Fine, Lawrence J.; Garcia, Melissa E.; Levy, Daniel F.; Gibbons, Gary H.] NHLBI, Bldg 31,Room 5A52,31 Ctr Dr MSC 2486, Bethesda, MD 20892 USA. RP Gibbons, GH (reprint author), NHLBI, Bldg 31,Room 5A52,31 Ctr Dr MSC 2486, Bethesda, MD 20892 USA. EM Gary.Gibbons@nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 55 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 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD JAN PY 2017 VL 69 IS 1 BP 5 EP 10 DI 10.1161/HYPERTENSIONAHA.116.06582 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EF5IA UT WOS:000390362700002 PM 27849567 ER PT J AU Piknova, B Schechter, AN AF Piknova, Barbora Schechter, Alan N. TI Acid Test for Nitrite Pharmacology SO HYPERTENSION LA English DT Editorial Material C1 [Piknova, Barbora; Schechter, Alan N.] NIDDK, Mol Med Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 9N312, Bethesda, MD 20892 USA. RP Piknova, B; Schechter, AN (reprint author), NIDDK, Mol Med Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 9N312, Bethesda, MD 20892 USA. EM piknovab@niddk.nih.gov; aschecht@helix.nih.gov FU Intramural NIH HHS [Z01 DK025104-02] NR 11 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 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD JAN PY 2017 VL 69 IS 1 BP 13 EP 14 DI 10.1161/HYPERTENSIONAHA.116.08222 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EF5IA UT WOS:000390362700004 PM 27802420 ER PT J AU Drawz, PE Pajewski, NM Bates, JT Bello, NA Cushman, WC Dwyer, JP Fine, LJ Goff, DC Haley, WE Krousel-Wood, M McWilliams, A Rifkin, DE Slinin, Y Taylor, A Townsend, R Wall, B Wright, JT Rahman, M AF Drawz, Paul E. Pajewski, Nicholas M. Bates, Jeffrey T. Bello, Natalie A. Cushman, William C. Dwyer, Jamie P. Fine, Lawrence J. Goff, David C., Jr. Haley, William E. Krousel-Wood, Marie McWilliams, Andrew Rifkin, Dena E. Slinin, Yelena Taylor, Addison Townsend, Raymond Wall, Barry Wright, Jackson T. Rahman, Mahboob TI Effect of Intensive Versus Standard Clinic-Based Hypertension Management on Ambulatory Blood Pressure: Results From the SPRINT (Systolic Blood Pressure Intervention Trial) Ambulatory Blood Pressure Study SO HYPERTENSION LA English DT Article DE blood pressure; circadian rhythm; goals; hypertension; stroke ID LEFT-VENTRICULAR HYPERTROPHY; SERVICES TASK-FORCE; RESISTANT HYPERTENSION; MASKED HYPERTENSION; EUROPEAN-SOCIETY; PROGNOSTIC VALUE; CKD; VARIABILITY; RECOMMENDATIONS; POPULATION AB The effect of clinic-based intensive hypertension treatment on ambulatory blood pressure (BP) is unknown. The goal of the SPRINT (Systolic Blood Pressure Intervention Trial) ambulatory BP ancillary study was to evaluate the effect of intensive versus standard clinic-based BP targets on ambulatory BP. Ambulatory BP was obtained within 3 weeks of the 27-month study visit in 897 SPRINT participants. Intensive treatment resulted in lower clinic systolic BP (mean difference between groups=16.0 mmHg; 95% confidence interval, 14.1-17.8 mmHg), nighttime systolic BP (mean difference=9.6 mmHg; 95% confidence interval, 7.7-11.5 mmHg), daytime systolic BP (mean difference=12.3 mmHg; 95% confidence interval, 10.6-13.9 mmHg), and 24-hour systolic BP (mean difference=11.2 mmHg; 95% confidence interval, 9.7-12.8 mmHg). The night/day systolic BP ratio was similar between the intensive (0.920.09) and standard-treatment groups (0.91 +/- 0.09). There was considerable lack of agreement within participants between clinic systolic BP and daytime ambulatory systolic BP with wide limits of agreement on Bland-Altman plots. In conclusion, targeting a systolic BP of <120 mmHg, when compared with <140 mmHg, resulted in lower nighttime, daytime, and 24-hour systolic BP, but did not change the night/day systolic BP ratio. Ambulatory BP monitoring may be required to assess the effect of targeted hypertension therapy on out of office BP. Further studies are needed to assess whether targeting hypertension therapy based on ambulatory BP improves clinical outcomes. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01835249. C1 [Drawz, Paul E.] Univ Minnesota, Div Renal Dis & Hypertens, 717 Delaware St SE,Suite 353, Minneapolis, MN 55414 USA. [Pajewski, Nicholas M.] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA. [Bates, Jeffrey T.; Taylor, Addison] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Bates, Jeffrey T.] Baylor Coll Med, Div Gen Internal Med, Houston, TX 77030 USA. [Bello, Natalie A.] Cornell Univ, Med Ctr, Div Cardiol, New York, NY 10021 USA. [Cushman, William C.] Vet Affairs Med Ctr, Dept Med, Memphis, TN USA. [Dwyer, Jamie P.] Vanderbilt Univ, Med Ctr, Div Nephrol & Hypertens, Nashville, TN USA. [Fine, Lawrence J.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. [Goff, David C., Jr.] Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA. [Haley, William E.] Mayo Clin, Div Nephrol & Hypertens, Jacksonville, FL 32224 USA. [Krousel-Wood, Marie] Tulane Univ, Dept Med, Ochsner Hlth Syst, New Orleans, LA 70118 USA. [Krousel-Wood, Marie] Tulane Univ, Dept Epidemiol, Ochsner Hlth Syst, New Orleans, LA 70118 USA. [McWilliams, Andrew] Carolinas HealthCare Syst, Dept Family Med, Charlotte, NC USA. [Rifkin, Dena E.] Vet Affairs Hlth Syst, Div Nephrol, San Diego, CA USA. [Rifkin, Dena E.] Univ Calif San Diego, San Diego, CA 92103 USA. [Slinin, Yelena] Vet Affairs Hlth Syst, Div Nephrol, Minneapolis, MN USA. [Slinin, Yelena] Univ Minnesota, Minneapolis, MN USA. [Taylor, Addison] Baylor Coll Med, Div Hypertens & Clin Pharmacol, Houston, TX 77030 USA. [Townsend, Raymond] Univ Penn, Med Ctr, Nephrol & Hypertens, Philadelphia, PA 19104 USA. [Wall, Barry] Vet Affairs Med Ctr, Memphis, TN USA. [Wall, Barry] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Wright, Jackson T.] Case Western Reserve Univ, Univ Hosp Cleveland Med Ctr, Div Nephrol & Hypertens, Cleveland, OH 44106 USA. [Rahman, Mahboob] Case Western Reserve Univ, Div Nephrol & Hypertens, Univ Hosp Cleveland Med Ctr, Louis Stokes Cleveland VAMC, Cleveland, OH 44106 USA. RP Drawz, PE (reprint author), Univ Minnesota, Div Renal Dis & Hypertens, 717 Delaware St SE,Suite 353, Minneapolis, MN 55414 USA. EM draw0003@umn.edu FU National Institutes of Health (NIH) [R03DK100530, K12HD043451, K23DK091521, R03DK105314]; University of Minnesota Chronic Kidney Disease Research Fund; Federal funds from the NIH; National Heart, Lung, and Blood Institute (NHLBI); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institute on Aging (NIA); National Institute of Neurological Disorders and Stroke (NINDS) [HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, HHSN2682009 00049C]; Clinical and Translational Science Awards - National Center for Advancing Translational Sciences (NCATS)-Case Western Reserve University [UL1TR000439]; Ohio State University [UL1RR025755]; University of Pennsylvania [UL1RR024134, UL1TR000003]; University of Illinois [UL1TR000050]; University of Pittsburgh [UL1TR000005]; University of Texas Southwestern [9U54TR000017-06]; University of Utah [UL1TR000105-05]; Vanderbilt University [UL1TR000445]; George Washington University [UL1TR000075]; University of CA, Davis [UL1TR000002]; University of Florida [UL1TR000064]; University of Michigan [UL1TR000433]; Tulane University Center of Biomedical Research Excellence Award, National Institute of General Medical Sciences [P30GM103337]; [A-HL-13-002-001]; [UL1RR025771]; [UL1TR000093]; [UL1RR025752]; [UL1TR000073]; [UL1TR001064] FX The SPRINT ambulatory blood pressure ancillary study was supported by grants R03DK100530 (P.E. Drawz), K12HD043451 (M. Krousel-Wood), K23DK091521 (D.E. Rifkin), and R03DK105314 (D.E. Rifkin) from the National Institutes of Health (NIH) and funds from the University of Minnesota Chronic Kidney Disease Research Fund. The SPRINT (Systolic Blood Pressure Intervention Trial) is funded with Federal funds from the NIH, including the National Heart, Lung, and Blood Institute (NHLBI), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute on Aging (NIA), and the National Institute of Neurological Disorders and Stroke (NINDS), under Contract Numbers HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, HHSN2682009 00049C, and Inter-Agency Agreement Number A-HL-13-002-001. It was also supported in part with resources and use of facilities through the Department of Veterans Affairs. The SPRINT investigators acknowledge the contribution of study medications (azilsartan and azilsartan combined with chlorthalidone) from Takeda Pharmaceuticals International, Inc. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, NHLBI, the US Department of Veterans Affairs, the US Department of Health and Human Services, the University of Minnesota, or the United States Government. We also acknowledge the support from the following: Clinical and Translational Science Awards funded by National Center for Advancing Translational Sciences (NCATS)-Case Western Reserve University: UL1TR000439; Ohio State University: UL1RR025755; University of Pennsylvania: UL1RR024134 and UL1TR000003; Boston: UL1RR025771; Stanford: UL1TR000093; Tufts: UL1RR025752, UL1TR000073, and UL1TR001064; University of Illinois: UL1TR000050; University of Pittsburgh: UL1TR000005; University of Texas Southwestern: 9U54TR000017-06; University of Utah: UL1TR000105-05; Vanderbilt University: UL1TR000445; George Washington University: UL1TR000075; University of CA, Davis: UL1TR000002; University of Florida: UL1TR000064; University of Michigan: UL1TR000433; and Tulane University: P30GM103337 Center of Biomedical Research Excellence Award, National Institute of General Medical Sciences. All components of the SPRINT study protocol were designed and implemented by the investigators. The investigative team collected, analyzed, and interpreted the data. All aspects of article writing and revision were performed by the coauthors. Scientists at the National Institutes of Health participated in the design of the study and as a group had 1 vote on the steering committee of the trial. NR 30 TC 5 Z9 5 U1 3 U2 3 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 JAN PY 2017 VL 69 IS 1 BP 42 EP 50 DI 10.1161/HYPERTENSIONAHA.116.08076 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EF5IA UT WOS:000390362700009 PM 27849563 ER PT J AU Varma, VR Watts, A AF Varma, Vijay R. Watts, Amber TI Daily Physical Activity Patterns During the Early Stage of Alzheimer's Disease SO JOURNAL OF ALZHEIMERS DISEASE LA English DT Article DE Alzheimer's disease; motor activity; physical conditioning; physical exertion; physical fitness ID MILD COGNITIVE IMPAIRMENT; OLDER-ADULTS; CIRCADIAN-RHYTHMS; SEDENTARY BEHAVIOR; WALKING ACTIVITY; MOTOR FUNCTION; DECLINE; HEALTH; LIFE; AGE AB Background: Alzheimer's disease (AD) is a neurodegenerative disease that results in severe disability. Very few studies have explored changes in daily physical activity patterns during early stages of AD when components of physical function and mobility may be preserved. Objective: Our study explored differences in daily physical activity profiles, independent of the effects of non-cognitive factors including physical function and age, among individuals with mild AD compared to controls. Methods: Patients with mild AD and controls (n = 92) recruited from the University of Kansas Alzheimer's Disease Center Registry, wore the Actigraph GT3X(+) for seven days, and provided objective physical function (VO2 max) and mobility data. Using multivariate linear regression, we explored whether individuals with mild AD had different daily average and diurnal physical activity patterns compared to controls independent of non-cognitive factors that may affect physical activity, including physical function and mobility. Results: We found that mild AD was associated with less moderate-intensity physical activity (p < 0.05), lower peak activity (p < 0.01), and lower physical activity complexity (p < 0.05) particularly during the morning. MildADwas not associated with greater sedentary activity or less lower-intensity physical activity across the day after adjusting for non-cognitive covariates. Conclusions: These findings suggest that factors independent of physical capacity and mobility may drive declines in moderate-intensity physical activity, and not lower-intensity or sedentary activity, during the early stage of AD. This underscores the importance of a better mechanistic understanding of how cognitive decline and AD pathology impact physical activity. Findings emphasize the potential value of designing and testing time-of-day specific physical activity interventions targeting individuals in the early stages of AD, prior to significant declines in mobility and physical function. C1 [Varma, Vijay R.] Natl Inst Aging NIA, Natl Inst Hlth NIH, Clin & Translat Neuroscience Unit, Lab Behav Neuroscience, Baltimore, MD 21224 USA. [Watts, Amber] Univ Kansas, Dept Clin Psychol, Lawrence, KS USA. RP Varma, VR (reprint author), Natl Inst Aging NIA, Natl Inst Hlth NIH, Clin & Translat Neuroscience Unit, Lab Behav Neuroscience, Baltimore, MD 21224 USA. EM vijay.varma01@gmail.com FU National Institute on Aging of the National Institutes of Health (NIA) [5P30AG035982-3]; National Center for Advancing Translational Sciences [UL1TR000001] FX This work was supported by the National Institute on Aging of the National Institutes of Health (NIA 5P30AG035982-3) and a Clinical Translational Science Award grant from the National Center for Advancing Translational Sciences awarded to the University of Kansas Medical Center for Frontiers: The Heartland Institute for Clinical and Translational Research (#UL1TR000001; formerly #UL1RR033179). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or NCATS. NR 50 TC 0 Z9 0 U1 11 U2 11 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 1387-2877 EI 1875-8908 J9 J ALZHEIMERS DIS JI J. Alzheimers Dis. PY 2017 VL 55 IS 2 BP 659 EP 667 DI 10.3233/JAD-160582 PG 9 WC Neurosciences SC Neurosciences & Neurology GA EE6CG UT WOS:000389695700019 PM 27716669 ER PT J AU Lopez, KC Leary, JB Pham, DL Chou, YY Dsurney, J Chan, L AF Lopez, Katherine C. Leary, Jacob B. Pham, Dzung L. Chou, Yi-Yu Dsurney, John Chan, Leighton TI Brain Volume, Connectivity, and Neuropsychological Performance in Mild Traumatic Brain Injury: The Impact of Post-Traumatic Stress Disorder Symptoms SO JOURNAL OF NEUROTRAUMA LA English DT Article DE DTI; head injury; learning; memory network; white matter integrity ID MEMORY; VETERANS; PTSD; METAANALYSIS; IRAQ; TBI; MRI; US AB Post-traumatic stress disorder (PTSD) is commonly associated with mild traumatic brain injury (mTBI). To better understand their relationship, we examined neuroanatomical structures and neuropsychological performance in a sample of individuals with mTBI, with and without PTSD symptoms. Thirty-nine subjects with mTBI were dichotomized into those with (n = 12) and without (n = 27) significant PTSD symptoms based on scores on the PTSD Checklist. Using a region-of-interest approach, fronto-temporal volumes, fiber bundles obtained by diffusion tensor imaging, and neuropsychological scores were compared between the two groups. After controlling for total intracranial volume and age, subjects with mTBI and PTSD symptoms exhibited volumetric differences in the entorhinal cortex, an area associated with memory networks, relative to mTBI-only patients (F = 4.28; p = 0.046). Additionally, subjects with PTSD symptoms showed reduced white matter integrity in the right cingulum bundle (axial diffusivity, F = 6.04; p = 0.020). Accompanying these structural alterations, mTBI and PTSD subjects also showed impaired performance in encoding (F = 5.98; p = 0.019) and retrieval (F = 7.32; p = 0.010) phases of list learning and in tests of processing speed (Wechsler Adult Intelligence Scale Processing Speed Index, F = 12.23; p = 0.001; Trail Making Test A, F = 5.56; p = 0.024). Increased volume and white matter disruptions in these areas, commonly associated with memory functions, may be related to functional disturbances during cognitively demanding tasks. Differences in brain volume and white matter integrity between mTBI subjects and those with mTBI and co-morbid PTSD symptoms point to neuroanatomical differences that may underlie poorer recovery of mTBI subjects who experience PTSD symptoms. These findings support theoretical models of PTSD and its relationship to learning deficits. C1 [Lopez, Katherine C.; Pham, Dzung L.; Chou, Yi-Yu; Dsurney, John; Chan, Leighton] NIH, Ctr Neurosci & Regenerat Med, Bldg 10, Bethesda, MD 20892 USA. [Leary, Jacob B.; Chan, Leighton] NIH, Ctr Clin, Dept Rehabil Med, Bethesda, MD 20892 USA. RP Dsurney, J (reprint author), NIH, Ctr Neurosci & Regenerat Med, Dept Rehabil Med, 10 Ctr Dr,Room 1-1468,MSC1604, Bethesda, MD 20892 USA. EM john.dsurney@nih.gov FU Department of Defense (Center for Neuroscience and Regenerative Medicine); National Institutes of Health FX This work was supported by the Department of Defense (Center for Neuroscience and Regenerative Medicine) and the National Institutes of Health Intramural Research Program. NR 42 TC 0 Z9 0 U1 16 U2 16 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JAN 1 PY 2017 VL 34 IS 1 BP 16 EP 22 DI 10.1089/neu.2015.4323 PG 7 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA EF6DE UT WOS:000390420100003 PM 26942337 ER PT J AU Ricciardi, MC Bokkers, RPH Butman, JA Hammoud, DA Pham, DL Warach, S Latour, LL AF Ricciardi, Maria Chiara Bokkers, Reinoud P. H. Butman, John A. Hammoud, Dima A. Pham, Dzung L. Warach, Steven Latour, Lawrence L. TI Trauma-Specific Brain Abnormalities in Suspected Mild Traumatic Brain Injury Patients Identified in the First 48 Hours after Injury: A Blinded Magnetic Resonance Imaging Comparative Study Including Suspected Acute Minor Stroke Patients SO JOURNAL OF NEUROTRAUMA LA English DT Article DE CT scanning; MRI; TBI ID DIFFUSE AXONAL INJURY; HEAD-INJURY; CT; LESIONS AB We assessed the utility of a brief MRI protocol, appropriate for the acute setting, to detect acute traumatic brain injury (TBI) in patients with suspected mild TBI (mTBI) and distinguish traumatic from nontraumatic brain injury by comparing trauma with nontrauma patients. Twenty-two patients with suspected mTBI were included in this exploratory study over a period of 9 months. Median time from injury to MR scanning was 5.4 h (interquartile range 3.6-15.3). To determine the specificity of certain findings for TBI, 61 patients presenting with suspected minor acute stroke were included as a comparative group using the same MRI methods. A selected series of MRI sequences (diffusion-weighted imaging, fluid attenuated inversion recovery [FLAIR], and T2* weighted) were independently evaluated by two neuroradiologists blinded to clinical diagnosis, for presence of specific findings. In a separate session, all cases in which at least one MRI sequence above was positive were classified as TBI, stroke, or indeterminate. Intracranial MRI abnormalities were observed in 47 (57%) of the 83 studied patients. Based on findings on MRI, 12 (55%) of 22 suspected mTBI patients were classified as having traumatic injury. Nine (47%) of the 19 suspected mTBI patients with a negative CT had findings on MRI. Abnormalities on MRI consistent with trauma were observed most frequently on postcontrast FLAIR (83%) and T2*-weighted (58%) sequences. We demonstrated the ability of a fast MRI protocol to identify trauma-related abnormalities not seen on CT, and differentiate acute trauma from nonspecific chronic disease in a blinded cohort of mTBI patients. C1 [Ricciardi, Maria Chiara; Latour, Lawrence L.] Natl Inst Neurol Disorders & Stroke, Stroke Diagnost & Therapeut Sect, Bethesda, MD USA. [Butman, John A.] NIH, Dept Diagnost Radiol, Bethesda, MD USA. [Hammoud, Dima A.] NIH, Ctr Clin, Ctr Infect Dis Imaging CIDI Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Ricciardi, Maria Chiara; Butman, John A.; Pham, Dzung L.; Latour, Lawrence L.] Ctr Neurosci & Regenerat Med, Bethesda, MD USA. [Bokkers, Reinoud P. H.] Univ Groningen, Univ Med Ctr Groningen, Dept Radiol, Groningen, Netherlands. [Warach, Steven] Univ Texas Austin, Stroke Inst, Seton Dell Med Sch, Austin, TX 78712 USA. RP Latour, LL (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, 10 Ctr Dr,Bldg 10,Room B1D733, Bethesda, MD 20892 USA. EM LatourL@ninds.nih.gov FU Intramural Research Program at NINDS; Department of Defense in the Center for Neuroscience and Regenerative Medicine; Dutch Heart Foundation [2013T047] FX We are grateful to the patients and their families without whom this research would not be possible. We wish to acknowledge the staff at Suburban Hospital, and the Investigators of the Center for Neuroscience and Regenerative Medicine THINC Study. Support for this work included funding from the Intramural Research Program at NINDS and the Department of Defense in the Center for Neuroscience and Regenerative Medicine. R. P. H. Bokkers receives support from the Dutch Heart Foundation (Grant 2013T047). The contents of this article are solely the responsibility of the authors and do not represent the official views of the Department of Defense or the Center for Neuroscience and Regenerative Medicine. NR 27 TC 1 Z9 1 U1 4 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JAN 1 PY 2017 VL 34 IS 1 BP 23 EP 30 DI 10.1089/neu.2015.4338 PG 8 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA EF6DE UT WOS:000390420100004 ER PT J AU Bogoslovsky, T Wilson, D Chen, Y Hanlon, D Gill, J Jeromin, A Song, LN Moore, C Gong, YH Kenney, K Diaz-Arrastia, R AF Bogoslovsky, Tanya Wilson, David Chen, Yao Hanlon, David Gill, Jessica Jeromin, Andreas Song, Linan Moore, Carol Gong, Yunhua Kenney, Kimbra Diaz-Arrastia, Ramon TI Increases of Plasma Levels of Glial Fibrillary Acidic Protein, Tau, and Amyloid beta up to 90 Days after Traumatic Brain Injury SO JOURNAL OF NEUROTRAUMA LA English DT Article DE diagnostic and prognostic biomarkers; GFAP; highly sensitive immunoassays; TBI; total tau ID C-TERMINAL HYDROLASE-L1; GLASGOW COMA SCALE; CEREBROSPINAL-FLUID; ALZHEIMERS-DISEASE; ELEVATED LEVELS; CLEAVED-TAU; SERUM; BIOMARKERS; CSF; MILD AB Glial fibrillary acidic protein (GFAP), microtubule-associated protein tau, and amyloid beta peptide (A beta 42) have been proposed as diagnostic and prognostic biomarkers in traumatic brain injury (TBI). Single molecule array (Simoa) is a novel technology that employs highly sensitive immunoassays for accurate measurements of candidate biomarkers found at low concentration in biological fluids. Our objective was to trace the trajectory of tau, GFAP, and A beta 42 levels in plasma from the acute through subacute stages after TBI, compared with controls. Samples from 34 TBI subjects enrolled in the Citicoline Brain Injury Treatment Trial (COBRIT) were studied. Injury severity was assessed by Glasgow Coma Scale (GCS) and admission CT. Glasgow Outcome Scale Extended (GOSE) was assessed 6 months after injury. Plasma was collected within 24 h (Day 0), and 30 and 90 days after the TBI. Plasma collected from 69 healthy volunteers was used for comparison. At every time point, increases were noted in plasma GFAP (p < 0.0001 for all comparisons), tau (p < 0.0001, p < 0.0001, and p = 0.0044, at Days 0, 30, and 90, respectively), and A beta 42 (p < 0.001, p < 0.0001, and p = 0.0203, respectively) in TBI cases compared with controls. The levels were maximal at Day 0 for GFAP and tau and at Day 30 for A beta 42. Area under curve (AUC) analyses for Day 0 GFAP and tau were excellent for discrimination of complicated mild TBI (cmTBI) from controls (0.936 and 0.901, correspondingly). Discriminant component analysis (DCA) for all three biomarkers at Days 0 and 30 differentiated controls from cmTBI (91.1% and 89.7% correctly classified, at each time point). Duration of post-traumatic amnesia (PTA) correlated weakly with tau levels at 30 days (Spearman's r = 0.40; 95% CI 0.0003-0.60, p = 0.044). The Marshall CT Grade on admission correlated weakly with Day 30 tau levels (Spearman's r = 0.41; 95% CI 0.04-0.68, p = 0.027). Day 30A beta 42 correlated with GOSE (standardized beta-0.486, p = 0.042). GFAP, tau and A beta 42 were increased up to 90 days after TBI compared with controls. Total tau levels correlated with clinical and radiological variables of TBI severity. Plasma A beta 42 correlated with clinical outcome. Combination of all three biomarkers at Days 0 and 30 can be used to differentiate controls from cmTBI populations, and may be useful as biomarkers of TBI in both acute and subacute phases. C1 [Bogoslovsky, Tanya; Gill, Jessica; Moore, Carol; Gong, Yunhua; Kenney, Kimbra; Diaz-Arrastia, Ramon] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, 12725 Twinbrook Pkwy, Rockville, MD 20852 USA. [Wilson, David; Chen, Yao; Hanlon, David; Jeromin, Andreas; Song, Linan] Quanterix Inc, Lexington, MA USA. [Gill, Jessica] NINR, NIH, Bethesda, MD 20892 USA. RP Bogoslovsky, T (reprint author), Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, 12725 Twinbrook Pkwy, Rockville, MD 20852 USA. EM tanya.bogoslovsky.ctr@usuhs.edu FU Center for Neuroscience and Regenerative Medicine (CNRM), GE/NFL TBI Award [U01 HD 42652] FX This work was supported by the Center for Neuroscience and Regenerative Medicine (CNRM), GE/NFL TBI Award, U01 HD 42652. NR 45 TC 1 Z9 1 U1 6 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JAN 1 PY 2017 VL 34 IS 1 BP 66 EP 73 DI 10.1089/neu.2015.4333 PG 8 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA EF6DE UT WOS:000390420100009 PM 27312416 ER PT J AU Tu, TW Lescher, JD Williams, RA Jikaria, N Turtzo, LC Frank, JA AF Tu, Tsang-Wei Lescher, Jacob D. Williams, Rashida A. Jikaria, Neekita Turtzo, L. Christine Frank, Joseph A. TI Abnormal Injury Response in Spontaneous Mild Ventriculomegaly Wistar Rat Brains: A Pathological Correlation Study of Diffusion Tensor and Magnetization Transfer Imaging in Mild Traumatic Brain Injury SO JOURNAL OF NEUROTRAUMA LA English DT Article DE animal studies; DTI; model of injury; rats; TBI ID NEONATAL HYDROCEPHALUS; CORPUS-CALLOSUM; REACTIVE ASTROCYTOSIS; INFLAMMATION; EDEMA; MODEL; PATHOPHYSIOLOGY; AQUAPORIN-4; DYSGENESIS; AGENESIS AB Spontaneous mild ventriculomegaly (MVM) was previously reported in similar to 43% of Wistar rats in association with vascular anomalies without phenotypic manifestation. This mild traumatic brain injury (TBI) weight drop model study investigates whether MVM rats (n = 15) have different injury responses that could inadvertently complicate the interpretation of imaging studies compared with normal rats (n = 15). Quantitative MRI, including diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI), and immunohistochemistry (IHC) analysis were used to examine the injury pattern up to 8 days post-injury in MVM and normal rats. Prior to injury, the MVM brain showed significant higher mean diffusivity, axial diffusivity, and radial diffusivity, and lower fractional anisotropy (FA) and magnetization transfer ratio (MTR) in the corpus callosum than normal brain (p < 0.05). Following TBI, normal brains exhibited significant decreases of FA in the corpus callosum, whereas MVM brains demonstrated insignificant changes in FA, suggesting less axonal injury. At day 8 after mild TBI, MTR of the normal brains significantly decreased whereas the MTR of the MVM brains significantly increased. IHC staining substantiated the MRI findings, demonstrating limited axonal injury with significant increase of microgliosis and astrogliosis in MVM brain compared with normal animals. The radiological-pathological correlation data showed that both DTI and MTI were sensitive in detecting mild diffuse brain injury, although DTI metrics were more specific in correlating with histologically identified pathologies. Compared with the higher correlation levels reflecting axonal injury pathology in the normal rat mild TBI, the DTI and MTR metrics were more affected by the increased inflammation in the MVM rat mild TBI. Because MVM Wistar rats appear normal, there was a need to screen rats prior to TBI research to rule out the presence of ventriculomegaly, which may complicate the interpretation of imaging and IHC observations. C1 [Tu, Tsang-Wei; Lescher, Jacob D.; Williams, Rashida A.; Jikaria, Neekita; Frank, Joseph A.] NIH, Ctr Clin, Frank Lab Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Turtzo, L. Christine] NIH, Acute Studies Core, Natl Inst Neurol Disorders & Stroke, Bldg 10, Bethesda, MD 20892 USA. [Frank, Joseph A.] NIH, Natl Inst Biomed Imaging & Bioengn, Bldg 10, Bethesda, MD 20892 USA. RP Tu, TW (reprint author), NIH, Radiol & Imaging Sci, Ctr Clin, USA Bldg 10,RM B1N256,10 Ctr Dr,MSC 1074, Bethesda, MD 20892 USA. EM tut@cc.nih.gov FU Department of Defense through the Center for Neuroscience and Regenerative Medicine (Henry M. Jackson Foundation) [300604-8.01-60855, 305500-8.01-60855]; Intramural Research Programs of the Clinical Center at the National Institutes of Health; National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health FX This work was supported by funding from the Department of Defense through the Center for Neuroscience and Regenerative Medicine (Henry M. Jackson Foundation Awards #300604-8.01-60855 and #305500-8.01-60855) and from the Intramural Research Programs of the Clinical Center and of the National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health. NR 37 TC 0 Z9 0 U1 2 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD JAN 1 PY 2017 VL 34 IS 1 BP 248 EP 256 DI 10.1089/neu.2015.4355 PG 9 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA EF6DE UT WOS:000390420100026 PM 26905805 ER PT J AU Kuban, KCK Joseph, RM O'Shea, TM Heeren, T Fichorova, RN Douglass, L Jara, H Frazier, JA Hirtz, D Rollins, JV Paneth, N AF Kuban, Karl C. K. Joseph, Robert M. O'Shea, Thomas M. Heeren, Timothy Fichorova, Raina N. Douglass, Laurie Jara, Hernan Frazier, Jean A. Hirtz, Deborah Rollins, Julie Vanier Paneth, Nigel CA Extremely Low Gestational Age TI Circulating Inflammatory-Associated Proteins in the First Month of Life and Cognitive Impairment at Age 10 Years in Children Born Extremely Preterm SO JOURNAL OF PEDIATRICS LA English DT Article ID LOW-BIRTH-WEIGHT; TRAUMATIC BRAIN-INJURY; WHITE-MATTER DAMAGE; SYSTEMIC INFLAMMATION; GESTATIONAL-AGE; DEVELOPMENTAL-DISABILITY; IMMUNE-RESPONSE; ISCHEMIC-STROKE; NEONATAL BRAIN; CELL-DEATH AB Objectives To evaluate whether in children born extremely preterm, indicators of sustained systemic inflammation in the first month of life are associated with cognitive impairment at school age. Study design A total of 873 of 966 eligible children previously enrolled in the multicenter Extremely Low Gestational Age Newborn Study from 2002 to 2004 were evaluated at age 10 years. We analyzed the relationship between elevated blood concentrations of inflammation-associated proteins in the first 2 weeks ("early elevations"; n = 812) and the third and fourth week ("late elevations"; n = 532) of life with neurocognition. Results Early elevations of C-reactive protein, tumor necrosis factor-alpha, interleukin (IL)-8, intercellular adhesion molecule (ICAM)-1, and erythropoietin were associated with IQ values >2 SD below the expected mean (ORs: 2.0-2.3) and with moderate to severe cognitive impairment on a composite measure of IQ and executive function (ORs: 2.1-3.6). Additionally, severe cognitive impairment was associated with late protein elevations of C-reactive protein (OR: 4.0; 95% CI 1.5, 10), IL-8 (OR: 5.0; 1.9, 13), ICAM-1 (OR: 6.5; 2.6, 16), vascular endothelial growth factor-receptor 2 (OR: 3.2; 1.2, 8.3), and thyroid-stimulating hormone (OR: 3.1; 1.3, 7.3). Moderate cognitive impairment was most strongly associated with elevations of IL-8, ICAM-1, and vascular endothelial growth factor-receptor 2. When 4 or more inflammatory proteins were elevated early, the risk of having an IQ <70 and having overall impaired cognitive ability was more than doubled (ORs: 2.1-2.4); the presence of 4 or more inflammatory protein elevated late was strongly linked to adverse cognitive outcomes (ORs: 2.9-4.8). Conclusions Extremely preterm children who had sustained elevations of inflammation-related proteins in the first postnatal month are more likely than extremely preterm peers without such elevations to have cognitive impairment at 10 years. C1 [Kuban, Karl C. K.; Douglass, Laurie; Rollins, Julie Vanier] Boston Med Ctr, Dept Pediat, Boston, MA USA. [Joseph, Robert M.] Boston Univ, Sch Med, Dept Anat & Neuroanat, Boston, MA 02118 USA. [O'Shea, Thomas M.] Univ N Carolina, Div Neonatal Perinatal Med, Dept Pediat, Chapel Hill, NC USA. [Heeren, Timothy] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Fichorova, Raina N.] Harvard Med Sch, Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Lab Genital Tract Biol, Boston, MA USA. [Jara, Hernan] Boston Univ, Sch Med, Dept Radiol, Boston, MA 02118 USA. [Frazier, Jean A.] Univ Massachusetts Mem Hlth Care, Sch Med, Dept Psychiat, Univ Massachusetts, Worcester, MA USA. [Hirtz, Deborah] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Paneth, Nigel] Michigan State Univ, Dept Epidemiol & Biostat & Pediat, E Lansing, MI 48824 USA. RP Kuban, KCK (reprint author), Boston Med Ctr, 1 Boston Med Ctr Pl,Dowling Bldg,3 South, Boston, MA 03118 USA. EM karl.kuban@bmc.org FU National Institute of Neurological Disorders and Stroke [5U01NS040069-05, 2R01NS040069-09]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [5P30HD018655-28]; Janssen Research and Development (MENTIS) [ASD002/CTI500085]; SyneuRex International Corp; Neuren Pharmaceuticals [20142016] FX Supported by the National Institute of Neurological Disorders and Stroke (5U01NS040069-05 and 2R01NS040069-09) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (5P30HD018655-28). J. F. has received research support from Janssen Research and Development (MENTIS ASD002/CTI500085), SyneuRex International Corp, and Neuren Pharmaceuticals (20142016); and she has served on a data safety monitoring board for Forrest Pharmaceuticals. The other authors declare no conflicts of interest. NR 76 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 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD JAN PY 2017 VL 180 BP 116 EP + DI 10.1016/j.jpeds.2016.09.054 PG 9 WC Pediatrics SC Pediatrics GA EF0PL UT WOS:000390028100025 PM 27788929 ER PT J AU Gordon, CM Zemel, BS Wren, TAL Leonard, MB Bachrach, LK Rauch, F Gilsanz, V Rosen, CJ Winer, KK AF Gordon, Catherine M. Zemel, Babette S. Wren, Tishya A. L. Leonard, Mary B. Bachrach, Laura K. Rauch, Frank Gilsanz, Vicente Rosen, Clifford J. Winer, Karen K. TI The Determinants of Peak Bone Mass SO JOURNAL OF PEDIATRICS LA English DT Editorial Material ID VITAMIN-D SUPPLEMENTATION; YOUNG-ADULT MEN; DEPOT MEDROXYPROGESTERONE ACETATE; INCIDENT VERTEBRAL FRACTURES; BROWN ADIPOSE-TISSUE; MINERAL DENSITY; ANOREXIA-NERVOSA; PHYSICAL-ACTIVITY; BODY-COMPOSITION; SKELETAL HEALTH C1 [Gordon, Catherine M.] Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Zemel, Babette S.] Univ Penn, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Wren, Tishya A. L.; Gilsanz, Vicente] Univ Southern Calif, Childrens Hosp Los Angeles, Los Angeles, CA USA. [Leonard, Mary B.; Bachrach, Laura K.] Stanford Univ, Sch Medicine, Stanford, CA 94305 USA. [Rauch, Frank] McGill Univ, Shriners Hosp Children, Montreal, PQ, Canada. [Rosen, Clifford J.] Maine Med Ctr, Res Inst, Scarborough, ME USA. [Winer, Karen K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Gordon, CM (reprint author), Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave,MLC 4000, Cincinnati, OH 45229 USA. EM catherine.gordon@cchmc.org NR 117 TC 0 Z9 0 U1 3 U2 3 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 JAN PY 2017 VL 180 BP 261 EP 269 DI 10.1016/j.jpeds.2016.09.056 PG 9 WC Pediatrics SC Pediatrics GA EF0PL UT WOS:000390028100052 PM 27816219 ER PT J AU Burch, PT Ravishankar, C Newburger, JW Lambert, LM Pemberton, VL Granger, S Floh, AA Anderson, JB Hill, GD Hill, KD Oster, ME Lewis, AB Schumacher, KR Zyblewski, SC Davies, RR Jacobs, JP Lai, WW Minich, LL AF Burch, Phillip T. Ravishankar, Chitra Newburger, Jane W. Lambert, Linda M. Pemberton, Victoria L. Granger, Suzanne Floh, Alejandro A. Anderson, Jeffrey B. Hill, Garick D. Hill, Kevin D. Oster, Matthew E. Lewis, Alan B. Schumacher, Kurt R. Zyblewski, Sinai C. Davies, Ryan R. Jacobs, Jeffrey P. Lai, Wyman W. Minich, L. Luann CA Pediat Heart Network Investigators TI Assessment of Growth 6 Years after the Norwood Procedure SO JOURNAL OF PEDIATRICS LA English DT Article ID SINGLE-VENTRICLE PHYSIOLOGY; INFANTS; SHUNT; OUTCOMES; FAILURE AB At 6 years of age, patients with hypoplastic left heart syndrome had mean age-adjusted z-scores for weight and height below the normative population, and body mass index was similar to the normative population. Males had the greatest increase in z-scores for body mass index. C1 [Burch, Phillip T.; Lambert, Linda M.] Univ Utah, Primary Childrens Hosp, Dept Surg, Salt Lake City, UT USA. [Minich, L. Luann] Univ Utah, Primary Childrens Hosp, Dept Pediat, Salt Lake City, UT USA. [Ravishankar, Chitra] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Newburger, Jane W.] Boston Childrens Hosp, Boston, MA USA. [Newburger, Jane W.] Harvard Med Sch, Boston, MA USA. [Pemberton, Victoria L.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Granger, Suzanne] New England Res Inst, 9 Galen St, Watertown, MA 02172 USA. [Floh, Alejandro A.] Hosp Sick Children, Toronto, ON, Canada. [Anderson, Jeffrey B.] Univ Cincinnati, Cincinnati, OH USA. [Hill, Garick D.] Childrens Hosp Wisconsin, Milwaukee, WI 53201 USA. [Hill, Kevin D.] Duke Univ, Med Ctr, Durham, NC USA. [Oster, Matthew E.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Oster, Matthew E.] Emory Univ, Sch Med, Atlanta, GA USA. [Lewis, Alan B.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Schumacher, Kurt R.] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Zyblewski, Sinai C.] Med Univ South Carolina, Charleston, SC USA. [Jacobs, Jeffrey P.] Nemours AI DuPont Hosp Children, Wilmington, DE USA. [Jacobs, Jeffrey P.] Johns Hopkins All Childrens Heart Inst, Orlando, FL USA. [Lai, Wyman W.] Columbia Univ, Med Ctr, New York, NY USA. RP Burch, PT (reprint author), Univ Utah, Dept Surg, Salt Lake City, UT 84112 USA. EM Phillip.Burch@hsc.ulah.edu OI Davies, Ryan/0000-0003-4631-9685 FU National Heart, Lung, and Blood Institute [HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288, HL085057] FX Supported by the National Heart, Lung, and Blood Institute (HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288, HL085057). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Heart, Lung, and Blood Institute. The authors declare no conflicts of interest. NR 11 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 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD JAN PY 2017 VL 180 BP 270 EP + DI 10.1016/j.jpeds.2016.09.048 PG 11 WC Pediatrics SC Pediatrics GA EF0PL UT WOS:000390028100053 PM 27855999 ER PT J AU Shankaran, S Laptook, AR McDonald, SA Hintz, SR Barnes, PD Das, A Higgins, RD AF Shankaran, Seetha Laptook, Abbot R. McDonald, Scott A. Hintz, Susan R. Barnes, Patrick D. Das, Abhik Higgins, Rosemary D. CA Eunice Kennedy Shriver Natl Inst Human Dev Neonatal Res Network TI Acute Perinatal Sentinel Events, Neonatal Brain Injury Pattern, and Outcome of Infants Undergoing a Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy SO JOURNAL OF PEDIATRICS LA English DT Article ID WHOLE-BODY HYPOTHERMIA; SYSTEMIC HYPOTHERMIA; RANDOMIZED-TRIAL; TERM; ANTECEDENTS; MODERATE AB Infants with perinatal sentinel events in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Hypothermia for Encephalopathy Trial had more basal ganglia and thalamus lesions on brain magnetic resonance imaging but similar neurodevelopmental outcomes at 18 months of age than infants without perinatal sentinel events. Outcomes correlated with the neonatal magnetic resonance imaging findings. C1 [Shankaran, Seetha] Wayne State Univ, Sch Med, Dept Pediat, Detroit, MI 48201 USA. [Laptook, Abbot R.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. [McDonald, Scott A.; Das, Abhik] RTI Int, Social Stat & Environm Sci Unit, Res Triangle Pk, NC USA. [Hintz, Susan R.] Stanford Univ, Sch Med, Dept Pediat, Palo Alto, CA 94304 USA. [Barnes, Patrick D.] Stanford Univ, Sch Med, Dept Radiol, Palo Alto, CA 94304 USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Shankaran, S (reprint author), Childrens Hosp Michigan, 3901 Beaubien Blvd, Detroit, MI 48201 USA. FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [U10 HD27904, U10 HD21364, M01 RR80, U10 HD27853, M01 RR8084, U10 HD40492, M01 RR30, U10 HD27851, M01 RR39, U10 HD27856, M01 RR750, U10 HD36790, U10 HD27880, M01 RR70, U10 HD34216, M01 RR32]; [U10 HD40461]; [U10 HD40521]; [M01 RR44]; [U10 HD21397]; [M01 RR16587]; [U10 HD40689]; [M01 RR633]; [U10 HD21373]; [M01 RR2588]; [U10 HD21385]; [U10 HD27871]; [M01 RR125]; [UL1 RR24139] FX Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U10 HD27904), (U10 HD21364); (M01 RR80), (U10 HD27853); (M01 RR8084), (U10 HD40492), (M01 RR30), (U10 HD27851), (M01 RR39), (U10 HD27856), (M01 RR750), (U10 HD36790), (U10 HD27880), (M01 RR70), (U10 HD34216), (M01 RR32), (U10 HD40461), (U10 HD40521), (M01 RR44), (U10 HD21397), (M01 RR16587), (U10 HD40689), (M01 RR633), (U10 HD21373), (M01 RR2588), (U10 HD21385), (U10 HD27871), (M01 RR125), and (UL1 RR24139). The authors declare no conflicts of interest. NR 20 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 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD JAN PY 2017 VL 180 BP 275 EP + DI 10.1016/j.jpeds.2016.09.026 PG 6 WC Pediatrics SC Pediatrics GA EF0PL UT WOS:000390028100054 PM 27776752 ER PT J AU Ikeda, K Kawakami, K Onimaru, H Okada, Y Yokota, S Koshiya, N Oku, Y Iizuka, M Koizumi, H AF Ikeda, Keiko Kawakami, Kiyoshi Onimaru, Hiroshi Okada, Yasumasa Yokota, Shigefumi Koshiya, Naohiro Oku, Yoshitaka Iizuka, Makito Koizumi, Hidehiko TI The respiratory control mechanisms in the brainstem and spinal cord: integrative views of the neuroanatomy and neurophysiology SO JOURNAL OF PHYSIOLOGICAL SCIENCES LA English DT Review DE Respiratory rhythm; Pons; Medulla; Spinal cord; Parafacial respiratory group (pFRG); Pre-Botzinger complex (preBotC) ID PRE-BOTZINGER COMPLEX; RECEPTOR-IMMUNOREACTIVE NEURONS; PARASTERNAL INTERCOSTAL MUSCLES; INSPIRATORY BULBOSPINAL NEURONS; MONO-SYNAPTIC CONNECTIONS; PERSISTENT SODIUM CURRENT; HOMEOBOX GENE PHOX2B; IN-VITRO; RHYTHM GENERATION; NEWBORN RAT AB Respiratory activities are produced by medullary respiratory rhythm generators and are modulated from various sites in the lower brainstem, and which are then output as motor activities through premotor efferent networks in the brainstem and spinal cord. Over the past few decades, new knowledge has been accumulated on the anatomical and physiological mechanisms underlying the generation and regulation of respiratory rhythm. In this review, we focus on the recent findings and attempt to elucidate the anatomical and functional mechanisms underlying respiratory control in the lower brainstem and spinal cord. C1 [Ikeda, Keiko] Hyogo Coll Med, Div Biol, Nishinomiya, Hyogo 6638501, Japan. [Kawakami, Kiyoshi] Jichi Med Univ, Div Biol, Ctr Mol Med, Shimotsuke, Tochigi 3290498, Japan. [Onimaru, Hiroshi; Iizuka, Makito] Showa Univ, Dept Physiol, Sch Med, Shinagawa Ku, Tokyo 1428555, Japan. [Okada, Yasumasa] Murayama Med Ctr, Clin Res Ctr, Tokyo 2080011, Japan. [Yokota, Shigefumi] Shimane Univ, Dept Anat & Morphol Neurosci, Sch Med, Izumo, Shimane 6938501, Japan. [Koshiya, Naohiro; Koizumi, Hidehiko] NINDS, Cellular & Syst Neurobiol Sect, NIH, Bethesda, MD 20892 USA. [Oku, Yoshitaka] Hyogo Coll Med, Dept Physiol, Nishinomiya, Hyogo 6638501, Japan. RP Ikeda, K (reprint author), Hyogo Coll Med, Div Biol, Nishinomiya, Hyogo 6638501, Japan.; Onimaru, H; Iizuka, M (reprint author), Showa Univ, Dept Physiol, Sch Med, Shinagawa Ku, Tokyo 1428555, Japan.; Okada, Y (reprint author), Murayama Med Ctr, Clin Res Ctr, Tokyo 2080011, Japan.; Koshiya, N (reprint author), NINDS, Cellular & Syst Neurobiol Sect, NIH, Bethesda, MD 20892 USA.; Oku, Y (reprint author), Hyogo Coll Med, Dept Physiol, Nishinomiya, Hyogo 6638501, Japan. EM kiikeda@hyo-med.ac.jp; oni@med.showa-u.ac.jp; yasumasaokada@1979.jukuin.keio.ac.jp; nk@mail.nih.gov; yoku@hyo-med.ac.jp; iizukam@med.showa-u.ac.jp FU JSPS [25540130, 26460311, 26670676, 15K00417]; Naito Foundation; MEXT (Ministry of Education, Culture, Sports, Science and Technology)-Supported Program for the Subsidies for Private Universities (Showa University of Medicine, Jichi Medical University, Hyogo College of Medicine) FX This work was supported by JSPS KAKENHI Grant Numbers 25540130, 26460311, 26670676, and 15K00417 to Y. Okada, and by a grant from the Naito Foundation to K.I., and MEXT (Ministry of Education, Culture, Sports, Science and Technology)-Supported Program for the Subsidies for Private Universities (Showa University of Medicine, Jichi Medical University, Hyogo College of Medicine). NR 119 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER JAPAN KK PI TOKYO PA CHIYODA FIRST BLDG EAST, 3-8-1 NISHI-KANDA, CHIYODA-KU, TOKYO, 101-0065, JAPAN SN 1880-6546 EI 1880-6562 J9 J PHYSIOL SCI JI J. Physiol. Sci. PD JAN PY 2017 VL 67 IS 1 BP 45 EP 62 DI 10.1007/s12576-016-0475-y PG 18 WC Physiology SC Physiology GA EE9ZR UT WOS:000389985600004 PM 27535569 ER PT J AU Jang, YH Choi, JK Jang, YH Moon, SY Lee, WJ Lee, SJ Choi, YA Kim, SH Kim, DW AF Jang, Yong Hyun Choi, Jin Kyeong Jang, Yun Hwan Moon, Sun Young Lee, Weon Ju Lee, Seok-Jong Choi, Young-Ae Kim, Sang-Hyun Kim, Do Won TI Increased blood levels of NKG2D(+)CD4(+) T cells in patients with alopecia areata SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Letter C1 [Jang, Yong Hyun; Jang, Yun Hwan; Moon, Sun Young; Lee, Weon Ju; Lee, Seok-Jong; Kim, Do Won] Kyungpook Natl Univ, Sch Med, Dept Dermatol, 200 Dongduk Ro, Daegu 41944, South Korea. [Choi, Jin Kyeong; Choi, Young-Ae; Kim, Sang-Hyun] Kyungpook Natl Univ, Sch Med, Dept Pharmacol, 200 Dongduk Ro, Daegu 700422, South Korea. [Choi, Jin Kyeong] NEI, Mol Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Kim, DW (reprint author), Kyungpook Natl Univ, Sch Med, Dept Dermatol, 200 Dongduk Ro, Daegu 41944, South Korea.; Kim, SH (reprint author), Kyungpook Natl Univ, Sch Med, Dept Pharmacol, 200 Dongduk Ro, Daegu 700422, South Korea. EM shkim72@knu.ac.kr; kimdw@knu.ac.kr NR 5 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 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD JAN PY 2017 VL 76 IS 1 BP 151 EP 153 DI 10.1016/j.jaad.2016.07.056 PG 7 WC Dermatology SC Dermatology GA EF0TC UT WOS:000390037900041 PM 27986136 ER PT J AU Schiffman, M Saraiya, M AF Schiffman, Mark Saraiya, Mona TI Control of HPV-associated cancers with HPV vaccination SO LANCET INFECTIOUS DISEASES LA English DT Editorial Material ID HUMAN-PAPILLOMAVIRUS VACCINE; TRIALS C1 [Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Saraiya, Mona] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Atlanta, GA USA. RP Schiffman, M (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM schiffmm@mail.nih.gov NR 12 TC 1 Z9 1 U1 8 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD JAN PY 2017 VL 17 IS 1 BP 6 EP 8 DI 10.1016/S1473-3099(16)30146-3 PG 3 WC Infectious Diseases SC Infectious Diseases GA EE8GW UT WOS:000389864700005 PM 27282423 ER PT J AU Shiroma, EJ Cook, NR Manson, JE Moorthy, MV Buring, JE Rimm, EB Lee, IM AF Shiroma, Eric J. Cook, Nancy R. Manson, Joann E. Moorthy, M. V. Buring, Julie E. Rimm, Eric B. Lee, I-Min TI Strength Training and the Risk of Type 2 Diabetes and Cardiovascular Disease SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE RESISTANCE TRAINING; EPIDEMIOLOGY; WOMEN; LONGITUDINAL STUDY ID RANDOMIZED CONTROLLED-TRIAL; CORONARY-HEART-DISEASE; PHYSICAL-ACTIVITY QUESTIONNAIRE; LOW-DOSE ASPIRIN; PRIMARY PREVENTION; WOMENS HEALTH; RESISTANCE EXERCISE; SKELETAL-MUSCLE; CANCER; MEN AB Purpose: This study aimed to examine the association of strength training with incident type 2 diabetes and cardiovascular disease risk. Methods: We followed 35,754 healthy women (mean age = 62.6 yr, range = 47.0-97.8) from the Women's Health Study, who responded to a health questionnaire that included physical activity questions in 2000, assessing health outcomes through annual health questionnaire through 2014 (mean +/- SD follow-up = 10.7 +/- 3.7 yr). Incident type 2 diabetes (N cases = 2120) and cardiovascular disease (N cases = 1742) were confirmed on medical record review. Cases of cardiovascular disease were defined as confirmed cases of myocardial infarction, stroke, coronary artery bypass graft, angioplasty, or cardiovascular disease death. Results: Compared with women who reported no strength training, women engaging in any strength training experienced a reduced rate of type 2 diabetes of 30% (hazard ratio = 0.70, 95% confidence interval = 0.61-0.80) when controlling for time spent in other activities and other confounders. A risk reduction of 17% was observed for cardiovascular disease among women engaging in strength training (hazard ratio = 0.83, 95% confidence interval = 0.72, 0.96). Participation in both strength training and aerobic activity was associated with additional risk reductions for both type 2 diabetes and cardiovascular disease compared with participation in aerobic activity only. Conclusions: These data support the inclusion of muscle-strengthening exercises in physical activity regimens for reduced risk of type 2 diabetes and cardiovascular disease, independent of aerobic exercise. Further research is needed to determine the optimum dose and intensity of muscle-strengthening exercises. C1 [Shiroma, Eric J.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Shiroma, Eric J.; Cook, Nancy R.; Manson, Joann E.; Buring, Julie E.; Lee, I-Min] Harvard Med Sch, Div Prevent Med, Brigham & Womens Hosp, Boston, MA USA. [Shiroma, Eric J.; Cook, Nancy R.; Manson, Joann E.; Moorthy, M. V.; Buring, Julie E.; Rimm, Eric B.; Lee, I-Min] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Rimm, Eric B.] Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA. RP Shiroma, EJ (reprint author), 7201 Wisconsin Ave,Gateway Bldg,Suite 3C309, Bethesda, MD 20814 USA. EM shiroma@nih.gov FU National Institutes of Health [CA154647, CA047988, HL043851, HL080467, HL099355, HL007575]; Intramural Research Program of the National Institutes of Health, National Institute on Aging FX This research was supported by the National Institutes of Health (research grant nos. CA154647, CA047988, HL043851, HL080467, HL099355, and HL007575). The National Institutes of Health played no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript. EJS was supported in part by and the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 29 TC 0 Z9 0 U1 28 U2 28 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 JAN PY 2017 VL 49 IS 1 BP 40 EP 46 DI 10.1249/MSS.0000000000001063 PG 7 WC Sport Sciences SC Sport Sciences GA EF0PH UT WOS:000390027700005 PM 27580152 ER PT J AU Keadle, SK Sampson, JN Li, HC Lyden, K Matthews, CE Carroll, RJ AF Keadle, Sarah Kozey Sampson, Joshua N. Li, Haocheng Lyden, Kate Matthews, Charles E. Carroll, Raymond J. TI An Evaluation of Accelerometer-derived Metrics to Assess Daily Behavioral Patterns SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE PHYSICAL ACTIVITY; EPIDEMIOLOGY; MEASUREMENT; ASSESSMENT; SEDENTARY BEHAVIOR ID CARDIOMETABOLIC RISK-FACTORS; SEDENTARY TIME; PHYSICAL-ACTIVITY; CANADIAN ADULTS; UNITED-STATES; US ADULTS; EXERCISE; WOMEN; BREAKING; REPRODUCIBILITY AB Introduction: The way physical activity (PA) and sedentary behavior (SB) are accumulated throughout the day (i. e., patterns) may be important for health, but identifying measurable and meaningful metrics of behavioral patterns is challenging. This study evaluated accelerometer-derived metrics to determine whether they predicted PA and SB patterns and were reliably measured. Methods: We defined and measured 55 metrics that describe daily PA and SB using data collected by using the activPAL monitor in four studies. The first two studies were randomized crossover designs that included recreationally active participants. Study 1 experimentally manipulated time spent in moderate-to-vigorous-intensity PA and sedentary time, and study 2 held time in exercise constant and manipulated SB. Study 3 included inactive participants who increased exercise, decreased sedentary time, or both. The study conditions induced distinct behavioral patterns; thus, we tested whether the new metrics could improve the prediction of an individual's study condition after adjusting for the overall volume of PA or SB using conditional logistic regression. In study 4, we measured the 3-month reliability for the pattern metrics by calculating intraclass correlation coefficients in a community-dwelling sample who wore the activPAL monitor twice for 7 d. Results: In each of the experimental studies, we identified new metrics that could improve the accuracy for predicting condition beyond SB and moderate-to-vigorous-intensity PA volume. In study 1, 23 metrics were predictive of a highly active condition, and in study 2, 24metrics were predictive of a highly sedentary condition. In study 4, the median intraclass correlation coefficients (25-75th percentiles) of the metrics were 0.59 (0.46-0.65). Conclusions: Several new metrics were predictive of patterns of SB, exercise, and nonexercise behavior and are moderately reliable for a 3-month period. Applying these metrics to determine whether daily behavioral patterns are associated with health-outcomes is an important area of future research. C1 [Keadle, Sarah Kozey; Matthews, Charles E.] NCI, Metabol Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Keadle, Sarah Kozey] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. [Sampson, Joshua N.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Li, Haocheng] Univ Calgary, Dept Oncol, Calgary, AB T2N 1N4, Canada. [Li, Haocheng] Univ Calgary, Dept Community Hlth Sci, Calgary, AB T2N 1N4, Canada. [Lyden, Kate] Misfit Inc, San Francisco, CA USA. [Carroll, Raymond J.] Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. [Carroll, Raymond J.] Univ Technol Sydney, Sch Math & Phys Sci, Sydney, NSW 2007, Australia. RP Keadle, SK (reprint author), NCI, Metab Epidemiol Branch, Div Canc Epidemiol & Genet, Med Ctr 9609, Dr 6E-318, Bethesda, MD 20892 USA. EM sarah.keadle@nih.gov FU National Institutes of Health [NR011477, U01-CA057030, RC1HL099557]; Natural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN-2015-04409]; Intramural Research Program at the National Cancer Institute; American College of Sports Medicine Paffenbarger Award FX The authors thank the study participants and staff and Drs. Patty Freedson and Jay Fowke. The study was supported by funding from the National Institutes of Health (NR011477 PI, Fowke; U01-CA057030 PI, Carroll; and RC1HL099557 PI, Freedson), the Natural Sciences and Engineering Research Council of Canada (NSERC, RGPIN-2015-04409, Li), the Intramural Research Program at the National Cancer Institute (Sampson, Keadle, and Matthews), and an American College of Sports Medicine Paffenbarger Award (Lyden). NR 46 TC 0 Z9 0 U1 9 U2 9 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 JAN PY 2017 VL 49 IS 1 BP 54 EP 63 DI 10.1249/MSS.0000000000001073 PG 10 WC Sport Sciences SC Sport Sciences GA EF0PH UT WOS:000390027700007 PM 27992396 ER PT J AU Meltzer, A Van de Water, J AF Meltzer, Amory Van de Water, Judy TI The Role of the Immune System in Autism Spectrum Disorder SO NEUROPSYCHOPHARMACOLOGY LA English DT Review ID HISTORIC BIRTH COHORT; FETAL-BRAIN PROTEINS; MATERNAL AUTOANTIBODIES; ANTIBRAIN ANTIBODIES; AUTOIMMUNE-DISEASES; CONGENITAL-RUBELLA; AMNIOTIC-FLUID; PHARMACOLOGICAL CHANGES; INFLAMMATORY CYTOKINES; SCHIZOPHRENIC-PATIENTS AB Autism is a neurodevelopmental disorder characterized by deficits in communication and social skills as well as repetitive and stereotypical behaviors. While much effort has focused on the identification of genes associated with autism, research emerging within the past two decades suggests that immune dysfunction is a viable risk factor contributing to the neurodevelopmental deficits observed in autism spectrum disorders (ASD). Further, it is the heterogeneity within this disorder that has brought to light much of the current thinking regarding the subphenotypes within ASD and how the immune system is associated with these distinctions. This review will focus on the two main axes of immune involvement in ASD, namely dysfunction in the prenatal and postnatal periods. During gestation, prenatal insults including maternal infection and subsequent immunological activation may increase the risk of autism in the child. Similarly, the presence of maternally derived anti-brain autoantibodies found in similar to 20% of mothers whose children are at risk for developing autism has defined an additional subphenotype of ASD. The postnatal environment, on the other hand, is characterized by related but distinct profiles of immune dysregulation, inflammation, and endogenous autoantibodies that all persist within the affected individual. Further definition of the role of immune dysregulation in ASD thus necessitates a deeper understanding of the interaction between both maternal and child immune systems, and the role they have in diagnosis and treatment. C1 [Meltzer, Amory; Van de Water, Judy] Univ Calif Davis, Dept Internal Med, Div Rheumatol Allergy & Clin Immunol, Davis, CA 95616 USA. [Van de Water, Judy] Univ Calif Davis, MIND Inst, Davis, CA 95616 USA. [Van de Water, Judy] Univ Calif Davis, NIEHS Ctr Childrens Environm Hlth, 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 NIEHS Center for Children's Environmental Health [2P01ES011269-11]; Environmental Protection Agency (EPA) [83543201]; NIEHS-funded CHARGE study [R01ES015359]; NICHD funded IDDRC 054 [U54HD079125]; Pediatric Bioscience FX This study was funded by the NIEHS Center for Children's Environmental Health and Environmental Protection Agency (EPA) grants (2P01ES011269-11, 83543201 respectively), the NIEHS-funded CHARGE study (R01ES015359), and the NICHD funded IDDRC 054 (U54HD079125). There are three patents associated with the work at UCD noted in this review: A provisional 'Maternal Diagnostic Marker for Autism Risk and Therapeutic Intervention' UC Case No. 2014-467-1. There are 2 issued patents: The US patent Methods of Diagnosing and Treating Autism, US Patent No. 8,383,360 B2 or Pat. 8,383,360 was filed on 12 August 2010 and issued on 26 February 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, US Patent No. US 7,452,681 B2. This patent was filed on 5 May 2006, and was issued 18 November 2008. This patent was filed in the US only. Dr Van de Water received consulting fees from Pediatric Bioscience from 1 Jan 2015 until October 2015. Amory Meltzer reports no biomedical financial interests or potential conflicts of interest. NR 156 TC 0 Z9 0 U1 25 U2 25 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JAN PY 2017 VL 42 IS 1 BP 284 EP 298 DI 10.1038/npp.2016.158 PG 15 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EF1KI UT WOS:000390083300018 PM 27534269 ER PT J AU Gould, TD Zanos, P Zarate, CA AF Gould, Todd D. Zanos, Panos Zarate, Carlos A., Jr. TI Ketamine Mechanism of Action: Separating the Wheat from the Chaff SO NEUROPSYCHOPHARMACOLOGY LA English DT Editorial Material ID METABOLITES; DEPRESSION C1 [Gould, Todd D.; Zanos, Panos] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Gould, Todd D.] Univ Maryland, Sch Med, Dept Pharmacol, Baltimore, MD 21201 USA. [Gould, Todd D.] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Gould, TD (reprint author), Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA.; Gould, TD (reprint author), Univ Maryland, Sch Med, Dept Pharmacol, Baltimore, MD 21201 USA.; Gould, TD (reprint author), Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. EM gouldlab@me.com NR 6 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JAN PY 2017 VL 42 IS 1 BP 368 EP 369 DI 10.1038/npp.2016.210 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA EF1KI UT WOS:000390083300031 PM 27909322 ER PT J AU Takyar, V Surana, P Kleiner, DE Wilkins, K Hoofnagle, JH Liang, TJ Heller, T Koh, C AF Takyar, V. Surana, P. Kleiner, D. E. Wilkins, K. Hoofnagle, J. H. Liang, T. J. Heller, T. Koh, C. TI Noninvasive markers for staging fibrosis in chronic delta hepatitis SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID CHRONIC LIVER-DISEASE; PLATELET RATIO INDEX; C VIRUS-INFECTION; ASPARTATE-AMINOTRANSFERASE; B-VIRUS; DIAGNOSTIC-ACCURACY; CIRRHOSIS; PREDICT; PREVALENCE; COHORT AB Background Serum fibrosis markers are useful in staging chronic hepatitis B (HBV) and C (HCV) virus but have not been evaluated in chronic hepatitis D virus (HDV). Aim To evaluate the utility of serum fibrosis markers [fibrosis-4 score (FIB-4), aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio, aspartate aminotransferase ratio (AAR), age-platelet index (API), AST-to-platelet-ratio-index (APRI) and Hui score] in HDV infection. Methods Clinical and histologic laboratory data from HBV, HCV and HDV patients were evaluated and serum fibrosis markers were calculated. The ability of fibrosis markers to detect advanced fibrosis (Ishak >= 4) and cirrhosis (Ishak = 6) were evaluated and compared between viral infections. Results A total of 1003 subjects (HCV = 701, HBV = 240 and HDV = 62) with mean age of 46 +/- 11 and 66% male were evaluated. HDV subjects had higher ALT and AST than HCV and lower platelets than both HBV and HCV. Histologically, HDV had the greatest percentage of Ishak >= 4 and necroinflammation. FIB-4 performed best in detecting advanced fibrosis and cirrhosis in all viral cohorts. In HDV, area under the receiver operator curve (AUROC) 95% confidence intervals for detecting advanced fibrosis were: FIB-4 = 0.70 (0.55-0.84), API = 0.69 (0.55-0.82), APRI = 0.68 (0.54-0.82), Hui score = 0.63 (0.49-0.78), AAR = 0.63 (0.48-0.77). The AUROC for detecting cirrhosis in HDV were: FIB-4 = 0.83 (0.69-0.97), API = 0.80 (0.66-0.95), APRI = 0.75 (0.61-0.89), Hui score = 0.70 (0.49-0.91) and AAR = 0.70 (0.48-0.93). Adjustment of published cut-offs led to marginal improvements in FIB4 for advanced fibrosis and of APRI for cirrhosis in HDV. Conclusions Serum fibrosis markers have lower performance accuracy in chronic HDV infected patients compared to HBV and HCV patients. Other noninvasive fibrosis markers should be explored to assist in the management of these patients. C1 [Takyar, V.; Surana, P.; Hoofnagle, J. H.; Liang, T. J.; Heller, T.; Koh, C.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Kleiner, D. E.] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Wilkins, K.] NIDDK, Off Director, NIH, Bethesda, MD 20892 USA. RP Koh, C (reprint author), NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. EM christopher.koh@nih.gov FU Intramural Division 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 Division of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute of the National Institutes of Health. NR 57 TC 4 Z9 4 U1 2 U2 2 PU WILEY-BLACKWELL 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 JAN PY 2017 VL 45 IS 1 BP 127 EP 138 DI 10.1111/apt.13834 PG 12 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA EE2UF UT WOS:000389439600013 PM 27813124 ER PT J AU Bridges, E McNeill, MM Munro, N AF Bridges, Elizabeth McNeill, Margaret M. Munro, Nancy TI URESEARCH IN REVIEW: ADVANCING CRITICAL CARE PRACTICE SO AMERICAN JOURNAL OF CRITICAL CARE LA English DT Review ID INTERNATIONAL CONSENSUS DEFINITIONS; SHARED DECISION-MAKING; SEPTIC SHOCK SEPSIS-3; POTENTIALLY INAPPROPRIATE TREATMENTS; GOAL-DIRECTED RESUSCITATION; PRESSURE ULCER PREVENTION; PAIN OBSERVATION TOOL; PROCEDURAL PAIN; CLINICAL-CRITERIA; POLICY STATEMENT AB Research published in 2016 identified strategies to enhance acute and critical care, initiated discussions on professional roles and responsibilities, clarified complex care issues, and led to robust debate. Some of this important work addressed strategies to prevent delirium and pressure ulcers, considerations for pain management within the context of the opioid abuse crisis, strategies to guide fluid resuscitation in patients with sepsis and heart failure, and ways to enhance care for family members of intensive care patients. The new sepsis definitions highlight the importance of detecting and providing care to patients with sepsis outside of critical care areas. Chimeric antigen receptor T-cell therapy is an example of the advancement of research in genomics and personalized medicine and of the need to understand the care implications of these therapies. Other research topics include interprofessional collaboration and shared decision-making as well as nurses' role in family conferences. Resources such as policies related to medical futility and inappropriate care and the American Association of Critical-Care Nurses' healthy work environment standards may inform conversations and provide strategies to address these complex issues. C1 [Bridges, Elizabeth] Univ Washington, Sch Nursing, 1959 NE Pacific,Box 357260, Seattle, WA 98195 USA. [Bridges, Elizabeth] Univ Washington, Med Ctr, Seattle, WA 98195 USA. [McNeill, Margaret M.] Frederick Reg Hlth Syst, Perianesthesia, Frederick, MD USA. [Munro, Nancy] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Bridges, E (reprint author), Univ Washington, Sch Nursing, 1959 NE Pacific,Box 357260, Seattle, WA 98195 USA. EM ebridges@u.washington.edu NR 96 TC 0 Z9 0 U1 10 U2 10 PU AMER ASSOC CRITICAL CARE NURSES PI ALISO VIEJO PA 101 COLUMBIA, ALISO VIEJO, CA 92656 USA SN 1062-3264 EI 1937-710X J9 AM J CRIT CARE JI Am. J. Crit. Care PD JAN PY 2017 VL 26 IS 1 BP 77 EP 88 DI 10.4037/ajcc2017609 PG 12 WC Critical Care Medicine; Nursing SC General & Internal Medicine; Nursing GA EE5GI UT WOS:000389633200012 PM 27965233 ER PT J AU Li, A Li, X Yu, XJ Li, W Zhao, RY An, X Cui, DX Chen, XY Li, WW AF Li, Ang Li, Xiang Yu, Xujiang Li, Wei Zhao, Ruyi An, Xiao Cui, Daxiang Chen, Xiaoyuan Li, Wanwan TI Synergistic thermoradiotherapy based on PEGylated Cu3BiS3 ternary semiconductor nanorods with strong absorption in the second near-infrared window SO BIOMATERIALS LA English DT Article DE Copper bismuth sulfide; Nanorods; The second near-infrared (NIR-II) window; Multimodel imaging; Thermoradiotherapy ID DRIVEN PHOTOTHERMAL AGENT; REDUCED GRAPHENE OXIDE; MESOPOROUS SILICA NANOPARTICLES; CELLS IN-VIVO; CANCER-CELLS; CARBON NANOTUBES; CONVERSION EFFICIENCY; RADIATION-THERAPY; GOLD NANOSTARS; DRUG-DELIVERY AB In this work, we report a successful synthesis of copper bismuth sulfide nanorods (NRs) with broad and strong photoabsorption ranging from ultraviolet (UV) to near-infrared (NIR) wavelengths, which can be used as a 1064 nm-laser-driven photothermal agent with the photothermal conversion efficiency of 40.7%, noticeably higher than most of the reported FIT agents working in NIR-II window. The as prepared PEGylated Cu3BiS3 NRs were used as photoacoustic imaging (PAD and CT imaging agents due to their strong NIR absorption and large X-ray attenuation coefficient of bismuth. We are the first to demonstrate that a small quantity of PEGylated Cu3BiS3 NRs in tumors can concentrate radiation energy and trigger mild PTT under NIR-II irradiation and thus, these particles could be used as a novel, synergistic thermoradiotheraputic agent that enhances the efficacy of radiotherapy. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Li, Ang; Yu, Xujiang; Li, Wei; Li, Wanwan] Shanghai Jiao Tong Univ, Sch Mat Sci & Engn, State Key Lab Met Matrix Composites, 800 Dongchuan Rd, Shanghai 200240, Peoples R China. [Li, Xiang; Zhao, Ruyi; An, Xiao] Shanghai Jiao Tong Univ, Peoples Hosp 1, Sch Med, 100 Haining Rd, Shanghai 200080, Peoples R China. [Cui, Daxiang] Shanghai Jiao Tong Univ, Inst Nano Biomed & Engn,Key Lab Thin Film & Micro, Dept Instrument Sci & Engn,Sch Elect Informat & E, Minist Educ,Natl Ctr Translat Med,Collaborat Inno, 800 Dongchuan Rd, Shanghai 200240, Peoples R China. [Chen, Xiaoyuan] NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. RP Li, WW (reprint author), Shanghai Jiao Tong Univ, Sch Mat Sci & Engn, State Key Lab Met Matrix Composites, 800 Dongchuan Rd, Shanghai 200240, Peoples R China.; An, X (reprint author), Shanghai Jiao Tong Univ, Peoples Hosp 1, Sch Med, 100 Haining Rd, Shanghai 200080, Peoples R China. EM 54andromeda@163.com; wwli@sjtu.edu.cn FU National Natural Science Foundation of China [81371645]; Science and Technology Committee of Shanghai [15PJD020, 15441905800, 16JC1400604]; Medicine & Engineering Cross Research Foundation of Shanghai Jiao Tong University [YG2014MS33] FX This work was financially supported by the National Natural Science Foundation of China (Project No. 81371645), Science and Technology Committee of Shanghai (Project No. 15PJD020, 15441905800, 16JC1400604), Medicine & Engineering Cross Research Foundation of Shanghai Jiao Tong University (Project No. YG2014MS33). We thank the Instrumental Analysis Center of SJTU for the assistance with B-TEM, XRD, XPS and ICP-MS characterizations. NR 65 TC 0 Z9 0 U1 63 U2 63 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 JAN PY 2017 VL 112 BP 164 EP 175 DI 10.1016/j.biomaterials.2016.10.024 PG 12 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA ED9CB UT WOS:000389166700015 PM 27768971 ER PT J AU Murray, AM Hsu, FC Williamson, JD Bryan, RN Gerstein, HC Sullivan, MD Miller, ME Leng, I Lovato, LL Launer, LJ AF Murray, Anne M. Hsu, Fang-Chi Williamson, Jeff D. Bryan, R. Nick Gerstein, Hertzel C. Sullivan, Mark D. Miller, Michael E. Leng, Iris Lovato, Laura L. Launer, Lenore J. CA Action Control Cardiovasc Risk TI ACCORDION MIND: results of the observational extension of the ACCORD MIND randomised trial SO DIABETOLOGIA LA English DT Article DE Abnormal white matter volume; Brain MRI; Cognitive impairment; Total brain volume; Type 2 diabetes ID WHITE-MATTER HYPERINTENSITIES; ALZHEIMERS-DISEASE; DIABETES-MELLITUS; RISK-FACTORS; BRAIN; DEMENTIA; HYPERGLYCEMIA; ATROPHY; IMAGES AB The Memory in Diabetes (MIND) substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, a double 2x2 factorial parallel-group randomised clinical trial, tested whether intensive compared with standard management of hyperglycaemia, BP or lipid levels reduced cognitive decline and brain atrophy in 2977 people with type 2 diabetes. We describe the results of the observational extension study, ACCORDION MIND (ClinicalTrials.gov registration no. NCT00182910), which aimed to measure the long-term effects of the three ACCORD interventions on cognitive and brain structure outcomes approximately 4 years after the trial ended. Participants (mean diabetes duration 10 years; mean age 62 years at baseline) received a fourth cognitive assessment and a third brain MRI, targeted at 80 months post-randomisation. Primary outcomes were performance on the Digit Symbol Substitution Test (DSST) and total brain volume (TBV). The contrast of primary interest compared glycaemic intervention groups at the ACCORDION visit; secondary contrasts were the BP and lipid interventions. Of the surviving ACCORD participants eligible for ACCORDION MIND, 1328 (68%) were re-examined at the ACCORDION follow-up visit, approximately 47 months after the intensive glycaemia intervention was stopped. The significant differences in therapeutic targets for each of the three interventions (glycaemic, BP and lipid) were not sustained. We found no significant difference in 80 month mean change from baseline in DSST scores or in TBV between the glycaemic intervention groups, or the BP and lipid interventions. Sensitivity analyses of the sites with >= 70% participation at 80 months revealed consistent results. The ACCORD interventions did not result in long-term beneficial or adverse effects on cognitive or brain MRI outcomes at approximately 80 months follow-up. Loss of separation in therapeutic targets between treatment arms and loss to follow-up may have contributed to the lack of detectable long-term effects. ClinicalTrials.gov NCT00182910. C1 [Murray, Anne M.] Hennepin Cty Med Ctr, Dept Med, Div Geriatr, Minneapolis, MN 55415 USA. [Murray, Anne M.] Univ Minnesota, Minneapolis, MN 55455 USA. [Murray, Anne M.] Hennepin Cty Med Ctr, Berman Ctr Clin Res, Minneapolis, MN 55415 USA. [Hsu, Fang-Chi; Miller, Michael E.; Leng, Iris; Lovato, Laura L.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Williamson, Jeff D.] Wake Forest Sch Med, Dept Internal Med, J Paul Sticht Ctr Hlth Aging & Alzheimers Prevent, Geriat Med, Winston Salem, NC USA. [Bryan, R. Nick] Univ Penn Hlth Syst, Dept Radiol, Philadelphia, PA USA. [Gerstein, Hertzel C.] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Gerstein, Hertzel C.] Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON, Canada. [Sullivan, Mark D.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Launer, Lenore J.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, Bethesda, MD 20892 USA. RP Murray, AM (reprint author), Hennepin Cty Med Ctr, Dept Med, Div Geriatr, Minneapolis, MN 55415 USA. EM amurray@bermancenter.org FU National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA Y1-HC-9035, IAA Y1-HC-1010]; National Institute on Aging (NIA); NHLBI [AG-0008]; NIA [HSN271201000023C]; National Institutes of Health; National Institute of Diabetes, and Digestive and Kidney Diseases; National Eye Institute; Centers for Disease Control and Prevention; General Clinical Research Centers FX ACCORD was funded by the National Heart, Lung, and Blood Institute (NHLBI) contracts N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA#Y1-HC-9035 and IAA#Y1-HC-1010. ACCORDION MIND was funded through an intra-agency agreement between the National Institute on Aging (NIA) and NHLBI (AG-0008), NIA contract (HSN271201000023C) and the NIA Intramural Research Program. Other components of the National Institutes of Health, including the National Institute of Diabetes, and Digestive and Kidney Diseases and the National Eye Institute, contributed funding. The Centers for Disease Control and Prevention funded ACCORD substudies of cost-effectiveness and health-related quality of life. General Clinical Research Centers provided support at many sites. NR 37 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD JAN PY 2017 VL 60 IS 1 BP 69 EP 80 DI 10.1007/s00125-016-4118-x PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EE5GQ UT WOS:000389634000010 PM 27766347 ER PT J AU Cohen, A Perozich, A Rajan, R Persky, S Parisi, J Bowie, J Fahle, J Cho, J Krishnan, A Cohen, Z Ezike, A Schulte, C Taylor, J Storey, D Ahmed, RS Cheskin, LJ AF Cohen, Anne Perozich, Alyssa Rajan, Radha Persky, Susan Parisi, Jeanine Bowie, Janice Fahle, Jenna Cho, Jeremy Krishnan, Aravind Cohen, Zoe Ezike, Adaora Schulte, Cara Taylor, Jarrett Storey, Douglas Ahmed, Rafay Syed Cheskin, Lawrence J. TI Framed, Interactive Theory-Driven Texting Effects of Message Framing on Health Behavior Change for Weight Loss SO FAMILY & COMMUNITY HEALTH LA English DT Article DE African American; mHealth; text-messaging; urban; weight loss ID PHYSICAL-ACTIVITY QUESTIONNAIRE; CONTROLLED-TRIAL; REGULATORY FIT; SELF-EFFICACY; PSYCHOTHERAPY; INFORMATION; RELIABILITY; VALIDATION; PREVENTION; VALIDITY AB More approaches to support weight control are needed, especially among racial minorities who shoulder a disproportionate obesity burden. Using an approach influenced by regulatory fit theory, we conducted a 28-day, 4-arm experimental trial with 89 obese adults recruited from urban, predominantly African American churches to ascertain the efficacy of framed text messages to motivate behaviors conducive to weight loss. Participants were assigned to receive message framing that was matched versus mismatched to their motivational orientation. Results were mixed overall; however, matched texts elicited greater motivation to change eating and exercise behavior, suggesting promise in using motivational approaches to tailor messages. C1 [Cohen, Anne; Perozich, Alyssa; Fahle, Jenna; Krishnan, Aravind; Cohen, Zoe; Ezike, Adaora; Schulte, Cara; Taylor, Jarrett; Ahmed, Rafay Syed; Cheskin, Lawrence J.] Johns Hopkins Univ, Johns Hopkins Weight Management Ctr, 550 North Broadway,Ste 1001, Baltimore, MD 21205 USA. [Rajan, Radha; Bowie, Janice; Storey, Douglas; Ahmed, Rafay Syed; Cheskin, Lawrence J.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Behav & Soc, Baltimore, MD USA. [Parisi, Jeanine] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Cheskin, Lawrence J.] Maryland Global Obes Prevent Ctr Johns Hopkins, Baltimore, MD USA. [Persky, Susan] NHGRI, NIH, Social & Behav Res Branch, Bethesda, MD 20892 USA. RP Cheskin, LJ (reprint author), Johns Hopkins Univ, Johns Hopkins Weight Management Ctr, 550 North Broadway,Ste 1001, Baltimore, MD 21205 USA. EM cheskin@jhu.edu FU Aetna Foundation FX This study has been funded by the Aetna Foundation. NR 31 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 0160-6379 EI 1550-5057 J9 FAM COMMUNITY HEALTH JI Fam. Community Health PD JAN-MAR PY 2017 VL 40 IS 1 BP 43 EP 51 DI 10.1097/FCH.0000000000000128 PG 9 WC Family Studies; Public, Environmental & Occupational Health SC Family Studies; Public, Environmental & Occupational Health GA EE0HO UT WOS:000389255300009 PM 27870754 ER PT J AU Imbrogno, S Mazza, R Pugliese, C Filice, M Angelone, T Loh, YP Tota, B Cerra, MC AF Imbrogno, S. Mazza, R. Pugliese, C. Filice, M. Angelone, T. Loh, Y. P. Tota, B. Cerra, M. C. TI The Chromogranin A-derived sympathomimetic serpinin depresses myocardial performance in teleost and amphibian hearts SO GENERAL AND COMPARATIVE ENDOCRINOLOGY LA English DT Article DE beta 3-Adrenoceptors; Cardiac performance; cGMP; ETB receptors; Negative inotropism; Sympatho-adrenergic signaling ID INHIBITORY PEPTIDE CATESTATIN; BETA-ADRENERGIC STIMULATION; CARASSIUS-AURATUS HEART; EEL ANGUILLA-ANGUILLA; NITRIC-OXIDE SYNTHASE; N-TERMINAL FRAGMENTS; RAT ADRENAL-MEDULLA; ISOLATED FROG-HEART; ENDOCARDIAL ENDOTHELIUM; CATECHOLAMINE RELEASE AB Chromogranin A (CgA) is an acidic protein co-stored with catecholamines, hormones and neuropeptides in the secretory granules of endocrine, neuronal and other cell types (including cardiomyocytes). Proteolytic cleavage in the C terminus of CgA generates a 2.9 kDa peptide named serpinin (Serp; Ala26Leu) that can be modified at its N terminus to form a pyroglutamate residue (pGlu-Serp). In the rat heart, both peptides increase contractility and relaxation through a beta-adrenergic-like action mechanism. Accordingly, Serp and pG1u-Serp were proposed as novel myocardial sympatho-adrenergic modulators in mammals. On a comparative basis, here we report the actions of Serp and pGlu-Serp on myocardial contractility in three poikilotherm vertebrate species: the eel (Anguilla anguilla), the goldfish (Carassius auratus) and the frog (Rana esculenta). Using isolated working heart preparations, we show that pGlu-Serp reduces stroke volume in all species tested, while Serp reduces contractility in the frog heart, but is uneffective in eel and goldfish hearts. In the goldfish and frog hearts, pGlu-Serp activates the Nitric Oxide/cGMP pathway involving Endothelin1 B receptors (frog) and 03 adrenergic receptors (goldfish). pGlu-Serp-treated hearts from goldfish and frog show increased cGMP content. Moreover, the exposure of the frog heart to pGlu-Serp is accompanied by an increased expression of activated eNOS and Akt. In conclusion, this first report showing that pGlu-Serp inhibits mechanical cardiac performance in teleost and amphibians supports an evolutionary role of the CgA system, and particularly its serpinin component, in the sympatho-adrenergic control of the vertebrate heart. (C) 2016 Elsevier Inc. All rights reserved. C1 [Imbrogno, S.; Mazza, R.; Pugliese, C.; Filice, M.; Angelone, T.; Tota, B.; Cerra, M. C.] Univ Calabria, Dept Biol Ecol & Earth Sci, BEST, Arcavacata Di Rende, CS, Italy. [Loh, Y. P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cellular Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Imbrogno, S (reprint author), Univ Calabria, Dept Biol Ecol & Earth Sci, Lab Organ Physiol, I-87036 Arcavacata Di Rende, CS, Italy. EM sandra.imbrogno@unical.it FU MIUR (Ministry of Education, University and Research of Italy) FX This work was supported by MIUR (Ministry of Education, University and Research of Italy). NR 63 TC 0 Z9 0 U1 4 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0016-6480 EI 1095-6840 J9 GEN COMP ENDOCR JI Gen. Comp. Endocrinol. PD JAN 1 PY 2017 VL 240 BP 1 EP 9 DI 10.1016/j.ygcen.2016.09.004 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EE6PG UT WOS:000389734100001 PM 27633326 ER PT J AU Udey, MC AF Udey, Mark C. TI Looking Back while Stepping Forward-A Path Made Possible by Serendipity, a Few Good Decisions, and Helpful Colleagues SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material C1 [Udey, Mark C.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10,Room 12N238,10 Ctr Dr, Bethesda, MD 20892 USA. RP Udey, MC (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10,Room 12N238,10 Ctr Dr, Bethesda, MD 20892 USA. EM udey@helix.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JAN PY 2017 VL 137 IS 1 BP 2 EP 3 DI 10.1016/j.jid.2016.11.002 PG 2 WC Dermatology SC Dermatology GA EF4QE UT WOS:000390316300003 PM 28010759 ER PT J AU Cui, CY Ishii, R Campbell, DP Michel, M Piao, YL Kume, T Schlessinger, D AF Cui, Chang-Yi Ishii, Ryuga Campbell, Dean P. Michel, Marc Piao, Yulan Kume, Tsutomu Schlessinger, David TI Foxc1 Ablated Mice Are Anhidrotic and Recapitulate Features of Human Miliaria Sweat Retention Disorder SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID FORKHEAD TRANSCRIPTION FACTOR; GLAND DEVELOPMENT; EPIDERMAL-CELLS; SECRETION; GROWTH; GENE; IDENTIFICATION; QUIESCENCE; EXPRESSION; DYSPLASIA AB Sweat glands are critical for thermoregulation. The single tubular structure of sweat glands has a lower secretory portion and an upper reabsorptive duct leading to the secretory pore in the skin. Genes that determine sweat gland structure and function are largely unidentified. Here we report that a Fox family transcription factor, Foxc1, is obligate for appreciable sweat duct activity in mice. When Foxc1 was specifically ablated in skin, sweat glands appeared mature, but the mice were severely hypohidrotic. Morphologic analysis revealed that sweat ducts were blocked by hyperkeratotic or parakeratotic plugs. Consequently, lumens in ducts and secretory portions were dilated, and blisters and papules formed on the skin surface in the knockout mice. The phenotype was strikingly similar to the human sweat retention disorder miliaria. We further show that Foxc1 deficiency ectopically induces the expression of keratinocyte terminal differentiation markers in the duct luminal cells, which most likely contribute to keratotic plug formation. Among those differentiation markers, we show that Sprr2a transcription is directly repressed by overexpressed Foxc1 in keratinocytes. In summary, Foxc1 regulates sweat duct luminal cell differentiation, and mutant mice mimic miliaria and provide a possible animal model for its study. C1 [Cui, Chang-Yi; Ishii, Ryuga; Campbell, Dean P.; Michel, Marc; Piao, Yulan; Schlessinger, David] NIA, Lab Genet & Genom, NIH, 251 Bayview Blvd Suite 100, Baltimore, MD 21224 USA. [Kume, Tsutomu] Northwestern Univ, Feinberg Cardiovasc Res Inst, Feinberg Sch Med, Chicago, IL 60611 USA. RP Cui, CY (reprint author), NIA, Lab Genet & Genom, NIH, 251 Bayview Blvd Suite 100, Baltimore, MD 21224 USA. EM cuic@mail.nih.gov FU National Institute on Aging, National Institutes of Health; National Institutes of Health [EY019484, HL126920] FX This work was supported by the Intramural Research Program of National Institute on Aging, National Institutes of Health, and by grants from the National Institutes of Health (EY019484 and HL126920) to TK. NR 33 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JAN PY 2017 VL 137 IS 1 BP 38 EP 45 DI 10.1016/j.jid.2016.08.012 PG 8 WC Dermatology SC Dermatology GA EF4QE UT WOS:000390316300011 PM 27592801 ER PT J AU Chaiworapongsa, T Romero, R Korzeniewski, SJ Chaemsaithong, P Hernandez-Andrade, E Segars, JH DeCherney, AH Mccoy, MC Kim, CJ Yeo, L Hassan, SS AF Chaiworapongsa, Tinnakorn Romero, Roberto Korzeniewski, Steven J. Chaemsaithong, Piya Hernandez-Andrade, Edgar Segars, James H. DeCherney, Alan H. Mccoy, M. Cathleen Kim, Chong Jai Yeo, Lami Hassan, Sonia S. TI Pravastatin for the prevention of adverse pregnancy outcome: preeclampsia and more? SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Letter ID FETAL-DEATH C1 [Chaiworapongsa, Tinnakorn; Romero, Roberto; Korzeniewski, Steven J.; Chaemsaithong, Piya; Hernandez-Andrade, Edgar; Kim, Chong Jai; Yeo, Lami; Hassan, Sonia S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD 20892 USA. [Chaiworapongsa, Tinnakorn; Romero, Roberto; Korzeniewski, Steven J.; Chaemsaithong, Piya; Hernandez-Andrade, Edgar; Kim, Chong Jai; Yeo, Lami; Hassan, Sonia S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Detroit, MI USA. [Chaiworapongsa, Tinnakorn; Korzeniewski, Steven J.; Chaemsaithong, Piya; Hernandez-Andrade, Edgar; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto; Korzeniewski, Steven J.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Segars, James H.; DeCherney, Alan H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Mccoy, M. Cathleen] Winchester Med Ctr, Perinatal Unit, Winchester Obstet & Gynecol, Winchester, VA USA. [Kim, Chong Jai] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul, South Korea. RP Romero, R (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Bethesda, MD 20892 USA.; Romero, R (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH, Detroit, MI USA. EM romeror@mail.nih.gov NR 7 TC 0 Z9 0 U1 2 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD JAN PY 2017 VL 30 IS 1 BP 3 EP 3 DI 10.3109/14767058.2015.1129779 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA ED9UJ UT WOS:000389218300002 PM 27161513 ER PT J AU Hu, X Tanaka, N Guo, R Lu, Y Nakajima, T Gonzalez, FJ Aoyama, T AF Hu, Xiao Tanaka, Naoki Guo, Ran Lu, Yu Nakajima, Takero Gonzalez, Frank J. Aoyama, Toshifumi TI PPAR alpha protects against trans-fatty-acid-containing diet-induced steatohepatitis SO JOURNAL OF NUTRITIONAL BIOCHEMISTRY LA English DT Article DE trans-Fatty acid; PPAR alpha; Nuclear factor-kappa B; Osteopontin; Toll-like receptor; Inflammasome ID CHOLINE-DEFICIENT DIET; NF-KAPPA-B; NONALCOHOLIC STEATOHEPATITIS; OXIDATIVE STRESS; LIVER-DISEASE; METABOLIC SYNDROME; CHOLESTEROL LEVELS; DOWN-REGULATION; MICE; OSTEOPONTIN AB Consumption of trans-fatty acids (TFA), unsaturated fatty acids (FA) containing trans double bonds, is a risk factor for metabolic syndrome and steatohepatitis. Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a master regulator of hepatic lipid homeostasis. To examine the contribution of PPAR alpha to changes in liver phenotypes induced by TFA, two diets were used: a purified control diet and an isocaloric diet in which most of the soybean oil, a major source of FA in the diet, was replaced with TFA-rich shortening. The diets were fed to wild-type and Ppara-null mice for 2 months. Ppara-null mice fed a TFA-containing diet showed more severe hepatic steatosis and liver damage compared with similarly treated wild-type mice, as revealed by increased hepatic triglyceride (TG) contents and serum alanine aminotransferase activities. While the TFA-rich diet increased the hepatic expression of enzymes involved in de novo FA synthesis and decreased TG-hydrolyzing enzymes in both genotypes, the expression of FA-catabolizing enzymes was decreased in Ppara-null mice, resulting in more severe hepatosteatosis. Additionally, the expression levels of key contributors to inflammation, such as osteopontin, were increased, and nuclear factor-kappa B was activated in TFA-containing diet-fed Ppara-null mice. Enhanced inflammatory signaling in these mice was presumably mediated by toll-like receptor 2, with no accompanying inflammasome activation. Collectively, these results suggest a protective role for PPARa. in the pathological changes in the liver following TFA consumption. PPAR alpha might prevent TFA-containing diet-induced steatohepatitis. (C) 2016 Elsevier Inc. All rights reserved. C1 [Hu, Xiao; Tanaka, Naoki; Guo, Ran; Lu, Yu; Nakajima, Takero; Aoyama, Toshifumi] Shinshu Univ, Grad Sch Med, Dept Metab Regulat, Matsumoto, Nagano 3908621, Japan. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Tanaka, N (reprint author), Shinshu Univ, Grad Sch Med, Dept Metab Regulat, Matsumoto, Nagano 3908621, Japan. EM naopi@shinshu-u.ac.jp NR 45 TC 0 Z9 0 U1 7 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0955-2863 EI 1873-4847 J9 J NUTR BIOCHEM JI J. Nutr. Biochem. PD JAN PY 2017 VL 39 BP 77 EP 85 DI 10.1016/jjnutbio.2016.09.015 PG 9 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA EE4IT UT WOS:000389566200009 PM 27816763 ER PT J AU Swomley, AM Triplett, JC Keeney, JT Warrier, G Pearson, KJ Mattison, JA de Cabo, R Cai, J Klein, JB Butterfield, DA AF Swomley, Aaron M. Triplett, Judy C. Keeney, Jeriel T. Warrier, Govind Pearson, Kevin J. Mattison, Julie A. de Cabo, Rafael Cai, Jian Klein, Jon B. Butterfield, D. Allan TI Comparative proteomic analyses of the parietal lobe from rhesus monkeys fed a high-fat/sugar diet with and without resveratrol supplementation, relative to a healthy diet: Insights into the roles of unhealthy diets and resveratrol on function SO JOURNAL OF NUTRITIONAL BIOCHEMISTRY LA English DT Article DE Resveratrol; Proteomics; Western diet; Rhesus monkey; Brain ID ALZHEIMERS-DISEASE BRAIN; AMYOTROPHIC-LATERAL-SCLEROSIS; PROTEIN-COUPLED RECEPTORS; HIGH-FAT/SUCROSE DIET; ACYL-COA HYDROLASE; NONHUMAN-PRIMATES; HIPPOCAMPAL-NEURONS; GLUCOSE-TOLERANCE; INDUCED APOPTOSIS; REDOX PROTEOMICS AB A diet consisting of a high intake of saturated fat and refined sugars is characteristic of a Western-diet and has been shown to have a substantial negative effect on human health. Expression proteomics were used to investigate changes to the parietal lobe proteome of rhesus monkeys consuming either a high fat and sugar (HFS) diet, a HFS diet supplemented with resveratrol (HFS+RSV), or a healthy control diet for 2 years. Here we discuss the modifications in the levels of 12 specific proteins involved in various cellular systems including metabolism, neurotransmission, structural integrity, and general cellular signaling following a nutritional intervention. Our results contribute to a better understanding of the mechanisms by which resveratrol functions through the up- or down-regulation of proteins in different cellular sub-systems to affect the overall health of the brain. (C) 2016 Elsevier Inc. All rights reserved. C1 [Swomley, Aaron M.; Triplett, Judy C.; Keeney, Jeriel T.; Warrier, Govind; Butterfield, D. Allan] Univ Kentucky, Dept Chem, Lexington, KY 40536 USA. [Cai, Jian; Klein, Jon B.] Univ Louisville, Prote Ctr, Louisville, KY 40202 USA. [Swomley, Aaron M.; Triplett, Judy C.; Pearson, Kevin J.; Butterfield, D. Allan] Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA. [Pearson, Kevin J.] Univ Kentucky, Mol & Biomed Pharmacol & Nutr, Lexington, KY 40536 USA. [Mattison, Julie A.; de Cabo, Rafael] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. RP Butterfield, DA (reprint author), Univ Kentucky, Dept Chem, Lexington, KY 40506 USA.; Butterfield, DA (reprint author), Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40506 USA. EM dabcns@uky.edu OI , rafael/0000-0003-2830-5693 FU Intramural Research program of the National Institute on Aging, NIH FX This study was funded in part by the Intramural Research program of the National Institute on Aging, NIH. We thank the National Institute on Aging for providing the brain samples used in this study. NR 70 TC 0 Z9 0 U1 11 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0955-2863 EI 1873-4847 J9 J NUTR BIOCHEM JI J. Nutr. Biochem. PD JAN PY 2017 VL 39 BP 169 EP 179 DI 10.1016/j.jnutbio.2016.10.006 PG 11 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA EE4IT UT WOS:000389566200019 PM 27840293 ER PT J AU Brynildsen, JK Hsu, LM Ross, TJ Stein, EA Yang, YH Lu, HB AF Brynildsen, Julia K. Hsu, Li-Ming Ross, Thomas J. Stein, Elliot A. Yang, Yihong Lu, Hanbing TI Physiological characterization of a robust survival rodent fMRI method SO MAGNETIC RESONANCE IMAGING LA English DT Article DE Functional MRI; Connectivity; Neurovascular coupling; Isoflurane; Dexmedetomidine ID CEREBRAL-BLOOD-FLOW; MINIMUM ALVEOLAR CONCENTRATION; FUNCTIONAL MRI; ORBITOFRONTAL CORTEX; CONSCIOUS RATS; DEXMEDETOMIDINE; BRAIN; MEDETOMIDINE; STIMULATION; ANESTHESIA AB Anesthetics are commonly used in preclinical functional MRI studies. It is well-appreciated that proper choice of anesthetics is of critical importance for maintaining a physiologically normal range of autonomic functioning. A recent study, using a low dose of dexmedetomidine (active isomer of medetomidine) in combination with a low dose of isoflurane, suggested stable measurements across repeated fMRI experiments in individual animals with each session lasting up to several hours. The rat default mode network has been successfully identified using this preparation, indicating that this protocol minimally disturbs brain network functions. However, medetomidine is known to cause peripheral vasoconstriction, respiratory suppression, and bradycardia, each of which could independently confound the BOLD signal. The goal of this study was to systematically characterize physiological conditions for fMRI experiments under this anesthetic regimen. To this end, we acquired somatosensory stimulation "task-evoked" and resting-state fMRI to evaluate the integrity of neurovascular coupling and brain network function during three time windows (0-30 min, 30-90 min, and 90-150 min) following dexmedetomidine initiation. Results demonstrate that both evoked BOLD response and resting-state fMRI signal remained stable during the 90-150 min time window, while autonomic physiological parameters maintained near-normal conditions during this period. Our data suggest that using a spontaneously-inhaled, low dose of isoflurane in combination with a continuous low dose of dexmedetomidine is a viable option for longitudinal imaging studies in rats. Published by Elsevier Inc. C1 [Brynildsen, Julia K.; Hsu, Li-Ming; Ross, Thomas J.; Stein, Elliot A.; Yang, Yihong; Lu, Hanbing] NIDA, Neuroimaging Res Branch, Intramural Res Program, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. [Brynildsen, Julia K.] Univ Penn, Neurosci Grad Grp, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Lu, HB (reprint author), NIDA, Neuroimaging Res Branch, Intramural Res Program, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM luha@intra.nida.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH) FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH). NR 43 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 0730-725X EI 1873-5894 J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD JAN PY 2017 VL 35 BP 54 EP 60 DI 10.1016/j.mri.2016.08.010 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EE6PI UT WOS:000389734300008 PM 27580522 ER PT J AU Madeen, EP Lohr, CV You, H Siddens, LK Krueger, SK Dashwood, RH Gonzalez, FJ Baird, WM Ho, E Bramer, L Waters, KM Williams, DE AF Madeen, Erin P. Lohr, Christiane V. You, Hannah Siddens, Lisbeth K. Krueger, Sharon K. Dashwood, Roderick H. Gonzalez, Frank J. Baird, William M. Ho, Emily Bramer, Lisa Waters, Katrina M. Williams, David E. TI Dibenzo[def,p]chrysene transplacental carcinogenesis in wild-type, Cyp1b1 knockout, and CYP1B1 humanized mice SO MOLECULAR CARCINOGENESIS LA English DT Article DE PAH carcinogenesis; transplacental cancer; cytochrome P450 1B1; CYP1B1 humanized mice ID POLYCYCLIC AROMATIC-HYDROCARBONS; CYTOCHROME P4501B1; AH RECEPTOR; MOUSE CYP1B1; DNA-ADDUCTS; CANCER; EXPRESSION; GENE; EXPOSURE; TISSUE AB The cytochrome P450 (CYP) 1 family is active toward numerous environmental pollutants, including polycyclic aromatic hydrocarbons (PAHs). Utilizing a mouse model, null for Cyp1b1 and expressing human CYP1B1, we tested the hypothesis that hCYP1B1 is important for dibenzo[def,p]chrysene (DBC) transplacental carcinogenesis. Wild-type mCyp1b1, transgenic hCYP1B1 (mCyp1b1 null background), and mCyp1b1 null mice were assessed. Each litter had an equal number of siblings with Ahr(b-1/d) and Ahr(d/d) alleles. Pregnant mice were dosed (gavage) on gestation day 17 with 6.5 or 12mg/kg of DBC or corn oil. At 10 months of age, mortality, general health, lymphoid disease and lung tumor incidence, and multiplicity were assessed. hCYP1B1 genotype did not impact lung tumor multiplicity, but tended to enhance incidence compared to Cyp1b1 wild-type mice (P=0.07). As with Cyp1b1 in wild-type mice, constitutive hCYP1B1 protein is non-detectable in liver but was induced with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Wild-type mice were 59% more likely to succumb to T-cell Acute Lymphoblastic Leukemia (T-ALL). Unlike an earlier examination of the Ahr genotype in this model (Yu et al., Cancer Res, 2006;66:755-762), but in agreement with a more recent study (Shorey et al., Toxicol Appl Pharmacol, 2013;270:60-69), this genotype was not associated with lung tumor incidence, multiplicity, or mortality. Sex was not significant with respect to lung tumor incidence or mortality but males exhibited significantly greater multiplicity. Lung tumor incidence was greater in mCyp1b1 nulls compared to wild-type mice. To our knowledge, this is the first application of a humanized mouse model in transplacental carcinogenesis. (c) 2016 Wiley Periodicals, Inc. C1 [Madeen, Erin P.; Siddens, Lisbeth K.; Baird, William M.; Williams, David E.] Oregon State Univ, Dept Mol & Environm Toxicol, Corvallis, OR 97331 USA. [Madeen, Erin P.; Lohr, Christiane V.; You, Hannah; Siddens, Lisbeth K.; Krueger, Sharon K.; Ho, Emily; Williams, David E.] Oregon State Univ, Canc Prevent & Intervent Program, Linus Pauling Inst, Corvallis, OR 97331 USA. [Madeen, Erin P.; Lohr, Christiane V.; Krueger, Sharon K.; Baird, William M.; Bramer, Lisa; Waters, Katrina M.; Williams, David E.] Oregon State Univ, Superfund Res Program, Corvallis, OR 97331 USA. [Lohr, Christiane V.] Oregon State Univ, Coll Vet Med, Corvallis, OR 97331 USA. [Dashwood, Roderick H.] Univ Texas MD Anderson Canc Ctr, Ctr Epigenet & Dis Prevent, Houston, TX 77030 USA. [Gonzalez, Frank J.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Ho, Emily] Oregon State Univ, Dept Nutr & Exercise Sci, Corvallis, OR 97331 USA. [Bramer, Lisa; Waters, Katrina M.] Pacific Northwest Natl Lab, Div Biol Sci, Richland, WA USA. RP Williams, DE (reprint author), Oregon State Univ, Dept Mol & Environm Toxicol, Corvallis, OR 97331 USA. EM david.williams@oregonstate.edu FU PHS NIH [P01CA90890, P42ES016465, T32ES07060]; Pacific Northwest National Laboratory [DE-AC05-76RLO1830] FX The authors would like to thank the following individuals for their contributions. Jamie Pennington assisted with handling and dosing of mice while Dr. Nancy Kerkvliet (Oregon State University) provided expertise and TCDD used for dosing. Tissue collection and preparation assistance was provided by David Sampson, Jessica Phillips, Dr. Tod Harper, and Melissa McDougal. The hCYP1B1 antibody was provided by Dr. Craig Marcus and the mCyp1a1 protein control was provided by Edward O'Donnell (both, Oregon State University). Funding was provided by PHS NIH grants P01CA90890, P42ES016465 and T32ES07060 (EPM). Pacific Northwest National Laboratory is a multi-program national laboratory operated by Battelle Memorial Institute for the DOE under contract number DE-AC05-76RLO1830. NR 54 TC 0 Z9 0 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 EI 1098-2744 J9 MOL CARCINOGEN JI Mol. Carcinog. PD JAN PY 2017 VL 56 IS 1 BP 163 EP 171 DI 10.1002/mc.22480 PG 9 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA EE9EZ UT WOS:000389930000012 PM 26990437 ER PT J AU Yuan, Y Meeker, JD Ferguson, KK AF Yuan, Ye Meeker, John D. Ferguson, Kelly K. TI Serumpolybrominated diphenyl ether (PBDE) concentrations in relation to biomarkers of oxidative stress and inflammation: The National Health and Nutrition Examination Survey 2003-2004 SO SCIENCE OF THE TOTAL ENVIRONMENT LA English DT Article DE Flame retardants; C-reactive protein; Blood biomarkers; Reactive oxygen species; National Health and Nutrition Examination Survey ID PERSISTENT ORGANIC POLLUTANTS; BROMINATED FLAME RETARDANTS; C-REACTIVE PROTEIN; IN-VITRO; ALKALINE-PHOSPHATASE; THYROID-HORMONE; FISH CONSUMERS; DNA-DAMAGE; VITAMIN-A; L02 CELLS AB Exposure to polybrominated diphenyl ethers (PBDEs) has been associated with various adverse health outcomes related to liver, neural and endocrine systems. Some of these may be the result of PBDE-induced oxidative stress or inflammation, but these associations have been explored minimally in humans. In the present study we examined the relationship between PBDE concentrations and biomarkers of oxidative stress and inflammation measured in blood samples among a representative US sample from the National Health and Nutrition Examination Survey. Oxidative stress biomarkers showed no significant associations with PBDEs in adjusted regression models. For inflammation biomarkers, we observed small but statistically significant positive associations between BDE-153 and alkaline phosphatase (percent change with an interquartile range [IQR] increase in BDE-153 = 0.82, 95% confidence interval [CI] = 0.01, 1.65) and absolute neutrophil count (percent change with IQR increase in BDE-153 = 0.53%, 95% CI = 0.03, 1.04). Associations with other PBDE congeners and inflammation markers were generally positive but did not reach statistical significance. These results are consistent with human research of oxidative stress and inflammation in response to PBDE congeners and mixtures, and support previous reports of inflammation in response to PBDE treatment in animal and in vitro studies. More detailed toxicological and epidemiologic research in humans is needed to confirm the present results, and to determine the potential clinical and public health significance of these findings. Published by Elsevier B.V. C1 [Yuan, Ye] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Meeker, John D.; Ferguson, Kelly K.] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Ferguson, Kelly K.] NIEHS, Epidemiol Branch, Durham, NC USA. RP Ferguson, KK (reprint author), 111 TW Alexander Dr,POB 12233,MD A3-05, Res Triangle Pk, NC 27709 USA. EM kelly.ferguson2@nih.gov OI Ferguson, Kelly/0000-0001-8467-3250 FU National Institute of Environmental Health Sciences, National Institutes of Health [R01ES018872, P42ES017198, P01ES022844, P50ES026049, R01ES022955, P30ES017885]; National Institute of Environmental Health Sciences, National Institutes of Health FX Funding for this project was provided by the National Institute of Environmental Health Sciences, National Institutes of Health (R01ES018872, P42ES017198, P01ES022844, P50ES026049, R01ES022955 and P30ES017885) and by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. NR 52 TC 0 Z9 0 U1 15 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0048-9697 EI 1879-1026 J9 SCI TOTAL ENVIRON JI Sci. Total Environ. PD JAN 1 PY 2017 VL 575 BP 400 EP 405 DI 10.1016/j.scitotenv.2016.10.028 PG 6 WC Environmental Sciences SC Environmental Sciences & Ecology GA EF5MD UT WOS:000390373400041 PM 27750136 ER PT J AU Sak, M Duric, N Littrup, P Bey-Knight, L Ali, H Vallieres, P Sherman, ME Gierach, GL AF Sak, Mark Duric, Neb Littrup, Peter Bey-Knight, Lisa Ali, Haythem Vallieres, Patricia Sherman, Mark E. Gierach, Gretchen L. TI USING SPEED OF SOUND IMAGING TO CHARACTERIZE BREAST DENSITY SO ULTRASOUND IN MEDICINE AND BIOLOGY LA English DT Article DE Breast density; Ultrasound tomography; Mammography; Breast Cancer; Sound speed; Dense and non-dense breast volumes; Risk assessment ID NONDENSE MAMMOGRAPHIC AREA; BODY-MASS INDEX; CANCER RISK; ULTRASOUND TOMOGRAPHY; VISUAL CLASSIFICATION; TISSUE DENSITY; SOFTWARE; AGE AB A population of 165 women with negative mammographic screens also received an ultrasound tomography (UST) examination at the Karmanos Cancer Institute in Detroit, ML Standard statistical techniques were employed to measure the associations between the various mammographic- and UST-related density measures and various participant characteristics such as age, weight and height. The mammographic percent density (MPD) was found to have similar strength associations with UST mean sound speed (Spearman coefficient, r(s) = 0.722, p < 0.001) and UST median sound speed (r(s) = 0.737, p < 0.001). Both were stronger than the associations between MPD with two separate measures of UST percent density, a k-means (r(s) = 0.568, p < 0.001) or a threshold (r(s) = 0.715, p < 0.001) measure. Segmentation of the UST sound speed images into dense and non-dense volumes showed weak to moderate associations with the mammographically equivalent measures. Relationships were found to be inversely and weakly associated between age and the UST mean sound speed (r(s) = 0.239, p = 0.002), UST median sound speed (r(s) = 0.226, p = 0.004) and MPD (r(s) = 0.204, p = 0.008). Relationships were found to be inversely and moderately associated between body mass index (BMI) and the UST mean sound speed (r(s) = 0.429, p < 0.001), UST median sound speed (r(s) = 0.447, p < 0.001) and MPD (r(s) = 0.489, p < 0.001). The results confirm and strengthen findings presented in previous work indicating that UST sound speed imaging yields viable markers of breast density in a manner consistent with mammography, the current clinical standard. These results lay the groundwork for further studies to assess the role of sound speed imaging in risk prediction. (E-mail: msakffnelphinwent.com) (C) 2016 World Federation for Ultrasound in Medicine & Biology. C1 [Sak, Mark; Duric, Neb; Littrup, Peter] Delphinus Med Technol, Plymouth, MI USA. [Littrup, Peter] Brown Univ, Rhode Isl Hosp, Providence, RI 02903 USA. [Bey-Knight, Lisa] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Ali, Haythem; Vallieres, Patricia] Henry Ford Hlth Syst, Detroit, MI USA. [Sherman, Mark E.] NCI, Canc Prevent Div, US Dept HHS, Bethesda, MD 20892 USA. [Gierach, Gretchen L.] NCI, Metab Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Sak, M (reprint author), Delphinus Med Technol, 45525 Grand River Ave, Novi, MI 48374 USA. EM msak@delphinusmt.com RI Gierach, Gretchen/E-1817-2016 OI Gierach, Gretchen/0000-0002-0165-5522 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute; National Institutes of Health [HHSN261201400038P]; National Cancer Institute [R44 CA165320] FX The authors wish to thank Dr. Norman Boyd for his work analyzing all mammograms and Ms. Vivian Linke for research assistance. The authors are indebted to the participants in the Ultrasound Study of Tamoxifen for their outstanding cooperation and to the physicians, pathologists, nurses and technologists for their efforts in the field. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The authors acknowledge the support of the National Institutes of Health through contract No HHSN261201400038P and grant No R44 CA165320 from the National Cancer Institute. NR 41 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 0301-5629 EI 1879-291X J9 ULTRASOUND MED BIOL JI Ultrasound Med. Biol. PD JAN PY 2017 VL 43 IS 1 BP 91 EP 103 DI 10.1016/j.ultrasmedbio.2016.08.021 PG 13 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA EE4CM UT WOS:000389549600008 PM 27692872 ER PT J AU Lamichhane, R Mukherjee, S Smolin, N Pauszek, RF Bradley, M Sastri, J Robia, SL Millar, D Campbell, EM AF Lamichhane, Rajan Mukherjee, Santanu Smolin, Nikolai Pauszek, Raymond F., III Bradley, Margret Sastri, Jaya Robia, Seth L. Millar, David Campbell, Edward M. TI Dynamic conformational changes in the rhesus TRIM5 alpha dimer dictate the potency of HIV-1 restriction SO VIROLOGY LA English DT Article DE Single molecule FRET; TRIM5alpha; HIV-1; Molecular dynamics simulation; smFRET; Restriction factor; Coiled coil; Dimer; Tripartite Motif ID SINGLE-MOLECULE FRET; PARTICLE MESH EWALD; RETROVIRAL RESTRICTION; CAPSID RECOGNITION; PRYSPRY DOMAIN; DNA-POLYMERASE; FORCE-FIELDS; SPRY DOMAIN; PROTEIN; DISTRIBUTIONS AB The TRIM5 alpha protein from rhesus macaques (rhTRIM5 alpha) mediates a potent inhibition of HIV-1 infection via a mechanism that involves the abortive disassembly of the viral core. We have demonstrated that alpha-helical elements within the Linker 2 (L2) region, which lies between the SPRY domain and the Coiled-Coil domain, influence the potency of restriction. Here, we utilize single-molecule FRET analysis to reveal that the L2 region of the TRIM5 alpha dimer undergoes dynamic conformational changes, which results in the displacement of L2 regions by 25 angstroms relative to each other. Analysis of restriction enhancing or abrogating mutations in the L2 region reveal that restriction defective mutants are unable to undergo dynamic conformational changes and do not assume compact, alpha-helical conformations in the L2 region. These data suggest a model in which conformational changes in the L2 region mediate displacement of CA bound SPRY domains to induce the destabilization of assembled capsid during restriction. C1 [Lamichhane, Rajan; Pauszek, Raymond F., III; Millar, David] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Mukherjee, Santanu; Bradley, Margret; Campbell, Edward M.] Loyola Univ, Stritch Sch Med, Dept Microbiol & Immunol, Chicago, IL 60611 USA. [Smolin, Nikolai; Robia, Seth L.] Loyola Univ, Stritch Sch Med, Dept Cell & Mol Physiol, Chicago, IL 60611 USA. [Sastri, Jaya] NCI, Viral Mutat Sect, HIV Dynam & Replicat Program, Frederick, MD 21701 USA. RP Campbell, EM (reprint author), Loyola Univ, Stritch Sch Med, Dept Microbiol & Immunol, Chicago, IL 60611 USA. RI Smolin, Nikolai/C-6606-2008; Lamichhane, Rajan/A-3555-2010 OI Lamichhane, Rajan/0000-0003-0089-6452 FU NIH [AI093258, 5P50GM082545, GM123538]; California HIV/AIDS Research program [F12-SRI-210]; National Science Foundation [ACI-1053575]; National Institute of Health grant "Loyola Research Computing Core" [1G20RR030939]; [1R01HL092321] FX EC was supported by NIH grants AI093258, 5P50GM082545 and GM123538. DM was supported by 5P50GM082545. RL was supported by Postdoctoral Training Award (ID # F12-SRI-210) from the California HIV/AIDS Research program. SLR was supported by 1R01HL092321. This work used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation grant number ACI-1053575. This research was supported by equipment and facilities provided by National Institute of Health grant "Loyola Research Computing Core" 1G20RR030939. NR 46 TC 0 Z9 0 U1 7 U2 7 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 JAN PY 2017 VL 500 BP 161 EP 168 DI 10.1016/j.virol.2016.10.003 PG 8 WC Virology SC Virology GA EE4EM UT WOS:000389555100017 PM 27821283 ER PT J AU Kosik, I Yewdell, JW AF Kosik, Ivan Yewdell, Jonathan W. TI Influenza A virus hemagglutinin specific antibodies interfere with virion neuraminidase activity via two distinct mechanisms SO VIROLOGY LA English DT Article DE Influenza; ELLA; TBAA; HA antibodies; Canonical antigenic sites; NA inhibition ID LINKED LECTIN ASSAY; PROTEINS; TITERS AB We studied the ability of monoclonal Abs (mAbs) recognizing the major hemagglutinin (HA) antigenic sites to inhibit neuraminidase (NA) cleavage of sialic acids on fetuin. We show that virion associated-NA activity in the enzyme linked lectin assay (ELLA) is largely dependent on HA-mediated attachment of virions to immobilized fetuin. For a Sb-antigenic site specific mAb, there is a nearly perfect correlation between neuraminidase inhibition and blocking virus attachment to immobilized fetuin. By contrast, Sa-, Ca-, and Cb- antigenic site specific mAbs block NA activity in ELLA or the traditional thiobarbituric acid assay by sterically interfering with NA access to substrate. We conclude first, that ELLA with intact virus can only be used to measure anti-NA Abs if sera lack HA-specific Abs, and second, that anti-HA Abs block NA activity by both limiting virion interaction with sialic acid containing surfaces and by sterically limiting NA access to sialic acids attached to macromolecules. C1 [Kosik, Ivan; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases FX We thank Glenys Reynoso for providing outstanding technical assistance. This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases. NR 25 TC 0 Z9 0 U1 4 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JAN PY 2017 VL 500 BP 178 EP 183 DI 10.1016/j.virol.2016.10.024 PG 6 WC Virology SC Virology GA EE4EM UT WOS:000389555100019 PM 27825034 ER PT J AU Lalwani, G D'agati, M Gopalan, A Rao, M Schneller, J Sitharaman, B AF Lalwani, Gaurav D'agati, Michael Gopalan, Anu Rao, Manisha Schneller, Jessica Sitharaman, Balaji TI Three-dimensional macroporous graphene scaffolds for tissue engineering SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A LA English DT Article DE three-dimensional; graphene; scaffolds; cytotoxicity; tissue engineering ID MESENCHYMAL STEM-CELLS; BIODEGRADABLE POLYMERIC NANOCOMPOSITES; CARBON NANOTUBES; OSTEOGENIC DIFFERENTIATION; BIOMEDICAL APPLICATIONS; NEURAL-NETWORKS; CONTRAST AGENT; ANTIBODY KI-67; CYTOCOMPATIBILITY; FABRICATION AB The assembly of carbon nanomaterials into three-dimensional (3D) porous scaffolds is critical to harness their unique physiochemical properties for tissue engineering and regenerative medicine applications. In this study, we report the fabrication, characterization, and in vitro cytocompatibility of true 3D (>1 mm in all three dimensions), macroscopic (3-8 mm in height and 4-6 mm in diameter), chemically cross-linked graphene scaffolds prepared via radical initiated thermal cross-linking of single- and multiwalled graphene oxide nanoribbons (SWGONRs and MWGONRs). SWGONR and MWGONR scaffolds possess tunable porosity (approximate to 65-80%) and interconnected macro-, micro-, and nanoscale pores. Human adipose derived stem cells (ADSCs) and murine MC3T3 preosteoblast cells show good cell viability on SWGONR and MWGONR scaffolds after 1, 3, and 5 days comparable to 3D poly(lactic-co-glycolic) acid (PLGA) scaffolds. Confocal live-cell imaging showed that cells were metabolically active and could spread on SWGONR and MWGONR scaffolds. Immunofluorescence imaging showed the presence of focal adhesion protein vinculin and expression of cell proliferation marker Ki-67 suggesting that cells could attach and proliferate on SWGONR and MWGONR scaffolds. These results indicate that cross-linked SWGONR and MWGONR scaffolds are cytocompatible and opens-avenues toward the development of 3D multifunctional graphene scaffolds for tissue engineering applications. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 73-83, 2017. C1 [Lalwani, Gaurav; D'agati, Michael; Gopalan, Anu; Rao, Manisha; Sitharaman, Balaji] SUNY Stony Brook, Dept Biomed Engn, Stony Brook, NY 11794 USA. [Schneller, Jessica] NIH, Dept Bioengn, Bethesda, MD 20892 USA. RP Sitharaman, B (reprint author), SUNY Stony Brook, Dept Biomed Engn, Stony Brook, NY 11794 USA. EM balaji.sitharaman@stonybrook.edu OI Lalwani, Gaurav /0000-0001-7769-7481 FU National Institutes of Health [1DP2OD007394-01]; U.S. Department of Energy, Office of Basic Energy Sciences [DE-AC02-98CH10886] FX Contract grant sponsor: National Institutes of Health; contract grant number: 1DP2OD007394-01; Contract grant sponsor: U.S. Department of Energy, Office of Basic Energy Sciences; contract grant number: DE-AC02-98CH10886 NR 57 TC 0 Z9 0 U1 32 U2 32 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1549-3296 EI 1552-4965 J9 J BIOMED MATER RES A JI J. Biomed. Mater. Res. Part A PD JAN PY 2017 VL 105 IS 1 BP 73 EP 83 DI 10.1002/jbm.a.35867 PG 11 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA ED8UC UT WOS:000389145400008 PM 27529473 ER PT J AU Metwalli, AR AF Metwalli, Adam R. TI Standardized Reporting of Microscopic Renal Tumor Margins: Introduction of the Renal Tumor Capsule Invasion Scoring System EDITORIAL COMMENTS SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 [Metwalli, Adam R.] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Metwalli, AR (reprint author), NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD JAN PY 2017 VL 197 IS 1 BP 29 EP 29 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA EE4XN UT WOS:000389609100008 PM 27746136 ER PT J AU Tsai, YC Chen, WY Siu, MK Tsai, HY Yin, JJ Huang, JT Liu, YN AF Tsai, Yuan-Chin Chen, Wei-Yu Siu, Man Kit Tsai, Hong-Yuan Yin, Juan Juan Huang, Jiaoti Liu, Yen-Nien TI Epidermal growth factor receptor signaling promotes metastatic prostate cancer through microRNA-96-mediated downregulation of the tumor suppressor ETV6 SO CANCER LETTERS LA English DT Article DE ETV6; Epidermal growth factor receptor (EGFR) microRNA (miR)-96; Prostate cancer; Bone metastasis ID BONE METASTASIS; EGF RECEPTOR; EXPRESSION; IDENTIFICATION; ACTIVATION; PTEN AB It has been suggested that ETV6 serves as a tumor suppressor; however, its molecular regulation and cellular functions remain unclear. We used prostate cancer as a model system and demonstrated a molecular mechanism in which ETV6 can be regulated by epidermal growth factor receptor (EGFR) signaling through microRNA-96 (miR-96)-mediated downregulation. In addition, EGFR acts as a transcriptional coactivator that binds to the promoter of primary miR-96 and transcriptionally regulates miR-96 levels. We analyzed two sets of clinical prostate cancer samples, confirmed association patterns that were consistent with the EGFR-miR-96-ETV6 signaling model and demonstrated that the reduced ETV6 levels were associated with malignant prostate cancer. Based on results derived from multiple approaches, we identified the biological functions of ETV6 as a tumor suppressor that inhibits proliferation and metastasis in prostate cancer. We present a molecular mechanism in which EGFR activation leads to the induction of miR-96 expression and suppression of ETV6, which contributes to prostate cancer progression. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Tsai, Yuan-Chin; Siu, Man Kit; Tsai, Hong-Yuan; Liu, Yen-Nien] Taipei Med Univ, Grad Inst Canc Biol & Drug Discovery, Coll Med Sci & Technol, Taipei, Taiwan. [Chen, Wei-Yu] Taipei Med Univ, Sch Med, Dept Pathol, Coll Med, Taipei, Taiwan. [Chen, Wei-Yu] Taipei Med Univ, Wan Fang Hosp, Dept Pathol, Taipei, Taiwan. [Siu, Man Kit] Taipei Med Univ, Wan Fang Hosp, Dept Anesthesiol, Taipei, Taiwan. [Yin, Juan Juan] NCI, Lab Genitourinary Canc Pathogenesis, NIH, Bethesda, MD 20892 USA. [Huang, Jiaoti] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. RP Liu, YN (reprint author), Taipei Med Univ, 250 Wu Hsing St, Taipei 11031, Taiwan. EM liuy@tmu.edu.tw FU Ministry of Science and Technology of Taiwan [MOST103-2314-B-038-051, MOST104-2314-B-038-045-MY3, MOST 104-2320-B-038-055-MY3]; National Health Research Institutes of Taiwan [NHRI-EX105-10308BC] FX We thank Dr. Susan Spence (MD, USA) and Dr. Ji-Hshiung Chen (Tzu Chi University, Taiwan) for reading the manuscript and for comments and helpful suggestions. This work was supported by the Ministry of Science and Technology of Taiwan (MOST103-2314-B-038-051, MOST104-2314-B-038-045-MY3) to YNL, (MOST 104-2320-B-038-055-MY3) to YCT, and by the National Health Research Institutes of Taiwan (NHRI-EX105-10308BC) to YNL. NR 30 TC 0 Z9 0 U1 7 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD JAN 1 PY 2017 VL 384 BP 1 EP 8 DI 10.1016/j.canlet.2016.10.014 PG 8 WC Oncology SC Oncology GA ED8GJ UT WOS:000389109700001 ER PT J AU Palmer, BW Harmell, AL Pinto, LL Dunn, LB Kim, SYH Golshan, S Jeste, DV AF Palmer, Barton W. Harmell, Alexandrea L. Pinto, Luz L. Dunn, Laura B. Kim, Scott Y. H. Golshan, Shahrokh Jeste, Dilip V. TI Determinants of Capacity to Consent to Research on Alzheimer's Disease SO CLINICAL GERONTOLOGIST LA English DT Article DE Competence; ethics; dementia; informed consent; autonomy ID ASSESSING DECISIONAL CAPACITY; MILD COGNITIVE IMPAIRMENT; INFORMED-CONSENT; CLINICAL-RESEARCH; DEMENTIA-RESEARCH; TRIAL; PARTICIPATION; SCHIZOPHRENIA; COMPETENCE; INSTRUMENT AB Objective: Investigators conducting Alzheimer's disease (AD) research need to consider participants' capacity to consent. Cognitive functioning is a significant predictor of decisional capacity, but there is a dearth of information on the influence of neuropsychiatric symptoms in AD on decisional capacity. We examined the rates of decisional capacity associated with two types of research protocols, and the association of capacity with neuropsychiatric symptoms and other participant characteristics.Methods: We comprehensively evaluated decisional capacity among 64 patients with mild-to-moderate AD and 70 healthy comparison (HC) subjects randomized to consider either a medium-risk or higher-risk hypothetical research protocol. Additional measures included sociodemographics, cognitive deficits, and neuropsychiatric symptoms.Results: Twenty AD patients (31.3%) and 67 HCs (95.7%) were deemed capable; 44 AD patients (68.8%) and 3 HCs (4.3%) incapable of consent. Age, education, and severity of cognitive deficits were associated with incapable status; there were no significant associations with severity of neuropsychiatric symptoms or protocol risk level.Conclusions: Findings highlight the importance of understanding of capacity and its assessment among people with AD, rather than treating AD diagnosis as synonymous with impaired capacity. As novel treatments move from bench to bedside, methods of assessing and addressing capacity impairment must similarly advance.Clinical Implications: In assessing research consent capacity, use structured assessments interpreted in the context of the person's background including education, culture, and language. Individuals should be encouraged to execute research proxy documents when able. C1 [Palmer, Barton W.; Harmell, Alexandrea L.; Pinto, Luz L.; Golshan, Shahrokh; Jeste, Dilip V.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Palmer, Barton W.] Vet Med Res Fdn, San Diego, CA USA. [Palmer, Barton W.; Golshan, Shahrokh] Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. [Palmer, Barton W.; Harmell, Alexandrea L.; Pinto, Luz L.; Jeste, Dilip V.] Univ Calif San Diego, Stein Inst Res Aging, Ctr Hlth Aging, La Jolla, CA 92093 USA. [Harmell, Alexandrea L.] Univ Calif San Diego, San Diego State Univ, Joint Doctoral Program Clin Psychol, San Diego, CA 92103 USA. [Dunn, Laura B.] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Kim, Scott Y. H.] NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. RP Palmer, BW (reprint author), Univ Calif San Diego, Psychiat, 8950 Villa La Jolla Dr,Suite B122, La Jolla, CA 92037 USA. EM bpalmer@ucsd.edu FU National Institutes of Health [R01AG028827, T32MH019934]; Department of Veterans Affairs FX Source(s) of Support: This project was supported, in part, by National Institutes of Health Grants R01AG028827 and T32MH019934, and by the Department of Veterans Affairs. NR 30 TC 0 Z9 0 U1 10 U2 10 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0731-7115 EI 1545-2301 J9 CLIN GERONTOLOGIST JI Clin. Gerontol. PY 2017 VL 40 IS 1 SI SI BP 24 EP 34 DI 10.1080/07317115.2016.1197352 PG 11 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA EC0PZ UT WOS:000387804400004 PM 28154452 ER PT J AU Brooks, CE Clayton, JA AF Brooks, Claudette Elise Clayton, Janine Austin TI Sex/Gender Influences on the Nervous System: Basic Steps Toward Clinical Progress SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Editorial Material DE women's health; preclinical research; biological variable; reproducibility; sex-based data ID MULTIPLE-SCLEROSIS; SEX BIAS AB A Commentary highlighting the progress that sex-based data and research have made in neuroscience and the complexities that research has revealed thus far. Basic and preclinical neuroscientific research that considers sex as a biological variable will continue to build on the foundation of knowledge that has been started by multiple predecessors. The expansion of knowledge in preclinical neuroscience that integrates the study of both sexes will have a significant role in informing clinical trial design. We applaud the efforts of the editors and authors who have contributed to this issue. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. C1 [Brooks, Claudette Elise; Clayton, Janine Austin] NIH, Off Director, ORWH, Bldg 10, Bethesda, MD 20892 USA. RP Brooks, CE (reprint author), NIH, Off Res Womens Hlth, 6707 Democracy Blvd,Suite 400, Bethesda, MD 20892 USA. EM Claudette.Brooks@nih.gov FU Intramural NIH HHS [Z99 OD999999] NR 24 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0360-4012 EI 1097-4547 J9 J NEUROSCI RES JI J. Neurosci. Res. PD JAN-FEB PY 2017 VL 95 IS 1-2 BP 14 EP 16 DI 10.1002/jnr.23902 PG 3 WC Neurosciences SC Neurosciences & Neurology GA EC9DI UT WOS:000388443900003 PM 27870446 ER PT J AU Fried, PJ Schilberg, L Brem, AK Saxena, S Wong, B Cypess, AM Horton, ES Pascual-Leone, A AF Fried, Peter J. Schilberg, Lukas Brem, Anna-Katharine Saxena, Sadhvi Wong, Bonnie Cypess, Aaron M. Horton, Edward S. Pascual-Leone, Alvaro TI Humans with Type-2 Diabetes Show Abnormal Long-Term Potentiation-Like Cortical Plasticity Associated with Verbal Learning Deficits SO JOURNAL OF ALZHEIMERS DISEASE LA English DT Article DE Cognitive aging; neuroplasticity; transcranial magnetic stimulation; type 2 diabetes mellitus; verbal learning ID THETA-BURST-STIMULATION; MILD COGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE PATIENTS; HUMAN MOTOR CORTEX; NMDA RECEPTOR BLOCKADE; INTRANASAL INSULIN; CEREBRAL-CORTEX; PHYSIOLOGICAL-BASIS; HEALTHY HUMANS; MEMORY AB Background: Type-2 diabetes mellitus (T2DM) accelerates cognitive aging and increases risk of Alzheimer's disease. Rodent models of T2DM show altered synaptic plasticity associated with reduced learning and memory. Humans with T2DM also show cognitive deficits, including reduced learning and memory, but the relationship of these impairments to the efficacy of neuroplastic mechanisms has never been assessed. Objective: Our primary objective was to compare mechanisms of cortical plasticity in humans with and without T2DM. Our secondary objective was to relate plasticity measures to standard measures of cognition. Methods: A prospective cross-sectional cohort study was conducted on 21 adults with T2DM and 15 demographically similar non-diabetic controls. Long-term potentiation-like plasticity was assessed in primary motor cortex by comparing the amplitude of motor evoked potentials (MEPs) from single-pulse transcranial magnetic stimulation before and after intermittent theta-burst stimulation (iTBS). Plasticity measures were compared between groups and related to neuropsychological scores. Results: In T2DM, iTBS-induced modulation of MEPs was significantly less than controls, even after controlling for potential confounds. Furthermore, in T2DM, modulation of MEPs 10-min post-iTBS was significantly correlated with Rey Auditory Verbal Learning Task (RAVLT) performance. Conclusion: Humans with T2DM show abnormal cortico-motor plasticity that is correlated with reduced verbal learning. Since iTBS after-effects and the RAVLT are both NMDA receptor-dependent measures, their relationship in T2DM may reflect brain-wide alterations in the efficacy of NMDA receptors. These findings offer novel mechanistic insights into the brain consequences of T2DM and provide a reliable means to monitor brain health and evaluate the efficacy of clinical interventions. C1 [Fried, Peter J.; Schilberg, Lukas; Brem, Anna-Katharine; Saxena, Sadhvi; Wong, Bonnie; Pascual-Leone, Alvaro] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Intervent Cognit Neurol, Berenson Allen Ctr Noninvas Brain Stimulat, Boston, MA USA. [Schilberg, Lukas] Maastricht Univ, Fac Psychol & Neurosci, Dept Cognit Neurosci, Maastricht, Netherlands. [Brem, Anna-Katharine] Univ Oxford, Dept Expt Psychol, Oxford, England. [Saxena, Sadhvi] Johns Hopkins Med Sch, Dept Psychiat & Behav Sci, Baltimore, MD USA. [Cypess, Aaron M.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD USA. [Cypess, Aaron M.; Horton, Edward S.] Harvard Med Sch, Joslin Diabet Ctr, Res Div, Boston, MA USA. [Wong, Bonnie] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Frontotemporal Dementia Unit, Charlestown, MA USA. RP Fried, PJ; Pascual-Leone, A (reprint author), Beth Israel Deaconess Med Ctr, Berenson Allen Ctr Noninvas Brain Stimulat, 330 Brookline Ave,KS 158, Boston, MA 02215 USA. EM pfried@bidmc.harvard.edu; apleone@bidmc.harvard.edu FU Young Academics Support; Stiefel-Zangger Foundation of the University of Zurich, Switzerland; Swiss National Foundation [PBZHP1_147196]; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Sidney R. Baer Jr. Foundation; National Institutes of Health (NIH) [R21 NS082870, R01 HD069776, R01 NS073601, R21 MH099196, R21 NS085491, R21 HD07616]; Harvard Catalyst \ The Harvard Clinical and Translational Science Center (NCRR and the NCATS NIH) [UL1 RR025758] FX This study was primarily funded by the National Institutes of Health (NIH R21 NS082870). Dr. Brem was further supported by the Young Academics Support and the Stiefel-Zangger Foundation of the University of Zurich, Switzerland, and the Swiss National Foundation (PBZHP1_147196). Dr. Cypess was further supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Dr. Pascual-Leone was further supported in part by the Sidney R. Baer Jr. Foundation, the NIH (R01 HD069776, R01 NS073601, R21 MH099196, R21 NS085491, R21 HD07616), and Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (NCRR and the NCATS NIH, UL1 RR025758). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, the National Institutes of Health, or the Sidney R. Baer Jr. Foundation. NR 58 TC 0 Z9 0 U1 3 U2 3 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 1387-2877 EI 1875-8908 J9 J ALZHEIMERS DIS JI J. Alzheimers Dis. PY 2017 VL 55 IS 1 BP 89 EP 100 DI 10.3233/JAD-160505 PG 12 WC Neurosciences SC Neurosciences & Neurology GA EB8WI UT WOS:000387671600009 PM 27636847 ER PT J AU Collingridge, GL Lodge, D Mayer, M Turrigiano, G Frenguelli, BG AF Collingridge, Graham L. Lodge, David Mayer, Mark Turrigiano, Gina Frenguelli, Bruno G. TI Ionotropic glutamate receptors: Still exciting after all these years SO NEUROPHARMACOLOGY LA English DT Editorial Material ID NMDA RECEPTOR; MOLECULAR DIVERSITY; ASPARTATE; MEMANTINE; CHANNELS; CLONING; FAMILY C1 [Collingridge, Graham L.; Lodge, David] Univ Bristol, Sch Physiol Pharmacol & Neurosci, Ctr Synapt Plast, Dorothy Hodgkin Bldg, Bristol BS1 3NY, Avon, England. [Collingridge, Graham L.] Univ Toronto, Dept Physiol, Toronto, ON M5S 1A8, Canada. [Collingridge, Graham L.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Mayer, Mark] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Turrigiano, Gina] Brandeis Univ, Dept Biol, Waltham, MA 02453 USA. [Frenguelli, Bruno G.] Univ Warwick, Sch Life Sci, Coventry CV4 7AL, W Midlands, England. RP Frenguelli, BG (reprint author), Univ Warwick, Sch Life Sci, Coventry CV4 7AL, W Midlands, England. EM b.g.frenguelli@warwick.ac.uk RI Collingridge, Graham/C-4605-2015 OI Collingridge, Graham/0000-0002-9572-5359 NR 43 TC 0 Z9 0 U1 10 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD JAN PY 2017 VL 112 SI SI BP 1 EP 3 DI 10.1016/j.neuropharm.2016.09.019 PN A PG 3 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA EB8FK UT WOS:000387626700001 PM 27659748 ER PT J AU Mayer, ML AF Mayer, Mark L. TI The structure and function of glutamate receptors: Mg2+ block to X-ray diffraction SO NEUROPHARMACOLOGY LA English DT Review DE Structural biology; Glutamate receptors ID SPINAL-CORD NEURONS; EXCITATORY AMINO-ACIDS; VOLTAGE-CLAMP ANALYSIS; LIGAND-BINDING DOMAIN; CRYSTAL-STRUCTURES; HIPPOCAMPAL-NEURONS; MAGNESIUM-IONS; DESENSITIZATION; NMDA; AMPA AB Experiments on the action of glutamate on mammalian and amphibian nervous systems started back in the 1950s but decades passed before it became widely accepted that glutamate was the major excitatory neurotransmitter in the CNS. The pace of research greatly accelerated in the 1980s when selective ligands that identified glutamate receptor subtypes became widely available, and voltage clamp techniques, coupled with rapid perfusion, began to resolve the unique functional properties of what cloning subsequently revealed to be a large family of receptors with numerous subtypes. More recently the power of X-ray crystallography and cryo-EM has been applied to the study of glutamate receptors, revealing their atomic structures, and the conformational changes that underlie their gating. In this review I summarize the history of this field, viewed through the lens of a career in which I spent 3 decades working on the structure and function of glutamate receptor ion channels. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'. Published by Elsevier Ltd. C1 [Mayer, Mark L.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Mayer, ML (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM mayerm@mail.nih.gov FU Intramural Research Program of the NIH; NICHD; NINDS FX This work was supported by the Intramural Research Program of the NIH, NICHD and NINDS. NR 38 TC 0 Z9 0 U1 13 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD JAN PY 2017 VL 112 SI SI BP 4 EP 10 DI 10.1016/j.neuropharm.2016.04.039 PN A PG 7 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA EB8FK UT WOS:000387626700002 PM 27131921 ER PT J AU Resnik, DB AF Resnik, David B. TI The Role of Intuition in Risk/Benefit Decision-Making in Human Subjects Research SO ACCOUNTABILITY IN RESEARCH-POLICIES AND QUALITY ASSURANCE LA English DT Article DE Benefits; human subjects research; institutional review boards; intuition; reasoning; risks ID MORAL JUDGMENT; RESEARCH RISKS; CLINICAL-RESEARCH; SPECIFIED PRINCIPLISM; BIOMEDICAL-RESEARCH; PEDIATRIC RESEARCH; IRB MEMBERS; BENEFIT; TRIALS; CASUISTRY AB One of the key principles of ethical research involving human subjects is that the risks of research to should be acceptable in relation to expected benefits. Institutional review board (IRB) members often rely on intuition to make risk/benefit decisions concerning proposed human studies. Some have objected to using intuition to make these decisions because intuition is unreliable and biased and lacks transparency. In this article, I examine the role of intuition in IRB risk/benefit decision-making and argue that there are practical and philosophical limits to our ability to reduce our reliance on intuition in this process. The fact that IRB risk/benefit decision-making involves intuition need not imply that it is hopelessly subjective or biased, however, since there are strategies that IRBs can employ to improve their decisions, such as using empirical data to estimate the probability of potential harms and benefits, developing classification systems to guide the evaluation of harms and benefits, and engaging in moral reasoning concerning the acceptability of risks. C1 [Resnik, David B.] NIEHS, NIH, 111 Alexander Dr,Box 12223,Mail Drop E1-06, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, 111 Alexander Dr,Box 12223,Mail Drop E1-06, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU National Institutes of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH) FX This research was supported by the intramural program of the National Institutes of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). It does not represent the views of the NIEHS, NIH, or U.S. federal government. NR 93 TC 1 Z9 1 U1 14 U2 14 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0898-9621 EI 1545-5815 J9 ACCOUNT RES JI Account. Res. PY 2017 VL 24 IS 1 BP 1 EP 29 DI 10.1080/08989621.2016.1198978 PG 29 WC Medical Ethics SC Medical Ethics GA DZ8JD UT WOS:000386115800001 PM 27294429 ER PT J AU Unger, ER Lin, JMS Brimmer, DJ Lapp, CW Komaroff, AL Nath, A Laird, S Iskander, J AF Unger, Elizabeth R. Lin, Jin-Mann Sally Brimmer, Dana J. Lapp, Charles W. Komaroff, Anthony L. Nath, Avindra Laird, Susan Iskander, John TI CDC Grand Rounds: Chronic Fatigue Syndrome - Advancing Research and Clinical Education SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article ID OF-HEALTH PATHWAYS; PREVENTION WORKSHOP; DEFINITION C1 [Unger, Elizabeth R.; Lin, Jin-Mann Sally; Brimmer, Dana J.] CDC, Div High Consequence Pathogens & Pathol, Natl Ctr Emerging & Zoonot Dis, Atlanta, GA 30333 USA. [Lapp, Charles W.] Hunter Hopkins Ctr, Charlotte, NC USA. [Komaroff, Anthony L.] Harvard Univ, Harvard Med Sch, Cambridge, MA 02138 USA. [Komaroff, Anthony L.] Harvard Univ, Brigham & Womens Hosp, Cambridge, MA 02138 USA. [Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Laird, Susan] CDC, Off Associate Director Commun, Atlanta, GA 30333 USA. [Iskander, John] CDC, Off Associate Director Sci, Atlanta, GA 30333 USA. RP Unger, ER (reprint author), CDC, Div High Consequence Pathogens & Pathol, Natl Ctr Emerging & Zoonot Dis, Atlanta, GA 30333 USA. EM eunger@cdc.gov NR 17 TC 0 Z9 0 U1 2 U2 2 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 DEC 30 PY 2016 VL 65 IS 50-51 BP 1434 EP 1438 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EH7LJ UT WOS:000391954200004 PM 28033311 ER PT J AU Bae, Y Green, ES Kim, GY Song, SJ Mun, JY Lee, S Park, JI Park, JS Ko, KS Han, J Choi, JS AF Bae, Yoonhee Green, Eric S. Kim, Goo-Young Song, Su Jeong Mun, Ji Young Lee, Sunray Park, Jong-Il Park, Jong-sang Ko, Kyung Soo Han, Jin Choi, Joon Sig TI Dipeptide-functionalized polyamidoamine dendrimer-mediated apoptin gene delivery facilitates apoptosis of human primary glioma cells SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Apoptin; Gene therapy; PAMAM dendrimer; Human primary glioma cells; Apoptosis ID TRANSFECTION EFFICIENCY; BIOLOGICAL APPLICATIONS; PAMAM DENDRIMER; BRAIN-TUMORS; PLASMID DNA; IN-VIVO; THERAPY; DEATH; CANCER; CYTOTOXICITY AB Glioblastoma multiform (GBM) is the most frequent and aggressive form of brain tumors in adults. However, the development of more efficient and safe nonviral vector gene therapy represents a promising therapeutic approach, using a tumor-specific killer gene, named apoptin. In this study, we describe the efficacy of non-viral gene delivery vectors, the amino acid-conjugated PAMAM derivatives (PAMAM-H-R and PAMAM-H-K) in delivering a therapeutic gene, displaying affinity toward human primary glioma cells (GBL-14 cells) and dermal fibroblasts. We analyzed transfection efficiency, using luciferase (Luci) and a pDNA encoding for enhanced fluorescent protein (EGFP), and cytotoxicity in both cells. The results show that transfection efficiency of PAMAM-H-R improved compared to native PAMAM dendrimer, but cytotoxicity of PAMAM-H-R and PAMAM-H-K were very low. We treated both cells with a polyplex formation of PAMAM-H-R or PAMAM-H-K/apoptin, and analyzed their cellular uptake and localization by flow cytometry and confocal microscopy. Furthermore, we analyzed the endosomal escape effect using TEM images, and found that PAMAM-H-R showed very fast escape from endosome to the cytosol. Caspase 3 activity assay, cell cycle distribution, and JC-1 analysis showed apoptosis induced by apoptin in GBL-14 cells. This indicates that PAMAM-H-R can be a potential nonviral vector gene delivery carrier for brain tumor therapy. The present study demonstrates that PAMAM-H-R/apoptin gene polyplex can be used as an effective therapeutic candidate for GBM due to its selective induction of apoptosis in primary glioma cells as a potential nonviral gene delivery carrier for brain tumor therapy. (C) 2016 Elsevier B.V. All rights reserved. C1 [Song, Su Jeong; Choi, Joon Sig] Chungnam Natl Univ, Dept Biochem, Coll Nat Sci, Daejeon 305764, South Korea. [Bae, Yoonhee; Han, Jin] Inje Univ, Dept Physiol, Coll Med, Cardiovasc & Metab Dis Ctr, Busan 614735, South Korea. [Ko, Kyung Soo] Inje Univ, Sanggye Paik Hosp, Dept Internal Med, Cardiovasc & Metab Dis Ctr, Seoul 139707, South Korea. [Park, Jong-sang] Seoul Natl Univ, Sch Chem, Seoul 151742, South Korea. [Park, Jong-Il] Chungnam Natl Univ, Sch Med, Daejeon 301747, South Korea. [Lee, Sunray] Cell Engn Origin Res Ctr, 46-21 Susong Dog, Seoul 110140, South Korea. [Mun, Ji Young] Eulji Univ, Dept Biomed Lab Sci, Coll Hlth Sci, Daejeon, South Korea. [Green, Eric S.] Salt Lake Community Coll, Salt Lake City, UT USA. [Kim, Goo-Young] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Differentiat, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Choi, JS (reprint author), Chungnam Natl Univ, Dept Biochem, Coll Nat Sci, Daejeon 305764, South Korea.; Han, J (reprint author), Inje Univ, Dept Physiol, Coll Med, Cardiovasc & Metab Dis Ctr, Busan 614735, South Korea. EM phyhanj@inje.ac.kr; joonsig@cnu.ac.kr FU Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education [NRF-2013R1A1A2064737]; Priority Research Centers Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [2010-0020224] FX This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2013R1A1A2064737) and by the Priority Research Centers Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0020224). NR 48 TC 0 Z9 0 U1 18 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 EI 1873-3476 J9 INT J PHARMACEUT JI Int. J. Pharm. PD DEC 30 PY 2016 VL 515 IS 1-2 BP 186 EP 200 DI 10.1016/j.ijpharm.2016.09.083 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA ED8WD UT WOS:000389150700017 PM 27732896 ER PT J AU Tseng, WL Thomas, LA Harkins, E Stoddard, J Zarate, CA Pine, DS Leibenluft, E Brotman, MA AF Tseng, Wan-Ling Thomas, Laura A. Harkins, Elizabeth Stoddard, Joel Zarate, Carlos A., Jr. Pine, Daniel S. Leibenluft, Ellen Brotman, Melissa A. TI Functional connectivity during masked and unmasked face emotion processing in bipolar disorder SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Bipolar disorder; Functional neuroimaging; Backward masking; Functional connectivity; Face emotion processing ID SEVERE MOOD DYSREGULATION; PREFRONTAL CORTEX; AMYGDALA RESPONSE; RATING-SCALE; ANGRY FACES; FMRI; DEPRESSION; YOUTH; NEUROANATOMY; METAANALYSIS AB Little is known regarding the neural connectivity and correlates during automatic, unconscious face emotion processing in individuals with bipolar disorder (BD). In this study, 14 adults with BD and 14 healthy volunteers (HV) underwent fMRI scanning while completing an affective priming task with unconsciously perceived and consciously perceived faces (angry, happy, neutral, blank oval). We found that, regardless of awareness level and emotion types, BD patients exhibited diminished functional connectivity between amygdala and ventromedial prefrontal cortex (vmPFC) compared to HV. This connectivity finding is present in the absence of activation differences in amygdala. In addition, in medial frontal gyrus, BD patients displayed greater activation while HV displayed less activation to angry and neutral faces compared to blank ovals. These results suggest that aberrant amygdala-vmPFC connectivity and neural dysfunction in areas implicated in appraisal and expression of emotions (medial frontal gyrus) may be the pathophysiological correlates of emotional processing in BD regardless of awareness level. C1 [Tseng, Wan-Ling; Harkins, Elizabeth; Stoddard, Joel; Pine, Daniel S.; Leibenluft, Ellen; Brotman, Melissa A.] NIMH, Emot & Dev Branch, NIH, Dept Hlth & Human Serv, Bldg 15,Room 208,15K North Dr, Bethesda, MD 20892 USA. [Thomas, Laura A.] Vet Affairs Med Ctr, War Related Illness & Injury Study Ctr, Washington, DC USA. [Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Tseng, WL (reprint author), NIMH, Emot & Dev Branch, NIH, Dept Hlth & Human Serv, Bldg 15,Room 208,15K North Dr, Bethesda, MD 20892 USA. EM wan-ling.tseng@nih.gov RI Brotman, Melissa/H-7409-2013 FU Intramural Research Program of the National Institute of Mental Health (NIMH), National Institutes of Health (NIH) [ZIAMH002778] FX This research was supported by the Intramural Research Program of the National Institute of Mental Health (NIMH), National Institutes of Health (NIH; ZIAMH002778), and it was conducted under NIH Clinical Study Protocol 00-M-0198 (ClinicalTrials. gov ID: NCT00006177). We thank the staff of the Emotion and Development Branch at the NIMH and the patients and healthy adults for their participation in this study. NR 49 TC 0 Z9 0 U1 13 U2 13 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 EI 1872-7506 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD DEC 30 PY 2016 VL 258 BP 1 EP 9 DI 10.1016/j.pscychresns.2016.10.006 PG 9 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EE3QV UT WOS:000389511600001 PM 27814457 ER PT J AU Bocchini, CE Nahmod, K Katsonis, P Kim, S Kasembeli, MM Freeman, A Lichtarge, O Makedonas, G Tweardy, DJ AF Bocchini, Claire E. Nahmod, Karen Katsonis, Panagiotis Kim, Sang Kasembeli, Moses M. Freeman, Alexandra Lichtarge, Olivier Makedonas, George Tweardy, David J. TI Protein stabilization improves STAT3 function in autosomal dominant hyper-IgE syndrome SO BLOOD LA English DT Article ID HYPERIMMUNOGLOBULIN-E SYNDROME; EPSTEIN-BARR VIRUS; SIGNAL TRANSDUCER; STABILITY CHANGES; MYCOBACTERIAL DISEASE; MUTATIONS; DEFICIENCY; ACTIVATOR; DOMAIN; TRANSCRIPTION AB Autosomal dominant hyper-IgE syndrome (AD-HIES) is caused by dominant-negative mutations in STAT3; however, the molecular basis for mutant STAT3 allele dysfunction is unclear and treatment remains supportive. We hypothesized that AD-HIES mutations decrease STAT3 protein stability and that mutant STAT3 activity can be improved by agents that increase chaperone protein activity. We used computer modeling to characterize the effect of STAT3 mutations on protein stability. We measured STAT3 protein half-life (t(1/2)) and determined levels of STAT3 phosphorylated on tyrosine (Y) 705 (pY-STAT3) and mRNA levels of STAT3 gene targets in Epstein-Barr virus-transformed B (EBV) cells, human peripheral blood mononuclear cells (PBMCs), and mouse splenocytes incubated without or with chaperone protein modulators-HSF1A, a small-molecule TRiC modulator, or geranylgeranylacetone (GGA), a drug that upregulates heat shock protein (HSP) 70 and HSP90. Computer modeling predicted that 81% of AD-HIES mutations are destabilizing. STAT3 protein t1/2 in EBV cells from AD-HIES patients with destabilizing STAT3 mutations was markedly reduced. Treatment of EBV cells containing destabilizing STAT3 mutations with either HSF1 A or GGA normalized STAT3t(1/2), increased pY-STAT3 levels, and increased mRNA levels of STAT3 target genes up to 79% of control. In addition, treatment of human PBMCs or mouse splenocytes containing destabilizing STAT3 mutations with either HSF1A or GGA increased levels of cytokine-activated pY-STAT3 within human CD4(+) and CD8(+) T cells and numbers of IL-17-producing CD4(+) mouse splenocytes, respectively. Thus, most AD-HIES STAT3 mutations are destabilizing; agents that modulate chaperone protein function improve STAT3 stability and activity in T cells and may provide a specific treatment. C1 [Bocchini, Claire E.; Nahmod, Karen; Makedonas, George] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Katsonis, Panagiotis; Lichtarge, Olivier] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Kim, Sang; Kasembeli, Moses M.; Tweardy, David J.] Univ Texas MD Anderson Canc Ctr, Div Internal Med, Houston, TX 77030 USA. [Freeman, Alexandra] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM djtweardy@mdanderson.org FU National Institutes of Health, National Eye Institute [PN1EY016525]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [K12 HD041648]; National Institute of General Medical Sciences [GM79656, GM66099]; Cancer Prevention and Treatment Institute of Texas [RP110291]; Stanley A. Plotkin Sanofi Pasteur Pediatric Infectious Disease Society Fellowship; National Science Foundation [CCF-0905536, DBI-1062455] FX This study was funded by the National Institutes of Health, National Eye Institute grant PN1EY016525 (D.J.T.), Eunice Kennedy Shriver National Institute of Child Health and Human Development grant K12 HD041648 (C.E.B.), and National Institute of General Medical Sciences grants GM79656 and GM66099 (O.L.); Cancer Prevention and Treatment Institute of Texas grant RP110291) (D.J.T.); the Stanley A. Plotkin Sanofi Pasteur Pediatric Infectious Disease Society Fellowship Award (D.J.T.); and National Science Foundation grants CCF-0905536 and DBI-1062455 (O.L.). NR 52 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 DEC 29 PY 2016 VL 128 IS 26 BP 3061 EP 3072 DI 10.1182/blood-2016-02-702373 PG 12 WC Hematology SC Hematology GA EI7CZ UT WOS:000392656400011 PM 27799162 ER PT J AU Post, K Olson, ED Naufer, MN Gorelick, RJ Rouzina, I Williams, MC Musier-Forsyth, K Levin, JG AF Post, Klara Olson, Erik D. Naufer, M. Nabuan Gorelick, Robert J. Rouzina, Ioulia Williams, Mark C. Musier-Forsyth, Karin Levin, Judith G. TI Mechanistic differences between HIV-1 and SIV nucleocapsid proteins and cross-species HIV-1 genomic RNA recognition SO RETROVIROLOGY LA English DT Article DE HIV-1; SIV; Nucleocapsid proteins; Nucleic acid chaperone activity; Psi RNA packaging signal; Minus-strand transfer; Small angle X-ray scattering; Single molecule DNA stretching; Nucleic acid binding; Reverse transcription ID SIMIAN IMMUNODEFICIENCY VIRUS; ACID-CHAPERONE ACTIVITY; MURINE LEUKEMIA-VIRUS; STRONG-STOP DNA; PRIMER BINDING-SITE; REVERSE TRANSCRIPTION; PACKAGING SIGNAL; STRAND TRANSFER; IN-VITRO; RETROVIRAL REPLICATION AB Background: The nucleocapsid (NC) domain of HIV-1 Gag is responsible for specific recognition and packaging of genomic RNA (gRNA) into new viral particles. This occurs through specific interactions between the Gag NC domain and the Psi packaging signal in gRNA. In addition to this critical function, NC proteins are also nucleic acid (NA) chaperone proteins that facilitate NA rearrangements during reverse transcription. Although the interaction with Psi and chaperone activity of HIV-1 NC have been well characterized in vitro, little is known about simian immunodeficiency virus (SIV) NC. Non-human primates are frequently used as a platform to study retroviral infection in vivo; thus, it is important to understand underlying mechanistic differences between HIV-1 and SIV NC. Results: Here, we characterize SIV NC chaperone activity for the first time. Only modest differences are observed in the ability of SIV NC to facilitate reactions that mimic the minus-strand annealing and transfer steps of reverse transcription relative to HIV-1 NC, with the latter displaying slightly higher strand transfer and annealing rates. Quantitative single molecule DNA stretching studies and dynamic light scattering experiments reveal that these differences are due to significantly increased DNA compaction energy and higher aggregation capability of HIV-1 NC relative to the SIV protein. Using salt-titration binding assays, we find that both proteins are strikingly similar in their ability to specifically interact with HIV-1 Psi RNA. In contrast, they do not demonstrate specific binding to an RNA derived from the putative SIV packaging signal. Conclusions: Based on these studies, we conclude that (1) HIV-1 NC is a slightly more efficient NA chaperone protein than SIV NC, (2) mechanistic differences between the NA interactions of highly similar retroviral NC proteins are revealed by quantitative single molecule DNA stretching, and (3) SIV NC demonstrates cross-species recognition of the HIV-1 Psi RNA packaging signal. C1 [Post, Klara; Levin, Judith G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Viral Gene Regulat, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Olson, Erik D.; Rouzina, Ioulia; Musier-Forsyth, Karin] Ohio State Univ, Dept Chem & Biochem, Ctr Retrovirus Res, Columbus, OH 43210 USA. [Olson, Erik D.; Rouzina, Ioulia; Musier-Forsyth, Karin] Ohio State Univ, Ctr RNA Biol, Columbus, OH 43210 USA. [Naufer, M. Nabuan; Williams, Mark C.] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Gorelick, Robert J.] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Levin, JG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Viral Gene Regulat, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA.; Musier-Forsyth, K (reprint author), Ohio State Univ, Dept Chem & Biochem, Ctr Retrovirus Res, Columbus, OH 43210 USA.; Musier-Forsyth, K (reprint author), Ohio State Univ, Ctr RNA Biol, Columbus, OH 43210 USA.; Williams, MC (reprint author), Northeastern Univ, Dept Phys, Boston, MA 02115 USA. EM ma.williams@northeastern.edu; musier-forsyth.1@osu.edu; levinju@mail.nih.gov FU National Institutes of Health [T32-GM008512, F31-AI120868, R01-GM065056, R01-GM072462]; Intramural Research Program at the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Leidos Biomedical Research, Inc.; Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy (DOE) [DE-AC02-05CH11231]; DOE Office of Biological and Environmental Research; National Institutes of Health project MINOS [R01-GM105404] FX We thank Dr. Mithun Mitra for valuable discussion and generous advice, Micah McCauley for preparation of labeled DNA used for the stretching experiments, and Cathy Hixon and Donald G. Johnson of Leidos Biomedical Research, Inc. for assistance in preparing the NC proteins used in this study. We also thank the AIDS Reagent Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, for SIV plasmids, as detailed in the text. EDO was supported by National Institutes of Health Grants T32-GM008512 and F31-AI120868. This work was supported by the Intramural Research Program at the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (JGL) and by National Institutes of Health Grants R01-GM065056 (KM-F) and R01-GM072462 (MCW). 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 HHSN261200800001E with Leidos Biomedical Research, Inc. (RJG). The SAXS measurements were performed at the Advanced Light Source (ALS), a national user facility operated by Lawrence Berkeley National Laboratory. The ALS is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy (DOE) under Contract No. DE-AC02-05CH11231, and through the Integrated Diffraction Analysis Technologies (IDAT) program, supported by the DOE Office of Biological and Environmental Research. Additional support comes from the National Institutes of Health project MINOS (R01-GM105404). 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 114 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 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD DEC 29 PY 2016 VL 13 AR 89 DI 10.1186/s12977-016-0322-5 PG 18 WC Virology SC Virology GA EG5EG UT WOS:000391065700001 PM 28034301 ER PT J AU Dombi, E Baldwin, A Marcus, LJ Fisher, MJ Weiss, B Kim, A Whitcomb, P Martin, S Aschbacher-Smith, LE Rizvi, TA Wu, JQ Ershler, R Wolters, P Therrien, J Glod, J Belasco, JB Schorry, E Brofferio, A Starosta, AJ Gillespie, A Doyle, AL Ratner, N Widemann, BC AF Dombi, Eva Baldwin, Andrea Marcus, Leigh J. Fisher, Michael J. Weiss, Brian Kim, AeRang Whitcomb, Patricia Martin, Staci Aschbacher-Smith, Lindsey E. Rizvi, Tilat A. Wu, Jianqiang Ershler, Rachel Wolters, Pamela Therrien, Janet Glod, John Belasco, Jean B. Schorry, Elizabeth Brofferio, Alessandra Starosta, Amy J. Gillespie, Andrea Doyle, Austin L. Ratner, Nancy Widemann, Brigitte C. TI Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID FARNESYLTRANSFERASE INHIBITOR TIPIFARNIB; CONSORTIUM PHASE-II; CLINICAL-TRIALS; TUMOR-SUPPRESSOR; HYPERACTIVE RAS; MEK INHIBITION; SOLID TUMORS; YOUNG-ADULTS; CHILDREN; CANCER AB BACKGROUND Effective medical therapies are lacking for the treatment of neurofibromatosis type 1-related plexiform neurofibromas, which are characterized by elevated RAS-mitogen-activated protein kinase (MAPK) signaling. METHODS We conducted a phase 1 trial of selumetinib (AZD6244 or ARRY-142886), an oral selective inhibitor of MAPK kinase (MEK) 1 and 2, in children who had neurofibromatosis type 1 and inoperable plexiform neurofibromas to determine the maximum tolerated dose and to evaluate plasma pharmacokinetics. Selumetinib was administered twice daily at a dose of 20 to 30 mg per square meter of body-surface area on a continuous dosing schedule (in 28-day cycles). We also tested selumetinib using a mouse model of neurofibromatosis type 1-related neurofibroma. Response to treatment (i.e., an increase or decrease from baseline in the volume of plexiform neurofibromas) was monitored by using volumetric magnetic resonance imaging analysis to measure the change in size of the plexiform neurofibroma. RESULTS A total of 24 children (median age, 10.9 years; range, 3.0 to 18.5) with a median tumor volume of 1205 ml (range, 29 to 8744) received selumetinib. Patients were able to receive selumetinib on a long-term basis; the median number of cycles was 30 (range, 6 to 56). The maximum tolerated dose was 25 mg per square meter (approximately 60% of the recommended adult dose). The most common toxic effects associated with selumetinib included acneiform rash, gastrointestinal effects, and asymptomatic creatine kinase elevation. The results of pharmacokinetic evaluations of selumetinib among the children in this trial were similar to those published for adults. Treatment with selumetinib resulted in confirmed partial responses (tumor volume decreases from baseline of >= 20%) in 17 of the 24 children (71%) and decreases from baseline in neurofibroma volume in 12 of 18 mice (67%). Disease progression (tumor volume increase from baseline of >= 20%) has not been observed to date. Anecdotal evidence of decreases in tumor-related pain, disfigurement, and functional impairment was observed. CONCLUSIONS Our early-phase data suggested that children with neurofibromatosis type 1 and inoperable plexiform neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803.) C1 [Dombi, Eva; Baldwin, Andrea; Marcus, Leigh J.; Whitcomb, Patricia; Martin, Staci; Ershler, Rachel; Wolters, Pamela; Therrien, Janet; Glod, John; Starosta, Amy J.; Gillespie, Andrea; Widemann, Brigitte C.] Ctr Canc Res, Pediatr Oncol Branch, Bethesda, MD USA. [Doyle, Austin L.] Canc Therapy Evaluat Program, Shady Grove, MD USA. [Brofferio, Alessandra] NCI, Bethesda, MD 20892 USA. [Brofferio, Alessandra] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Marcus, Leigh J.; Ershler, Rachel] NIH, Silver Spring, MD USA. [Marcus, Leigh J.; Ershler, Rachel] US FDA, Silver Spring, MD USA. [Fisher, Michael J.; Belasco, Jean B.] Univ Penn, Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Fisher, Michael J.; Belasco, Jean B.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kim, AeRang] Childrens Natl Hlth Syst, Washington, DC USA. [Weiss, Brian; Aschbacher-Smith, Lindsey E.; Rizvi, Tilat A.; Wu, Jianqiang; Schorry, Elizabeth; Ratner, Nancy] Cincinnati Childrens Hosp, Cincinnati, OH USA. RP Widemann, BC (reprint author), NCI, Pediat Oncol Branch, 10 Ctr Dr,Bldg 10 CRC,Rm 1-3752,MSC 1101, Bethesda, MD 20892 USA. EM widemanb@mail.nih.gov FU National Institutes of Health FX Funded by the National Institutes of Health and others NR 43 TC 3 Z9 3 U1 5 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 29 PY 2016 VL 375 IS 26 BP 2550 EP 2560 DI 10.1056/NEJMoa1605943 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA EG6SC UT WOS:000391175300008 PM 28029918 ER PT J AU Ramsden, CE AF Ramsden, Christopher E. TI Breathing Easier with Fish Oil - A New Approach to Preventing Asthma? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID INFLAMMATION; RESOLUTION; THERAPY; ACIDS C1 [Ramsden, Christopher E.] NIA, Lipid Mediators Inflammat & Pain Unit, Lab Clin Invest, Baltimore, MD 21224 USA. [Ramsden, Christopher E.] NIAAA, Bethesda, MD 20892 USA. RP Ramsden, CE (reprint author), NIA, Lipid Mediators Inflammat & Pain Unit, Lab Clin Invest, Baltimore, MD 21224 USA.; Ramsden, CE (reprint author), NIAAA, Bethesda, MD 20892 USA. NR 9 TC 3 Z9 3 U1 3 U2 3 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 DEC 29 PY 2016 VL 375 IS 26 BP 2596 EP 2598 DI 10.1056/NEJMe1611723 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA EG6SC UT WOS:000391175300015 PM 28029914 ER PT J AU Mohammadi, M Li, Y Abebe, DG Xie, YR Kandil, R Kraus, T Gomez-Lopez, N Fujiwara, T Merkel, OM AF Mohammadi, Mariam Li, Ying Abebe, Daniel G. Xie, Yuran Kandil, Rima Kraus, Teresa Gomez-Lopez, Nardhy Fujiwara, Tomoko Merkel, Olivia M. TI Folate receptor targeted three-layered micelles and hydrogels for gene delivery to activated macrophages SO JOURNAL OF CONTROLLED RELEASE LA English DT Article; Proceedings Paper CT 14th European Symposium on Controlled Drug Delivery (ESCDD) CY APR 13-15, 2016 CL Egmond aan Zee, NETHERLANDS DE Three layered micelles; Nanotechnology; Macrophages; Folate receptor; Rheumatoid arthritis, hydrogel, depot, degradation ID RHEUMATOID-ARTHRITIS; BINDING-PROTEIN; OVARIAN-CARCINOMA; SYNOVIAL TISSUE; IMAGING AGENTS; PLASMID DNA; IN-VIVO; COPOLYMERS; CELLS; BETA AB New folic acid (FA) coupled three layered micelles (3LM) were designed to encapsulate DNA, and their application as delivery system that specifically targets activated macrophages was investigated for new treatment options in rheumatoid arthritis (RA). FA coupled poly(L-lactide)-b-poly(ethylene glycol) (FA-PEG-PLLA) was synthesized via the NHS-ester activated/amine coupling method. Fluorescein labeled folic acid was used for flow cytometric detection of the expression of functional folic receptor beta in LPS-activated and resting macrophages. FA coupled 3LM were formulated in a two-step procedure and characterized regarding hydrodynamic diameters and zeta potentials. The presence of the targeting ligand was shown not to increase the size of the 3LM compared to their non-targeted counterparts. Targeted and non-targeted 3LM were used in vitro to optimize uptake conditions in the RAW 264.7 macrophage cell line. The amount of FA coupled polymer in the final formulation was found to be optimal at 75% FA-PEG-PLLA and 25% PLLA-PEG-PLLA. Subsequently, transgene expression in vitro in RAW 264.7 cells and ex vivo in primary activated and resting mouse macrophages was determined as a function of FR-mediated internalization of 3LM encapsulating GFP expressing plasmid. FR-overexpressing activated cells, as successfully identified by internalization of FA-fluorescein, showed significantly higher GFP expression in vitro and ex vivo than resting macrophages with only a basal level of FR expression. Lastly, injectable hydrogels as depot formulation were formed by stereocomplexation, and their degradation, DNA release profiles, and dissociation into intact 3LM were found to be beneficial for potential in vivo application. Our findings confirm that FA-3LM are taken up by activated macrophages via folate receptor mediated endocytosis and that their hydrogels release intact 3LM for efficient transfection of primary macrophages. Therefore, FA-3LM could become a promising delivery system for receptor-mediated drug or gene delivery and novel therapy for rheumatoid arthritis in an in situ forming gel formulation. (C) 2016 Elsevier B.V. All rights reserved. C1 [Mohammadi, Mariam; Li, Ying; Xie, Yuran; Kandil, Rima; Kraus, Teresa; Merkel, Olivia M.] Wayne State Univ, Dept Pharmaceut Sci, 259 Mack Ave, Detroit, MI 48201 USA. [Mohammadi, Mariam; Kandil, Rima; Kraus, Teresa; Merkel, Olivia M.] Ludwig Maximilian Univ Munich, Dept Pharm Pharmaceut Technol & Biopharmaceut, Butenandtstr 5-13, D-81377 Munich, Germany. [Abebe, Daniel G.; Fujiwara, Tomoko] Univ Memphis, Dept Chem, Memphis, TN 38152 USA. [Gomez-Lopez, Nardhy] Wayne State Univ, Sch Med, Dept Obstet & Gynecol & Immunol & Microbiol, CS Mott Ctr Human Growth & Dev, 275 E Hancock, Detroit, MI 48201 USA. [Gomez-Lopez, Nardhy] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Merkel, Olivia M.] Wayne State Univ, Dept Oncol, Mol Therapeut Program, 4100 John R St, Detroit, MI 48201 USA. [Abebe, Daniel G.] Univ Mississippi, Dept Chem & Biochem, University, MS 38677 USA. RP Merkel, OM (reprint author), Ludwig Maximilian Univ Munich, Dept Pharm Pharmaceut Technol & Biopharmaceut, Butenandtstr 5-13, D-81377 Munich, Germany. EM Olivia.merkel@lmu.de OI Gomez-Lopez, Nardhy/0000-0002-3406-5262 FU Wayne State Start-Up fund; BOOST grant; NSF under Thrust 2 [EPS-1004083]; Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health FX This work was supported by the Wayne State Start-Up fund and BOOST grant to OMM, and partially supported by NSF EPS-1004083 under Thrust 2 to TF. NGL is supported by the Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health. We would like to acknowledge expert technical support from Barani Govindarajan (Department of Pharmaceutical Sciences, WSU) and Dr. Philip S. Low (Purdue University) for expert advice and critical reading of the manuscript. NR 43 TC 2 Z9 2 U1 12 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 EI 1873-4995 J9 J CONTROL RELEASE JI J. Control. Release PD DEC 28 PY 2016 VL 244 BP 269 EP 279 DI 10.1016/j.jconrel.2016.08.020 PN B PG 11 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA EJ3RB UT WOS:000393128200014 PM 27565213 ER PT J AU Shi, CS Kehrl, JH AF Shi, Chong-Shan Kehrl, John H. TI Cytochrome c Negatively Regulates NLRP3 Inflammasomes SO PLOS ONE LA English DT Article ID ACTIVATION; APOPTOSIS; MITOCHONDRIA; CARDIOLIPIN; PLATFORM; NEK7; COMPONENT; PROTEIN AB The release of cytochrome c from the inner mitochondrial membrane, where it is anchored by caridolipin, triggers the formation of the Apaf-1 apoptosome. Cardiolipin also interacts with NLRP3 recruiting NLRP3 to mitochondria and facilitating inflammasome assembly. In this study we investigated whether cytosolic cytochrome c impacts NLRP3 inflammasome activation in macrophages. We report that cytochrome c binds to the LRR domain of NLRP3 and that cytochrome c reduces the interactions between NLRP3 and cardiolipin and between NLRP3 and NEK7, a recently recognized component of the NLRP3 inflammasome needed for NLRP3 oligomerization. Protein transduction of cytochrome c impairs NLRP3 inflammasome activation, while partially silencing cytochrome c expression enhances it. The addition of cytochrome c to an in vitro inflammasome assay severely limited caspase-1 activation. We propose that there is a crosstalk between the NLRP3 inflammasome and apoptosome pathways mediated by cytochrome c, whose release during apoptosis acts to limit NLRP3 inflammasome activation. C1 [Shi, Chong-Shan; Kehrl, John H.] NIAID, Cell Mol Immunol Sect B, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Shi, CS (reprint author), NIAID, Cell Mol Immunol Sect B, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM cshi@niaid.nih.gov NR 24 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 DEC 28 PY 2016 VL 11 IS 12 AR e0167636 DI 10.1371/journal.pone.0167636 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG7JB UT WOS:000391222000013 PM 28030552 ER PT J AU Son, GY Bak, EJ Kim, JH Lee, DE Kang, SM Lee, SY Choi, L Sun, JS Kim, SK Park, W Kim, BI Yoo, YJ Chang, I Shin, DM AF Son, Ga-Yeon Bak, Eun-Jung Kim, Ji-Hye Lee, Dong Eun Kang, Si-Mook Lee, So Yun Choi, Lin Sun, Ji Su Kim, Seul Ki Park, Wonse Kim, Baek Il Yoo, Yun-Jung Chang, Inik Shin, Dong Min TI Endothelin Regulates Porphyromonas gingivalis-Induced Production of Inflammatory Cytokines SO PLOS ONE LA English DT Article ID EPITHELIAL-CELLS; ADULT PERIODONTITIS; BONE LOSS; RECEPTOR ANTAGONIST; CONVERTING ENZYME; EXPRESSION; DISEASE; GENE; SYSTEM; MACROPHAGES AB Periodontitis is a very common oral inflammatory disease that results in the destruction of supporting connective and osseous tissues of the teeth. Although the exact etiology is still unclear, Gram-negative bacteria, especially Porphyromonas gingivalis in subgingival pockets are thought to be one of the major etiologic agents of periodontitis. Endothelin (ET) is a family of three 21-amino acid peptides, ET-1, -2, and -3, that activate G protein-coupled receptors, ETA and ETB. Endothelin is involved in the occurrence and progression of various inflammatory diseases. Previous reports have shown that ET-1 and its receptors, ETA and ETB are expressed in the periodontal tissues and, that ET-1 levels in gingival crevicular fluid are increased in periodontitis patients. Moreover, P. gingivalis infection has been shown to induce the production of ET-1 along with other inflammatory cytokines. Despite these studies, however, the functional significance of endothelin in periodontitis is still largely unknown. In this study, we explored the cellular and molecular mechanisms of ET-1 action in periodontitis using human gingival epithelial cells (HGECs). ET-1 and ETA, but not ETB, were abundantly expressed in HGECs. Stimulation of HGECs with P. gingivalis or P. gingivalis lipopolysaccharide increased the expression of ET-1 and ETA suggesting the activation of the endothelin signaling pathway. Production of inflammatory cytokines, IL-1 beta, TNF alpha, and IL-6, was significantly enhanced by exogenous ET-1 treatment, and this effect depended on the mitogen-activated protein kinases via intracellular Ca2+ increase, which resulted from the activation of the phospholipase C/inositol 1,4,5-trisphosphate pathway. The inhibition of the endothelin receptor-mediated signaling pathway with the dual receptor inhibitor, bosentan, partially ameliorated alveolar bone loss and immune cell infiltration. These results suggest that endothelin plays an important role in P. gingivalis-mediated periodontitis. Thus, endothelin antagonism may be a potential therapeutic approach for periodontitis treatment. C1 [Son, Ga-Yeon; Bak, Eun-Jung; Lee, Dong Eun; Lee, So Yun; Choi, Lin; Sun, Ji Su; Kim, Seul Ki; Yoo, Yun-Jung; Chang, Inik; Shin, Dong Min] Yonsei Univ, Coll Dent, Dept Oral Biol, Seoul, South Korea. [Son, Ga-Yeon; Lee, Dong Eun; Kang, Si-Mook; Lee, So Yun; Sun, Ji Su; Kim, Seul Ki; Kim, Baek Il; Shin, Dong Min] Yonsei Univ, Coll Dent, PLUS Project BK21, Seoul, South Korea. [Kim, Ji-Hye] Jeonju Kijeon Coll, Dept Dent Hyg, Jeonju, South Korea. [Kang, Si-Mook; Kim, Baek Il] Yonsei Univ, Coll Dent, Dept Prevent Dent & Publ Oral Hlth, Seoul, South Korea. [Park, Wonse] Yonsei Univ, Coll Dent, Dept Adv Gen Dent, Seoul, South Korea. [Son, Ga-Yeon] NIDCR, Secretory Physiol Sect, Mol Physiol & Therapeut Branch, Bethesda, MD USA. [Son, Ga-Yeon] NIH, Secretory Physiol Sect, Mol Physiol & Therapeut Branch, Bldg 10, Bethesda, MD 20892 USA. RP Chang, I; Shin, DM (reprint author), Yonsei Univ, Coll Dent, Dept Oral Biol, Seoul, South Korea.; Shin, DM (reprint author), Yonsei Univ, Coll Dent, PLUS Project BK21, Seoul, South Korea. EM ichang@yuhs.ac; dmshin@yuhs.ac FU Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education [2013R1A1A2061305]; Ministry of Science, ICT and future Planning [2015R1A2A1A15054157, 2016R1A5A2008630] FX This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2013R1A1A2061305 for Inik Chang) and the Ministry of Science, ICT and future Planning (2015R1A2A1A15054157 for Dong Min Shin and 2016R1A5A2008630 for Inik Chang and Dong Min Shin). 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 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 DEC 28 PY 2016 VL 11 IS 12 AR e0167713 DI 10.1371/journal.pone.0167713 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG7JB UT WOS:000391222000018 PM 28030574 ER PT J AU Emdin, CA Khera, AV Natarajan, P Klarin, D Won, HH Peloso, GM Stitziel, NO Nomura, A Zekavat, SM Bick, AG Gupta, N Asselta, R Duga, S Merlini, PA Correa, A Kessler, T Wilson, JG Bown, MJ Hall, AS Braund, PS Samani, NJ Schunkert, H Marrugat, J Elosua, R McPherson, R Farrall, M Watkins, H Willer, C Abecasis, GR Felix, JF Vasan, RS Lander, E Rader, DJ Danesh, J Ardissino, D Gabriel, S Saleheen, D Kathiresan, S AF Emdin, Connor A. Khera, Amit V. Natarajan, Pradeep Klarin, Derek Won, Hong-Hee Peloso, Gina M. Stitziel, Nathan O. Nomura, Akihiro Zekavat, Seyedeh M. Bick, Alexander G. Gupta, Namrata Asselta, Rosanna Duga, Stefano Merlini, Piera Angelica Correa, Adolfo Kessler, Thorsten Wilson, James G. Bown, Matthew J. Hall, Alistair S. Braund, Peter S. Samani, Nilesh J. Schunkert, Heribert Marrugat, Jaume Elosua, Roberto McPherson, Ruth Farrall, Martin Watkins, Hugh Willer, Cristen Abecasis, Goncalo R. Felix, Janine F. Vasan, Ramachandran S. Lander, Eric Rader, Daniel J. Danesh, John Ardissino, Diego Gabriel, Stacey Saleheen, Danish Kathiresan, Sekar CA CHARGE Heart Failure Consortium CARDIoGRAM Exome Consortium TI Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE coronary heart disease; genetics; phenome-wide association study; single nucleotide polymorphism ID CORONARY-HEART-DISEASE; ATHEROSCLEROSIS RISK; LARGE-SCALE; ELEVATED LIPOPROTEIN(A); CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; BIOLOGICAL PATHWAYS; GENOME-WIDE; APOLIPOPROTEIN(A); ASSOCIATION AB BACKGROUND Genomic analyses have suggested that the LPA gene and its associated plasma biomarker, lipoprotein(a) (Lp[a]), represent a causal risk factor for coronary heart disease (CHD). As such, lowering Lp(a) levels has emerged as a therapeutic strategy. Beyond target identification, human genetics may contribute to the development of new therapies by defining the full spectrum of beneficial and adverse consequences and by developing a dose-response curve of target perturbation. OBJECTIVES The goal of this study was to establish the full phenotypic impact of LPA gene variation and to estimate a dose-response curve between genetically altered plasma Lp(a) and risk for CHD. METHODS We leveraged genetic variants at the LPA gene from 3 data sources: individual-level data from 112,338 participants in the U.K. Biobank; summary association results from large-scale genome-wide association studies; and LPA gene sequencing results from case subjects with CHD and control subjects free of CHD. RESULTS One SD genetically lowered Lp(a) level was associated with a 29% lower risk of CHD (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.69 to 0.73), a 31% lower risk of peripheral vascular disease (OR: 0.69; 95% CI: 0.59 to 0.80), a 13% lower risk of stroke (OR: 0.87; 95% CI: 0.79 to 0.96), a 17% lower risk of heart failure (OR: 0.83; 95% CI: 0.73 to 0.94), and a 37% lower risk of aortic stenosis (OR: 0.63; 95% CI: 0.47 to 0.83). We observed no association with 31 other disorders, including type 2 diabetes and cancer. Variants that led to gain of LPA gene function increased the risk for CHD, whereas those that led to loss of gene function reduced the CHD risk. CONCLUSIONS Beyond CHD, genetically lowered Lp(a) levels are associated with a lower risk of peripheral vascular disease, stroke, heart failure, and aortic stenosis. As such, pharmacological lowering of plasma Lp(a) may influence a range of atherosclerosis-related diseases. (C) 2016 by the American College of Cardiology Foundation. C1 [Emdin, Connor A.; Khera, Amit V.; Natarajan, Pradeep; Klarin, Derek; Nomura, Akihiro; Zekavat, Seyedeh M.; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA USA. [Emdin, Connor A.; Khera, Amit V.; Natarajan, Pradeep; Klarin, Derek; Nomura, Akihiro; Zekavat, Seyedeh M.; Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Massachusetts Gen Hosp, Boston, MA USA. [Emdin, Connor A.; Khera, Amit V.; Natarajan, Pradeep; Klarin, Derek; Peloso, Gina M.; Nomura, Akihiro; Zekavat, Seyedeh M.; Bick, Alexander G.; Gupta, Namrata; Lander, Eric; Gabriel, Stacey; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Won, Hong-Hee] Sungkyunkwan Univ, Samsung Med Ctr, Samsung Adv Inst Hlth Sci & Technol, Seoul, South Korea. [Peloso, Gina M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, McDonnell Genome Inst, St Louis, MO USA. [Asselta, Rosanna; Duga, Stefano] Humanitas Univ, Dept Biomed Sci, Milan, Italy. [Asselta, Rosanna; Duga, Stefano] Humanitas Clin & Res Ctr, Milan, Italy. [Merlini, Piera Angelica] Osped Niguarda Ca Granda, Milan, Italy. [Correa, Adolfo] Univ Mississippi, Med Ctr, Dept Med, Jackson Heart Study, Jackson, MS 39216 USA. [Kessler, Thorsten] Tech Univ Munich, Deutsch Herzzentrum munchen, Deutsch Zentrum Herz Kreislauf Forsch, Munich, Germany. [Kessler, Thorsten] Munich Heart Alliance, Munich, Germany. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Bown, Matthew J.; Braund, Peter S.; Samani, Nilesh J.; Schunkert, Heribert] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Bown, Matthew J.; Braund, Peter S.; Samani, Nilesh J.; Schunkert, Heribert] Univ Leicester, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England. [Hall, Alistair S.] Univ Leeds, Leeds Inst Cardiovasc & Metab Med, Leeds, W Yorkshire, England. [Marrugat, Jaume; Elosua, Roberto] IMIM Hosp del Mar Res Inst, Cardiovasc Epidemiol & Genet, Barcelona, Spain. [McPherson, Ruth] Univ Ottawa, Inst Heart, Ottawa, ON, Canada. [Farrall, Martin; Watkins, Hugh] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford, England. [Farrall, Martin; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Willer, Cristen] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Willer, Cristen] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Willer, Cristen] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Abecasis, Goncalo R.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Felix, Janine F.] Univ Med Ctr Rotterdam, Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Vasan, Ramachandran S.] Natl Heart Lung & Blood Inst & Boston Univ Framin, Framingham, MA USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Sect Cardiol, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Sect Epidemiol, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Publ Hlth, Dept Med, Sect Cardiol, Boston, MA USA. [Vasan, Ramachandran S.] Boston Univ, Sch Publ Hlth, Dept Med, Sect Prevent Med, Boston, MA USA. [Vasan, Ramachandran S.] Boston Univ, Sch Publ Hlth, Dept Med, Sect Epidemiol, Boston, MA USA. [Rader, Daniel J.] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. [Danesh, John] Univ Cambridge, Publ Hlth & Primary Care, Cambridge, England. [Danesh, John] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge, England. [Danesh, John] Univ Cambridge, Dept Publ Hlth & Primary Care, Natl Inst Hlth Res, Blood & Transplant Res Unit Donor Hlth & Gen, Cambridge, England. [Ardissino, Diego] Univ Parma, Azienda Osped Univ Parma, Div Cardiol, Parma, Italy. [Ardissino, Diego] ASTC, Pavia, Italy. [Saleheen, Danish] Univ Penn, Perelman Sch Med, Biostat & Epidemiol, Philadelphia, PA 19104 USA. RP Kathiresan, S (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 185 Cambridge St,CPZN 5-252, Boston, MA 02114 USA.; Kathiresan, S (reprint author), Massachusetts Gen Hosp, Ctr Human Genet, 185 Cambridge St,CPZN 5-252, Boston, MA 02114 USA. EM skathiresan1@mgh.harvard.edu OI Watkins, Hugh/0000-0002-5287-9016 FU Spanish Ministry of Economy and Innovation through the Carlos III Health Institute (Red Investigacion Cardiovascular) [RD12/0042, PI09/90506]; European Funds for Development (ERDF-FEDER); Catalan Research and Technology Innovation Interdepartmental Commission [2014SGR240]; British Heart Foundation (British Heart Foundation Family Heart Study) [RG2000010]; British Heart Foundation (U.K. Aneurysm Growth Study) [CS/14/2/30841]; National Institute for Health Research (NIHR Leicester Cardiovascular Biomedical Research Unit Biomedical Research Informatics Centre for Cardiovascular Science) [IS_BRU_0211_20033]; German Federal Ministry of Education and Research (BMBF); FP7 European Union project CVgenes@target [261123]; Fondation Leducq [12CVD02]; Deutsche Forschungsgemeinschaft; Programma di ricerca Regione-Universita Area 1-Strategic Programmes-Regione Emilia-Romagna; Rhodes Trust; John S. Ladue Memorial Fellowship in Cardiology; Harvard Catalyst [TR001100]; Merck; Amarin; National Research Foundation of Korea - Ministry of Science, ICT & Future Planning [2016R1C1B2007920]; National Heart, Lung, and Blood Institute of the National Institutes of Health [K01HL125751]; AstraZeneca; Regeneron; British Heart Foundation Centre of Research Excellence, Oxford [RE/13/1/30181]; Wellcome Trust [090532/Z/09/Z]; Aegerion Pharmaceuticals; Alnylam Pharmaceuticals; Eli Lilly and Company; Pfizer; Sanofi; Novartis; British Heart Foundation; BUPA Foundation; diaDexus; European Research Council; European Union; Evelyn Trust; Fogarty International Centre; GlaxoSmithKline; National Heart, Lung, and Blood Institute; National Health Service Blood and Transplant; National Institute for Health Research; National Institute of Neurological Disorders and Stroke; Roche; Takeda; Wellcome Trust, U. K.; Biobank; University of British Columbia; U. K. Medical Research Council; Boehringer Ingelheim; Johnson Johnson; Bayer; Daiichi-Sankyo; Boston Scientific; Bristol-Myers Squibb; Menarini Group; National Institutes of Health; Massachusetts General Hospital; Donovan Family Foundation; Bayer Healthcare; Leerink Partners; Noble Insights; Quest Diagnostics; Genomics PLC; [SFB 1123]; [RFPS-2007-3-644382]; [RC2 HL103010]; [RC2 HL102923]; [RC2 HL102924]; [5U54HG003067]; [K08HL114642]; [R01HL131961]; [R01 HL127564] FX 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. The REGICOR study was supported by the Spanish Ministry of Economy and Innovation through the Carlos III Health Institute (Red Investigacion Cardiovascular RD12/0042, PI09/90506), European Funds for Development (ERDF-FEDER), and by the Catalan Research and Technology Innovation Interdepartmental Commission (2014SGR240). Samples for the Leicester cohort were collected as part of projects funded by the British Heart Foundation (British Heart Foundation Family Heart Study, RG2000010; U.K. Aneurysm Growth Study, CS/14/2/30841) and the National Institute for Health Research (NIHR Leicester Cardiovascular Biomedical Research Unit Biomedical Research Informatics Centre for Cardiovascular Science, IS_BRU_0211_20033). The Munich MI Study is supported by the German Federal Ministry of Education and Research (BMBF) in the context of the e:Med program (e:AtheroSysMed) and the FP7 European Union project CVgenes@target (261123). Additional grants were received from the Fondation Leducq (CADgenomics: Understanding Coronary Artery Disease Genes, 12CVD02). This study was also supported through the Deutsche Forschungsgemeinschaft cluster of excellence "Inflammation at Interfaces" and SFB 1123. The Italian Atherosclerosis, Thrombosis, and Vascular Biology (ATVB) Study was supported by a grant from RFPS-2007-3-644382 and Programma di ricerca Regione-Universita 2010-2012 Area 1-Strategic Programmes-Regione Emilia-Romagna. Funding for the exome sequencing project was provided by RC2 HL103010 (HeartGO), RC2 HL102923 (LungGO), and RC2 HL102924 (WHISP). Exome sequencing was performed through RC2 HL102925 (BroadGO) and RC2 HL102926 (SeattleGO). Exome sequencing in ATVB, PROCARDIS, Ottawa, and the Southern German Myocardial Infarction Study was supported by 5U54HG003067 (to Drs. Lander and Gabriel). For a full list of CHARGE-HF (Cohorts for Heart and Aging Research in Genomic Epidemiology-Heart Failure) working group members contributing to this work and for CHARGE-HF acknowledgements, please see PMID 20445134. Mr. Emdin is supported by the Rhodes Trust. Dr. Khera is supported by a John S. Ladue Memorial Fellowship in Cardiology and a KL2/Catalyst Medical Research Investigator Training award (an appointed KL2 award: TR001100) from Harvard Catalyst and has received consulting fees from Merck and Amarin. Dr. Won was supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (2016R1C1B2007920). Dr. Peloso is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number K01HL125751. Dr. Stitziel has received funding from K08HL114642 and R01HL131961; has received a research grant from AstraZeneca; and has received consulting fees from Regeneron. Dr. Farrall has received the British Heart Foundation Centre of Research Excellence, Oxford (RE/13/1/30181), award; the Wellcome Trust core award (090532/Z/09/Z); and funding from the Wellcome Trust Institutional Support Scheme. Dr. Abecasis has served as a consultant for Regeneron. Dr.; Rader has received consulting fees from Aegerion Pharmaceuticals, Alnylam Pharmaceuticals, Eli Lilly and Company, Pfizer, Sanofi, and Novartis; is an inventor on a patent related to lomitapide that is owned by the University of Pennsylvania and licensed to Aegerion Pharmaceuticals; and is a cofounder of Vascular Strategies and Staten Biotechnology. Dr. Danesh has served as a consultant for Takeda; has been a member of the Novartis Cardiovascular & Metabolic Advisory Board, the International Cardiovascular and Metabolism Research and Development portfolio committee for Novartis, the Merck Sharp & Dohme UK Atherosclerosis Advisory Board, the Pfizer Population Research Advisory Panel, and the Sanofi Advisory Board; and has received funding from the British Heart Foundation, the BUPA Foundation, diaDexus, European Research Council, the European Union, Evelyn Trust, Fogarty International Centre, GlaxoSmithKline, Merck, the National Heart, Lung, and Blood Institute, the National Health Service Blood and Transplant, the National Institute for Health Research, the National Institute of Neurological Disorders and Stroke, Novartis, Pfizer, Roche, Sanofi, Takeda, The Wellcome Trust, U. K. Biobank, the University of British Columbia, and the U. K. Medical Research Council. Dr. Ardissino has received speaker fees from AstraZeneca, Boehringer Ingelheim, Johnson & Johnson, Bayer, Daiichi-Sankyo, GlaxoSmithKline, Eli Lilly and Company, Boston Scientific, Bristol-Myers Squibb, Menarini Group, Novartis, and Sanofi; and research grants from GlaxoSmithKline, Eli Lilly and Company, Pfizer, and Novartis. Dr. Saleheen has received grants from Pfizer, Regeneron, and the National Institutes of Health. Dr. Kathiresan is supported by a research scholar award from the Massachusetts General Hospital, the Donovan Family Foundation, and R01 HL127564; has received grants from Bayer Healthcare, Aegerion Pharmaceuticals, and Regeneron Pharmaceuticals; has received consulting fees from Merck, Novartis, Sanofi, AstraZeneca, Alnylam Pharmaceuticals, Leerink Partners, Noble Insights, Quest Diagnostics, Genomics PLC, and Eli Lilly and Company; and holds equity in San Therapeutics and Catabasis Pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Emdin and Khera contributed equally to this work. NR 39 TC 2 Z9 2 U1 12 U2 12 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 DEC 27 PY 2016 VL 68 IS 25 BP 2761 EP 2772 DI 10.1016/j.jacc.2016.10.033 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EJ1SN UT WOS:000392990600007 PM 28007139 ER PT J AU Lam, MPY Ping, PP Murphy, E AF Lam, Maggie P. Y. Ping, Peipei Murphy, Elizabeth TI Proteomics Research in Cardiovascular Medicine and Biomarker Discovery SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE mass spectrometry; molecular phenotyping; post-translational modifications; protein arrays; protein dynamics; protein signatures ID ACUTE MYOCARDIAL-INFARCTION; RESOLUTION MASS-SPECTROMETRY; EPSILON SIGNALING COMPLEXES; HUMAN PLASMA PROTEOME; FAILING HUMAN HEART; CARDIAC TROPONIN-I; S-NITROSYLATION; AFFINITY PURIFICATION; GENE-EXPRESSION; EARLY-DIAGNOSIS AB Proteomics is a systems physiology discipline to address the large-scale characterization of protein species within a biological system, be it a cell, a tissue, a body biofluid, an organism, or a cohort population. Building on advances from chemical analytical platforms (e.g., mass spectrometry and other technologies), proteomics approaches have contributed powerful applications in cardiovascular biomedicine, most notably in: 1) the discovery of circulating protein biomarkers of heart diseases from plasma samples; and 2) the identification of disease mechanisms and potential therapeutic targets in cardiovascular tissues, in both preclinical models and translational studies. Contemporary proteomics investigations offer powerful means to simultaneously examine tens of thousands of proteins in various samples, and understand their molecular phenotypes in health and disease. This concise review introduces study design considerations, example applications and use cases, as well as interpretation and analysis of proteomics data in cardiovascular biomedicine. Published by Elsevier on behalf of the American College of Cardiology Foundation. C1 [Lam, Maggie P. Y.; Ping, Peipei] Univ Calif Los Angeles, NIH Ctr Excellence BD2K, Los Angeles, CA USA. [Lam, Maggie P. Y.; Ping, Peipei] Univ Calif Los Angeles, Dept Physiol Med & Bioinformat, Los Angeles, CA USA. [Murphy, Elizabeth] NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Lam, MPY (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol & Bioinformat, 675 Charles E Young Dr,MRL Bldg,Suite 1-625, Los Angeles, CA 90095 USA.; Murphy, E (reprint author), NHLBI, NIH, Bldg 10,Room 8N202,10 Ctr Dr, Bethesda, MD 20892 USA. EM magelpy@ucla.edu; murphy1@mail.nih.gov FU NIH [K99-HL127302, R37-HL063901, U54-GM114833, ZIA-HL006059, ZIA-HL002066] FX This work was supported by NIH K99-HL127302 to Dr. Lam; NIH R37-HL063901 and NIH U54-GM114833 to Dr. Ping; and NIH ZIA-HL006059 and NIH ZIA-HL002066 to Dr. Murphy. NR 109 TC 1 Z9 1 U1 6 U2 6 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 DEC 27 PY 2016 VL 68 IS 25 BP 2819 EP 2830 DI 10.1016/j.jacc.2016.10.031 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EJ1SN UT WOS:000392990600012 PM 28007144 ER PT J AU Jochems, C Hodge, JW Fantini, M Fujii, R Morillon, YM Greiner, JW Padget, MR Tritsch, SR Tsang, KY Campbell, KS Klingemann, H Boissel, L Rabizadeh, S Soon-Shiong, P Schlom, J AF Jochems, Caroline Hodge, James W. Fantini, Massimo Fujii, Rika Morillon, Y. Maurice, II Greiner, John W. Padget, Michelle R. Tritsch, Sarah R. Tsang, Kwong Yok Campbell, Kerry S. Klingemann, Hans Boissel, Laurent Rabizadeh, Shahrooz Soon-Shiong, Patrick Schlom, Jeffrey TI An NK cell line (haNK) expressing high levels of granzyme and engineered to express the high affinity CD16 allele SO ONCOTARGET LA English DT Article DE ADCC; NK lysis; immunotherapy; high affinity CD16; cetuximab ID NATURAL-KILLER-CELLS; FC-GAMMA-RIIIA; RECEPTOR POLYMORPHISMS; MONOCLONAL-ANTIBODIES; TUMOR-CELLS; CANCER; NK-92; CYTOTOXICITY; RITUXIMAB; CETUXIMAB AB Natural killer (NK) cells are known to play a role in mediating innate immunity, in enhancing adaptive immune responses, and have been implicated in mediating anti-tumor responses via antibody-dependent cell-mediated cytotoxicity (ADCC) by reactivity of CD16 with the Fc region of human IgG1 antibodies. The NK-92 cell line, derived from a lymphoma patient, has previously been well characterized and adoptive transfer of irradiated NK-92 cells has demonstrated safety and shown preliminary evidence of clinical benefit in cancer patients. The NK-92 cell line, devoid of CD16, has now been engineered to express the high affinity (ha) CD16 V158 Fc.RIIIa receptor, as well as engineered to express IL-2; IL-2 has been shown to replenish the granular stock of NK cells, leading to enhanced perforinand granzyme-mediated lysis of tumor cells. The studies reported here show high levels of granzyme in haNK cells, and demonstrate the effects of irradiation of haNK cells on multiple phenotypic markers, viability, IL-2 production, and lysis of a spectrum of human tumor cells. Studies also compare endogenous irradiated haNK lysis of tumor cells with that of irradiated haNK-mediated ADCC using cetuximab, trastuzumab and pertuzumab monoclonal antibodies. These studies thus provide the rationale for the potential use of irradiated haNK cells in adoptive transfer studies for a range of human tumor types. Moreover, since only approximately 10% of humans are homozygous for the high affinity V CD16 allele, these studies also provide the rationale for the use of irradiated haNK cells in combination with IgG1 anti-tumor monoclonal antibodies. C1 [Jochems, Caroline; Hodge, James W.; Fantini, Massimo; Fujii, Rika; Morillon, Y. Maurice, II; Greiner, John W.; Padget, Michelle R.; Tritsch, Sarah R.; Tsang, Kwong Yok; Schlom, Jeffrey] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, Bethesda, MD 20892 USA. [Campbell, Kerry S.] Fox Chase Canc Ctr, Immune Cell Dev & Host Def Program, Inst Canc Res, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Klingemann, Hans; Boissel, Laurent; Soon-Shiong, Patrick] NantKwest Inc, Culver City, CA USA. [Rabizadeh, Shahrooz; Soon-Shiong, Patrick] NantCell LLC, Culver City, CA USA. RP Schlom, J (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, Bethesda, MD 20892 USA. EM js141c@nih.gov RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH; NantBioScience; National Cancer Institute FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH, as well as through a Cooperative Research and Development Agreement (CRADA) between NantBioScience and the National Cancer Institute. NR 35 TC 1 Z9 1 U1 2 U2 2 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD DEC 27 PY 2016 VL 7 IS 52 BP 86359 EP 86373 DI 10.18632/oncotarget.13411 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EG9ZT UT WOS:000391422500057 PM 27861156 ER PT J AU Malamas, AS Gameiro, SR Knudson, KM Hodge, JW AF Malamas, Anthony S. Gameiro, Sofia R. Knudson, Karin M. Hodge, James W. TI Sublethal exposure to alpha radiation (Ra-223 dichloride) enhances various carcinomas' sensitivity to lysis by antigenspecific cytotoxic T lymphocytes through calreticulin-mediated immunogenic modulation SO ONCOTARGET LA English DT Article DE radium-223; alpha radiation; CTL-mediated lysis; immunogenic modulation; calreticulin ID HUMAN CARCINOEMBRYONIC ANTIGEN; METASTATIC PROSTATE-CANCER; TUMOR-CELLS; BONE-METASTASES; AGONIST EPITOPE; THERAPY; VACCINE; RADIUM-223; INHIBITORS; PHENOTYPE AB Radium-223 dichloride (Xofigo (R); Ra-223) is an alpha-emitting radiopharmaceutical FDA-approved for the treatment of bone metastases in patients with advanced castration-resistant prostate cancer. It is also being examined clinically in patients with breast and lung carcinoma and patients with multiple myeloma. As with other forms of radiation, the aim of Ra-223 is to reduce tumor burden by directly killing tumor cells. External beam (photon) and proton radiation have been shown to augment tumor sensitivity to antigen-specific CD8(+) cytotoxic T lymphocytes (CTLs). However, little is known about whether treatment with Ra-223 can also induce such immunogenic modulation in tumor cells that survive irradiation. We examined these effects in vitro by exposing human prostate, breast, and lung carcinoma cells to sublethal doses of Ra-223. Ra-223 significantly enhanced T cell-mediated lysis of each tumor type by CD8(+) CTLs specific for MUC-1, brachyury, and CEA tumor antigens. Immunofluorescence analysis revealed that the increase in CTL killing was accompanied by augmented protein expression of MHC-I and calreticulin in each tumor type, molecules that are essential for efficient antigen presentation. Enhanced tumor-cell lysis was facilitated by calreticulin surface translocation following Ra-223 exposure. The phenotypic changes observed after treatment appear to be mediated by induction of the endoplasmic reticulum stress response pathway. By rendering tumor cells more susceptible to T cell-mediated lysis, Ra-223 may potentially be effective in combination with various immunotherapies, particularly cancer vaccines that are designed to generate and expand patients' endogenous antigen-specific T-cell populations against specific tumor antigens. C1 [Malamas, Anthony S.; Gameiro, Sofia R.; Knudson, Karin M.; Hodge, James W.] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Hodge, JW (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM jh241d@nih.gov RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 44 TC 0 Z9 0 U1 3 U2 3 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD DEC 27 PY 2016 VL 7 IS 52 BP 86937 EP 86947 DI 10.18632/oncotarget.13520 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EG9ZT UT WOS:000391422500103 PM 27893426 ER PT J AU Ye, XY Chan, KC Waters, AM Bess, M Harned, A Wei, BR Loncarek, J Luke, BT Orsburn, BC Hollinger, BD Stephens, RM Bagni, R Martinko, A Wells, JA Nissley, DV McCormick, F Whiteley, G Blonder, J AF Ye, Xiaoying Chan, King C. Waters, Andrew M. Bess, Matthew Harned, Adam Wei, Bih-Rong Loncarek, Jadranka Luke, Brian T. Orsburn, Benjamin C. Hollinger, Bradley D. Stephens, Robert M. Bagni, Rachel Martinko, Alex Wells, James A. Nissley, Dwight V. McCormick, Frank Whiteley, Gordon Blonder, Josip TI Comparative proteomics of a model MCF10A-KRas(G12V) cell line reveals a distinct molecular signature of the KRas(G12V) cell surface SO ONCOTARGET LA English DT Article DE KRas(G12V); cell surface proteome; drug targets; proteomics; mass spectrometry ID COLORECTAL-CANCER CELLS; DNA-DAMAGE RESPONSE; K-RAS; LUNG-CANCER; PANCREATIC-CANCER; MASS-SPECTROMETRY; BREAST-CANCER; MEMBRANE-PROTEINS; TARGETED PROTEOMICS; TUMOR ANGIOGENESIS AB Oncogenic Ras mutants play a major role in the etiology of most aggressive and deadly carcinomas in humans. In spite of continuous efforts, effective pharmacological treatments targeting oncogenic Ras isoforms have not been developed. Cell-surface proteins represent top therapeutic targets primarily due to their accessibility and susceptibility to different modes of cancer therapy. To expand the treatment options of cancers driven by oncogenic Ras, new targets need to be identified and characterized at the surface of cancer cells expressing oncogenic Ras mutants. Here, we describe a mass spectrometry-based method for molecular profiling of the cell surface using KRas(G12V) transfected MCF10A (MCF10A-KRas(G12V)) as a model cell line of constitutively activated KRas and native MCF10A cells transduced with an empty vector (EV) as control. An extensive molecular map of the KRas surface was achieved by applying, in parallel, targeted hydrazide-based cell-surface capturing technology and global shotgun membrane proteomics to identify the proteins on the KRas(G12V) surface. This method allowed for integrated proteomic analysis that identified more than 500 cell-surface proteins found unique or upregulated on the surface of MCF10A-KRas(G12V) cells. Multistep bioinformatic processing was employed to elucidate and prioritize targets for cross-validation. Scanning electron microscopy and phenotypic cancer cell assays revealed changes at the cell surface consistent with malignant epithelialto- mesenchymal transformation secondary to KRas(G12V) activation. Taken together, this dataset significantly expands the map of the KRas(G12V) surface and uncovers potential targets involved primarily in cell motility, cellular protrusion formation, and metastasis. C1 [Ye, Xiaoying; Chan, King C.; Waters, Andrew M.; Bess, Matthew; Harned, Adam; Hollinger, Bradley D.; Stephens, Robert M.; Bagni, Rachel; Nissley, Dwight V.; Whiteley, Gordon; Blonder, Josip] Leidos Biomed Res Inc, Canc Res Technol Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Wei, Bih-Rong] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Loncarek, Jadranka] NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, Frederick, MD 21702 USA. [Luke, Brian T.] Leidos Biomed Res Inc, Adv Biomed Comp Ctr, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Orsburn, Benjamin C.] Thermo Fisher Sci, Waltham, MA 02451 USA. [Martinko, Alex; Wells, James A.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA. [McCormick, Frank] UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA. RP Blonder, J (reprint author), Leidos Biomed Res Inc, Canc Res Technol Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM blonderj@mail.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 113 TC 0 Z9 0 U1 3 U2 3 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD DEC 27 PY 2016 VL 7 IS 52 BP 86948 EP 86971 DI 10.18632/oncotarget.13566 PG 24 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EG9ZT UT WOS:000391422500104 PM 27894102 ER PT J AU Jeyifous, O Lin, EI Chen, X Antinone, SE Mastro, R Drisdel, R Reese, TS Green, WN AF Jeyifous, Okunola Lin, Eric I. Chen, Xiaobing Antinone, Sarah E. Mastro, Ryan Drisdel, Renaldo Reese, Thomas S. Green, William N. TI Palmitoylation regulates glutamate receptor distributions in postsynaptic densities through control of PSD95 conformation and orientation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE palmitoylation; PSD95; SAP97; NMDA receptor; AMPA receptor ID MAGUK SCAFFOLDING PROTEINS; AMPA RECEPTORS; GUANYLATE KINASES; NMDA RECEPTORS; SYNAPTIC TRAFFICKING; DISTINCT MECHANISMS; PSD-95; SAP97; MEMBRANE; STARGAZIN AB Postsynaptic density protein 95 (PSD95) and synapse-associated protein 97 (SAP97) are homologous scaffold proteins with different N-terminal domains, possessing either a palmitoylation site (PSD95) or an L27 domain (SAP97). Here, we measured PSD95 and SAP97 conformation in vitro and in postsynaptic densities (PSDs) using FRET and EM, and examined how conformation regulated interactions with AMPA-type and NMDA-type glutamate receptors (AMPARs/NMDARs). Palmitoylation of PSD95 changed its conformation from a compact to an extended configuration. PSD95 associated with AMPARs (via transmembrane AMPAR regulatory protein subunits) or NMDARs [via glutamate ionotropic receptor NMDA-type subunit 2B (GluN2B) subunits] only in its palmitoylated and extended conformation. In contrast, in its extended conformation, SAP97 associates with NMDARs, but not with AMPARs. Within PSDs, PSD95 and SAP97 were largely in the extended conformation, but had different orientations. PSD95 oriented perpendicular to the PSD membrane, with its palmitoylated, N-terminal domain at the membrane. SAP97 oriented parallel to the PSD membrane, likely as a dimer through interactions of its N-terminal L27 domain. Changing PSD95 palmitoylation in PSDs altered PSD95 and AMPAR levels but did not affect NMDAR levels. These results indicate that in PSDs, PSD95 palmitoylation, conformation, and its interactions are dynamic when associated with AMPARs and more stable when associated with NMDARs. Altogether, our results are consistent with differential regulation of PSD95 palmitoylation in PSDs resulting from the clustering of palmitoylating and depalmitoylating enzymes into AMPAR nanodomains segregated away from NMDAR nanodomains. C1 [Jeyifous, Okunola; Lin, Eric I.; Antinone, Sarah E.; Mastro, Ryan; Drisdel, Renaldo; Green, William N.] Univ Chicago, Dept Neurobiol, Chicago, IL 60637 USA. [Jeyifous, Okunola; Lin, Eric I.; Chen, Xiaobing; Reese, Thomas S.; Green, William N.] Marine Biol Lab, Woods Hole, MA 02543 USA. [Chen, Xiaobing; Reese, Thomas S.] NINDS, Lab Neurobiol, NIH, Bethesda, MD 20892 USA. RP Green, WN (reprint author), Univ Chicago, Dept Neurobiol, Chicago, IL 60637 USA.; Reese, TS; Green, WN (reprint author), Marine Biol Lab, Woods Hole, MA 02543 USA. EM treese@mbl.edu; wgreen@uchicago.edu FU NIH [NS043782, MH081251, DA019695]; National Institute of Neurological Disorders and Stroke; National Center for Research Resources; National Center for Advancing Translational Sciences of the NIH [UL1 RR024999] FX We thank Drs. Simon Alford and Nicolas Brunel for extensive discussions and help with the model proposed in Fig. 5 and Dr. Anitha Govind for her critical reading and helpful comments on the manuscript. We thank Drs. Vytas Bindokas and Paul Selvin for their technical support with FRET experiments. We also thank Drs. Christine Winters, Rita Azzam, Susan Cheng, and Virginia Crocker for help on immuno-EM and Drs. Alioscka Sousa and Richard Leapman for help on EM tomography data acquisition. This work was supported by the NIH under Grants NS043782, MH081251, and DA019695 (to W.N.G.) and by National Institute of Neurological Disorders and Stroke intramural funds (to T.S.R.). This project was also supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences of the NIH through Grant UL1 RR024999 (to O.J.). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 0 Z9 0 U1 4 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 27 PY 2016 VL 113 IS 52 BP E8482 EP E8491 DI 10.1073/pnas.1612963113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG5NL UT WOS:000391090800014 PM 27956638 ER PT J AU Saczko-Brack, D Warchol, E Rogez, B Kroess, M Heissler, SM Sellers, JR Batters, C Veigel, C AF Saczko-Brack, Dario Warchol, Ewa Rogez, Benoit Kroess, Markus Heissler, Sarah M. Sellers, James R. Batters, Christopher Veigel, Claudia TI Self-organization of actin networks by a monomeric myosin SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE electron microscopy; unconventional myosin; actin network ID CELL-MIGRATION; ELECTRON-MICROSCOPY; PROCESSIVE MOTOR; CALMODULIN; IX; MECHANISM; FILAMENTS; MOTILITY; DIMERIZATION; DYNAMICS AB The organization of actomyosin networks lies at the center of many types of cellular motility, including cell polarization and collective cell migration during development and morphogenesis. Myosin-IXa is critically involved in these processes. Using total internal reflection fluorescence microscopy, we resolved actin bundles assembled by myosin-IXa. Electron microscopic data revealed that the bundles consisted of highly ordered lattices with parallel actin polarity. The myosin-IXa motor domains aligned across the network, forming crosslinks at a repeat distance of precisely 36 nm, matching the helical repeat of actin. Single-particle image processing resolved three distinct conformations of myosin-IXa in the absence of nucleotide. Using cross-correlation of a modeled actomyosin crystal structure, we identified sites of additional mass, which can only be accounted for by the large insert in loop 2 exclusively found in the motor domain of class IX myosins. We show that the large insert in loop 2 binds calmodulin and creates two coordinated actin-binding sites that constrain the actomyosin interactions generating the actin lattices. The actin lattices introduce orientated tracks at specific sites in the cell, which might install platforms allowing Rho-GTPase-activating protein (RhoGAP) activity to be focused at a definite locus. In addition, the lattices might introduce amyosin-related, force-sensing mechanism into the cytoskeleton in cell polarization and collective cell migration. C1 [Saczko-Brack, Dario; Warchol, Ewa; Rogez, Benoit; Kroess, Markus; Batters, Christopher; Veigel, Claudia] Ludwig Maximilians Univ Munchen, Dept Cellular Physiol, D-80336 Munich, Germany. [Saczko-Brack, Dario; Warchol, Ewa; Rogez, Benoit; Kroess, Markus; Batters, Christopher; Veigel, Claudia] Ctr Nanosci Munchen, D-80799 Munich, Germany. [Heissler, Sarah M.; Sellers, James R.] NHLBI, Lab Mol Physiol, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Batters, C; Veigel, C (reprint author), Ludwig Maximilians Univ Munchen, Dept Cellular Physiol, D-80336 Munich, Germany.; Batters, C; Veigel, C (reprint author), Ctr Nanosci Munchen, D-80799 Munich, Germany. EM chris.batters@med.uni-muenchen.de; claudia.veigel@med.uni-muenchen.de FU Deutsche Forschungsgemeinschaft Grant [SFB-863-B6]; Friedrich-Baur-Stiftung; Munchner Medizinische Wochenschrift FX We thank Joachim Radler (Physics Department, Ludwig-Maximilians- Universitat Munchen) and Hendrick Dietz (Physics Department, TU Munich) for making their transmission electron microscopes available. We acknowledge the members of the Center for Nanosciences Munchen and Steve Martin (The Crick Institute) for stimulating discussions. We also acknowledge Deutsche Forschungsgemeinschaft Grant SFB-863-B6, Friedrich-Baur-Stiftung, and Munchner Medizinische Wochenschrift for financial support. NR 50 TC 0 Z9 0 U1 6 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 27 PY 2016 VL 113 IS 52 BP E8387 EP E8395 DI 10.1073/pnas.1612719113 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG5NL UT WOS:000391090800004 PM 27956608 ER PT J AU Bhat, A Edwards, LW Fu, X Badman, DL Huo, S Jin, AJ Lu, Q AF Bhat, Anupama Edwards, Lance W. Fu, Xiao Badman, Dillon L. Huo, Samuel Jin, Albert J. Lu, Qi TI Effects of gold nanoparticles on lipid packing and membrane pore formation SO APPLIED PHYSICS LETTERS LA English DT Article ID CELL-MEMBRANES; GENERALIZED POLARIZATION; BIOMEDICAL APPLICATIONS; CANCER-CELLS; BILAYERS; PHASE; MODEL; NANOTECHNOLOGY; CYTOTOXICITY; MICROSCOPY AB Gold nanoparticles (AuNPs) have been increasingly integrated in biological systems, making it imperative to understand their interactions with cell membranes, the first barriers to be crossed to enter cells. Herein, liposomes composed of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) as a model membrane system were treated with citrate stabilized AuNPs from 5 to 30nm at various concentrations. The fluorescence shifts of Laurdan probes reveal that AuNPs in general made liposomes more fluidic. The increased fluidity is expected to result in an increased surface area, and thus liposome shape changes from circular to less circular, which was further confirmed with fluorescence microscopy. The localized stress in lipids induced by electrostatically adsorbed AuNPs was hypothesized to cause the dominant long-range effect of fluidization of unbound lipid membranes. A secondary effect of the AuNP-induced lateral pressure is the membrane rupture or formation of pores, which was probed by AFM under fluid. We found in this study a nanoparticle-mediated approach of modulating the stiffness of lipid membranes: by adsorption of AuNPs, lipids at the binding sites are stiffened whereas lipids afar are fluidized. Understanding the factors that modulate lipid packing is important for the discovery of alternative therapeutic methods for diseases linked to membrane integrity such as high blood pressure and cancer metastasis. Published by AIP Publishing. C1 [Bhat, Anupama; Badman, Dillon L.; Lu, Qi] Delaware State Univ, Dept Phys & Engn, Delaware, OH 19901 USA. [Edwards, Lance W.] Delaware State Univ, Dept Biol Sci, Delaware, OH 19901 USA. [Fu, Xiao; Jin, Albert J.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Fu, Xiao] Beijing Inst Technol, Sch Life Sci, Dept Biomed Engn, Beijing 100081, Peoples R China. [Huo, Samuel] Wilmington Friends Sch, Wilmington, DC 19803 USA. [Badman, Dillon L.] Univ Rochester, Dept Biomed Engn, Rochester, NY 14672 USA. RP Lu, Q (reprint author), Delaware State Univ, Dept Phys & Engn, Delaware, OH 19901 USA. EM qilu@desu.edu FU National Institute of General Medical Sciences-NIGMS from the National Institutes of Health [P20 GM103446]; state of Delaware; CREST Program of National Science Foundation [1242067]; Intramural Research Program of the National Institutes of Health; National Institute of Biomedical Imaging and [ZIA EB000015-09] FX This work was made possible by the Delaware INBRE program, supported by a grant from the National Institute of General Medical Sciences-NIGMS (P20 GM103446) from the National Institutes of Health and the state of Delaware. This work was also supported by grants from the CREST Program (No. 1242067) of National Science Foundation, and the Intramural Research Program of the National Institutes of Health, including National Institute of Biomedical Imaging and Bioengineering (ZIA EB000015-09 to A.J.). Q.L. wishes to thank OSCAR Imaging Facility at Delaware State University for access to ISS-K2 spectrofluorometer and fluorescence microscopes. NR 42 TC 0 Z9 0 U1 10 U2 10 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0003-6951 EI 1077-3118 J9 APPL PHYS LETT JI Appl. Phys. Lett. PD DEC 26 PY 2016 VL 109 IS 26 AR 263106 DI 10.1063/1.4972868 PG 5 WC Physics, Applied SC Physics GA EI9ND UT WOS:000392834000031 PM 28104921 ER PT J AU Singhal, A Leaman, R Catlett, N Lemberger, T McEntyre, J Polson, S Xenarios, I Arighi, C Lu, ZY AF Singhal, Ayush Leaman, Robert Catlett, Natalie Lemberger, Thomas McEntyre, Johanna Polson, Shawn Xenarios, Ioannis Arighi, Cecilia Lu, Zhiyong TI Pressing needs of biomedical text mining in biocuration and beyond: opportunities and challenges SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID HIGH-THROUGHPUT DATA; GENE NORMALIZATION; MUCOSAL IMMUNITY; BIOCREATIVE III; MICROBIOME; IDENTIFICATION; ANNOTATION; ARTICLES; MODELS; SYSTEM AB Text mining in the biomedical sciences is rapidly transitioning from small-scale evaluation to large-scale application. In this article, we argue that text-mining technologies have become essential tools in real-world biomedical research. We describe four large scale applications of text mining, as showcased during a recent panel discussion at the BioCreative V Challenge Workshop. We draw on these applications as case studies to characterize common requirements for successfully applying text-mining techniques to practical biocuration needs. We note that system 'accuracy' remains a challenge and identify several additional common difficulties and potential research directions including (i) the 'scalability' issue due to the increasing need of mining information from millions of full-text articles, (ii) the 'interoperability' issue of integrating various text-mining systems into existing curation workflows and (iii) the 'reusability' issue on the difficulty of applying trained systems to text genres that are not seen previously during development. We then describe related efforts within the text-mining community, with a special focus on the BioCreative series of challenge workshops. We believe that focusing on the near-term challenges identified in this work will amplify the opportunities afforded by the continued adoption of text-mining tools. Finally, in order to sustain the curation ecosystem and have text-mining systems adopted for practical benefits, we call for increased collaboration between text-mining researchers and various stakeholders, including researchers, publishers and biocurators. C1 [Singhal, Ayush; Leaman, Robert; Arighi, Cecilia; Lu, Zhiyong] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Catlett, Natalie] Selventa, Cambridge, MA 02140 USA. [Lemberger, Thomas] EMBO, Meyerhofstr 1, D-69117 Heidelberg, Germany. [McEntyre, Johanna] EBI, EMBL, Wellcome Genome Campus, Cambridge CB10 1SD, England. [Polson, Shawn; Arighi, Cecilia] Univ Delaware, Ctr Bioinformat & Computat Biol, Newark, DE 19711 USA. [Polson, Shawn; Arighi, Cecilia] Univ Delaware, Dept Comp & Informat Sci, Delaware Biotechnol Inst, Newark, DE 19711 USA. [Xenarios, Ioannis] SIB Swiss Inst Bioinformat, Lausanne, Switzerland. RP Arighi, C; Lu, ZY (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA.; Arighi, C (reprint author), Univ Delaware, Ctr Bioinformat & Computat Biol, Newark, DE 19711 USA.; Arighi, C (reprint author), Univ Delaware, Dept Comp & Informat Sci, Delaware Biotechnol Inst, Newark, DE 19711 USA. EM arighi@dbi.udel.edu; zhiyong.lu@nih.gov OI McEntyre, Jo/0000-0002-1611-6935 FU National Institutes of Health [R13-GM109648-01A1, P20-GM103446]; Intramural Research Program at National Library of Medicine; US Department of Energy [DE-SC0010838]; US National Science Foundation [DBI-1356374]; Swiss Federal Government through the State Secretariat for Education, Research and Innovation (SERI); SyBIT project of the SystemsX.ch; Swiss Initiative in Systems Biology; Robert Bosch Foundation; EMBO; Wellcome Grant, UK PubMed Central Phase 3 Developments [098231/Z/12/Z] FX This work was supported by the National Institutes of Health [R13-GM109648-01A1 to CNA, P20-GM103446 to SWP, Intramural Research Program at National Library of Medicine to A.S., R.L., Z.L.], the US Department of Energy [DE-SC0010838 to C.N.A.], the US National Science Foundation [DBI-1356374 to S.W.P.] for the VIROME project and the Swiss Federal Government through the State Secretariat for Education, Research and Innovation (SERI); SyBIT project of the SystemsX.ch, the Swiss Initiative in Systems Biology (in part) (to IX). The Robert Bosch Foundation and EMBO are acknowledged for funding of the SourceData project. The Wellcome Grant, UK PubMed Central Phase 3 Developments 2012-2016 (grant number 098231/Z/12/Z) for the EuropePMC project. NR 59 TC 0 Z9 0 U1 6 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD DEC 26 PY 2016 AR baw161 DI 10.1093/database/baw161 PG 10 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA EH0ZC UT WOS:000391492000001 ER PT J AU Morgan, SJ Neumann, S Marcus-Samuels, B Gershengorn, MC AF Morgan, Sarah J. Neumann, Susanne Marcus-Samuels, Bernice Gershengorn, Marvin C. TI Thyrotropin Stimulates Differentiation Not Proliferation of Normal Human Thyrocytes in Culture SO FRONTIERS IN ENDOCRINOLOGY LA English DT Article DE TSH; IGF-1; proliferation; TSHR; TG; cell count; differentiation ID HUMAN THYROID-CELLS; RECEPTORS; GROWTH; LINE; TSH AB Although TSH has been suggested to be a proliferative agent for thyrocytes, the effect of TSH on human thyroid cells remains controversial. In particular, most of the reported studies relied primarily on changes in DNA synthesis but have not included measurement of the number of cells. We argue that only a direct count of cell number, demonstrating classical exponential expansion, serves as a valid measurement of proliferation. Thus, although some data support TSH as a proliferative agent, most do not provide conclusive evidence. To generate conclusive evidence with regard to a proliferative effect of TSH in human thyrocytes, we performed various experiments using primary cultures of human thyrocytes. In contrast to previous reports, TSH [+/- insulin-like growth factor 1 (IGF-1)] did not induce proliferation of thyrocytes under a variety of different conditions. However, TSH/IGF-1 cotreatment did upregulate thyroid-specific gene expression including thyroglobulin (TG) and TSHR in a manner consistent with cellular differentiation. Evidence for a proliferative effect of TSH has been used to inform the American Thyroid Association's guidelines for the management of thyroid cancer patients, which include TSH suppression. While these recommendations are admittedly based on lowto moderate-quality evidence, TSH suppression is still widely used. We present data that question the consensus view that TSH promotes proliferation of human thyrocytes (upon which the American Thyroid Association's guidelines are based) and suggest that additional studies, including randomized controlled trials, are warranted to address this important clinical question. C1 [Morgan, Sarah J.; Neumann, Susanne; Marcus-Samuels, Bernice; Gershengorn, Marvin C.] Natl Inst Diabet & Digest & Kidney Dis, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. RP Gershengorn, MC (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. EM marving@intra.niddk.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [Z01 DK011006] 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 (Z01 DK011006). NR 12 TC 0 Z9 0 U1 1 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2392 J9 FRONT ENDOCRINOL JI Front. Endocrinol. PD DEC 26 PY 2016 VL 7 AR 168 DI 10.3389/fendo.2016.00168 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG0WH UT WOS:000390752500001 PM 28082948 ER PT J AU Koonin, EV AF Koonin, Eugene V. TI Splendor and misery of adaptation, or the importance of neutral null for understanding evolution SO BMC BIOLOGY LA English DT Article ID LONG NONCODING RNAS; GENOME EVOLUTION; PERVASIVE TRANSCRIPTION; TRANSPOSABLE ELEMENTS; SPLICEOSOMAL INTRONS; EUKARYOTIC GENOME; MUTATION-RATE; SENSE EXCEPT; JUNK DNA; COMPLEXITY AB The study of any biological features, including genomic sequences, typically revolves around the question: what is this for? However, population genetic theory, combined with the data of comparative genomics, clearly indicates that such a "pan-adaptationist"approach is a fallacy. The proper question is: how has this sequence evolved? And the proper null hypothesis posits that it is a result of neutral evolution: that is, it survives by sheer chance provided that it is not deleterious enough to be efficiently purged by purifying selection. To claim adaptation, the neutral null has to be falsified. The adaptationist fallacy can be costly, inducing biologists to relentlessly seek function where there is none. C1 [Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU intramural funds of the US Department of Health and Human Services FX The author's research is supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). NR 86 TC 0 Z9 0 U1 6 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7007 J9 BMC BIOL JI BMC Biol. PD DEC 23 PY 2016 VL 14 AR 114 DI 10.1186/s12915-016-0338-2 PG 8 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EG6JW UT WOS:000391151800001 PM 28010725 ER PT J AU Cruz, AC Ramaswamy, M Ouyang, C Klebanoff, CA Sengupta, P Yamamoto, TN Meylan, F Thomas, SK Richoz, N Eil, R Price, S Casellas, R Rao, VK Lippincott-Schwartz, J Restifo, NP Siegel, RM AF Cruz, Anthony C. Ramaswamy, Madhu Ouyang, Claudia Klebanoff, Christopher A. Sengupta, Prabuddha Yamamoto, Tori N. Meylan, Francoise Thomas, Stacy K. Richoz, Nathan Eil, Robert Price, Susan Casellas, Rafael Rao, V. Koneti Lippincott-Schwartz, Jennifer Restifo, Nicholas P. Siegel, Richard M. TI Fas/CD95 prevents autoimmunity independently of lipid raft localization and efficient apoptosis induction SO NATURE COMMUNICATIONS LA English DT Article ID PROGRAMMED CELL-DEATH; SYSTEMIC AUTOIMMUNITY; T-CELLS; B-CELLS; CD40 LIGAND; LYMPHOPROLIFERATIVE SYNDROME; FAS-LIGAND; IN-VIVO; CD95; MICE AB Mutations affecting the apoptosis-inducing function of the Fas/CD95 TNF-family receptor result in autoimmune and lymphoproliferative disease. However, Fas can also costimulate T-cell activation and promote tumour cell growth and metastasis. Palmitoylation at a membrane proximal cysteine residue enables Fas to localize to lipid raft microdomains and induce apoptosis in cell lines. Here, we show that a palmitoylation-defective Fas C194V mutant is defective in inducing apoptosis in primary mouse T cells, B cells and dendritic cells, while retaining the ability to enhance naive T-cell differentiation. Despite inability to efficiently induce cell death, the Fas C194V receptor prevents the lymphoaccumulation and autoimmunity that develops in Fas-deficient mice. These findings indicate that induction of apoptosis through Fas is dependent on receptor palmitoylation in primary immune cells, and Fas may prevent autoimmunity by mechanisms other than inducing apoptosis. C1 [Cruz, Anthony C.; Ramaswamy, Madhu; Ouyang, Claudia; Meylan, Francoise; Thomas, Stacy K.; Richoz, Nathan; Siegel, Richard M.] Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, Immunoregulat Sect, Autoimmun Branch, Intramural Res Program,NIH, Bethesda, MD 20892 USA. [Klebanoff, Christopher A.] Mem Sloan Kettering Canc Ctr, Ctr Cell Engn, New York, NY 10065 USA. [Klebanoff, Christopher A.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Klebanoff, Christopher A.; Yamamoto, Tori N.; Eil, Robert; Restifo, Nicholas P.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Sengupta, Prabuddha; Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Yamamoto, Tori N.] Univ Penn, Immunol Grad Grp, Philadelphia, PA 19104 USA. [Price, Susan; Rao, V. Koneti] NIAID, Clin Genom Unit, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Casellas, Rafael] NIAMS, Genom & Immun Branch, Bethesda, MD 20892 USA. [Restifo, Nicholas P.] NCI, Ctr Cell Based Therapy, NIH, Bethesda, MD 20892 USA. [Ramaswamy, Madhu] MedImmune LLC, Oncol Res, Gaithersburg, MD 20878 USA. RP Siegel, RM (reprint author), Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, Immunoregulat Sect, Autoimmun Branch, Intramural Res Program,NIH, Bethesda, MD 20892 USA. EM rsiegel@nih.gov FU NIAMS; NCI; NIAID; NICHD FX We would like to thank Susan Lim for technical assistance with BAC recombineering; Steevenson Nelson and Nathan Pruett for assistance with B-cell isolation and culture; David Scott, Andrew Snow, Leonid Pobezinsky, Al Singer and Ann Marshak-Rothststein for helpful advice; Lionel Feigenbaum and the NCI mouse genetics core facility for generation of the Fas C194V BAC transgenic mice; the NIAMS laboratory animal care unit for maintenance of the animals in this work; the NIAMS Flow Cytometry Core for technical assistance and helpful advice and KC Dowdell for performing apoptosis assays on the ALPS patient samples. This work was supported by the intramural research programs of NIAMS, NCI, NIAID and NICHD. NR 67 TC 0 Z9 0 U1 10 U2 10 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 DEC 23 PY 2016 VL 7 AR 13895 DI 10.1038/ncomms13895 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EF5GM UT WOS:000390358700001 PM 28008916 ER PT J AU Xia, L Schrump, DS Gildersleeve, JC AF Xia, Li Schrump, David S. Gildersleeve, Jeffrey C. TI Whole-Cell Cancer Vaccines Induce Large Antibody Responses to Carbohydrates and Glycoproteins SO Cell Chemical Biology LA English DT Article ID FETAL CALF SERUM; METASTATIC PANCREATIC-CANCER; SECRETING TUMOR VACCINE; IMMUNE ACTIVATION; BIOMARKER DISCOVERY; GLYCAN MICROARRAYS; PROSTATE-CANCER; PROSTVAC-VF; GANGLIOSIDES; SURVIVAL AB Whole-cell cancer vaccines are a promising strategy for treating cancer, but the characteristics of a favorable immune response are not fully understood. New insights could enable development of better vaccines, discovery of new antigens, and identification of biomarkers of efficacy. Using glyco-antigen microarrays, we demonstrate that GVAX Pancreas (a granulocyte macrophage colony-stimulating factor- modified whole-cell tumor vaccine) induces large immunoglobulin G and immunoglobulinMresponses to many antigens, including tumor-associated carbohydrates, blood group antigens, alpha-Gal, and bovine fetuin. Antibody responses to alpha-Gal, a glycan found in fetal bovine serum (FBS) used to produce the vaccine, correlated inversely with overall survival and appear to compete with productive responses to the vaccine. H1299 lysate vaccine, produced with FBS, also induced responses to alpha-Gal and fetuin but not K562-GM, which is produced in serum-free medium. Our results provide new potential biomarkers to evaluate productive/unproductive immune responses and suggest that removal/reduction of FBS could improve the efficacy of whole-cell vaccines. C1 [Xia, Li; Gildersleeve, Jeffrey C.] NCI, Biol Chem Lab, Ctr Canc Res, NIH, 376 Boyles St,Room 208, Frederick, MD 21702 USA. [Schrump, David S.] NCI, Thorac Oncol Sect, Thorac & GI Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Gildersleeve, JC (reprint author), NCI, Biol Chem Lab, Ctr Canc Res, NIH, 376 Boyles St,Room 208, Frederick, MD 21702 USA. EM gildersj@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH [1ZIABC011055-08] FX We thank the Consortium for Functional Glycomics (GM62116; The Scripps Research Institute), Professors Tom Tolbert (University of Kansas), Lai-Xi Wang (University of Maryland), Xuefei Huang (Michigan State University), Todd Lowary (University of Alberta), and Dr. Joseph Barchi (National Cancer Institute) for contributing glycans for the array. We thank Dr. Elizabeth Jaffee (Johns Hopkins University) for providing serum samples for this study and Dr. Eric Sterner for assistance in the permutation test. This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH (1ZIABC011055-08). NR 50 TC 1 Z9 1 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2451-9448 J9 CELL CHEM BIOL JI Cell Chem. Biol. PD DEC 22 PY 2016 VL 23 IS 12 BP 1515 EP 1525 DI 10.1016/j.chembiol.2016.10.012 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EI9PZ UT WOS:000392842300012 PM 27889407 ER PT J AU Tota, JE Jiang, MZ Ramanakumar, AV Walter, SD Kaufman, JS Coutlee, F Richardson, H Burchell, AN Koushik, A Mayrand, MH Villa, LL Franco, EL AF Tota, Joseph E. Jiang, Mengzhu Ramanakumar, Agnihotram V. Walter, Stephen D. Kaufman, Jay S. Coutlee, Francois Richardson, Harriet Burchell, Ann N. Koushik, Anita Mayrand, Marie Helene Villa, Luisa L. Franco, Eduardo L. TI Epidemiologic Evaluation of Human Papillomavirus Type Competition and the Potential for Type Replacement Post-Vaccination SO PLoS One LA English DT Article ID INVASIVE CERVICAL-CANCER; HPV TYPES; INTRAEPITHELIAL NEOPLASIA; CLUSTERING PATTERNS; PARTICLE VACCINE; INFECTION; WOMEN; RISK; DNA; COINFECTION AB Background Millions of women have been vaccinated with one of two first-generation human papillomavirus (HPV) vaccines. Both vaccines remain in use and target two oncogenic types (HPVs 16 and 18); however, if these types naturally compete with others that are not targeted, type replacement may occur following reductions in the circulating prevalence of targeted types. To explore the potential for type replacement, we evaluated natural HPV type competition in unvaccinated females. Methods Valid HPV DNA typing information was available from five epidemiological studies conducted in Canada and Brazil (n = 14,685; enrollment across studies took place between1993 and 2010), which used similar consensus-primer PCR assays, capable of detecting up to 40 HPV types. A total of 38,088 cervicovaginal specimens were available for inclusion in our analyses evaluating HPV type-type interactions involving vaccine-targeted types (6, 11, 16, and 18), and infection with each of the other HPV types. Results Across the studies, the average age of participants ranged from 21.0 to 43.7 years. HPV16 was the most common type (prevalence range: 1.0% to 13.8%), and in general HPV types were more likely to be detected as part of a multiple infection than as single infections. In our analyses focusing on each of the vaccine-targeted HPV types separately, many significant positive associations were observed (particularly involving HPV16); however, we did not observe any statistically significant negative associations. Conclusions Our findings suggest that natural HPV type competition does not exist, and that type replacement is unlikely to occur in vaccinated populations. C1 [Tota, Joseph E.; Jiang, Mengzhu; Ramanakumar, Agnihotram V.; Franco, Eduardo L.] McGill Univ, Dept Oncol, Montreal, PQ, Canada. [Tota, Joseph E.; Kaufman, Jay S.; Franco, Eduardo L.] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada. [Tota, Joseph E.] NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, Rockville, MD 20892 USA. [Walter, Stephen D.] McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada. [Coutlee, Francois] Univ Montreal, Dept Microbiol & Infectiol, Montreal, PQ, Canada. [Coutlee, Francois; Koushik, Anita; Mayrand, Marie Helene] Univ Montreal, Hosp Res Ctr, Montreal, PQ, Canada. [Richardson, Harriet] Queens Univ, Dept Publ Hlth Sci, Kingston, ON, Canada. [Burchell, Ann N.] St Michaels Hosp, Dept Family & Community Med, Toronto, ON, Canada. [Burchell, Ann N.] Li Ka Shing Knowledge Inst, Ctr Res Inner City Hlth, Toronto, ON, Canada. [Koushik, Anita] Univ Montreal, Dept Med Sociale & Prevent, Montreal, PQ, Canada. [Mayrand, Marie Helene] Univ Montreal, Dept Obstet Gynecol & Med Sociale & Prevent, Montreal, PQ, Canada. [Villa, Luisa L.] Univ Sao Paulo, Sch Med, Dept Radiol & Oncol, Sao Paulo, Brazil. RP Tota, JE (reprint author), McGill Univ, Dept Oncol, Montreal, PQ, Canada.; Tota, JE (reprint author), McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada.; Tota, JE (reprint author), NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, Rockville, MD 20892 USA. EM joseph.tota@nih.gov FU Canadian Institutes of Health Research [MOP-53111, MOP-49396, MOP-68893, MOP-42532, MCT-54063, MOP-67155, CRN-83320]; Canadian Cancer Society [12030]; US National Institutes of Health [CA70269, AI073889]; Society of Gynecologic Oncology of Canada; Roseau FRSQ SIDA maladies infectieuses; CIHR New Investigator awards; Canada Research Chairs program FX Funding for this study and for the parent investigations was provided by the Canadian Institutes of Health Research (grants MOP-53111, MOP-49396, MOP-68893, MOP-42532, MCT-54063, MOP-67155, CRN-83320), Canadian Cancer Society (grant 12030), the US National Institutes of Health (grants CA70269, AI073889), the Society of Gynecologic Oncology of Canada, and by the Roseau FRSQ SIDA maladies infectieuses. A.N.B. and A.K. are supported by CIHR New Investigator awards. J.S.K. was supported by the Canada Research Chairs program. NR 48 TC 0 Z9 0 U1 4 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 22 PY 2016 VL 11 IS 12 AR e0166329 DI 10.1371/journal.pone.0166329 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI9QH UT WOS:000392843200005 PM 28005904 ER PT J AU Pavasini, R Guralnik, J Brown, JC di Bari, M Cesari, M Landi, F Vaes, B Legrand, D Verghese, J Wang, CL Stenholm, S Ferrucci, L Lai, JC Bartes, AA Espaulella, J Ferrer, M Lim, JY Ensrud, KE Cawthon, P Turusheva, A Frolova, E Rolland, Y Lauwers, V Corsonello, A Kirk, GD Ferrari, R Volpato, S Campo, G AF Pavasini, Rita Guralnik, Jack Brown, Justin C. di Bari, Mauro Cesari, Matteo Landi, Francesco Vaes, Bert Legrand, Delphine Verghese, Joe Wang, Cuiling Stenholm, Sari Ferrucci, Luigi Lai, Jennifer C. Arnau Bartes, Anna Espaulella, Joan Ferrer, Montserrat Lim, Jae-Young Ensrud, Kristine E. Cawthon, Peggy Turusheva, Anna Frolova, Elena Rolland, Yves Lauwers, Valerie Corsonello, Andrea Kirk, Gregory D. Ferrari, Roberto Volpato, Stefano Campo, Gianluca TI Short Physical Performance Battery and all-cause mortality: systematic review and meta-analysis SO BMC MEDICINE LA English DT Review DE Short Physical Performance Battery; All-cause mortality; Physical function; Meta-analysis ID LOWER-EXTREMITY PERFORMANCE; LOWER-LIMB FUNCTION; OLDER-ADULTS; MOBILITY DISABILITY; MUSCLE STRENGTH; HEART-FAILURE; FRAILTY; HOSPITALIZATION; PREDICTORS; SURVIVAL AB Background: The Short Physical Performance Battery (SPPB) is a well-established tool to assess lower extremity physical performance status. Its predictive ability for all-cause mortality has been sparsely reported, but with conflicting results in different subsets of participants. The aim of this study was to perform a meta-analysis investigating the relationship between SPPB score and all-cause mortality. Methods: Articles were searched in MEDLINE, the Cochrane Library, Google Scholar, and BioMed Central between July and September 2015 and updated in January 2016. Inclusion criteria were observational studies; > 50 participants; stratification of population according to SPPB value; data on all-cause mortality; English language publications. Twenty-four articles were selected from available evidence. Data of interest (i.e., clinical characteristics, information after stratification of the sample into four SPPB groups [0-3, 4-6, 7-9, 10-12]) were retrieved from the articles and/or obtained by the study authors. The odds ratio (OR) and/or hazard ratio (HR) was obtained for all-cause mortality according to SPPB category (with SPPB scores 10-12 considered as reference) with adjustment for age, sex, and body mass index. Results: Standardized data were obtained for 17 studies (n = 16,534, mean age 76 +/- 3 years). As compared to SPPB scores 10-12, values of 0-3 (OR 3.25, 95% CI 2.86-3.79), 4-6 (OR 2.14, 95% CI 1.92-2.39), and 7-9 (OR 1.50, 95% CI 1. 32-1.71) were each associated with an increased risk of all-cause mortality. The association between poor performance on SPPB and all-cause mortality remained highly consistent independent of follow-up length, subsets of participants, geographic area, and age of the population. Random effects meta-regression showed that OR for all-cause mortality with SPPB values 7-9 was higher in the younger population, diabetics, and men. Conclusions: An SPPB score lower than 10 is predictive of all-cause mortality. The systematic implementation of the SPPB in clinical practice settings may provide useful prognostic information about the risk of all-cause mortality. Moreover, the SPPB could be used as a surrogate endpoint of all-cause mortality in trials needing to quantify benefit and health improvements of specific treatments or rehabilitation programs. C1 [Pavasini, Rita; Ferrari, Roberto; Campo, Gianluca] Univ S Anna, Azienda Osped, Cardiol Unit, Via Aldo Moro 8, I-44124 Ferrara, Italy. [Guralnik, Jack] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Brown, Justin C.] Dana Farber Canc Inst, Dept Med Oncol, Div Populat Sci, Boston, MA 02115 USA. [di Bari, Mauro] Univ Florence, Dept Crit Care Med & Surg, Unit Gerontol & Geriatr Med, Florence, Italy. [di Bari, Mauro] Univ Careggi, Azienda Osped, Florence, Italy. [Cesari, Matteo; Rolland, Yves] Ctr Hosp Univ Toulouse, Gerontopole, Toulouse, France. [Cesari, Matteo; Rolland, Yves] Univ Toulouse III Paul Sabatier, INSERM UMR1027, Toulouse, France. [Landi, Francesco] Univ Cattolica Sacro Cuore, Dept Geriatr Neurosci & Orthopaed, Rome, Italy. [Vaes, Bert] Catholic Univ Louvain, Inst Hlth & Soc, Brussels, Belgium. [Vaes, Bert] Katholieke Univ Leuven, Dept Publ Hlth & Primary Care, Leuven, Belgium. [Legrand, Delphine; Turusheva, Anna] Catholic Univ Louvain, Inst Rech Sante & Soc, Brussels, Belgium. [Verghese, Joe] Albert Einstein Coll Med, Dept Neurol & Med, Bronx, NY 10467 USA. [Wang, Cuiling] Albert Einstein Coll Med, Dept Epidemiol, Bronx, NY 10467 USA. [Stenholm, Sari] Univ Turku, Dept Publ Hlth, Turku, Finland. [Ferrucci, Luigi] Harbor Hosp, NIA, Longitudinal Studies Sect, Clin Res Branch,NIA ASTRA Unit, Baltimore, MD USA. [Lai, Jennifer C.] Univ Calif San Francisco, Dept Med, Div Gastroenterol & Hepatol, San Francisco, CA USA. [Arnau Bartes, Anna] Althaia Xarxa Assistencial Univ Manresa, Clin Res Unit, Manresa, Barcelona, Spain. [Espaulella, Joan] Hosp Univ Santa Creu, Serv Geriatria & Cures Palliat, Vic, Barcelona, Spain. [Ferrer, Montserrat] Hosp del Mar, Med Res Inst, IMIM, Hlth Serv Res Grp, Barcelona, Spain. [Ferrer, Montserrat] CIBER Epidemiol & Salud Publ CIBERESP, Barcelona, Spain. [Lim, Jae-Young] Seoul Natl Univ, Seoul Natl Univ Bundang Hosp, Coll Med, Dept Rehabil Med, Seongnam, Gyeonggi, South Korea. [Ensrud, Kristine E.] Univ Minnesota, Med & Epidemiol & Community Hlth, Minneapolis, MN USA. [Ensrud, Kristine E.] Minneapolis VA Hlth Care Syst, Gen Internal Med, Minneapolis, MN USA. [Cawthon, Peggy] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Frolova, Elena] North Western State Med Univ, Dept Family Med, St Petersburg, Russia. [Lauwers, Valerie] Fac Med, Lab Epidemiol & Sante Commun, Unite Inserm 558, Allees Jules Guesde, Toulouse, France. [Corsonello, Andrea] Res Hosp Cosenza, INRCA, Unit Geriatr Pharmacoepidemiol, Cosenza, Italy. [Kirk, Gregory D.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Kirk, Gregory D.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Ferrari, Roberto] Maria Cecilia Hosp, ES Hlth Sci Fdn, GVM Care & Res, Cotignola, Italy. [Volpato, Stefano] Univ Ferrara, Dept Med Sci, Sect Internal & Cardiorespiratory Med, Ferrara, Italy. RP Pavasini, R (reprint author), Univ S Anna, Azienda Osped, Cardiol Unit, Via Aldo Moro 8, I-44124 Ferrara, Italy. EM pvsrti@unife.it RI Cesari, Matteo/A-4649-2008; OI Cesari, Matteo/0000-0002-0348-3664; ARNAU, ANNA/0000-0001-8939-3469; Frolova, Elena/0000-0002-5569-5175 FU Fondation Louvain [B40320084685]; US National Institute on Aging [P01 AGO3949, R01 AGO25119]; National Institute on Aging [P01 AGO3949, R01 AG039330, R01 AGO44007, AGO44829, R01 AG036921, R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, R01 AG027576]; Fund for Health Research of Spain [PI042370]; European Regional Development Fund (FEDER); National Institutes of Health [U01-DA-036297, R01-DA-04334, R01-DA-12568, RC1-AI-086053, K24-AI118591]; Russian Federation [192-RP] FX B. Vaes and D. Legrand participated in the BELFRAIL study (B40320084685), which was supported by an unconditional grant from the Fondation Louvain. The Fondation Louvain is the support unit of the Universite catholique de Louvain and is charged with developing the educational and research projects of the university by collecting gifts from corporations, foundations, and alumni.; J. Verghese participated in The Einstein Aging Study, which was supported by US National Institute on Aging grants (P01 AGO3949 and R01 AGO25119). Dr. Verghese received funding support from National Institute on Aging grants (R01 AG039330, R01 AGO44007, AGO44829, and R01 AG036921). C. Wang received funding support from National Institute on Aging grants (P01 AGO3949, R01 AG039330, R01 AGO44007, AGO44829, and R01 AG036921).; A. Arnau Bartes received a grant from the Fund for Health Research of Spain (PI042370) and the European Regional Development Fund (FEDER). K. Ensrud and P. Cawthon participated in the Study of Osteoporotic Fractures (SOF), which is supported by National Institutes of Health funding. The National Institute on Aging provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576.; A. Turusheva and E. Frolova received a Grant of the President of the Russian Federation (grant 192-RP) and the Foundation Louvain.; G. Kirk participated in the AIDS Linked to the IntraVenous Experience (ALIVE) study, which was supported by the National Institutes of Health (grants U01-DA-036297, R01-DA-04334, R01-DA-12568, RC1-AI-086053, and K24-AI118591). NR 41 TC 0 Z9 0 U1 9 U2 9 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 DEC 22 PY 2016 VL 14 AR 215 DI 10.1186/s12916-016-0763-7 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA EG5FX UT WOS:000391070100001 PM 28003033 ER PT J AU Shreif, ZZ Gatti, DM Periwal, V AF Shreif, Zeina Z. Gatti, Daniel M. Periwal, Vipul TI Block network mapping approach to quantitative trait locus analysis SO BMC BIOINFORMATICS LA English DT Article DE QTL mapping; Interval mapping; Bayes' theorem ID FRAGMENT-LENGTH-POLYMORPHISMS; MENDELIAN FACTORS; HIGH-RESOLUTION; MULTIPLE LOCI; INBRED LINES; LINKAGE MAPS; QTL; POPULATION; PARAMETERS; CHARACTER AB Background: Advances in experimental biology have enabled the collection of enormous troves of data on genomic variation in living organisms. The interpretation of this data to extract actionable information is one of the keys to developing novel therapeutic strategies to treat complex diseases. Network organization of biological data overcomes measurement noise in several biological contexts. Does a network approach, combining information about the linear organization of genomic markers with correlative information on these markers in a Bayesian formulation, lead to an analytic method with higher power for detecting quantitative trait loci? Results: Block Network Mapping, combining Similarity Network Fusion (Wang et al., NM 11:333-337, 2014) with a Bayesian locus likelihood evaluation, leads to large improvements in area under the receiver operating characteristic and power over interval mapping with expectation maximization. The method has a monotonically decreasing false discovery rate as a function of effect size, unlike interval mapping. Conclusions: Block Network Mapping provides an alternative data-driven approach to mapping quantitative trait loci that leverages correlations in the sampled genotypes. The evaluation methodology can be combined with existing approaches such as Interval Mapping. C1 [Shreif, Zeina Z.; Periwal, Vipul] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. [Gatti, Daniel M.] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. RP Periwal, V (reprint author), NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. EM vipulp@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, NIDDK; [R01 GM070683-10] FX This work was supported by the Intramural Research Program of the National Institutes of Health, NIDDK. DMG was funded by R01 GM070683-10 awarded to Gary Churchill. NR 32 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 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD DEC 22 PY 2016 VL 17 AR 544 DI 10.1186/s12859-016-1351-8 PG 13 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA EG2YB UT WOS:000390908900001 PM 28007037 ER PT J AU Chiurillo, MA Barros, RRM Souza, RT Marini, MM Antonio, CR Cortez, DR Curto, MA Lorenz', HA Schijman, AG Ramirez, JL da Silveira, JF AF Chiurillo, Miguel A. Moraes Barros, Roberto R. Souza, Renata T. Marini, Marjorie M. Antonio, Cristiane R. Cortez, Danielle R. Curto, Maria A. Lorenz, Hernan A. Schijman, Alejandro G. Ramirez, Jose L. da Silveira, Jose F. TI Subtelomeric I-Scel-Mediated Double-Strand Breaks Are Repaired by Homologous Recombination in Trypanosoma cruzi SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE T. cruzi; telomere; I-Scel meganuclease; double-strand break; homologous recombination; DNA repair; artificial chromosomes ID AFRICAN TRYPANOSOMES; ANTIGENIC VARIATION; MULTIGENE FAMILIES; BRUCEI; EXPRESSION; DIVERSITY; SEQUENCE; EVOLUTION; TELOMERES; PATHWAYS AB Trypanosoma cruzi chromosome ends are enriched in surface protein genes and pseudogenes (e.g., trans-sialidases) surrounded by repetitive sequences. It has been proposed that the extensive sequence variability among members of these protein families could play a role in parasite infectivity and evasion of host immune response. In previous reports we showed evidence suggesting that sequences located in these regions are subjected to recombination. To support this hypothesis we introduced a double-strand break (DSB) at a specific target site in a I cruzi subtelomeric region cloned into an artificial chromosome (pTAC). This construct was used to transfect T. cruzi epimastigotes expressing the I-Scel meganuclease. Examination of the repaired sequences showed that DNA repair occurred only through homologous recombination (HR) with endogenous subtelomeric sequences. Our findings suggest that DSBs in subtelomeric repetitive sequences followed by HR between them may contribute to increased variability in T. cruzi multigene families. C1 [Chiurillo, Miguel A.] Univ Centroccidental Lisandro Alvarado, Lab Genet Mol Dr Yunis Turbay, Ciencias Salud, Barquisimeto, Venezuela. [Moraes Barros, Roberto R.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Souza, Renata T.; Marini, Marjorie M.; Antonio, Cristiane R.; Cortez, Danielle R.; da Silveira, Jose F.] Univ Fed Sao Paulo, Escola Paulista Med, Dept Microbiol Imunol & Parasitol, Sao Paulo, Brazil. [Curto, Maria A.; Schijman, Alejandro G.] Consejo Nacl Invest Cient & Tecn, Inst Invest Ingn Genet & Biol Mol, Lab Biol Mol Enfermedad Chagas, Buenos Aires, DF, Argentina. [Lorenz, Hernan A.] J Craig Venter Inst, Dept Infect Dis, Rockville, MD USA. [Ramirez, Jose L.] Fdn Inst Estudios Avanzados, Ctr Biotecnol, Caracas, Venezuela. [Chiurillo, Miguel A.] Univ Estadual Campinas, Fac Ciencias Med, Dept Patol Clin, Campinas, SP, Brazil. RP da Silveira, JF (reprint author), Univ Fed Sao Paulo, Escola Paulista Med, Dept Microbiol Imunol & Parasitol, Sao Paulo, Brazil. EM jose.franco@unifesp.br FU FAPESP [11/51693-0, 11/51475-3]; CNPq [306591/2015-4] FX This work was supported by grants from FAPESP (11/51693-0, MAC; 11/51475-3, JFDS) and CNPq (306591/2015-4). NR 33 TC 0 Z9 0 U1 1 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PD DEC 22 PY 2016 VL 7 AR 2041 DI 10.3389/fmicb.2016.02041 PG 8 WC Microbiology SC Microbiology GA EF9MP UT WOS:000390654600001 PM 28066363 ER PT J AU Chung, SI Horton, JA Ramalingam, TR White, AO Chung, EJ Hudak, KE Scroggins, BT Arron, JR Wynn, TA Citrin, DE AF Chung, Su I. Horton, Jason A. Ramalingam, Thirumalai R. White, Ayla O. Chung, Eun Joo Hudak, Kathryn E. Scroggins, Bradley T. Arron, Joseph R. Wynn, Thomas A. Citrin, Deborah E. TI IL-13 is a therapeutic target in radiation lung injury SO SCIENTIFIC REPORTS LA English DT Article ID ALLERGIC AIRWAY DISEASE; PULMONARY-FIBROSIS; RANDOMIZED MULTICENTER; TISSUE FIBROSIS; CLINICAL-TRIAL; TGF-BETA; ASTHMA; INTERLEUKIN-13; MICE; RECEPTOR-ALPHA-2 AB Pulmonary fibrosis is a potentially lethal late adverse event of thoracic irradiation. Prior research indicates that unrestrained TGF-beta 1 and/or type 2 cytokine-driven immune responses promote fibrosis following radiation injury, but the full spectrum of factors governing this pathology remains unclear. Interleukin 13 (IL-13) is a key factor in fibrotic disease associated with helminth infection, but it is unclear whether it plays a similar role in radiation-induced lung fibrosis. Using a mouse model, we tested the hypothesis that IL-13 drives the progression of radiation-induced pulmonary fibrosis. Irradiated lungs from wild-type c57BL/6NcR mice accumulated alternatively-activated macrophages, displayed elevated levels of IL-13, and extensive fibrosis, whereas IL-13 deficient mice were resistant to these changes. Furthermore, plasma from irradiated wild-type mice showed a transient increase in the IL-13 saturated fraction of the circulating decoy receptor IL-13Ra2. Finally, we determined that therapeutic neutralization of IL-13, during the period of IL-13Ra2 saturation was sufficient to protect mice from lung fibrosis. Taken together, our results demonstrate that IL-13 is a major regulator of radiation-induced lung injury and demonstrates that strategies focusing on IL-13 may be useful in screening for timely delivery of anti-IL-13 therapeutics. C1 [Chung, Su I.; White, Ayla O.; Chung, Eun Joo; Hudak, Kathryn E.; Scroggins, Bradley T.; Citrin, Deborah E.] NIH, Radiat Oncol Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Horton, Jason A.] Upstate Med Univ, Dept Orthoped Surg, Musculoskeletal Sci Res Ctr, Syracuse, NY USA. [Ramalingam, Thirumalai R.; Arron, Joseph R.] Genentech Inc, Biomarker Discovery OMNI, MS 231c,1 DNA way, San Francisco, CA 94080 USA. [Wynn, Thomas A.] NIAID, Parasit Dis Lab, 4 Mem Dr,Room 211C, Bethesda, MD 20892 USA. RP Citrin, DE (reprint author), NIH, Radiat Oncol Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. EM citrind@mail.nih.gov FU Intramural Research Program of the National Institutes of Health; National Cancer Institute; National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute and National Institute of Allergy and Infectious Diseases. NR 50 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 DEC 22 PY 2016 VL 6 AR 39714 DI 10.1038/srep39714 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG2HT UT WOS:000390865000001 PM 28004808 ER PT J AU Kunos, CA AF Kunos, Charles A. TI Commentary: Phase I Trial of Carboplatin and Gemcitabine Chemotherapy and Stereotactic Ablative Radiosurgery for the Palliative Treatment of Persistent or Recurrent Gynecologic Cancer SO FRONTIERS IN ONCOLOGY LA English DT Editorial Material DE women's cancer; radiation oncology; breast cancer; ovarian cancer; uterine cancer; cervix cancer; stereotactic body radiation therapy ID CLINICAL-TRIALS C1 [Kunos, Charles A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Kunos, CA (reprint author), NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. EM charles.kunos@nih.gov NR 9 TC 0 Z9 0 U1 1 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2234-943X J9 FRONT ONCOL JI Front. Oncol. PD DEC 22 PY 2016 VL 6 AR 263 DI 10.3389/fonc.2016.00263 PG 2 WC Oncology SC Oncology GA EF4AF UT WOS:000390266000002 PM 28066719 ER PT J AU Tosh, DK Ciancetta, A Warnick, E Crane, S Gao, ZG Jacobson, KA AF Tosh, Dilip K. Ciancetta, Antonella Warnick, Eugene Crane, Steven Gao, Zhan-Guo Jacobson, Kenneth A. TI Structure-Based Scaffold Repurposing for G Protein-Coupled Receptors: Transformation of Adenosine Derivatives into 5HT(2B)/5HT(2C) Serotonin Receptor Antagonists SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CHRONIC NEUROPATHIC PAIN; FORCE-FIELD; MOLECULAR-DYNAMICS; 5-HT2B RECEPTOR; (N)-METHANOCARBA NUCLEOSIDES; LIGAND RECOGNITION; CRYSTAL-STRUCTURE; AGONISTS; DESIGN; DRUG AB Adenosine derivatives developed to activate adenosine receptors (ARs) revealed micromolar activity at serotonin 5HT(2B) and 5HT(2C) receptors (5HTRs). We explored the structure activity relationship at 5HT(2)Rs and modeled receptor interactions in order to optimize affinity and simultaneously reduce AR affinity. Depending on N-6 substitution, small 5'-alkylamide modification maintained 5HT(2B)R affinity, which was enhanced upon ribose substitution with rigid bicyclo [3.1.0]-hexane (North (N)-methanocarba), e.g., N-6-dicydopropylmethyl 4'-CH2OH derivative 14 (K-i 11 nM). 5'-Methylamide 23 was 170-fold selective as antagonist for 5HT(2B)R vs 5HT(2C)R. 5'-Methyl 25 and ethyl 26 esters potently antagonized 5HT(2)Rs with moderate selectivity in comparison to ARs; related 6-N,N-dimethylamino analogue 30 was 5HT(2)R-selective. 5' position flexibility of substitution was indicated in 5HT(2B)R docking. Both 5'-ester and 5'-amide derivatives displayed in vivo t(1/2) of 3-4 h. Thus, we used G protein-coupled receptor modeling to repurpose nucleoside scaffolds in favor of binding at nonpurine receptors as novel 5HT(2)R antagonists, with potential for cardioprotection, liver protection, or central nervous system activity. C1 [Tosh, Dilip K.; Ciancetta, Antonella; Warnick, Eugene; Crane, Steven; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov OI Jacobson, Kenneth/0000-0001-8104-1493 FU National Institutes of Health (Intramural Research Program of the NIDDK); National Institutes of Health [R01HL077707]; National Institute of Mental Health's Psychoactive Drug Screening Program [HHSN-271-2008-00025-C] FX We thank Dr. John Lloyd and Dr. Noel Whittaker (NIDDK) for mass spectral determinations. This research was supported by the National Institutes of Health (Intramural Research Program of the NIDDK and R01HL077707). We thank Dr. Bryan L. Roth and Dr. X. P. Huang (Univ. North Carolina at Chapel Hill) and National Institute of Mental Health's Psychoactive Drug Screening Program (contract no. HHSN-271-2008-00025-C) for screening data. NR 77 TC 0 Z9 0 U1 4 U2 4 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 DEC 22 PY 2016 VL 59 IS 24 BP 11006 EP 11026 DI 10.1021/acs.jmedchem.6b01183 PG 21 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA EG0PU UT WOS:000390735500012 PM 27933810 ER PT J AU Abulwerdi, FA Shortridge, MD Sztuba-Solinska, J Wilson, R Le Grice, SFJ Varani, G Schneekloth, JS AF Abulwerdi, Fardokht A. Shortridge, Matthew D. Sztuba-Solinska, Joanna Wilson, Robert Le Grice, Stuart F. J. Varani, Gabriele Schneekloth, John S., Jr. TI Development of Small Molecules with a Noncanonical Binding Mode to HIV-1 Trans Activation Response (TAR) RNA SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; REVERSE TRANSCRIPTION; GENE-EXPRESSION; TARGETING RNA; PROTEIN; RECOGNITION; DISCOVERY; BULGE; INHIBITORS; ELEMENT AB Small molecules that bind to RNA potently and specifically are relatively rare. The study of molecules that bind to the HIV-1 transactivation response (TAR) hairpin, a cis-acting HIV genomic element, has long been an important model system for the chemistry of targeting RNA. Here we report the synthesis, biochemical, and structural evaluation of a series of molecules that bind to HIV-1 TAR RNA. A promising analogue, 15, retained the TAR binding affinity of the initial hit and displaced a Tat derived peptide with an IC50 of 40 ItM. NMR characterization of a soluble analogue, 2, revealed a noncanonical binding mode for this class of compounds. Finally, evaluation of 2 and 15 by selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) indicates specificity in binding to TAR within the context of an in vitro-synthesized 365-nt HIV-1 5'-untranslated region (UTR). Thus, these compounds exhibit a novel and specific mode of interaction with TAR, providing important suggestions for RNA ligand design. C1 [Abulwerdi, Fardokht A.; Wilson, Robert; Schneekloth, John S., Jr.] NCI, Biol Chem Lab, 376 Boyles St,Room 225C, Frederick, MD 21702 USA. [Abulwerdi, Fardokht A.; Sztuba-Solinska, Joanna; Le Grice, Stuart F. J.] NCI, Basic Res Labs, Frederick, MD 21702 USA. [Shortridge, Matthew D.; Varani, Gabriele] Univ Washington, Dept Chem, Seattle, WA 98195 USA. RP Schneekloth, JS (reprint author), NCI, Biol Chem Lab, 376 Boyles St,Room 225C, Frederick, MD 21702 USA. EM schneeklothjs@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, Center for Cancer Research, the National Cancer Institute (NCI); IATAP program, National Institutes of Health; NIH-NIGMS [GM110569]; American Cancer Society fellowship [PF-13-056-01-RMC] FX This work was supported by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, the National Cancer Institute (NCI), and the IATAP program, National Institutes of Health. Work at the University of Washington was supported by NIH-NIGMS GM110569. M. Shortridge was supported by an American Cancer Society fellowship (PF-13-056-01-RMC). We thank the Biophysics Resource in the Structural Biophysics Laboratory, NCI at Frederick, for assistance with QTOF LC-MS studies. NR 51 TC 0 Z9 0 U1 9 U2 9 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 DEC 22 PY 2016 VL 59 IS 24 BP 11148 EP 11160 DI 10.1021/acs.jmedchem.6b01450 PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA EG0PU UT WOS:000390735500022 PM 28002966 ER PT J AU Kim, HA Kyungdo-Han Lee, YA Choi, JA Park, YM AF Kim, Hyun-Ah Kyungdo-Han Lee, Yun-Ah Choi, Jin A. Park, Yong-Moon TI Differential Association of Metabolic Risk Factors with Open Angle Glaucoma according to Obesity in a Korean Population SO SCIENTIFIC REPORTS LA English DT Article ID NUTRITION EXAMINATION SURVEY; OCULAR PERFUSION-PRESSURE; HIGH INTRAOCULAR-PRESSURE; SINGAPORE-MALAY-EYE; NORMAL-WEIGHT; NATIONAL-HEALTH; BLOOD-FLOW; PREVALENCE; DISEASE; LEPTIN AB The associations of the metabolic syndrome (MetS) with intraocular pressure and primary open angle glaucoma (OAG) have been reported. This study aimed to determine whether a difference in association exists between OAG and metabolic risk factors according to obesity status among Korean adults. A total of 8,816 participants (>= 40 years) in the Korea National Health and Nutrition Examination Survey were classified into obese, body mass index (BMI) >= 25 kg/m(2) and non-obese, BMI < 25 kg/m(2). The prevalence of MetS was 40.1% in non-obese OAG and 66.0% in obese OAG. The prevalence of OAG increased with increasing number components for MetS in total population and in non-obese subjects (P < 0.001, respectively), while the prevalence of OAG was not associated with number of components for MetS in obese subjects (P = 0.14). In non-obese individuals, subjects with high triglycerides, high blood pressure (BP), and MetS were more likely to have OAG compared with those without high triglycerides, high BP, and MetS after adjusting for potential confounders. However, MetS or its components exhibited no significant association with glaucoma status in obese individuals. Our study provides understanding on the differences in association of OAG with MetS and its components according to obesity status. C1 [Kim, Hyun-Ah] Catholic Univ Korea, Dept Ophthalmol, Coll Med, Seoul, South Korea. [Kyungdo-Han] Catholic Univ Korea, Dept Biostat, Coll Med, Seoul, South Korea. [Lee, Yun-Ah] Catholic Univ Korea, St Vincents Hosp, Dept Family Med, Coll Med, Seoul, South Korea. [Choi, Jin A.] Catholic Univ Korea, St Vincents Hosp, Dept Ophthalmol, Coll Med, Seoul, South Korea. [Park, Yong-Moon] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Choi, JA (reprint author), Catholic Univ Korea, St Vincents Hosp, Dept Ophthalmol, Coll Med, Seoul, South Korea.; Park, YM (reprint author), NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. EM jinah616@catholic.ac.kr; markparkjecos@gmail.com OI PARK, YONG-MOON/0000-0002-5879-6879 NR 53 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 DEC 22 PY 2016 VL 6 AR 38283 DI 10.1038/srep38283 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EF4MN UT WOS:000390303300001 PM 28004731 ER PT J AU Polanco, MJ Parodi, S Piol, D Stack, C Chivet, M Contestabile, A Miranda, HC Lievens, PMJ Espinoza, S Jochum, T Rocchi, A Grunseich, C Gainetdinov, RR Cato, ACB Lieberman, AP La Spada, AR Sambataro, F Fischbeck, KH Gozes, I Pennuto, M AF Polanco, Maria Jose Parodi, Sara Piol, Diana Stack, Conor Chivet, Mathilde Contestabile, Andrea Miranda, Helen C. Lievens, Patricia M. -J. Espinoza, Stefano Jochum, Tobias Rocchi, Anna Grunseich, Christopher Gainetdinov, Raul R. Cato, Andrew C. B. Lieberman, Andrew P. La Spada, Albert R. Sambataro, Fabio Fischbeck, Kenneth H. Gozes, Illana Pennuto, Maria TI Adenylyl cyclase activating polypeptide reduces phosphorylation and toxicity of the polyglutamine-expanded androgen receptor in spinobulbar muscular atrophy SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID VASOACTIVE-INTESTINAL-PEPTIDE; CYCLIN-DEPENDENT KINASE-5; TRANSGENIC MOUSE MODEL; PROSTATE-CANCER; CELL-CYCLE; NEURODEGENERATIVE DISEASES; HUNTINGTONS-DISEASE; ALZHEIMERS-DISEASE; GENE-EXPRESSION; LIGAND-BINDING AB Spinobulbar muscular atrophy (SBMA) is an X-linked neuromuscular disease caused by polyglutamine (polyQ) expansion in the androgen receptor (AR) gene. SBMA belongs to the family of polyQ diseases, which are fatal neurodegenerative disorders mainly caused by protein-mediated toxic gain-of-function mechanisms and characterized by deposition of mis-folded proteins in the form of aggregates. The neurotoxicity of the polyQ proteins can be modified by phosphorylation at specific sites, thereby providing the rationale for the development of disease-specific treatments. We sought to identify signaling pathways that modulate polyQ-AR phosphorylation for therapy development. We report that cyclin-dependent kinase 2 (CDK2) phosphorylates polyQ-AR specifically at Ser(96). Phosphorylation of polyQ-AR by CDK2 increased protein stabilization and toxicity and is negatively regulated by the adenylyl cyclase (AC)/protein kinase A (PKA) signaling pathway. To translate these findings into therapy, we developed an analog of pituitary adenylyl cyclase activating polypeptide (PACAP), a potent activator of the AC/PKA pathway. Chronic intranasal administration of the PACAP analog to knock-in SBMA mice reduced Ser(96) phosphorylation, promoted polyQ-AR degradation, and ameliorated disease outcome. These results provide proof of principle that noninvasive therapy based on the use of PACAP analogs is a therapeutic option for SBMA. C1 [Polanco, Maria Jose; Piol, Diana; Chivet, Mathilde; Pennuto, Maria] Univ Trento, Ctr Integrat Biol, Dulbecco Telethon Inst, I-38123 Trento, Italy. [Polanco, Maria Jose; Parodi, Sara; Contestabile, Andrea; Espinoza, Stefano; Rocchi, Anna; Pennuto, Maria] Ist Italiano Tecnol, Dept Neurosci & Brain Technol, I-16163 Genoa, Italy. [Parodi, Sara; Stack, Conor; Grunseich, Christopher; Fischbeck, Kenneth H.] NINDS, Neurogenet Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Miranda, Helen C.; La Spada, Albert R.] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Miranda, Helen C.; La Spada, Albert R.] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. [Miranda, Helen C.; La Spada, Albert R.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Miranda, Helen C.; La Spada, Albert R.] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA. [Miranda, Helen C.; La Spada, Albert R.] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA. [Lievens, Patricia M. -J.] Univ Verona, Dept Neurosci Biomed & Movement Sci, Sect Biol & Genet, I-37134 Verona, Italy. [Jochum, Tobias] Karlsruhe Inst Technol, Lab Applicat Synchrotron Radiat, Karlsruhe, Germany. [Jochum, Tobias] Abcr GmbH, Karlsruhe, Germany. [Gainetdinov, Raul R.] St Petersburg State Univ, Inst Translat Biomed, St Petersburg 199034, Russia. [Gainetdinov, Raul R.] Skolkovo Inst Sci & Technol, Moscow 143025, Russia. [Cato, Andrew C. B.] Karlsruhe Inst Technol, Inst Toxicol & Genet, D-76344 Eggenstein Leopoldshafen, Germany. [Lieberman, Andrew P.] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA. [Sambataro, Fabio] Univ Udine, Dept Expt & Clin Med Sci DISM, I-33100 Udine, Italy. [Gozes, Illana] Tel Aviv Univ, Dept Human Mol Genet & Biochem, Sackler Fac Med, Sagol Sch Neurosci, IL-69978 Tel Aviv, Israel. [Gozes, Illana] Tel Aviv Univ, Adams Super Ctr Brain Studies, IL-69978 Tel Aviv, Israel. RP Pennuto, M (reprint author), Univ Trento, Ctr Integrat Biol, Dulbecco Telethon Inst, I-38123 Trento, Italy.; Pennuto, M (reprint author), Ist Italiano Tecnol, Dept Neurosci & Brain Technol, I-16163 Genoa, Italy. EM mpennuto@dti.telethon.it OI Contestabile, Andrea/0000-0002-5417-4722 FU Kennedy's Disease Association; Muscular Dystrophy Association [196646, 277469]; Telethon-Italy and Provincia Autonoma di Trento-Italy [TCP12013]; Bando Progetti Strategici di Ateneo-University of Trento; Marie Curie Reintegration Grants [FP7-256448, FP7-276981]; Italian Ministry of Health [RF-2011-02350097]; Association Francaise contre les Myopathies [18722]; Russian Science Foundation [14-50-00069]; NIH [R01 NS055746, R01 NS041648]; Fondazione Umberto Veronesi Fellowship; Marie Curie International Outgoing Fellowships [PIOF-GA-2011-300723] FX This work was supported by Kennedy's Disease Association (to M.P., S.P., and H.C.M.), the Muscular Dystrophy Association (196646 to M.P. and 277469 to A.R.L.S.), Telethon-Italy and Provincia Autonoma di Trento-Italy (TCP12013 to M.P.), Bando Progetti Strategici di Ateneo-University of Trento (to M.P.), Marie Curie Reintegration Grants (FP7-256448 to M.P. and FP7-276981 to F.S.), the Italian Ministry of Health (RF-2011-02350097 to M.P.), Association Francaise contre les Myopathies (18722 to M.P.), the Russian Science Foundation (14-50-00069 to R.R.G.), NIH (R01 NS055746 to A.P.L. and R01 NS041648 to A.R.L.S.), Fondazione Umberto Veronesi Fellowship (to M.C.), and Marie Curie International Outgoing Fellowships (PIOF-GA-2011-300723 to S.P.). NR 72 TC 1 Z9 1 U1 1 U2 1 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 DEC 21 PY 2016 VL 8 IS 370 AR 370ra181 DI 10.1126/scitranslmed.aaf9526 PG 16 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EG5US UT WOS:000391110700002 PM 28003546 ER PT J AU Dagdug, L Vazquez, MV Berezhkovskii, AM Zitserman, VY AF Dagdug, Leonardo Vazquez, Marco-Vinicio Berezhkovskii, Alexander M. Zitserman, Vladimir Yu. TI Boundary homogenization for a sphere with an absorbing cap of arbitrary size SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID DIFFUSION-CONTROLLED REACTION; ORIENTATION CONSTRAINTS; ROTATIONAL DIFFUSION; BROWNIAN DYNAMICS; LIGAND-BINDING; REACTION-RATES; ANISOTROPIC REACTIVITY; PROTEIN ASSOCIATION; SOLUTION KINETICS; ACTIVE-SITE AB This paper focuses on trapping of diffusing particles by a sphere with an absorbing cap of arbitrary size on the otherwise reflecting surface. We approach the problem using boundary homogenization which is an approximate replacement of non-uniform boundary conditions on the surface of the sphere by an effective uniform boundary condition with appropriately chosen effective trapping rate. One of the main results of our analysis is an expression for the effective trapping rate as a function of the surface fraction occupied by the absorbing cap. As the cap surface fraction increases from zero to unity, the effective trapping rate increases from that for a small absorbing disk on the otherwise reflecting sphere to infinity which corresponds to a perfectly absorbing sphere. The obtained expression for the effective trapping rate is applied to find the rate constant describing trapping of diffusing particles by an absorbing cap on the surface of the sphere. Finally, we find the capacitance of a metal cap of arbitrary size on a dielectric sphere using the relation between the capacitance and the rate constant of the corresponding diffusion-limited reaction. The relative error of our approximate expressions for the rate constant and the capacitance is less than 5% over the entire range of the cap surface fraction from zero to unity. Published by AIP Publishing. C1 [Dagdug, Leonardo; Vazquez, Marco-Vinicio] Univ Autonoma Metropolitana Iztapalapa, Dept Fis, Mexico City 09340, DF, Mexico. [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat BioSci, Ctr Informat Technol, Bethesda, MD 20819 USA. [Zitserman, Vladimir Yu.] Russian Acad Sci, Joint Inst High Temp, Izhorskaya 13,Bldg 2, Moscow 125412, Russia. RP Dagdug, L (reprint author), Univ Autonoma Metropolitana Iztapalapa, Dept Fis, Mexico City 09340, DF, Mexico. FU National Institutes of Health, the Center for Information Technology; [I.33P] FX The authors thank Sergey Bezrukov for numerous fruitful and stimulating discussions as well as for helpful comments on the manuscript, and Cyrill Muratov and Michael Ward for helpful discussions. V. Yu.Z. is grateful for the partial support to the Program of Basic Research of Presidium of Russian Academy of Sciences No. I.33P (under the supervision of Academicians V. B. Betelin, V. A. Babeshko, and B. N. Chetverushkin). This study was partially supported by the Intramural Research Program of the National Institutes of Health, the Center for Information Technology. NR 45 TC 0 Z9 0 U1 2 U2 2 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD DEC 21 PY 2016 VL 145 IS 21 AR 214101 DI 10.1063/1.4968598 PG 6 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA EF8TU UT WOS:000390603500037 ER PT J AU Stobart, CC Rostad, CA Ke, ZL Dillard, RS Hampton, CM Strauss, JD Yi, H Hotard, AL Meng, J Pickles, RJ Sakamoto, K Lee, S Currier, MG Moin, SM Graham, BS Boukhvalova, MS Gilbert, BE Blanco, JCG Piedra, PA Wright, ER Moore, ML AF Stobart, Christopher C. Rostad, Christina A. Ke, Zunlong Dillard, Rebecca S. Hampton, Cheri M. Strauss, Joshua D. Yi, Hong Hotard, Anne L. Meng, Jia Pickles, Raymond J. Sakamoto, Kaori Lee, Sujin Currier, Michael G. Moin, Syed M. Graham, Barney S. Boukhvalova, Marina S. Gilbert, Brian E. Blanco, Jorge C. G. Piedra, Pedro A. Wright, Elizabeth R. Moore, Martin L. TI A live RSV vaccine with engineered thermostability is immunogenic in cotton rats despite high attenuation SO NATURE COMMUNICATIONS LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; REPLICATION IN-VITRO; FUSION GLYCOPROTEIN; F-PROTEIN; CRYOELECTRON TOMOGRAPHY; NEUTRALIZING EPITOPES; STRUCTURAL-ANALYSIS; EPITHELIAL-CELLS; SH GENE; ANTIBODY AB Respiratory syncytial virus (RSV) is a leading cause of infant hospitalization and there remains no pediatric vaccine. RSV live-attenuated vaccines (LAVs) have a history of safe testing in infants; however, achieving an effective balance of attenuation and immunogenicity has proven challenging. Here we seek to engineer an RSV LAV with enhanced immunogenicity. Genetic mapping identifies strain line 19 fusion (F) protein residues that correlate with pre-fusion antigen maintenance by ELISA and thermal stability of infectivity in live RSV. We generate a LAV candidate named OE4 which expresses line 19F and is attenuated by codon-deoptimization of non-structural (NS1 and NS2) genes, deletion of the small hydrophobic (SH) gene, codon-deoptimization of the attachment (G) gene and ablation of the secreted form of G. OE4 (RSV-A2-dNS1-dNS2-Delta SH-dG(m)-Gs(null)-line19F) exhibits elevated pre-fusion antigen levels, thermal stability, immunogenicity, and efficacy despite heavy attenuation in the upper and lower airways of cotton rats. C1 [Stobart, Christopher C.; Rostad, Christina A.; Dillard, Rebecca S.; Hampton, Cheri M.; Strauss, Joshua D.; Hotard, Anne L.; Meng, Jia; Lee, Sujin; Currier, Michael G.; Wright, Elizabeth R.; Moore, Martin L.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30322 USA. [Stobart, Christopher C.; Rostad, Christina A.; Dillard, Rebecca S.; Hampton, Cheri M.; Strauss, Joshua D.; Hotard, Anne L.; Meng, Jia; Lee, Sujin; Currier, Michael G.; Wright, Elizabeth R.; Moore, Martin L.] Childrens Healthcare Atlanta, Atlanta, GA 30322 USA. [Ke, Zunlong] Georgia Inst Technol, Sch Biol, Atlanta, GA 30332 USA. [Yi, Hong; Wright, Elizabeth R.] Emory Univ, Robert P Apkarian Integrated Electron Microscopy, Atlanta, GA 30322 USA. [Pickles, Raymond J.] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. [Sakamoto, Kaori] Univ Georgia, Coll Vet Med, Dept Pathol, Athens, GA 30602 USA. [Moin, Syed M.; Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Rockville, MD 20852 USA. [Boukhvalova, Marina S.; Blanco, Jorge C. G.] Sigmovir Biosyst Inc, Rockville, MD 20850 USA. [Gilbert, Brian E.; Piedra, Pedro A.] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. [Piedra, Pedro A.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Stobart, Christopher C.] Butler Univ, Dept Biol Sci, Indianapolis, IN 46208 USA. [Hotard, Anne L.] Ctr Dis Control & Prevent, Viral Special Pathogens Branch, Atlanta, GA 30329 USA. [Meng, Jia] Alios BioPharma Inc, San Francisco, CA 94080 USA. RP Wright, ER; Moore, ML (reprint author), Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30322 USA.; Wright, ER; Moore, ML (reprint author), Childrens Healthcare Atlanta, Atlanta, GA 30322 USA.; Wright, ER (reprint author), Emory Univ, Robert P Apkarian Integrated Electron Microscopy, Atlanta, GA 30322 USA. EM erwrigh@emory.edu; martin.moore@emory.edu FU Emory Children's Center for Childhood Infections and Vaccines (CCIV); Emory University; Children's Healthcare of Atlanta; Georgia Research Alliance; Center for AIDS Research at Emory University [P30 AI050409]; James B. Pendleton Charitable Trust; NIH [R21 AI101775, R01 GM114561]; NSF [0923395, S10 RR025679]; Division of Microbiology and Infectious Diseases (DMID) of the National Institute of Allergy and Infectious Diseases (NIAID) [HHSN272201000004I]; [R01 AI087798]; [U19 AI095227]; [T32 AI074492]; [K12 HD072245] FX This work was supported by R01 AI087798 (M.L.M.), U19 AI095227 (M.L.M.), T32 AI074492 (C.C.S.), K12 HD072245 (C.A.R.), and the Emory Children's Center for Childhood Infections and Vaccines (CCIV). This work was also supported in part by Emory University, Children's Healthcare of Atlanta, and the Georgia Research Alliance to E.R.W.; the Center for AIDS Research at Emory University (P30 AI050409); the James B. Pendleton Charitable Trust to E.R.W.; public health service grants R21 AI101775, R01 GM114561, to E.R.W. from the NIH, and NSF grant 0923395 to E.R.W., and S10 RR025679. We thank Ursula Buchholz (National Institute of Allergy and Infectious Diseases, Bethesda, MD) for the BSR-T7/5 cells used for virus recovery; Michael Teng (University of South Florida, Tampa, FL) for the rabbit antisera against NS1 and NS2 used for Western blot analysis; Nancy Ulbrandt (MedImmune, Inc., Gaithersburg, MD) for motavizumab; Jeannette Taylor (Emory University, Atlanta, GA) for her assistance and guidance with the TEM immunolabeling experiments; John Heumann (University of Colorado, Boulder, CO) for his advice using PEET; and the Robert P. Apkarian Integrated Electron Microscopy Core of Emory University for microscopy services. The cotton rat studies performed at Baylor College of Medicine were supported by the Division of Microbiology and Infectious Diseases (DMID) of the National Institute of Allergy and Infectious Diseases (NIAID) (HHSN272201000004I). NR 56 TC 0 Z9 0 U1 14 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD DEC 21 PY 2016 VL 7 AR 13916 DI 10.1038/ncomms13916 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EF3JW UT WOS:000390221700001 PM 28000669 ER PT J AU Sparks, R Lau, WW Tsang, JS AF Sparks, Rachel Lau, William W. Tsang, John S. TI Expanding the Immunology Toolbox: Embracing Public-Data Reuse and Crowdsourcing SO IMMUNITY LA English DT Article ID GENOME-WIDE ASSOCIATION; SYSTEMIC-LUPUS-ERYTHEMATOSUS; GENE-EXPRESSION DATA; MICROARRAY EXPERIMENT MIAME; PROTEIN-PROTEIN INTERACTION; MOLECULAR CLASSIFICATION; RHEUMATOID-ARTHRITIS; METAANALYSIS METHODS; IMMUNE CELLS; BIG DATA AB New technologies have been propelling dramatic increases in the volume and diversity of large-scale public data, which can potentially be reused to answer questions beyond those originally envisioned. However, this often requires computational and statistical skills beyond the reach of most bench scientists. The development of educational and accessible computational tools is thus critical, as are crowdsourcing efforts that utilize the community's expertise to curate public data for hypothesis generation and testing. Here we review the history of public-data reuse and argue for greater incorporation of computational and statistical sciences into the biomedical education curriculum and the development of biologist-friendly crowdsourcing tools. Finally, we provide a resource list for the reuse of public data and highlight an illustrative crowdsourcing exercise to explore public gene-expression data of human autoimmune diseases and corresponding mouse models. Through education, tool development, and community engagement, immunologists will be poised to transform public data into biological insights. C1 [Sparks, Rachel; Tsang, John S.] NIAID, Syst Genom & Bioinformat Unit, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lau, William W.] NIH, Off Intramural Res, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. RP Tsang, JS (reprint author), NIAID, Syst Genom & Bioinformat Unit, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM john.tsang@nih.gov FU Intramural Programs of the National Institute of Allergy and Infectious Diseases (NIAID) at the NIH; Center for Information Technology (CIT) at the NIH FX We thank the jamboree participants for their contributions, including data gathering, annotation, comparison-group formation via OMiCC, as well as feedback on the manuscript. Participants include (listed alphabetically by last name): James Austin, Julian Candia, William Coley, Ehren Dancy, Karen L. Elkins, Sara Faghihi-Kashani, Julio Gomez-Rodriguez, Liliana Guedez, Maria J. Gutierrez, Trung Ho, Reiko Horai, Sunmee Huh, Chie Iwamura, Jaimy Joy, Ju-Gyeong Kang, Sunil Kaul, Laura B. Lewandowski, Nathan P. Manes, Mary J. Mattapallil, Sarfraz Memon, M. Jubayer Rahman, Kameron B. Rodrigues, Bruno Silva, Amit Singh, Anthony J. St. Leger, Jessica Tang, Hang Xie, Yongge Zhao, and Ofer Zimmerman. We also thank Neha Bansal, Candace Liu, and Abigail Thorpe for assisting with the jamboree; Yongjian Guo and Yong Lu for OMiCC support; BCBB/OCICB of NIAID for providing computing support and web hosting; NIH Facilities for providing the OMiCC Jamboree hosting venue; and members of the J.S.T. lab for discussions. This research was funded by the Intramural Programs of the National Institute of Allergy and Infectious Diseases (NIAID) and the Center for Information Technology (CIT) at the NIH. NR 145 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD DEC 20 PY 2016 VL 45 IS 6 BP 1191 EP 1204 DI 10.1016/j.immuni.2016.12.008 PG 14 WC Immunology SC Immunology GA EJ0RN UT WOS:000392918100007 PM 28002728 ER PT J AU Gerlach, C Moseman, EA Loughhead, SM Alvarez, D Zwijnenburg, AJ Waanders, L Garg, R de la Torre, JC von Andrian, UH AF Gerlach, Carmen Moseman, E. Ashley Loughhead, Scott M. Alvarez, David Zwijnenburg, Anthonie J. Waanders, Lisette Garg, Rohit de la Torre, Juan C. von Andrian, Ulrich H. TI The Chemokine Receptor CX3CR1 Defines Three Antigen-Experienced CD8 T Cell Subsets with Distinct Roles in Immune Surveillance and Homeostasis SO IMMUNITY LA English DT Article ID PERIPHERAL-TISSUES; MIGRATORY PROPERTIES; PROTECTIVE IMMUNITY; RESIDENT MEMORY; LYMPH-NODES; EFFECTOR; EXPRESSION; LYMPHOCYTES; SKIN; IMMUNOSURVEILLANCE AB Infections induce pathogen-specific T cell differentiation into diverse effectors (Teff) that give rise to memory (Tmem) subsets. The cell-fate decisions and lineage relationships that underlie these transitions are poorly understood. Here, we found that the chemokine receptor CX3CR1 identifies three distinct CD8(+) Teff and Tmem subsets. Classical central (Tcm) and effector memory (Tem) cells and their corresponding Teff precursors were CX3CR1(-) and CX3CR1(high), respectively. Viral infection also induced a numerically stable CX3CR1(int) subset that represented similar to 15% of blood-borne Tmem cells. CX3CR1(int) Tmem cells underwent more frequent homeostatic divisions than other Tmem subsets and not only self-renewed, but also contributed to the expanding CX3CR1-Tcm pool. Both Tcm and CX3CR1(int) cells homed to lymph nodes, but CX3CR1(int) cells, and not Tem cells, predominantly surveyed peripheral tissues. As CX3CR1(int) Tmem cells present unique phenotypic, homeostatic, and migratory properties, we designate this subset peripheral memory (tpm) cells and propose that tpm cells are chiefly responsible for the global surveillance of non-lymphoid tissues. C1 [Gerlach, Carmen; Moseman, E. Ashley; Loughhead, Scott M.; Alvarez, David; Zwijnenburg, Anthonie J.; Waanders, Lisette; Garg, Rohit; von Andrian, Ulrich H.] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Gerlach, Carmen; Moseman, E. Ashley; Loughhead, Scott M.; Alvarez, David; Zwijnenburg, Anthonie J.; Waanders, Lisette; Garg, Rohit; von Andrian, Ulrich H.] Harvard Med Sch, HMS Ctr Immune Imaging, Boston, MA 02115 USA. [de la Torre, Juan C.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [von Andrian, Ulrich H.] MIT & Harvard, Ragon Inst MGH, Cambridge, MA 02139 USA. [Moseman, E. Ashley] NINDS, NIH, Bethesda, MD 20892 USA. RP von Andrian, UH (reprint author), Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA.; von Andrian, UH (reprint author), Harvard Med Sch, HMS Ctr Immune Imaging, Boston, MA 02115 USA.; von Andrian, UH (reprint author), MIT & Harvard, Ragon Inst MGH, Cambridge, MA 02139 USA. EM uva@hms.harvard.edu FU Rubicon fellowship (Netherlands Organization for Scientific Research, NWO); Cancer Research Institute Irvington Fellowship Program; NIH T32 Training Grant in Hematology [HL07623-20]; NIH F31 grant [CA171339]; NIH T32 grant [HL066987]; Ragon Institute of MGH, MIT, and Harvard; NIH/NIAID [RO1 AI069259, PO1 AI078897, PO1 AI112521]; HMS Center for Immune Imaging FX The authors thank N.H. Ruddle for Lta-/- mice, D. Higgins for LM-ova, I. B. Mazo, R.J. Gonzales, and M. Perro for technical assistance, and A.K. Chakraborty, A. Thiriot, and Y. Nemoto for fruitful discussions. This study was supported by a Rubicon fellowship (Netherlands Organization for Scientific Research, NWO) and a postdoctoral fellowship of the Cancer Research Institute Irvington Fellowship Program to C.G., NIH T32 Training Grant in Hematology HL07623-20 to E.A.M., NIH F31 grant CA171339 to S.M.L., NIH T32 grant HL066987 to D.A., the Ragon Institute of MGH, MIT, and Harvard, the HMS Center for Immune Imaging, and NIH/NIAID RO1 AI069259, PO1 AI078897 and PO1 AI112521 to U.H.v.A. NR 44 TC 0 Z9 0 U1 4 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD DEC 20 PY 2016 VL 45 IS 6 BP 1270 EP 1284 DI 10.1016/j.immuni.2016.10.018 PG 15 WC Immunology SC Immunology GA EJ0RN UT WOS:000392918100013 PM 27939671 ER PT J AU Chisholm, CL Wang, HT Wong, AHH Vazquez-Ortiz, G Chen, WP Xu, XL Deng, CX AF Chisholm, Cristine L. Wang, Haitao Wong, Ada Hang-Heng Vazquez-Ortiz, Guelaguetza Chen, Weiping Xu, Xiaoling Deng, Chu-Xia TI Ammonium tetrathiomolybdate treatment targets the copper transporter ATP7A and enhances sensitivity of breast cancer to cisplatin SO ONCOTARGET LA English DT Article DE cisplatin; breast cancer; ATP7A; copper; resistance; sequestering ID OVARIAN-CARCINOMA CELLS; RESISTANCE; BRCA1; TRAFFICKING; EXPRESSION; THERAPY; AMPLIFICATION; LOCALIZATION; MECHANISMS; CHECKPOINT AB Cisplatin is an effective breast cancer drug but resistance often develops over prolonged chemotherapy. Therefore, we performed a candidate approach RNAi screen in combination with cisplatin treatment to identify molecular pathways conferring survival advantages. The screen identified ATP7A as a therapeutic target. ATP7A is a copper ATPase transporter responsible for intercellular movement and sequestering of cisplatin. Pharmaceutical replacement for ATP7A by ammonium tetrathiomolybdate (TM) enhanced cisplatin treatment in breast cancer cells. Allograft and xenograft models in athymic nude mice treated with cisplatin/TM exhibited retarded tumor growth, reduced accumulation of cancer stem cells and decreased cell proliferation as compared to mono-treatment with cisplatin or TM. Cisplatin/TM treatment of cisplatin-resistant tumors reduced ATP7A protein levels, attenuated cisplatin sequestering by ATP7A, increased nuclear availability of cisplatin, and subsequently enhanced DNA damage and apoptosis. Microarray analysis of gene ontology pathways that responded uniquely to cisplatin/TM double treatment depicted changes in cell cycle regulation, specifically in the G1/S transition. These findings offer the potential to combat platinum-resistant tumors and sensitize patients to conventional breast cancer treatment by identifying and targeting the resistant tumors' unique molecular adaptations. C1 [Wang, Haitao; Wong, Ada Hang-Heng; Xu, Xiaoling; Deng, Chu-Xia] Univ Macau, Fac Hlth Sci, Macau, Peoples R China. [Chisholm, Cristine L.; Vazquez-Ortiz, Guelaguetza; Deng, Chu-Xia] Natl Inst Diabet Digest & Kidney Dis, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Chen, Weiping] Natl Inst Diabet Digest & Kidney Dis, Gen Core Facil, NIH, Bethesda, MD USA. RP Deng, CX (reprint author), Univ Macau, Fac Hlth Sci, Macau, Peoples R China.; Deng, CX (reprint author), Natl Inst Diabet Digest & Kidney Dis, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. EM cxdeng@umac.mo NR 48 TC 0 Z9 0 U1 3 U2 3 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD DEC 20 PY 2016 VL 7 IS 51 BP 84439 EP 84452 DI 10.18632/oncotarget.12992 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EG9BT UT WOS:000391353200052 PM 27806319 ER PT J AU Izzotti, A Balansky, R Ganchev, G Iltcheva, M Longobardi, M Pulliero, A Geretto, M Micale, RT La Maestra, S Miller, MS Steele, VE De Flora, S AF Izzotti, Alberto Balansky, Roumen Ganchev, Gancho Iltcheva, Marietta Longobardi, Mariagrazia Pulliero, Alessandra Geretto, Marta Micale, Rosanna T. La Maestra, Sebastiano Miller, Mark Steven Steele, Vernon E. De Flora, Silvio TI Blood and lung microRNAs as biomarkers of pulmonary tumorigenesis in cigarette smoke-exposed mice SO ONCOTARGET LA English DT Article DE lung microRNA; blood microRNA; lung carcinogenesis; cigarette smoke; intergender differences ID EPITHELIAL-MESENCHYMAL TRANSITION; INHIBITS CELL-PROLIFERATION; BREAST-CANCER CELLS; DOWN-REGULATION; GASTRIC-CANCER; HEPATOCELLULAR-CARCINOMA; TUMOR-SUPPRESSOR; COLORECTAL-CANCER; PROSTATE-CANCER; BLADDER-CANCER AB Cigarette smoke (CS) is known to dysregulate microRNA expression profiles in the lungs of mice, rats, and humans, thereby modulating several pathways involved in lung carcinogenesis and other CS-related diseases. We designed a study aimed at evaluating (a) the expression of 1135 microRNAs in the lung of Swiss H mice exposed to mainstream CS during the first 4 months of life and thereafter kept in filtered air for an additional 3.5 months, (b) the relationship between lung microRNA profiles and histopathological alterations in the lung, (c) intergender differences in microRNA expression, and (d) the comparison with microRNA profiles in blood serum. CS caused multiple histopathological alterations in the lung, which were almost absent in sham-exposed mice. An extensive microRNA dysregulation was detected in the lung of CS-exposed mice. Modulation of microRNA profiles was specifically related to the histopathological picture, no effect being detected in lung fragments with nonneoplastic lung diseases (emphysema or alveolar epithelial hyperplasia), whereas a close association occurred with the presence and multiplicity of preneoplastic lesions (microadenomas) and benign lung tumors (adenomas). Three microRNAs regulating estrogen and HER2-dependent mechanisms were modulated in the lung of adenomabearing female mice. Blood microRNAs were also modulated in mice affected by early neoplastic lesions. However, there was a poor association between lung microRNAs and circulating microRNAs, which can be ascribed to an impaired release of mature microRNAs from the damaged lung. Studies in progress are evaluating the feasibility of analyzing blood microRNAs as a molecular tool for lung cancer secondary prevention. C1 [Izzotti, Alberto; Longobardi, Mariagrazia; Pulliero, Alessandra; Geretto, Marta; Micale, Rosanna T.; La Maestra, Sebastiano; De Flora, Silvio] Univ Genoa, Dept Hlth Sci, Genoa, Italy. [Izzotti, Alberto] IRCCS AOU San Martino IST, Genoa, Italy. [Balansky, Roumen; Ganchev, Gancho; Iltcheva, Marietta] Natl Oncol Ctr, Sofia, Bulgaria. [Miller, Mark Steven; Steele, Vernon E.] NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP De Flora, S (reprint author), Univ Genoa, Dept Hlth Sci, Genoa, Italy. EM sdf@unige.it FU NCI NIH HHS [HHSN261201200015C] NR 122 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD DEC 20 PY 2016 VL 7 IS 51 BP 84758 EP 84774 DI 10.18632/oncotarget.12475 PG 17 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EG9BT UT WOS:000391353200079 PM 27713172 ER PT J AU Puverel, S Kiris, E Singh, S Klarmann, KD Coppola, V Keller, JR Tessarollo, L AF Puverel, Sandrine Kiris, Erkan Singh, Satyendra Klarmann, Kimberly D. Coppola, Vincenzo Keller, Jonathan R. Tessarollo, Lino TI RanBPM (RanBP9) regulates mouse c-Kit receptor level and is essential for normal development of bone marrow progenitor cells SO ONCOTARGET LA English DT Article DE RanBP9; c-Kit signaling; hematopoietic system; spermatogenesis; stem cells ID HEMATOPOIETIC STEM-CELLS; PROTEIN RANBPM; SCAFFOLDING PROTEIN; ENDOPLASMIC-RETICULUM; TYROSINE KINASES; EXPRESSION; ACTIVATION; PROLIFERATION; HOMOLOG; BINDING AB c-Kit is a tyrosine kinase receptor important for gametogenesis, hematopoiesis, melanogenesis and mast cell biology. Dysregulation of c-Kit function is oncogenic and its expression in the stem cell niche of a number of tissues has underlined its relevance for regenerative medicine and hematopoietic stem cell biology. Yet, very little is known about the mechanisms that control c-Kit protein levels. Here we show that the RanBPM/RanBP9 scaffold protein binds to c-Kit and is necessary for normal c-Kit protein expression in the mouse testis and subset lineages of the hematopoietic system. RanBPM deletion causes a reduction in c-Kit protein but not its mRNA suggesting a posttranslational mechanism. This regulation is specific to the c-Kit receptor since RanBPM reduction does not affect other membrane proteins examined. Importantly, in both mouse hematopoietic system and testis, RanBPM deficiency causes defects consistent with c-Kit loss of expression suggesting that RanBPM is an important regulator of c-Kit function. The finding that this regulatory mechanism is also present in human cells expressing endogenous RanBPM and c-Kit suggests a potential new strategy to target oncogenic c-Kit in malignancies. C1 [Puverel, Sandrine; Kiris, Erkan; Singh, Satyendra; Klarmann, Kimberly D.; Keller, Jonathan R.; Tessarollo, Lino] NCI, Ctr Canc Res, Mouse Canc Genet Program, Frederick, MD 21702 USA. [Klarmann, Kimberly D.; Keller, Jonathan R.] NCI, Leidos Biomed Res Inc, Basic Sci Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Coppola, Vincenzo] Ohio State Univ, Wexner Med Ctr, Dept Canc Biol & Genet, Columbus, OH 43210 USA. [Coppola, Vincenzo] Ohio State Univ, James Comprehens Canc Ctr, Columbus, OH 43210 USA. RP Tessarollo, L (reprint author), NCI, Ctr Canc Res, Mouse Canc Genet Program, Frederick, MD 21702 USA. EM tessarol@mail.nih.gov NR 48 TC 0 Z9 0 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD DEC 20 PY 2016 VL 7 IS 51 BP 85109 EP 85123 DI 10.18632/oncotarget.13198 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EG9BT UT WOS:000391353200106 PM 27835883 ER PT J AU Boyiadzis, M Bishop, MR Abonour, R Anderson, KC Ansell, SM Avigan, D Barbarotta, L Barrett, AJ Van Besien, K Bergsagel, PL Borrello, I Brody, J Brufsky, J Cairo, M Chari, A Cohen, A Cortes, J Forman, SJ Friedberg, JW Fuchs, EJ Gore, SD Jagannath, S Kahl, BS Kline, J Kochenderfer, JN Kwak, LW Levy, R de Lima, M Litzow, MR Mahindra, A Miller, J Munshi, NC Orlowski, RZ Pagel, JM Porter, DL Russell, SJ Schwartz, K Shipp, MA Siegel, D Stone, RM Tallman, MS Timmerman, JM Van Rhee, F Waller, EK Welsh, A Werner, M Wiernik, PH Dhodapkar, MV AF Boyiadzis, Michael Bishop, Michael R. Abonour, Rafat Anderson, Kenneth C. Ansell, Stephen M. Avigan, David Barbarotta, Lisa Barrett, Austin John Van Besien, Koen Bergsagel, P. Leif Borrello, Ivan Brody, Joshua Brufsky, Jill Cairo, Mitchell Chari, Ajai Cohen, Adam Cortes, Jorge Forman, Stephen J. Friedberg, Jonathan W. Fuchs, Ephraim J. Gore, Steven D. Jagannath, Sundar Kahl, Brad S. Kline, Justin Kochenderfer, James N. Kwak, Larry W. Levy, Ronald de Lima, Marcos Litzow, Mark R. Mahindra, Anuj Miller, Jeffrey Munshi, Nikhil C. Orlowski, Robert Z. Pagel, John M. Porter, David L. Russell, Stephen J. Schwartz, Karl Shipp, Margaret A. Siegel, David Stone, Richard M. Tallman, Martin S. Timmerman, John M. Van Rhee, Frits Waller, Edmund K. Welsh, Ann Werner, Michael Wiernik, Peter H. Dhodapkar, Madhav V. TI The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of hematologic malignancies: multiple myeloma, lymphoma, and acute leukemia SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Article DE Cancer immunotherapy; Hematologic malignancies; Acute leukemia; Lymphoma; Multiple myeloma; Immunotherapy ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CHIMERIC ANTIGEN RECEPTOR; STEM-CELL TRANSPLANTATION; CYTOTOXIC T-LYMPHOCYTES; NATURAL-KILLER-CELLS; COLONY-STIMULATING FACTOR; LOW-DOSE DEXAMETHASONE; LARGE B-CELL; WT1 PEPTIDE VACCINATION; LENALIDOMIDE PLUS DEXAMETHASONE AB Increasing knowledge concerning the biology of hematologic malignancies as well as the role of the immune system in the control of these diseases has led to the development and approval of immunotherapies that are resulting in impressive clinical responses. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a hematologic malignancy Cancer Immunotherapy Guidelines panel consisting of physicians, nurses, patient advocates, and patients to develop consensus recommendations for the clinical application of immunotherapy for patients with multiple myeloma, lymphoma, and acute leukemia. These recommendations were developed following the previously established process based on the Institute of Medicine's clinical practice guidelines. In doing so, a systematic literature search was performed for high-impact studies from 2004 to 2014 and was supplemented with further literature as identified by the panel. The consensus panel met in December of 2014 with the goal to generate consensus recommendations for the clinical use of immunotherapy in patients with hematologic malignancies. During this meeting, consensus panel voting along with discussion were used to rate and review the strength of the supporting evidence from the literature search. These consensus recommendations focus on issues related to patient selection, toxicity management, clinical endpoints, and the sequencing or combination of therapies. Overall, immunotherapy is rapidly emerging as an effective therapeutic strategy for the management of hematologic malignances. Evidence-based consensus recommendations for its clinical application are provided and will be updated as the field evolves. C1 [Boyiadzis, Michael] Univ Pittsburgh, Div Hematol Oncol, Sch Med, Dept Med,Canc Inst,Med Ctr, 5150 Ctr Ave,Suite 564, Pittsburgh, PA 15232 USA. [Bishop, Michael R.] Univ Chicago, Hematopoiet Cellular Therapy Program, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Abonour, Rafat] Indiana Univ Sch Med, 980 W Walnut St,Walther Hall R3,C400, Indianapolis, IN 46202 USA. [Anderson, Kenneth C.; Stone, Richard M.] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Ansell, Stephen M.; Russell, Stephen J.] Mayo Clin, 200 First St SW, Rochester, MN 55905 USA. [Avigan, David] Beth Israel Deaconess Med Ctr, 330 Brookline Ave, Boston, MA 02215 USA. [Barbarotta, Lisa] Yale New Haven, Smilow Canc Hosp, 35 Pk St, New Haven, CT 06519 USA. [Barrett, Austin John] NIH, Bldg 10 CRC Room 3-5330, Bethesda, MD 20814 USA. [Van Besien, Koen] Weill Cornell Med Coll, 407 E 71st St, New York, NY 10065 USA. [Bergsagel, P. Leif] Mayo Clin, 13400 E Shea Blvd, Scottsdale, AZ 85259 USA. [Borrello, Ivan] Johns Hopkins Sch Med, 1650 Orleans St, Baltimore, MD 21231 USA. [Brody, Joshua; Chari, Ajai; Jagannath, Sundar] Icahn Sch Med Mt Sinai, One Gustave L Levy Pl, New York, NY 10029 USA. [Brufsky, Jill] Univ Pittsburgh, Inst Canc, 5150 Ctr Ave, Pittsburgh, PA 15232 USA. [Cairo, Mitchell] Maria Fareri Childrens Hosp, New York Med Coll, 100 Woods Rd, Valhalla, NY 10595 USA. [Chari, Ajai] Univ Penn, Abramson Canc Ctr, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. [Cortes, Jorge] Univ Texas MD Anderson Canc Ctr, 1515 Holcombe Blvd, Houston, TX 77030 USA. [Forman, Stephen J.] City Hope Natl Med Ctr, 1500 East Duarte Rd, Duarte, CA 91010 USA. [Friedberg, Jonathan W.] Univ Rochester, Wilmot Canc Inst, 601 Elmwood Ave,Box 704, Rochester, NY 14642 USA. [Fuchs, Ephraim J.] Johns Hopkins Univ, Sch Med, 401 N Broadway, Baltimore, MD 21231 USA. [Gore, Steven D.] Yale Canc Ctr, 333 Cedar St, New Haven, CT 06511 USA. [Kahl, Brad S.] Washington Univ, Sch Med, 660 S Euclid Ave, St Louis, MO 63110 USA. [Kline, Justin] Univ Chicago, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Kochenderfer, James N.] NCI, NIH, 8500 Roseweood Dr, Bethesda, MD 20814 USA. [Kwak, Larry W.] City Hope Natl Med Ctr, 1500 E Duarte Rd,Beckman Bldg,Room 4117, Duarte, CA 91010 USA. [Levy, Ronald] Stanford Univ, Div Med Oncol, Sch Med, 269 Campus Dr, Stanford, CA 94305 USA. [de Lima, Marcos] Case Western Reserve Univ, Dept Med Hematol & Oncol, 11100 Euclid Ave, Cleveland, OH 44106 USA. [Litzow, Mark R.] Mayo Clin, Ctr Canc, Dept Hematol, 200 First St SW, Rochester, MN 55905 USA. [Mahindra, Anuj] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, Box 0324, San Francisco, CA 94143 USA. [Miller, Jeffrey] Univ Minnesota, Div Hematol Oncol, 420 Delaware St SE, Minneapolis, MN 55455 USA. [Munshi, Nikhil C.] Dana Farber Canc Inst, 450 Brookline Ave,Dana B106, Boston, MA 02215 USA. [Orlowski, Robert Z.] Univ Texas MD Anderson Canc Ctr, 1515 Holcombe Blvd,Unit 429, Houston, TX 77030 USA. [Pagel, John M.] Swedish Canc Inst, 1221 Madison St,Suite 1020, Seattle, WA 98104 USA. [Porter, David L.] Univ Penn, 3400 Civ Ctr Blvd,PCAM 12 South Pavil, Philadelphia, PA 19104 USA. [Schwartz, Karl] Patients Lymphoma, 3774 Buckwampum Rd, Riegelsville, PA 18077 USA. [Shipp, Margaret A.] Dana Farber Canc Inst, 450 Brookline Ave,Mayer 513, Boston, MA 02215 USA. [Siegel, David] Hackensack Univ, Med Ctr, 92 2nd St, Hackensack, NJ 07601 USA. [Tallman, Martin S.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10065 USA. [Timmerman, John M.] Univ Calif Los Angeles, 10833 LeConte Ave, Los Angeles, CA 90095 USA. [Van Rhee, Frits] Univ Arkansas Med Sci, Myeloma Inst, 4301 W Markham 816, Little Rock, AR 72205 USA. [Waller, Edmund K.] Emory Univ, Winship Canc Inst, 1365B Clifton Rd NE, Atlanta, GA 30322 USA. [Welsh, Ann] Univ Pittsburgh, Med Ctr, 200 Lothrop St, Pittsburgh, PA 15213 USA. [Werner, Michael] Patient Advocate, 33 East Bellevue Pl, Chicago, IL 60611 USA. [Wiernik, Peter H.] Canc Res Fdn New York, 43 Longview Lane, Chappaqua, NY 10514 USA. [Dhodapkar, Madhav V.] Yale Univ, Dept Hematol & Immunobiol, 333 Cedar St,Box 208021, New Haven, CT 06510 USA. RP Dhodapkar, MV (reprint author), Yale Univ, Dept Hematol & Immunobiol, 333 Cedar St,Box 208021, New Haven, CT 06510 USA. EM madhav.dhodapkar@yale.edu FU Bristol-Myers Squibb; Cellplex; Seattle Genetics; Novartis; Millennium (Takeda); Celgene; Array BioPharma; Onyx; Janssen Pharmaceuticals; Pharmacylics; Pfizer; Janssen; Dynavax; Pharmacyclics; Amgen; Fate Therapeutics; Oxis Biotech; Onyx (Amgen); Spectrum Pharma; FORMA Therapeutics; Merck; Valor Biotherapeutics; Kite Pharma FX RA acts as a consultant to Celgene. KCA participates on an advisory board for Celgene, Millennium (Takeda), and Gilead. He is also the scientific founder of Acetlyon, Oncopep, and C4Therapies. SMA has received research funding from Bristol-Myers Squibb, Cellplex, and Seattle Genetics. DA participates On scientific advisory boards for Celgene and Seattle Genetics. LB selves on the speaker's bureau for Celgene and Bristol-Myers Squibb. PLB acts as a consultant and has received research funding from Novartis. MC acts as a consultant for Sanofi, Celgene, Roche, Gilead, and Jazz Pharmaceuticals. AC1 participates on an advisory board and has received research funding from Millennium (Takeda), Celgene, Array BioPharma, Novartis, and Onyx. In addition, he am as a consultant for Janssen Pharmaceuticals as well as Bristol-Myers Squibb and has received research funding from Janssen Pharmaceuticals and Pharmacylics. AC2 participates on an advisory, board and has receive research funding from Bristol-Myers Squibb. In addition he acts on an advisory board for Janssen Pharmaceuticals and has received institutional research funding from Novartis. JC has received research support. from Bristol-Myers Squibb, Pfizer, and Janssen and acts as a consultant to Bristol-Meyers Squibb, Pfizer, Janssen, Amphivena, and Merus. JWF participates on an advisory board for Bayer. SJ has received he and participates on an advisory board for Celgene, Bristol-Myers Squibb, and Janssen Pharmaceuticals. BBK acts as a consultant to Genentech (Roche), Juno, and Celgene. Through the National Cancer Institute, INK has cooperative research and development agreements with Kite Pharma and Bluebird Bio. LWK is a founder of XEME Biopharma and acts as a consultant for Sellas and Celltrion. RL has received research funding from Bristol-Myers Squibb, Dynavax, Pfizer, and Pharmacyclics. MRL has received research funding from Amgen. AM participates on an advisory board for Novartis. JM acts as a consultant and has received research funding from Fate Therapeutics and Oxis Biotech. He also participates on a scientific advisory Board for Celegene. NCM has ownership interest in Oncopep and acts as a consultant for Celgene, Merck, Pfizer, Takeda, and Janssen Pharmaceuticals. RZO has receive research funding from Bristol-Myers Squibb, Celgene, Millennium (Takeda), Onyx (Amgen), and Spectrum Pharma. In addition, he participates on advisory boards for Array BioPharma, Bristol-Myers Squibb, Celgene, FORMA Therapeutics, Janssen Pharmaceuticals, Millennium (Takeda), and Onyx (Amgen). DLP has received research funding and holds royalties as well as intellectual property interests with Novartis. DLP's spouse is also employed by Genentech (Roche). SJR is the co-founder/co-owner as well as CEO and Board Member of Vyriad, Inc. MAS has received research funding and participates on a scientific advisory board for Bristol-Myers Squibb and Merck. DS acts on advisory boards and on speaker's bureaus nor Celgene, Millennium (Takeda), Amgen, and Bristol-Myers Squibb. RMS acts as a consultant or on an advisory board for AbbVie, Abios, Amgen, Pfizer, Roche, Celator, Celgene, Janssen, Novartis, Sunesis, Juno, Kaypharm, Merck, Seattle Genetics, and Xenetic. JWT acts as a consultant for Celgene as well as Genmab and has received research funding from Bristol-Myers Squibb, Janssen Pharmaceuticals, Valor Biotherapeutics, and Kite Pharma. AJB, KVB, MRB, IB, MB, JB1, JB2, JC, MVD, SJF, EJF, SDG, JK, MdL, JP, KS, MST, EKW, AW, MW, PHW, and FVR declare no competing interests. NR 219 TC 0 Z9 0 U1 7 U2 7 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 DEC 20 PY 2016 VL 4 AR 90 DI 10.1186/s40425-016-0188-z PG 25 WC Oncology SC Oncology GA EG8WW UT WOS:000391338800007 PM 28018601 ER PT J AU Gordy, JT Luo, K Zhang, H Biragyn, A Markham, RB AF Gordy, James T. Luo, Kun Zhang, Hong Biragyn, Arya Markham, Richard B. TI Fusion of the dendritic cell-targeting chemokine MIP3 alpha to melanoma antigen Gp100 in a therapeutic DNA vaccine significantly enhances immunogenicity and survival in a mouse melanoma model SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Article DE DNA Vaccine; MIP3 alpha; MIP3alpha; or CCL20; B16 Melanoma; Gp100; Therapeutic cancer vaccine; Chemokine-antigen fusion; In vivo electroporation ID ANTITUMOR IMMUNITY; IN-VITRO; T-CELLS; PHASE-I; ELECTROPORATION; VIRUS; CANCER; EFFICACY; DELIVERY; INFILTRATION AB Background: Although therapeutic cancer vaccines have been mostly disappointing in the clinic, the advent of novel immunotherapies and the future promise of neoantigen-based therapies have created the need for new vaccine modalities that can easily adapt to current and future developments in cancer immunotherapy. One such novel platform is a DNA vaccine fusing the chemokine Macrophage Inflammatory Protein-3 alpha (MIP-3 alpha) to an antigen, here melanoma antigen gp100. Previous published work has indicated that MIP-3 alpha targets nascent peptides to immature dendritic cells, leading to processing by class I and II MHC pathways. This platform has shown enhanced efficacy in prophylactic melanoma and therapeutic lymphoma model systems. Methods: The B16F10 melanoma syngeneic mouse model system was utilized, with a standard therapeutic protocol: challenge with lethal dose of B16F10 cells (5 x 10(4)) on day 0 and then vaccinate by intramuscular electroporation with 50 mu g plasmid on days three, 10, and 17. Efficacy was assessed by analysis of tumor burden, tumor growth, and mouse survival, using the statistical tests ANOVA, mixed effects regression, and log-rank, respectively. Immunogenicity was assessed by ELISA and flow cytometric methods, including intracellular cytokine staining to assess vaccine-specific T-cell responses, all tested by ANOVA. Results: We demonstrate that the addition of MIP3 alpha to gp100 significantly enhances systemic anti-gp100 immunological parameters. Further, chemokine-fusion vaccine therapy significantly reduces tumor burden, slows tumor growth, and enhances mouse overall survival compared to antigen-only, irrelevant-antigen, and mock vaccines, with efficacy mediated by both CD4+ and CD8+ effector T cells. Antigen-only, irrelevant-antigen, and chemokine-fusion vaccines elicit significantly higher and similar CD4+ and CD8+ tumor-infiltrating lymphocyte (TIL) levels compared to mock vaccine. However, vaccine-specific CD8+ TILs are significantly higher in the chemokine-fusion vaccine group, indicating that the critical step induced by the fusion vaccine construct is the enhancement of vaccine-specific T-cell effectors. Conclusions: The current study shows that fusion of MIP3 alpha to melanoma antigen gp100 enhances the immunogenicity and efficacy of a DNA vaccine in a therapeutic B16F10 mouse melanoma model. This study analyzes an adaptable and easily produced MIP3 alpha-antigen modular vaccine platform that could lend itself to a variety of functionalities, including combination treatments and neoantigen vaccination in the pursuit of personalized cancer therapy. C1 [Gordy, James T.; Luo, Kun; Zhang, Hong; Markham, Richard B.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, 615 N Wolfe St, Baltimore, MD 21205 USA. [Biragyn, Arya] NIA, Immunoregulat Sect, Lab Mol Biol & Immunol, NIH, 251 Bayview,Blvd,Suite 100, Baltimore, MD 21224 USA. RP Markham, RB (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, 615 N Wolfe St, Baltimore, MD 21205 USA. EM Rmarkha1@jhu.edu FU National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health [1UL1TR001079] FX We would like to acknowledge Dr. Fidel Zavala (Johns Hopkins School of Public Health, Baltimore, MD) for his generous gift of T-cell depletion antibodies. We would also like to acknowledge Dr. TC Wu (Johns Hopkins School of Medicine, Baltimore, MD) for allowing us to utilize his electroporator. We would like to acknowledge support for the statistical analysis from the National Center for Research Resources and the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health through Grant Number 1UL1TR001079, and more specifically Carol Thompson of the Johns Hopkins Biostatistics Center. NR 46 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 2051-1426 J9 J IMMUNOTHER CANCER JI J. Immunother. Cancer PD DEC 20 PY 2016 VL 4 AR 96 DI 10.1186/s40425-016-0189-y PG 11 WC Oncology SC Oncology GA EG8WY UT WOS:000391339000005 PM 28018602 ER PT J AU McNeel, DG Bander, NH Beer, TM Drake, CG Fong, L Harrelson, S Kantoff, PW Madan, RA Oh, WK Peace, DJ Petrylak, DP Porterfield, H Sartor, O Shore, ND Slovin, SF Stein, MN Vieweg, J Gulley, JL AF McNeel, Douglas G. Bander, Neil H. Beer, Tomasz M. Drake, Charles G. Fong, Lawrence Harrelson, Stacey Kantoff, Philip W. Madan, Ravi A. Oh, William K. Peace, David J. Petrylak, Daniel P. Porterfield, Hank Sartor, Oliver Shore, Neal D. Slovin, Susan F. Stein, Mark N. Vieweg, Johannes Gulley, James L. TI The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of prostate carcinoma SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Article DE Guidelines; Immunotherapy; Prostate Cancer; Treatment ID SIPULEUCEL-T IMMUNOTHERAPY; PLACEBO-CONTROLLED PHASE-3; ACETATE PLUS PREDNISONE; DOUBLE-BLIND; ABIRATERONE ACETATE; SURVIVAL ANALYSIS; CELLULAR IMMUNOTHERAPY; PSA-TRICOM; II TRIAL; ANTIGEN AB Prostate cancer is the most commonly diagnosed malignancy and second leading cause of cancer death among men in the United States. In recent years, several new agents, including cancer immunotherapies, have been approved or are currently being investigated in late-stage clinical trials for the management of advanced prostate cancer. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel, including physicians, nurses, and patient advocates, to develop consensus recommendations for the clinical application of immunotherapy for prostate cancer patients. To do so, a systematic literature search was performed to identify high-impact papers from 2006 until 2014 and was further supplemented with literature provided by the panel. Results from the consensus panel voting and discussion as well as the literature review were used to rate supporting evidence and generate recommendations for the use of immunotherapy in prostate cancer patients. Sipuleucel-T, an autologous dendritic cell vaccine, is the first and currently only immunotherapeutic agent approved for the clinical management of metastatic castrate resistant prostate cancer (mCRPC). The consensus panel utilized this model to discuss immunotherapy in the treatment of prostate cancer, issues related to patient selection, monitoring of patients during and post treatment, and sequence/combination with other anti-cancer treatments. Potential immunotherapies emerging from late-stage clinical trials are also discussed. As immunotherapy evolves as a therapeutic option for the treatment of prostate cancer, these recommendations will be updated accordingly. C1 [McNeel, Douglas G.] Univ Wisconsin, Carbone Canc Ctr, 7007 WIMR,1111 Highland Ave, Madison, WI 53705 USA. [Bander, Neil H.] Cornell Univ, Weill Med Coll, Lab Urol Oncol, E-300,525 East 68th St, New York, NY 10021 USA. [Beer, Tomasz M.] Oregon Hlth & Sci Univ, Knight Canc Inst, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. [Drake, Charles G.] Johns Hopkins Univ, 1650 Orleans St Room 410, Baltimore, MD 21287 USA. [Fong, Lawrence] Univ Calif San Francisco, 513 Parnassus Ave,Room HSF 301,Box 1270, San Francisco, CA 94143 USA. [Harrelson, Stacey; Shore, Neal D.] Carolina Urol Res Ctr, 823 82nd Pkwy,Suite B, Myrtle Beach, SC 29572 USA. [Kantoff, Philip W.; Slovin, Susan F.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Madan, Ravi A.] NCI, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. [Oh, William K.] Mt Sinai Sch Med, One Gustave L Levy Pl,Box 1079, New York, NY 10029 USA. [Peace, David J.] Univ Illinois, 840 S Wood St,Suite 820, Chicago, IL 60612 USA. [Petrylak, Daniel P.] Yale Canc Ctr, POB 208032, New Haven, CT 06520 USA. [Porterfield, Hank] Alliance Prostate Canc Prevent, 17660 Tamiami Trail,Suite 106, Ft Myers, FL 33908 USA. [Sartor, Oliver] Tulane Univ, Sch Med, 1430 Tulane Ave,SL-42, New Orleans, LA 70112 USA. [Stein, Mark N.] Rutgers Canc Inst New Jersey, 195 Little Albany St, New Brunswick, NJ 08903 USA. [Vieweg, Johannes] Nova Southeastern Univ, 3200 South Univ Dr, Ft Lauderdale, FL 33328 USA. [Gulley, James L.] Genitourinary Malignancies Branch, 10 Ctr Dr,13N240, Bethesda, MD 20892 USA. RP Gulley, JL (reprint author), Genitourinary Malignancies Branch, 10 Ctr Dr,13N240, Bethesda, MD 20892 USA. EM gulleyj@mail.nih.gov NR 61 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 DEC 20 PY 2016 VL 4 AR 92 DI 10.1186/s40425-016-0198-x PG 12 WC Oncology SC Oncology GA EG8WY UT WOS:000391339000001 PM 28031820 ER PT J AU Leang, R Khu, NH Mukaka, M Debackere, M Tripura, R Kheang, ST Chy, S Kak, N Buchy, P Tarantola, A Menard, D Roca-Felterer, A Fairhurst, RM Kheng, S Muth, S Ngak, S Dondorp, AM White, NJ Taylor, WRJ AF Leang, Rithea Khu, Naw Htee Mukaka, Mavuto Debackere, Mark Tripura, Rupam Kheang, Soy Ty Chy, Say Kak, Neeraj Buchy, Philippe Tarantola, Arnaud Menard, Didier Roca-Felterer, Arantxa Fairhurst, Rick M. Kheng, Sim Muth, Sinoun Ngak, Song Dondorp, Arjen M. White, Nicholas J. Taylor, Walter Robert John TI An optimised age-based dosing regimen for single low-dose primaquine for blocking malaria transmission in Cambodia (vol 14, 171, 2016) SO BMC MEDICINE LA English DT Correction C1 [Leang, Rithea; Kheng, Sim; Muth, Sinoun] Natl Ctr Parasitol Entomol & Malaria Control, Corner St 92, Khan Sen Sok, Phnom Penh, Cambodia. [Khu, Naw Htee; Mukaka, Mavuto; Tripura, Rupam; Dondorp, Arjen M.; White, Nicholas J.; Taylor, Walter Robert John] Mahidol Oxford Trop Med Res Unit MORU, 420-6 Rajvithi Rd, Bangkok 10400, Thailand. [Mukaka, Mavuto; Dondorp, Arjen M.; White, Nicholas J.; Taylor, Walter Robert John] Univ Oxford, Oxford Ctr Trop Med & Global Hlth, Nuffield Dept Med, Res Bldg,Old Rd Campus,Roosevelt Dr, Oxford OX3 7FZ, England. [Debackere, Mark] MSF Belgium Cambodia Malaria Program, 19,St 388,Sangkat Tuol Svay Prey,POB 1933, Phnom Penh, Cambodia. [Kheang, Soy Ty; Chy, Say] Univ Res Co LLC, MK Bldg,House 10 2nd Floor,St 214, Daun Penh, Phnom Penh, Cambodia. [Kak, Neeraj] Univ Res Co LLC Washington DC, 7200 Wisconsin Ave, Bethesda, MD 20814 USA. [Buchy, Philippe; Tarantola, Arnaud; Menard, Didier] Inst Pasteur Cambodge, 5 Monivong Blvd,POB 983, Phnom Penh 12201, Cambodia. [Roca-Felterer, Arantxa] Malaria Consortium, House 91 St 95, Chamkar Morn, Phnom Penh, Cambodia. [Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Ngak, Song] FHI 360, Cambodia Off, 03,St 330 Boeung Keng Kang 3 Khan Chamkamon, Phnom Penh, Cambodia. [Taylor, Walter Robert John] Hop Univ Geneve, Ctr Med Humanitaire, Geneva, Switzerland. RP Taylor, WRJ (reprint author), Mahidol Oxford Trop Med Res Unit MORU, 420-6 Rajvithi Rd, Bangkok 10400, Thailand.; Taylor, WRJ (reprint author), Univ Oxford, Oxford Ctr Trop Med & Global Hlth, Nuffield Dept Med, Res Bldg,Old Rd Campus,Roosevelt Dr, Oxford OX3 7FZ, England.; Taylor, WRJ (reprint author), Hop Univ Geneve, Ctr Med Humanitaire, Geneva, Switzerland. EM bob@tropmedres.ac NR 1 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 1741-7015 J9 BMC MED JI BMC Med. PD DEC 20 PY 2016 VL 14 AR 213 DI 10.1186/s12916-016-0765-5 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA EG5FW UT WOS:000391070000001 PM 27993160 ER PT J AU Zeng, XK Willi, M Shin, HY Hennighausen, L Wang, CC AF Zeng, Xianke Willi, Michaela Shin, Ha Youn Hennighausen, Lothar Wang, Chaochen TI Lineage-Specific and Non-specific Cytokine-Sensing Genes Respond Differentially to the Master Regulator STAT5 SO CELL REPORTS LA English DT Article ID MOUSE MAMMARY EPITHELIUM; SEQ DATA; EXPRESSION; ACTIVATION; GROWTH; LIVER; PROLIFERATION; PREGNANCY; ENHANCER; RNA AB STAT5, a member of the family of signal transducers and activators of transcription, senses cytokines and controls the biology of cell lineages, including mammary, liver, and T cells. Here, we show that STAT5 activates lineage-specific and widely expressed genes through different mechanisms. STAT5 preferentially binds to promoter sequences of cytokine-responsive genes expressed across cell types and to putative enhancers of lineage-specific genes. While chromatin accessibility of STAT5-based enhancers was dependent on cytokine exposure, STAT5-responsive promoters of widely expressed target genes were generally constitutively accessible. While the contribution of STAT5 to enhancers is well established, its role on promoters is poorly understood. To address this, we focused on Socs2, a widely expressed cytokine-sensing gene. Upon deletion of the STAT5 response elements from the Socs2 promoter in mice, cytokine induction was abrogated, while basal activity remained intact. Our data suggest that promoter-bound STAT5 modulates cytokine responses and enhancer-bound STAT5 is mandatory for gene activation. C1 [Zeng, Xianke; Willi, Michaela; Shin, Ha Youn; Hennighausen, Lothar; Wang, Chaochen] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. [Willi, Michaela] Med Univ Innsbruck, Bioctr, Div Bioinformat, A-6020 Innsbruck, Austria. RP Hennighausen, L; Wang, CC (reprint author), NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. EM lotharh@mail.nih.gov; wangcn@mail.nih.gov OI Willi, Michaela/0000-0002-2248-1998 FU NIDDK/NIH [1ZIADK061000-16] FX We thank Dr. Harold Smith from the NIDDK genomics core for help with next generation sequencing (NGS) and Dr. Chengyu Liu from the NHLBI transgenic core for generating the CRISPR/Cas9-based mouse mutants. M.W. is a graduate student of the Individual Graduate Partnership Program (GPP) of NIH/NIDDK and the Medical University of Innsbruck. This research was funded by intramural research project 1ZIADK061000-16 of the NIDDK/NIH. NR 47 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD DEC 20 PY 2016 VL 17 IS 12 BP 3333 EP 3346 DI 10.1016/j.celrep.2016.11.079 PG 14 WC Cell Biology SC Cell Biology GA EG2SY UT WOS:000390895600022 PM 28009300 ER PT J AU Golestaneh, N Chu, Y Cheng, SK Cao, H Poliakov, E Berinstein, DM AF Golestaneh, Nady Chu, Yi Cheng, Shuk Kei Cao, Hong Poliakov, Eugenia Berinstein, Daniel M. TI Repressed SIRT1/PGC-1 alpha pathway and mitochondrial disintegration in iPSC-derived RPE disease model of age-related macular degeneration SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE AMD; RPE; Oxidative stress; Mitochondria; Cell viability; ROS; PGC-1 alpha; SIRT1 ID PLURIPOTENT STEM-CELLS; RETINAL-PIGMENT EPITHELIUM; OXIDATIVE STRESS; ENERGY-EXPENDITURE; DIRECT PHOSPHORYLATION; EPIGENETIC MEMORY; SKELETAL-MUSCLE; ARPE-19 CELLS; PGC-1-ALPHA; AMPK AB Background: Study of age related macular degeneration (AMD) has been hampered by lack of human models that represent the complexity of the disease. Here we have developed a human in vitro disease model of AMD to investigate the underlying AMD disease mechanisms. Methods: Generation of iPSCs from retinal pigment epithelium (RPE) of AMD donors, age-matched normal donors, skin fibroblasts of a dry AMD patient, and differentiation of iPSCs into RPE (AMD RPE-iPSC-RPE, normal RPE-iPSC-RPE and AMD Skin-iPSC-RPE, respectively). Immunostaining, cell viability assay and reactive oxygen species (ROS) production under oxidative stress conditions, electron microscopy (EM) imaging, ATP production and glycogen concentration assays, quantitative real time PCR, western blot, karyotyping. Results: The AMD RPE-iPSC-RPE and AMD Skin-iPSC-RPE present functional impairment and exhibit distinct disease phenotypes compared to RPE-iPSC-RPE generated from normal donors (Normal RPE-iPSC-RPE). The AMD RPE-iPSC-RPE and AMD Skin-iPSC-RPE show increased susceptibility to oxidative stress and produced higher levels of reactive oxygen species (ROS) under stress in accordance with recent reports. The susceptibility to oxidative stress-induced cell death in AMD RPE-iPSC-RPE and Skin-iPSC-RPE was consistent with inability of the AMD RPE-iPSC-RPE and Skin-iPSC-RPE to increase SOD2 expression under oxidative stress. Phenotypic analysis revealed disintegrated mitochondria, accumulation of autophagosomes and lipid droplets in AMD RPE-iPSC-RPE and AMD Skin-iPSC-RPE. Mitochondrial activity was significantly lower in AMD RPE-iPSC-RPE and AMD Skin-iPSC-RPE compared to normal cells and glycogen concentration was significantly increased in the diseased cells. Furthermore, Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha), a regulator of mitochondrial biogenesis and function was repressed, and lower expression levels of NAD-dependent deacetylase sirtuin1 (SIRT1) were found in AMD RPE-iPSC-RPE and AMD Skin-iPSC-RPE as compared to normal RPE-iPSC-RPE. Conclusions: Our studies suggest SIRT1/PGC-1 alpha as underlying pathways contributing to AMD pathophysiology, and open new avenues for development of targeted drugs for treatment of this devastating neurodegenerative disease of the visual system. C1 [Golestaneh, Nady; Chu, Yi; Cheng, Shuk Kei; Cao, Hong] Georgetown Univ, Med Ctr, Dept Ophthalmol, 3900 Reservoir Rd NW,Med Dent Bldg,Room NE203, Washington, DC 20057 USA. [Golestaneh, Nady] Georgetown Univ, Med Ctr, Dept Neurol, Washington, DC 20007 USA. [Golestaneh, Nady] Georgetown Univ, Med Ctr, Dept Biochem & Mol & Cellular Biol, Washington, DC 20007 USA. [Poliakov, Eugenia] NEI, Retinal Cell & Mol Biol LRCMB, NIH, Bethesda, MD 20892 USA. [Berinstein, Daniel M.] Retina Grp Washington, Chevy Chase, MD 20815 USA. RP Golestaneh, N (reprint author), Georgetown Univ, Med Ctr, Dept Ophthalmol, 3900 Reservoir Rd NW,Med Dent Bldg,Room NE203, Washington, DC 20057 USA.; Golestaneh, N (reprint author), Georgetown Univ, Med Ctr, Dept Neurol, Washington, DC 20007 USA.; Golestaneh, N (reprint author), Georgetown Univ, Med Ctr, Dept Biochem & Mol & Cellular Biol, Washington, DC 20007 USA. EM ncg8@georgetown.edu OI Golestaneh, Nady/0000-0001-7573-0962 FU Macular Degeneration Research, a program of BrightFocus Foundation [M2014039]; Prevention of Blindness Society of Metropolitan Washington (POB) FX This work was funded in part by the Macular Degeneration Research (M2014039), a program of BrightFocus Foundation, and the Prevention of Blindness Society of Metropolitan Washington (POB). NR 69 TC 0 Z9 0 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD DEC 20 PY 2016 VL 14 AR 344 DI 10.1186/s12967-016-1101-8 PG 17 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EG5EQ UT WOS:000391066700005 PM 27998274 ER PT J AU Butler, J Konstam, MA Felker, M Kalogeropoulos, AP Givertz, MM Mann, DL Margulies, KB Redfield, MM Semigran, MJ Tang, W Whellan, DJ McNulty, SE Anstrom, KJ Desvigne-Nickens, P Hernandez, AF Braunwald, E AF Butler, Javed Konstam, Marvin A. Felker, Michael Kalogeropoulos, Andreas P. Givertz, Michael M. Mann, Douglas L. Margulies, Kenneth B. Redfield, Margaret M. Semigran, Marc J. Tang, Wilson Whellan, David J. McNulty, Stephen E. Anstrom, Kevin J. Desvigne-Nickens, Patrice Hernandez, Adrian F. Braunwald, Eugene TI Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy in Heart Failure (ATHENA-HF) Trial SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium CY NOV 12-16, 2016 CL New Orleans, LA SP Amer Heart Assoc C1 [Butler, Javed] SUNY Stony Brook, Med, Atlanta, GA USA. [Konstam, Marvin A.] Tufts Univ, Med, Boston, MA 02111 USA. [Felker, Michael] Duke Univ, Med, Durham, NC USA. [Kalogeropoulos, Andreas P.] Emory, Med, Atlanta, GA USA. [Givertz, Michael M.] Brigham & Womens Hosp, Med, Boston, MA 02115 USA. [Mann, Douglas L.; Braunwald, Eugene] Washington Univ, Med, St Louis, MO USA. [Margulies, Kenneth B.] Univ Penn, Med, Philadelphia, PA 19104 USA. [Redfield, Margaret M.] Mayo Clin, Med, Rochester, MN USA. [Semigran, Marc J.; Braunwald, Eugene] Mass Gen Hosp, Med, Boston, MA USA. [Tang, Wilson] Cleveland Clin, Med, Cleveland, OH 44106 USA. [Whellan, David J.] Thomas Jefferson Univ, Med, Philadelphia, PA 19107 USA. [McNulty, Stephen E.] Duke, DCRI, Durham, NC USA. [Anstrom, Kevin J.; Hernandez, Adrian F.] Duke, Med, Durham, NC USA. [Desvigne-Nickens, Patrice] NHLBI, 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 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD DEC 20 PY 2016 VL 134 IS 25 MA 21206 BP E707 EP E708 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EF8DY UT WOS:000390560100015 ER PT J AU Kudenchuk, PJ Daya, M Leroux, B Rea, T Nichol, G Morrison, LJ Vaillancourt, C Wittwer, L Callaway, CW Christenson, J Egan, D Ornate, JP Weisfeldt, ML Stiell, IG Idris, AG Aufderheide, TP Dunford, JV Colella, MR Vilke, GM Brienza, AM Desvigne-Nickens, P Gray, P Gray, R Seals, N Strait, R Dorian, P AF Kudenchuk, Peter J. Daya, Mohamud Leroux, Brian Rea, Tom Nichol, Graham Morrison, Laurie J. Vaillancourt, Christian Wittwer, Lynn Callaway, Clifton W. Christenson, James Egan, Debra Ornate, Joe P. Weisfeldt, Myron L. Stiell, Ian G. Idris, Ahamed G. Aufderheide, Tom P. Dunford, James V. Colella, M. R. Vilke, Gary M. Brienza, Ashley M. Desvigne-Nickens, Patrice Gray, Pamela Gray, Randal Seals, Norman Strait, Ron Dorian, Paul TI Antiarrhythmic Drugs for Shock Refractory Secondary Ventricular Fibrillation Following Initial Nonshockable Out-of-Hospital Cardiac Arrest: The Resuscitation Outcomes Consortium Amiodarone, Lidocaine or Placebo Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium CY NOV 12-16, 2016 CL New Orleans, LA SP Amer Heart Assoc C1 [Kudenchuk, Peter J.] Univ Washington, Med Cardiol, Seattle, WA 98195 USA. [Daya, Mohamud] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Leroux, Brian; Rea, Tom; Nichol, Graham] Univ Washington, Seattle, WA 98195 USA. [Morrison, Laurie J.; Dorian, Paul] Univ Toronto, Toronto, ON, Canada. [Vaillancourt, Christian; Stiell, Ian G.] Univ Ottawa, Ottawa, ON, Canada. [Wittwer, Lynn] Clark Cty Emergency Med Serv, Vancouver, WA USA. [Callaway, Clifton W.; Brienza, Ashley M.] Univ Pittsburgh, Pittsburgh, PA USA. [Christenson, James] Univ British Columbia, Vancouver, BC, Canada. [Egan, Debra; Desvigne-Nickens, Patrice] NHLBI, Washington, DC USA. [Ornate, Joe P.] Virginia Commonwealth Univ, Richmond, VA USA. [Weisfeldt, Myron L.] Johns Hopkins Univ, Baltimore, MD USA. [Idris, Ahamed G.] Univ Texas Southwestern, Dallas, TX USA. [Aufderheide, Tom P.; Colella, M. R.] Coll Wisconsin, Med, Milwaukee, WI USA. [Dunford, James V.; Vilke, Gary M.] Univ Calif San Diego, San Diego, CA 92103 USA. [Gray, Pamela; Gray, Randal] Univ Alabama Birmingham, Birmingham, AL USA. [Seals, Norman] Dallas Fire Rescue, Dallas, TX USA. [Strait, Ron] British Columbia Emergency Med Serv, Vancouver, BC, Canada. 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 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD DEC 20 PY 2016 VL 134 IS 25 MA 23510 BP E718 EP E718 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EF8DY UT WOS:000390560100040 ER PT J AU Perin, EC Murphy, M March, K Bolli, R Leeper, NJ Yang, PC Alexander, J Henry, TD Traverse, JH Pepine, CJ Willerson, JT Velasquez, O Hare, JM Kasi, VS Lima, JA Hiatt, WR Taylor, DA Gee, AP Moye, L Ebert, RF Simari, RD Hirsch, AT AF Perin, Emerson C. Murphy, Michael March, Keith Bolli, Roberto Leeper, Nicholas J. Yang, Phillip C. Alexander, Jason Henry, Timothy D. Traverse, Jay H. Pepine, Carl J. Willerson, James T. Velasquez, Omaida Hare, Joshua M. Kasi, Vijaykumar S. Lima, Joao A. Hiatt, William R. Taylor, Doris A. Gee, Adrian P. Moye, Lem Ebert, Ray F. Simari, Robert D. Hirsch, Alan T. TI Administration of ALDH Bright Cells to Patients With Intermittent Claudication: The NHLBI CCTRN PACE Trial SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium CY NOV 12-16, 2016 CL New Orleans, LA SP Amer Heart Assoc C1 [Perin, Emerson C.; Willerson, James T.] Texas Heart Inst, Cardiol, Houston, TX 77025 USA. [Murphy, Michael] Indiana Univ Sch Med, Clin Cell Therapy Ctr, Indianapolis, IN 46202 USA. [Bolli, Roberto] Univ Louisville, Div Cardiovasc Med, Louisville, KY 40292 USA. [Leeper, Nicholas J.] Stanford Univ, Sch Med, Vasc Surg & Med, Stanford, CA 94305 USA. [Yang, Phillip C.] Stanford Univ, Sch Med, Cardiovasc Med, Stanford, CA 94305 USA. [Alexander, Jason] Abbott NW Hosp, Minneapolis Heart Inst Fdn, Vasc & Endovasc Serv, Minneapolis, MN USA. [Henry, Timothy D.] Cedars Sinai Heart Inst, Cardiol, Los Angeles, CA USA. [Traverse, Jay H.] Abbott NW Hosp, Minneapolis Heart Inst Fdn, Cardiol, Minneapolis, MN USA. [Pepine, Carl J.] Univ Florida, Sch Med, Cardiol, Gainesville, FL USA. [Velasquez, Omaida] Univ Miami, Miller Sch Med, Vasc Surg, Miami, FL 33136 USA. [Hare, Joshua M.] Univ Miami, Miller Sch Med, Cardiol, Miami, FL 33136 USA. [Kasi, Vijaykumar S.] Orlando Hlth Heart Inst, Cardiol, Orlando, FL USA. [Kasi, Vijaykumar S.] Orlando Hlth Heart Inst, Cardiol, Orlando, FL USA. [Lima, Joao A.] Johns Hopkins Univ, Cardiovasc Imaging, Baltimore, MD USA. [Hiatt, William R.] Univ Colorado, Sch Med, Med, Aurora, CO USA. [Taylor, Doris A.] Texas Heart Inst, Regenerat Med, Houston, TX 77025 USA. [Gee, Adrian P.] Baylor Coll Med, Ctr Cell & Gene Therapy, Cell & Gene Therapy, Houston, TX 77030 USA. [Moye, Lem] Univ Texas Hlth Sci Ctr Houston, Soh Publ Hlth, Biostat, Houston, TX 77030 USA. [Ebert, Ray F.] NHLBI, Stem Cell & Gene Therapy Cardiovasc, NIH, Bethesda, MD 20892 USA. [Simari, Robert D.] Univ Kansas, Sch Med, Deans Off, Kansas City, KS USA. [Hirsch, Alan T.] Univ Minnesota, Sch Med, Lillehei Heart Inst, Cardiovasc Div, Minneapolis, MN 55455 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 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD DEC 20 PY 2016 VL 134 IS 25 MA 21201 BP E709 EP E709 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EF8DY UT WOS:000390560100020 ER PT J AU Pollack, RA Brown, S Rea, T Aufderheide, T Buick, J Christenson, J Idris, A Jasti, J Kampp, M Kudenchuk, P May, S Morrison, L Muhr, M Nichol, G Ornate, JP Sopke, G Vaillancourt, C Weisfeldt, M AF Pollack, Ross A. Brown, Siobhan Rea, Tom Aufderheide, Tom Buick, Jason Christenson, Jim Idris, Ahamed Jasti, Jamie Kampp, Mike Kudenchuk, Peter May, Susanne Morrison, Laurie Muhr, Marc Nichol, Graham Ornate, Joseph P. Sopke, George Vaillancourt, Christian Weisfeldt, Myron TI Impact of Bystander AED Use on Survival And Functional Outcomes in Shockable Observed Public Cardiac Arrest SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium CY NOV 12-16, 2016 CL New Orleans, LA SP Amer Heart Assoc C1 [Pollack, Ross A.; Weisfeldt, Myron] Johns Hopkins Sch Med, Baltimore, MD USA. [Brown, Siobhan; Rea, Tom; Kudenchuk, Peter; May, Susanne; Nichol, Graham] Univ Washington, Seattle, WA 98195 USA. [Aufderheide, Tom; Jasti, Jamie] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Buick, Jason; Morrison, Laurie] Univ Toronto, Toronto, ON, Canada. [Christenson, Jim] Univ British Columbia, Vancouver, BC, Canada. [Idris, Ahamed] UT Southwestern, Dallas, TX USA. [Kampp, Mike] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Muhr, Marc] Clark Cty EMS, Vancouver, WA USA. [Ornate, Joseph P.] Virginia Commonwealth Univ Hlth Syst, Richmond, VA USA. [Sopke, George] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Vaillancourt, Christian] Univ Ottawa, Ottawa, ON, Canada. 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 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD DEC 20 PY 2016 VL 134 IS 25 MA 23382 BP E716 EP E716 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EF8DY UT WOS:000390560100036 ER PT J AU Traverse, JH Henry, TD Pepine, CJ Willerson, JT Perin, EC Taylor, DA Chugh, AR Yang, PC Ellis, SG Zhao, DX Penn, MS Forder, JR Ebert, RF Moye, LA Simari, RJ AF Traverse, Jay H. Henry, Timothy D. Pepine, Carl J. Willerson, James T. Perin, Emerson C. Taylor, Doris A. Chugh, Atul R. Yang, Phillip C. Ellis, Stephen G. Zhao, David X. Penn, Marc S. Forder, John R. Ebert, Ray F. Moye, Lem A. Simari, Robert J. TI The NHLBI TIME Trial: Role of Microvascular Obstruction in 2-Year Clinical and MRI Follow-up SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium CY NOV 12-16, 2016 CL New Orleans, LA SP Amer Heart Assoc C1 [Traverse, Jay H.] Minneapolis Heart Inst Fdn, Dept Med, Abbott Northwestern Hosp, Minneapolis, MN USA. [Henry, Timothy D.] Cedars Sinai Med Ctr, Dept Cardiol, Los Angeles, CA 90048 USA. [Pepine, Carl J.] Univ Florida, Dept Cardiol, Gainesville, FL USA. [Willerson, James T.; Perin, Emerson C.] Texas Heart Inst, Dept Cardiol, Houston, TX 77025 USA. [Taylor, Doris A.] Texas Heart Inst, Stem Cell Inst, Houston, TX 77025 USA. [Chugh, Atul R.] St Francis Heart Ctr, Cardiol, Indianapolis, IN USA. [Yang, Phillip C.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Ellis, Stephen G.] Cleveland Clin Fdn, Dept Cardiol, Cleveland, OH 44195 USA. [Zhao, David X.] Wake Forest Sch Med, Dept Cardiol, Winston Salem, NC USA. [Penn, Marc S.] Summa Phys, Dept Cardiol, Akron, OH USA. [Forder, John R.] Univ Florida, Dept Radiol, Gainesville, FL 32610 USA. [Ebert, Ray F.] NHLBI, Clin Trials, Rockville, MD USA. [Moye, Lem A.] UT Hlth, Sch Publ Hlth, Houston, TX USA. [Simari, Robert J.] Univ Kansas, Sch Med, Kansas City, KS 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 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD DEC 20 PY 2016 VL 134 IS 25 MA 18019 BP E710 EP E710 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EF8DY UT WOS:000390560100022 ER PT J AU Becker, AD Birger, RB Teillant, A Gastanaduy, PA Wallace, GS Grenfella, BT AF Becker, Alexander D. Birger, Ruthie B. Teillant, Aude Gastanaduy, Paul A. Wallace, Gregory S. Grenfell, Bryan T. TI Estimating enhanced prevaccination measles transmission hotspots in the context of cross-scale dynamics SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cross-scale dynamics; measles; mathematical model; childhood infection; vaccine refusal ID DISEASE DYNAMICS; EPIDEMICS; MODELS; VACCINATION; IMMUNIZATION; POPULATION; INFERENCE; OUTBREAKS; RATES; PATTERNS AB A key question in clarifying human-environment interactions is how dynamic complexity develops across integrative scales from molecular to population and global levels. Apart from its public health importance, measles is an excellent test bed for such an analysis. Simple mechanistic models have successfully illuminated measles dynamics at the city and country levels, revealing seasonal forcing of transmission as a major driver of long-term epidemic behavior. Seasonal forcing ties closely to patterns of school aggregation at the individual and community levels, but there are few explicit estimates of school transmission due to the relative lack of epidemic data at this scale. Here, we use data from a 1904 measles outbreak in schools in Woolwich, London, coupled with a stochastic Susceptible-Infected-Recovered model to analyze measles incidence data. Our results indicate that transmission within schools and age classes is higher than previous population-level serological data would suggest. This analysis sheds quantitative light on the role of school-aged children in measles cross-scale dynamics, as we illustrate with references to the contemporary vaccination landscape. C1 [Becker, Alexander D.; Birger, Ruthie B.; Teillant, Aude; Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Gastanaduy, Paul A.; Wallace, Gregory S.] Ctr Dis Control, Natl Ctr Immunizat & Resp Dis, Div Viral Dis, Atlanta, GA 30329 USA. [Wallace, Gregory S.] Princeton Univ, Woodrow Wilson Sch Publ & Int Affairs, Princeton, NJ 08544 USA. [Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Becker, AD (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. EM adbecker@princeton.edu FU Center for Health and Wellbeing at Princeton University; Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Bill and Melinda Gates Foundation FX We thank the Wellcome Collection for digitalizing the original documents. A.D.B. was supported by the Center for Health and Wellbeing at Princeton University. B.T.G. was supported by the Research and Policy for Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security, the Fogarty International Center, National Institutes of Health, and the Bill and Melinda Gates Foundation. The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention. NR 49 TC 1 Z9 1 U1 1 U2 1 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 DEC 20 PY 2016 VL 113 IS 51 BP 14595 EP 14600 DI 10.1073/pnas.1604976113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EF0VR UT WOS:000390044900039 PM 27872300 ER PT J AU Boltz, VF Rausch, J Shao, W Hattori, J Luke, B Maldarelli, F Mellors, JW Kearney, MF Coffin, JM AF Boltz, Valerie F. Rausch, Jason Shao, Wei Hattori, Junko Luke, Brian Maldarelli, Frank Mellors, John W. Kearney, Mary F. Coffin, John M. TI Ultrasensitive single-genome sequencing: accurate, targeted, next generation sequencing of HIV-1 RNA SO RETROVIROLOGY LA English DT Article DE HIV; Single-genome sequencing; SGS; Primer ID; Supermajority correction; Allele linkage; Targeted next-generation sequencing; NGS; Deep sequencing; Minority variants; HIV drug resistance ID DRUG-RESISTANCE MUTATIONS; ERROR RATE; IN-VITRO; DNA; POPULATIONS; PCR; RECOMBINATION; CONSTRUCTION; MOLECULES; LIGATION AB Background: Although next generation sequencing (NGS) offers the potential for studying virus populations in unprecedented depth, PCR error, amplification bias and recombination during library construction have limited its use to population sequencing and measurements of unlinked allele frequencies. Here we report a method, termed ultrasensitive Single-Genome Sequencing (uSGS), for NGS library construction and analysis that eliminates PCR errors and recombinants, and generates single-genome sequences of the same quality as the "gold-standard" of HIV-1 single-genome sequencing assay but with more than 100-fold greater depth. Results: Primer ID tagged cDNA was synthesized from mixtures of cloned BH10 wild-type and mutant HIV-1 transcripts containing ten drug resistance mutations. First, the resultant cDNA was divided and NGS libraries were generated in parallel using two methods: uSGS and a method applying long PCR primers to attach the NGS adaptors (LP-PCR-1). Second, cDNA was divided and NGS libraries were generated in parallel comparing 3 methods: uSGS and 2 methods adapted from more recent reports using variations of the long PCR primers to attach the adaptors (LP-PCR-2 and LP-PCR-3). Consistently, the uSGS method amplified a greater proportion of cDNAs, averaging 30% compared to 13% for LP-PCR-1, 21% for LP-PCR-2 and 14% for LP-PCR-3. Most importantly, when the uSGS sequences were binned according to their primer IDs, 94% of the bins did not contain PCR recombinant sequences versus only 55, 75 and 65% for LP-PCR-1, 2 and 3, respectively. Finally, when uSGS was applied to plasma samples from HIV-1 infected donors, both frequent and rare variants were detected in each sample and neighbor-joining trees revealed clusters of genomes driven by the linkage of these mutations, showing the lack of PCR recombinants in the datasets. Conclusions: The uSGS assay can be used for accurate detection of rare variants and for identifying linkage of rare alleles associated with HIV-1 drug resistance. In addition, the method allows accurate in-depth analyses of the complex genetic relationships of viral populations in vivo. C1 [Boltz, Valerie F.; Rausch, Jason; Hattori, Junko; Maldarelli, Frank; Kearney, Mary F.] NCI, HIV Dynam & Replicat Program, CCR, NIH,Translat Res Unit, 105 Boyles St,Bldg 535 Room 111, Frederick, MD 21702 USA. [Shao, Wei; Luke, Brian] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Adv Biomed Comp Ctr, Frederick, MD USA. [Mellors, John W.] Univ Pittsburgh, Div Infect Dis, Pittsburgh, PA USA. [Coffin, John M.] Tufts Univ, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. RP Boltz, VF (reprint author), NCI, HIV Dynam & Replicat Program, CCR, NIH,Translat Res Unit, 105 Boyles St,Bldg 535 Room 111, Frederick, MD 21702 USA. EM boltzv@mail.nih.gov FU National Cancer Institute's Intramural Center for Cancer Research; Bench to Bedside grant [B11-A-14]; Leidos Biomedical Research, Inc. through the National Cancer Institute [12XS547] FX Funding for this research was also provided by the National Cancer Institute's Intramural Center for Cancer Research, which supports the HIV Dynamics and Replication Program, and Bench to Bedside grant B11-A-14 Kearney (PI). J.M.C. was a research professor of the American Cancer Society. J.W.M receives support from Leidos Biomedical Research, Inc. contract 12XS547 through the National Cancer Institute. NR 31 TC 0 Z9 0 U1 8 U2 8 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 DEC 20 PY 2016 VL 13 AR 87 DI 10.1186/s12977-016-0321-6 PG 17 WC Virology SC Virology GA EF4BX UT WOS:000390270600004 PM 27998286 ER PT J AU Li, XT Jun, YG Erickstad, MJ Brown, SD Parks, A Court, DL Jun, S AF Li, Xin-tian Jun, Yonggun Erickstad, Michael J. Brown, Steven D. Parks, Adam Court, Donald L. Jun, Suckjoon TI tCRISPRi: tunable and reversible, one-step control of gene expression SO SCIENTIFIC REPORTS LA English DT Article ID SEQUENCE-SPECIFIC CONTROL; CRISPR-CAS SYSTEMS; ESCHERICHIA-COLI; CELL-DIVISION; ARABAD PROMOTER; LACTOSE OPERON; SINGLE CELLS; Z-RING; REPRESSION; IMMUNITY AB The ability to control the level of gene expression is a major quest in biology. A widely used approach employs deletion of a nonessential gene of interest (knockout), or multi-step recombineering to move a gene of interest under a repressible promoter (knockdown). However, these genetic methods are laborious, and limited for quantitative study. Here, we report a tunable CRISPR-cas system, "tCRISPRi", for precise and continuous titration of gene expression by more than 30-fold. Our tCRISPRi system employs various previous advancements into a single strain: (1) We constructed a new strain containing a tunable arabinose operon promoter P-BAD to quantitatively control the expression of CRISPR-(d) Cas protein over two orders of magnitude in a plasmid-free system. (2) tCRISPRi is reversible, and gene expression is repressed under knockdown conditions. (3) tCRISPRi shows significantly less than 10% leaky expression. (4) Most important from a practical perspective, construction of tCRISPRi to target a new gene requires only one-step of oligo recombineering. Our results show that tCRISPRi, in combination with recombineering, provides a simple and easy-to-implement tool for gene expression control, and is ideally suited for construction of both individual strains and high-throughput tunable knockdown libraries. C1 [Li, Xin-tian; Jun, Yonggun; Erickstad, Michael J.; Brown, Steven D.; Jun, Suckjoon] Univ Calif San Diego, Sect Mol Biol, Div Biol Sci, La Jolla, CA 92093 USA. [Li, Xin-tian; Jun, Yonggun; Erickstad, Michael J.; Brown, Steven D.; Jun, Suckjoon] Univ Calif San Diego, Dept Phys, La Jolla, CA 92093 USA. [Parks, Adam; Court, Donald L.] NCI, RNA Biol Lab, Ctr Canc Res, Ft Detrick, MD 21702 USA. [Li, Xin-tian] Leidos Biomed Res Inc, Basic Sci Program, GRCBL Mol Control & Genet Sect, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Jun, Yonggun] Natl Cent Univ, Dept Phys, Taoyuan, Taiwan. RP Li, XT; Jun, S (reprint author), Univ Calif San Diego, Sect Mol Biol, Div Biol Sci, La Jolla, CA 92093 USA.; Li, XT; Jun, S (reprint author), Univ Calif San Diego, Dept Phys, La Jolla, CA 92093 USA.; Li, XT (reprint author), Leidos Biomed Res Inc, Basic Sci Program, GRCBL Mol Control & Genet Sect, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM xintianli@gmail.com; suckjoon.jun@gmail.com FU Paul G. Allen Foundation; Pew Charitable Trusts; National Science Foundation CAREER Award; NIH [R01 GM118565-01] FX This work was supported by the Paul G. Allen Foundation, the Pew Charitable Trusts, the National Science Foundation CAREER Award, and NIH R01 GM118565-01 (to S.J.); The Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (to D.L.C.). We thank Dongyang Li, Fangwei Si, and Cindy Sou in Jun lab for their critical help with strain construction, imaging, and image analysis. NR 51 TC 0 Z9 0 U1 11 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD DEC 20 PY 2016 VL 6 AR 39076 DI 10.1038/srep39076 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EF1CN UT WOS:000390062800001 PM 27996021 ER PT J AU Canepa, GE Molina-Cruz, A Barillas-Mury, C AF Canepa, Gaspar E. Molina-Cruz, Alvaro Barillas-Mury, Carolina TI Molecular Analysis of Pfs47-Mediated Plasmodium Evasion of Mosquito Immunity SO PLoS One LA English DT Article ID VECTOR ANOPHELES-GAMBIAE; FALCIPARUM; COMPLEMENT; SELECTION; SYSTEM AB Malaria is a life-threatening disease caused by Plasmodium falciparum parasites that is transmitted through the bites of infected anopheline mosquitoes. P. falciparum dispersal from Africa, as a result of human migration, required adaptation of the parasite to several different indigenous anopheline species. The mosquito immune system can greatly limit infection and P. falciparum evolved a strategy to evade these responses that is mediated by the Pfs47 gene. Pfs47 is a polymorphic gene with signatures of diversifying selection and a strong geographic genetic structure at a continental level. Here, we investigated the role of single four amino acid differences between the Pfs47 gene from African (GB4 and NF54) and a New World (7G8) strains that differ drastically in their ability to evade the immune system of A. gambiae L35 refractory mosquitoes. Wild type NF54 and GB4 parasites can survive in this mosquito strain, while 7G8 parasites are eliminated. Our studies indicate that replacement in any of these four single amino acids in Pfs47 from the NF54 strain by those present in 7G8, completely disrupts the ability of NF54 parasites to hide from the mosquito immune system. One of these amino acid replacements had the opposite effect on A. albimanus mosquitoes, and enhanced infection. We conclude that malaria transmission involves a complex interplay between the genetic background of the parasite and the mosquito and that Pfs47 can be critical in this interaction as it mediates Plasmodium immune evasion through molecular interactions that need to be precise in some parasite/vector combinations. C1 [Canepa, Gaspar E.; Molina-Cruz, Alvaro; Barillas-Mury, Carolina] NINDS, Lab Malaria & Vector Res, NIH, Rockville, MD 20892 USA. RP Barillas-Mury, C (reprint author), NINDS, Lab Malaria & Vector Res, NIH, Rockville, MD 20892 USA. EM cbarillas@niaid.nih.gov FU Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 20 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 DEC 19 PY 2016 VL 11 IS 12 AR e0168279 DI 10.1371/journal.pone.0168279 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI9QC UT WOS:000392842600046 PM 27992481 ER PT J AU Schmidt, T Walti, MA Baber, JL Hustedt, EJ Clore, GM AF Schmidt, Thomas Walti, Marielle A. Baber, James L. Hustedt, Eric J. Clore, G. Marius TI Long Distance Measurements up to 160 angstrom in the GroEL Tetradecamer Using Q-Band DEER EPR Spectroscopy SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE biophysics; chemical physics; EPR spectroscopy; spectroscopic methods; structural biology ID ELECTRON-ELECTRON RESONANCE; SPIN-ECHO; PULSE EPR; RELAXATION; CHANNEL; SOLIDS; PELDOR; ELDOR; MODEL; KCSA AB Current distance measurements between spin-labels on multimeric protonated proteins using double electron-electron resonance (DEER) EPR spectroscopy are generally limited to the 15-60 angstrom range. Here we show how DEER experiments can be extended to dipolar evolution times of ca. 80s, permitting distances up to 170 angstrom to be accessed in multimeric proteins. The method relies on sparse spin-labeling, supplemented by deuteration of protein and solvent, to minimize the deleterious impact of multispin effects and substantially increase the apparent spin-label phase memory relaxation time, complemented by high sensitivity afforded by measurements at Q-band. We demonstrate the approach using the tetradecameric molecular machine GroEL as an example. Two engineered surface-exposed mutants, R268C and E315C, are used to measure pairwise distance distributions with mean values ranging from 20 to 100 angstrom and from 30 to 160 angstrom, respectively, both within and between the two heptameric rings of GroEL. The measured distance distributions are consistent with the known crystal structure of apo GroEL. The methodology presented here should significantly expand the use of DEER for the structural characterization of conformational changes in higher order oligomers. C1 [Schmidt, Thomas; Walti, Marielle A.; Baber, James L.; Clore, G. Marius] Natl Inst Diabet & Digest & Kidney Dis, NIH, Chem Phys Lab, Bethesda, MD 20892 USA. [Hustedt, Eric J.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. RP Clore, GM (reprint author), Natl Inst Diabet & Digest & Kidney Dis, NIH, Chem Phys Lab, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov FU Intramural Research Program of NIDDK, NIH; Intramural AIDS Targeted Antiviral Program of the Office oft he Director of the NIH FX This work was supported by funds from the Intramural Research Program of NIDDK, NIH, and from the Intramural AIDS Targeted Antiviral Program of the Office oft he Director of the NIH (to G.M.C.). NR 32 TC 1 Z9 1 U1 9 U2 9 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 DEC 19 PY 2016 VL 55 IS 51 BP 15905 EP 15909 DI 10.1002/anie.201609617 PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA EF8SJ UT WOS:000390599400036 PM 27860003 ER PT J AU Best, SM AF Best, Sonja M. TI Flaviviruses SO CURRENT BIOLOGY LA English DT Editorial Material ID ZIKA VIRUS; INFECTION C1 [Best, Sonja M.] NIAID, Virol Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Best, SM (reprint author), NIAID, Virol Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM sbest@niaid.nih.gov NR 9 TC 0 Z9 0 U1 4 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD DEC 19 PY 2016 VL 26 IS 24 BP R1258 EP R1260 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EF9RB UT WOS:000390666200004 PM 27997831 ER PT J AU Pizarro, RA Cheng, X Barnett, A Lemaitre, H Verchinski, BA Goldman, AL Xiao, E Luo, Q Berman, KF Callicott, JH Weinberger, DR Mattay, VS AF Pizarro, Ricardo A. Cheng, Xi Barnett, Alan Lemaitre, Herve Verchinski, Beth A. Goldman, Aaron L. Xiao, Ena Luo, Qian Berman, Karen F. Callicott, Joseph H. Weinberger, Daniel R. Mattay, Venkata S. TI Automated Quality Assessment of Structural Magnetic Resonance Brain Images Based on a Supervised Machine Learning Algorithm SO FRONTIERS IN NEUROINFORMATICS LA English DT Article DE structural magnetic resonance imaging; database management; automated quality assessment; machine learning; support vector machine; artifact detection; region of interest AB High-resolution three-dimensional magnetic resonance imaging (3D-MRI) is being increasingly used to delineate morphological changes underlying neuropsychiatric disorders. Unfortunately, artifacts frequently compromise the utility of 3D-MRI yielding irreproducible results, from both type I and type II errors. It is therefore critical to screen 3D-MRIs for artifacts before use. Currently, quality assessment involves slice-wise visual inspection of 3D-MRI volumes, a procedure that is both subjective and time consuming. Automating the quality rating of 3D-MRI could improve the efficiency and reproducibility of the procedure. The present study is one of the first efforts to apply a support vector machine (SVM) algorithm in the quality assessment of structural brain images, using global and region of interest (ROI) automated image quality features developed in-house. SVM is a supervised machine-learning algorithm that can predict the category of test datasets based on the knowledge acquired from a learning dataset. The performance (accuracy) of the automated SVM approach was assessed, by comparing the SVM predicted quality labels to investigator-determined quality labels. The accuracy for classifying 1457 3D-MRI volumes from our database using the SVM approach is around 80%. These results are promising and illustrate the possibility of using SVM as an automated quality assessment tool for 3D-MRI. C1 [Pizarro, Ricardo A.; Cheng, Xi; Barnett, Alan; Lemaitre, Herve; Verchinski, Beth A.; Goldman, Aaron L.; Xiao, Ena; Callicott, Joseph H.; Weinberger, Daniel R.; Mattay, Venkata S.] NIMH, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [Pizarro, Ricardo A.] Univ Wisconsin, Dept Biomed Engn, Madison, WI 53706 USA. [Cheng, Xi; Verchinski, Beth A.; Goldman, Aaron L.; Xiao, Ena; Weinberger, Daniel R.; Mattay, Venkata S.] Lieber Inst Brain Dev, Baltimore, MD 21205 USA. [Cheng, Xi] NIAID, Bioinformat & Computat Biosci Branch, OCICB, NIH, Rockville, MD 20852 USA. [Lemaitre, Herve] Univ Paris 11, INSERM, UMR 1000,Fac Med, Neuroimaging & Psychiat,Serv Hosp Frederic Joliot, Orsay, France. [Luo, Qian] Walter Reed Army Res Inst, Behav Biol Branch, Silver Spring, MD USA. [Berman, Karen F.; Callicott, Joseph H.] NIMH, Clin & Translat Neurosci Branch, NIH, Bethesda, MD 20892 USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Weinberger, Daniel R.; Mattay, Venkata S.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD USA. [Mattay, Venkata S.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. RP Pizarro, RA; Cheng, X; Mattay, VS (reprint author), NIMH, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA.; Pizarro, RA (reprint author), Univ Wisconsin, Dept Biomed Engn, Madison, WI 53706 USA.; Cheng, X; Mattay, VS (reprint author), Lieber Inst Brain Dev, Baltimore, MD 21205 USA.; Cheng, X (reprint author), NIAID, Bioinformat & Computat Biosci Branch, OCICB, NIH, Rockville, MD 20852 USA.; Mattay, VS (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA.; Mattay, VS (reprint author), Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. EM rpizarro@wisc.edu; xi.cheng2@nih.gov; anand.mattay@libd.org FU Intramural Research Program of the National Institute of Mental Health, NUL Bethesda, MD, USA; Office of Science Management and Operations (OSMO) of the NIAID, Bethesda, MD, USA; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA; National Institute of General Medical Sciences [R25GM083252] FX This research was supported by (1) the Intramural Research Program of the National Institute of Mental Health, NUL Bethesda, MD 20892, USA, (2) the Office of Science Management and Operations (OSMO) of the NIAID, Bethesda, MD 20892, USA, and (3) the Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA. RP, Ph.D. was supported (in part) by Award Number R25GM083252 from the National Institute of General Medical Sciences. NR 15 TC 0 Z9 0 U1 12 U2 12 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5196 J9 FRONT NEUROINFORM JI Front. Neuroinformatics PD DEC 19 PY 2016 VL 10 AR 52 DI 10.3389/fninf.2016.00052 PG 12 WC Mathematical & Computational Biology; Neurosciences SC Mathematical & Computational Biology; Neurosciences & Neurology GA EE9KY UT WOS:000389946500001 PM 28066227 ER PT J AU Numaga-Tomita, T Kitajima, N Kuroda, T Nishimura, A Miyano, K Yasuda, S Kuwahara, K Sato, Y Ide, T Birnbaumer, L Sumimoto, H Mori, Y Nishida, M AF Numaga-Tomita, Takuro Kitajima, Naoyuki Kuroda, Takuya Nishimura, Akiyuki Miyano, Kei Yasuda, Satoshi Kuwahara, Koichiro Sato, Yoji Ide, Tomomi Birnbaumer, Lutz Sumimoto, Hideki Mori, Yasuo Nishida, Motohiro TI TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis SO SCIENTIFIC REPORTS LA English DT Article ID PLURIPOTENT STEM-CELLS; TRPC3 CHANNELS; HYPERTROPHY; HEART; ACTIVATION; STRESS; FIBROBLASTS; CONTRIBUTES; DYSFUNCTION; MODULATION AB Structural cardiac remodeling, accompanying cytoskeletal reorganization of cardiac cells, is a major clinical outcome of diastolic heart failure. A highly local Ca2+ influx across the plasma membrane has been suggested to code signals to induce Rho GTPase-mediated fibrosis, but it is obscure how the heart specifically decodes the local Ca2+ influx as a cytoskeletal reorganizing signal under the conditions of the rhythmic Ca2+ handling required for pump function. We found that an inhibition of transient receptor potential canonical 3 (TRPC3) channel activity exhibited resistance to Rho-mediated maladaptive fibrosis in pressure-overloaded mouse hearts. Proteomic analysis revealed that microtubule-associated Rho guanine nucleotide exchange factor, GEF-H1, participates in TRPC3-mediated RhoA activation induced by mechanical stress in cardiomyocytes and transforming growth factor (TGF)beta stimulation in cardiac fibroblasts. We previously revealed that TRPC3 functionally interacts with microtubuleassociated NADPH oxidase (Nox) 2, and inhibition of Nox2 attenuated mechanical stretch-induced GEF-H1 activation in cardiomyocytes. Finally, pharmacological TRPC3 inhibition significantly suppressed fibrotic responses in human cardiomyocytes and cardiac fibroblasts. These results strongly suggest that microtubule-localized TRPC3-GEF-H1 axis mediates fibrotic responses commonly in cardiac myocytes and fibroblasts induced by physico-chemical stimulation. C1 [Numaga-Tomita, Takuro; Kitajima, Naoyuki; Nishimura, Akiyuki; Nishida, Motohiro] Natl Inst Nat Sci, Okazaki Inst Integrat Biosci, Natl Inst Physiol Sci, Div Cardiocirculatory Signaling, Okazaki, Aichi 4448787, Japan. [Numaga-Tomita, Takuro; Nishimura, Akiyuki; Nishida, Motohiro] Grad Univ Adv Studies, Sch Life Sci, SOKENDAI, Dept Physiol Sci, Okazaki, Aichi 4448787, Japan. [Kitajima, Naoyuki; Sato, Yoji; Nishida, Motohiro] Kyushu Univ, Grad Sch Pharmaceut Sci, Dept Translat Pharmaceut Sci, Fukuoka 8128582, Japan. [Kuroda, Takuya; Yasuda, Satoshi; Sato, Yoji] Natl Inst Hlth Sci, Div Cell Based Therapeut Prod, Setagaya Ku, Tokyo 1588501, Japan. [Miyano, Kei; Sumimoto, Hideki] Kyushu Univ, Grad Sch Med Sci, Dept Biochem, Fukuoka 8128582, Japan. [Kuwahara, Koichiro] Shinshu Univ, Sch Med, Dept Cardiovasc Med, Nagano 3908621, Japan. [Ide, Tomomi] Kyushu Univ, Grad Sch Med Sci, Dept Cardiovasc Med, Fukuoka 8128582, Japan. [Birnbaumer, Lutz] NIEHS, Neurosci Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Birnbaumer, Lutz] Catholic Univ Argentina, Inst Biomed Res BIOMED, C1107AFF, Buenos Aires, DF, Argentina. [Mori, Yasuo] Kyoto Univ, Grad Sch Engn, Dept Synthet Chem & Biol Chem, Kyoto 6158510, Japan. [Nishida, Motohiro] JST, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 3320012, Japan. RP Nishida, M (reprint author), Natl Inst Nat Sci, Okazaki Inst Integrat Biosci, Natl Inst Physiol Sci, Div Cardiocirculatory Signaling, Okazaki, Aichi 4448787, Japan.; Nishida, M (reprint author), Grad Univ Adv Studies, Sch Life Sci, SOKENDAI, Dept Physiol Sci, Okazaki, Aichi 4448787, Japan.; Nishida, M (reprint author), Kyushu Univ, Grad Sch Pharmaceut Sci, Dept Translat Pharmaceut Sci, Fukuoka 8128582, Japan.; Nishida, M (reprint author), JST, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 3320012, Japan. EM nishida@nips.ac.jp FU Functional Genomics Facility, NIBB Core Research Facilities; Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology Program; Ministry of Education, Culture, Sports, Science, and Technology of Japan [25293018, 16H05092, 26670144]; Daiko Foundation; Naito Memorial Foundation; Intramural Research Program of the NIH [ZO1-ES-101684] FX pmEmerald-tubulin plasmid was kindly provided from Yuko Mimori-Kiyosue of Riken CDB, Kobe, Japan. Confocal images were acquired at Spectrography and Bioimaging Facility, and LC-MS analysis was supported by Functional Genomics Facility, NIBB Core Research Facilities. This research was funded by grants from the Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology Program (to M.N.); Grants-in-Aid for Scientific Research (No. 25293018 and 16H05092 to M.N.; No. 26670144 to T.N.-T.) and Scientific Research on Innovative Areas (Research in a Proposed Research Area 'Oxygen Biology' to M.N. and 'Living in Space' to T.N.-T.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; Daiko Foundation and Naito Memorial Foundation (to M.N.); and by the Intramural Research Program of the NIH (Project ZO1-ES-101684 to L.B.). NR 32 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 DEC 19 PY 2016 VL 6 AR 39383 DI 10.1038/srep39383 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE8QB UT WOS:000389889600001 PM 27991560 ER PT J AU Klar, AJS AF Klar, Amar J. S. TI Split hand/foot malformation genetics supports the chromosome 7 copy segregation mechanism for human limb development SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Review DE limb development; human split hand/foot malformation; selective chromatid segregation mechanism; selective DNA strand segregation mechanism; asymmetric cell division mechanism; DNA chirality-based developmental mechanism ID SELECTIVE CHROMATID SEGREGATION; ASYMMETRIC CELL-DIVISION; HAND FOOT MALFORMATION; CLEFT-LIP PALATE; FISSION YEAST; DNA STRANDS; ECTODERMAL DYSPLASIA; HOXD CLUSTER; VERTEBRATE LIMB; DLX5 MUTATION AB Genetic aberrations of several unlinked loci cause human congenital split hand/foot malformation (SHFM) development. Mutations of the DLX5 (distalless) transcription factor-encoding gene in chromosome 7 cause SHFM through haploinsufficiency, but the vast majority of cases result from heterozygous chromosomal aberrations of the region without mutating the DLX5 gene. To resolve this paradox, we invoke a chromosomal epigenetic mechanism for limb development. It is composed of a monochromatid gene expression phenomenon that we discovered in two fission yeasts with the selective chromosome copy segregation phenomenon that we discovered in mouse cells. Accordingly, one daughter cell inherits both expressed DLX5 copies while the other daughter inherits both epigenetically silenced ones from a single deterministic cell of the developing limb. Thus, differentiated daughter cells after further proliferation will correspondingly produce proximal/distal-limb tissues. Published results of a Chr. 7 translocation with a centromere-proximal breakpoint situated over 41 million bases away from the DLX locus, centromeric and DLX5-region inversions have satisfied key genetic and developmental biology predictions of the mechanism. Further genetic tests of the mechanism are proposed. We propose that the DNA double helical structure itself causes the development of sister cells' gene regulation asymmetry. We also argue against the conventionally invoked morphogen model of development. This article is part of the themed issue 'Provocative questions in left-right asymmetry'. C1 [Klar, Amar J. S.] NCI, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res, NIH, Bldg 539,Room 154, Frederick, MD 21702 USA. RP Klar, AJS (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res, NIH, Bldg 539,Room 154, Frederick, MD 21702 USA. EM klara@mail.nih.gov FU Intramural Research Program of the National Cancer Institute, National Institutes of Health FX The Intramural Research Program of the National Cancer Institute, National Institutes of Health, supports this research. NR 74 TC 1 Z9 1 U1 11 U2 11 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 EI 1471-2970 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD DEC 19 PY 2016 VL 371 IS 1710 AR 20150415 DI 10.1098/rstb.2015.0415 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA ED5WS UT WOS:000388924200015 ER PT J AU Levin, M Klar, AJS Ramsdell, AF AF Levin, Michael Klar, Amar J. S. Ramsdell, Ann F. TI Introduction to provocative questions in left-right asymmetry SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Editorial Material DE developmental biology; epigenetic mechanisms; asymmetric cell division; DNA chirality; developmental disorders; human genetics ID EPITHELIAL MORPHOGENESIS; CHIRALITY; REVEALS; EMBRYO; MOUSE; FROG AB Left-right asymmetry is a phenomenon that has a broad appeal-to anatomists, developmental biologists and evolutionary biologists-because it is a morphological feature of organisms that spans scales of size and levels of organization, from unicellular protists, to vertebrate organs, to social behaviour. Here, we highlight a number of important aspects of asymmetry that encompass several areas of biology-cell-level, physiological, genetic, anatomical and evolutionary components-and that are based on research conducted in diverse model systems, ranging from single cells to invertebrates to human developmental disorders. Together, the contributions in this issue reveal a heretofore-unsuspected variety in asymmetry mechanisms, including ancient chirality elements that could underlie a much more universal basis to asymmetry development, and provide much fodder for thought with far reaching implications in biomedical, developmental, evolutionary and synthetic biology. The new emerging theme of binary cell-fate choice, promoted by asymmetric cell division of a deterministic cell, has focused on investigating asymmetry mechanisms functioning at the single cell level. These include cytoskeleton and DNA chain asymmetry-mechanisms that are amplified and coordinated with those employed for the determination of the anterior-posterior and dorsal-ventral axes of the embryo. This article is part of the themed issue 'Provocative questions in left-right asymmetry'. C1 [Levin, Michael] Tufts Univ, Allen Discovery Ctr, Dept Biol, Medford, MA 02155 USA. [Klar, Amar J. S.] NCI, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Ramsdell, Ann F.] Univ South Carolina, Coll Arts & Sci, Sch Med, Dept Cell Biol & Anat, Columbia, SC 29208 USA. [Ramsdell, Ann F.] Univ South Carolina, Coll Arts & Sci, Program Womens & Gender Studies, Columbia, SC 29208 USA. RP Levin, M (reprint author), Tufts Univ, Allen Discovery Ctr, Dept Biol, Medford, MA 02155 USA.; Klar, AJS (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res, Frederick, MD 21702 USA.; Ramsdell, AF (reprint author), Univ South Carolina, Coll Arts & Sci, Sch Med, Dept Cell Biol & Anat, Columbia, SC 29208 USA.; Ramsdell, AF (reprint author), Univ South Carolina, Coll Arts & Sci, Program Womens & Gender Studies, Columbia, SC 29208 USA. EM michael.levin@tufts.edu; klara@mail.nih.gov; ann.ramsdell@uscmed.sc.edu RI Levin, Michael Levin/A-5918-2011; OI Levin, Michael Levin/0000-0001-7292-8084; Ramsdell, Ann F/0000-0003-2469-7079 NR 42 TC 0 Z9 0 U1 11 U2 11 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 EI 1471-2970 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD DEC 19 PY 2016 VL 371 IS 1710 AR 20150399 DI 10.1098/rstb.2015.0399 PG 7 WC Biology SC Life Sciences & Biomedicine - Other Topics GA ED5WS UT WOS:000388924200001 ER PT J AU Agniswamy, J Louis, JM Roche, J Harrison, RW Weber, IT AF Agniswamy, Johnson Louis, John M. Roche, Julien Harrison, Robert W. Weber, Irene T. TI Structural Studies of a Rationally Selected Multi-Drug Resistant HIV-1 Protease Reveal Synergistic Effect of Distal Mutations on Flap Dynamics SO PLOS ONE LA English DT Article ID VIRUS TYPE-1 PROTEASE; BINDING FREE-ENERGY; MOLECULAR-DYNAMICS; CLINICAL INHIBITORS; CRYSTAL-STRUCTURES; DRUG-RESISTANCE; ACTIVE-SITE; MUTANTS; DARUNAVIR; SAQUINAVIR AB We report structural analysis of HIV protease variant PRS17 which was rationally selected by machine learning to represent wide classes of highly drug-resistant variants. Crystal structures were solved of PRS17 in the inhibitor-free form and in complex with antiviral inhibitor, darunavir. Despite its 17 mutations, PRS17 has only one mutation (V82S) in the inhibitor/substrate binding cavity, yet exhibits high resistance to all clinical inhibitors. PRS17 has none of the major mutations (I47V, I50V, I54ML, L76V and I84V) associated with darunavir resistance, but has 10,000-fold weaker binding affinity relative to the wild type PR. Comparable binding affinity of 8000-fold weaker than PR is seen for drug resistant mutant PR20, which bears 3 mutations associated with major resistance to darunavir (I47V, I54L and I84V). Inhibitor-free PRS17 shows an open flap conformation with a curled tip correlating with G48V flap mutation. NMR studies on inactive PRD25NS17 unambiguously confirm that the flaps adopt mainly an open conformation in solution very similar to that in the inhibitor-free crystal structure. In PRS17 , the hinge loop cluster of mutations, E35D, M36I and S37D, contributes to the altered flap dynamics by a mechanism similar to that of PR20. An additional K20R mutation anchors an altered conformation of the hinge loop. Flap mutations M46L and G48V in PRS17 /DRV complex alter the Phe53 conformation by steric hindrance between the side chains. Unlike the L10F mutation in PR20, L10I in PRS17 does not break the inter-subunit ion pair or diminish the dimer stability, consistent with a very low dimer dissociation constant comparable to that of wild type PR. Distal mutations A71V, L90M and I93L propagate alterations to the catalytic site of PRS17 . PRS17 exhibits a molecular mechanism whereby mutations act synergistically to alter the flap dynamics resulting in significantly weaker binding yet maintaining active site contacts with darunavir. C1 [Agniswamy, Johnson; Harrison, Robert W.; Weber, Irene T.] Georgia State Univ, Dept Biol, Atlanta, GA 30302 USA. [Louis, John M.; Roche, Julien] NIDDK, Chem Phys Lab, NIH, DHHS, Bethesda, MD 20892 USA. [Roche, Julien] Iowa State Univ, Roy J Carver Dept Biochem Biophys & Mol Biol, Ames, IA USA. [Harrison, Robert W.] Georgia State Univ, Dept Comp Sci, Atlanta, GA 30303 USA. [Weber, Irene T.] Georgia State Univ, Dept Chem, Atlanta, GA 30303 USA. RP Weber, IT (reprint author), Georgia State Univ, Dept Biol, Atlanta, GA 30302 USA.; Weber, IT (reprint author), Georgia State Univ, Dept Chem, Atlanta, GA 30303 USA. EM iweber@gsu.edu FU National Institutes of Health [GM062920]; Intramural Research Program of the NIDDK, National Institutes of Health (NIH); Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX The research was supported in part by the National Institutes of Health grant GM062920 (ITW, RWH) and by the Intramural Research Program of the NIDDK, National Institutes of Health (NIH), Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH (JML). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We thank Jane M. Sayer for discussions and critical reading of the manuscript, and Annie Aniana for technical assistance. We thank the staff at the Southeast Regional-Collaborative Access Team (SER-CAT) at the Advanced Photon Source, Argonne National Laboratory, for assistance during X-ray data collection. Supporting institutions may be found at http://www.ser-cat.org/members.html. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. NR 53 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 DEC 16 PY 2016 VL 11 IS 12 AR e0168616 DI 10.1371/journal.pone.0168616 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI8LN UT WOS:000392758000067 PM 27992544 ER PT J AU Lopata, A Leveles, I Bendes, AA Viskolcz, B Vertessy, BG Jojart, B Toth, J AF Lopata, Anna Leveles, Ibolya Bendes, Abris Adam Viskolcz, Bela Vertessy, Beata G. Jojart, Balazs Toth, Judit TI A Hidden Active Site in the Potential Drug Target Mycobacterium tuberculosis dUTPase Is Accessible through Small Amplitude Protein Conformational Changes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; PHOSPHATE ESTER HYDROLYSIS; INFECTIOUS-ANEMIA VIRUS; ESCHERICHIA-COLI; CATALYTIC MECHANISM; RANDOM ACCELERATION; C-TERMINUS; CYTOCHROME P450CAM; TRIMERIC DUTPASES; COUPLED RECEPTOR AB dUTPases catalyze the hydrolysis of dUTP into dUMP and pyrophosphate to maintain the proper nucleotide pool for DNA metabolism. Recent evidence suggests that dUTPases may also represent a selective drug target in mycobacteria because of the crucial role of these enzymes in maintaining DNA integrity. Nucleotide-hydrolyzing enzymes typically harbor a buried ligand-binding pocket at interdomain or intersubunit clefts, facilitating proper solvent shielding for the catalyzed reaction. The mechanism by which substrate binds this hidden pocket and product is released in dUTPases is unresolved because of conflicting crystallographic and spectroscopic data. We sought to resolve this conflict by using a combination of random acceleration molecular dynamics (RAMD) methodology and structural and biochemical methods to study the dUTPase from Mycobacterium tuberculosis. In particular, the RAMD approach used in this study provided invaluable insights into the nucleotide dissociation process that reconciles all previous experimental observations. Specifically, our data suggest that nucleotide binding takes place as a small stretch of amino acids transiently slides away and partially uncovers the active site. The in silico data further revealed a new dUTPase conformation on the pathway to a relatively open active site. To probe this model, we developed the Trp(21) reporter and collected crystallographic, spectroscopic, and kinetic data that confirmed the interaction of Trp(21) with the active site shielding C-terminal arm, suggesting that the RAMD method is effective. In summary, our computational simulations and spectroscopic results support the idea that small loop movements in dUTPase allow the shuttling of the nucleotides between the binding pocket and the solvent. C1 [Lopata, Anna; Leveles, Ibolya; Bendes, Abris Adam; Vertessy, Beata G.; Toth, Judit] Hungarian Acad Sci, Res Ctr Nat Sci, Inst Enzymol, Magyar Tudosok Korutja 2, H-1117 Budapest, Hungary. [Viskolcz, Bela] Univ Miskolc, Inst Chem, H-3529 Miskolc, Hungary. [Vertessy, Beata G.] Budapest Univ Technol & Econ, Dept Appl Biotechnol, H-1111 Budapest, Hungary. [Jojart, Balazs] Univ Szeged, Dept Chem Informat, H-6725 Szeged, Hungary. [Lopata, Anna] NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. [Lopata, Anna] Univ Leeds, Fac Biol Sci, Sch Mol & Cellular Biol, Leeds LS2 9JT, W Yorkshire, England. [Bendes, Abris Adam] Univ Oulu, Fac Biochem & Mol Med, Oulu 90014, Finland. [Bendes, Abris Adam] Univ Oulu, Bioctr Oulu, Oulu 90014, Finland. RP Toth, J (reprint author), Hungarian Acad Sci, Res Ctr Nat Sci, Inst Enzymol, Magyar Tudosok Korutja 2, H-1117 Budapest, Hungary. EM toth.judit@ttk.mta.hu FU National Institutes of Health [1R01TW008130]; National Research, Development and Innovation Office Hungarian Scientific Research Fund Grants OTKA [K109486, K115993, K119493]; Hungarian Academy of Sciences MedInProt Program; International Centre for Genetic Engineering and Biotechnology (ICGEB) Research Grant [CRP/HUN14-01]; Hungarian Scientific Research Funds; Hungarian Academy of Sciences FX This work was supported by National Institutes of Health Grant 1R01TW008130; National Research, Development and Innovation Office Hungarian Scientific Research Fund Grants OTKA K109486, K115993, and K119493; the Hungarian Academy of Sciences MedInProt Program; International Centre for Genetic Engineering and Biotechnology (ICGEB) Research Grant CRP/HUN14-01; and Hungarian Scientific Research Funds. 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.; Recipient of the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences. To whom correspondence should be addressed: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudosok korutja 2, Budapest, Hungary, H1117. Tel.: 36-1-3826707; Fax: 36-1-4631401; E-mail: toth.judit@ttk.mta.hu. NR 66 TC 0 Z9 0 U1 2 U2 2 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 DEC 16 PY 2016 VL 291 IS 51 BP 26320 EP 26331 DI 10.1074/jbc.M116.734012 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EH1ZY UT WOS:000391568200007 PM 27815500 ER PT J AU Razzaghi, H Quesnel-Crooks, S Sherman, R Joseph, R Kohler, B Andall-Brereton, G Ivey, MA Edwards, BK Mery, L Gawryszewski, V Saraiya, M AF Razzaghi, Hilda Quesnel-Crooks, Sarah Sherman, Recinda Joseph, Rachael Kohler, Betsy Andall-Brereton, Glennis Ivey, Marsha A. Edwards, Brenda K. Mery, Les Gawryszewski, Vilma Saraiya, Mona TI Leading Causes of Cancer Mortality - Caribbean Region, 2003-2013 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article C1 [Razzaghi, Hilda; Joseph, Rachael; Saraiya, Mona] CDC, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Razzaghi, Hilda; Joseph, Rachael; Saraiya, Mona] US PHS, Washington, DC 20201 USA. [Quesnel-Crooks, Sarah; Andall-Brereton, Glennis; Ivey, Marsha A.] Caribbean Publ Hlth Agcy, Port Of Spain, Trinid & Tobago. [Sherman, Recinda; Kohler, Betsy] North Amer Assoc Cent Canc Registries, Springfield, IL USA. [Edwards, Brenda K.] NCI, Rockville, MD USA. [Mery, Les] WHO, Int Agcy Res Canc, Lyon, France. [Gawryszewski, Vilma] WHO, Pan Amer Hlth Org, Washington, DC USA. RP Razzaghi, H (reprint author), CDC, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA.; Razzaghi, H (reprint author), US PHS, Washington, DC 20201 USA. EM Hrazzaghi@cdc.gov NR 8 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 DEC 16 PY 2016 VL 65 IS 49 BP 1395 EP 1400 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EF8YJ UT WOS:000390617600002 PM 27977639 ER PT J AU Jayashankar, L Hafner, R AF Jayashankar, Lakshmi Hafner, Richard TI Adjunct Strategies for Tuberculosis vaccines: Modulating Key immune Cell Regulatory Mechanisms to Potentiate vaccination SO FRONTIERS IN IMMUNOLOGY LA English DT Review DE tuberculosis; vaccines; immunometabolism; immuno-oncology ID TUMOR-ASSOCIATED MACROPHAGES; GLYCOGEN-SYNTHASE KINASE-3; ACTIVATED T-CELLS; BACILLE CALMETTE-GUERIN; SOUTH-AFRICAN ADULTS; MYCOBACTERIUM-TUBERCULOSIS; SUPPRESSOR-CELLS; BCG VACCINE; INDOLEAMINE 2,3-DIOXYGENASE; THERAPEUTIC TARGETS AB Tuberculosis (TB) remains a global health threat of alarming proportions, resulting in 1.5 million deaths worldwide. The only available licensed vaccine, Bacillus Calmette-Guerin, does not confer lifelong protection against active TB. To date, development of an effective vaccine against TB has proven to be elusive, and devising newer approaches for improved vaccination outcomes is an essential goal. Insights gained over the last several years have revealed multiple mechanisms of immune manipulation by Mycobacterium tuberculosis (Mtb) in infected macrophages and dendritic cells that support disease progression and block development of protective immunity. This review provides an assessment of the known immunoregulatory mechanisms altered by Mtb, and how new interventions may reverse these effects. Examples include blocking of inhibitory immune cell coreceptor checkpoints (e.g., programed death-1). Conversely, immune mechanisms that strengthen immune cell effector functions may be enhanced by interventions, including stimulatory immune cell coreceptors (e.g., OX40). Modification of the activity of key cell "immunometabolism" signaling pathway molecules, including mechanistic target of rapamycin, glycogen synthase kinase-3 beta, wnt/beta-catenin, adenosine monophosophate-activated protein kinase, and sirtuins, related epigenetic changes, and preventing induction of immune regulatory cells (e.g., regulatory T cells, myeloid-derived suppressor cells) are powerful new approaches to improve vaccine responses. Interventions to favorably modulate these components have been studied primarily in oncology to induce efficient antitumor immune responses, often by potentiation of cancer vaccines. These agents include antibodies and a rapidly increasing number of small molecule drug classes that have contributed to the dramatic immune-based advances in treatment of cancer and other diseases. Because immune responses to malignancies and to Mtb share many similar mechanisms, studies to improve TB vaccine responses using interventions based on "immuno-oncology" are needed to guide possible repurposing. Understanding the regulation of immune cell functions appropriated by Mtb to promote the imbalance between protective and pathogenic immune responses may guide the development of innovative drug-based adjunct approaches to substantially enhance the clinical efficacy of TB vaccines. C1 [Jayashankar, Lakshmi] Columbus Technol Inc, NIAID, NIH, Bethesda, MD USA. [Hafner, Richard] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. RP Hafner, R (reprint author), NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. EM rhafner@niaid.nih.gov NR 200 TC 0 Z9 0 U1 9 U2 9 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 DEC 16 PY 2016 VL 7 AR 577 DI 10.3389/fimmu.2016.00577 PG 14 WC Immunology SC Immunology GA EE8EM UT WOS:000389858100001 PM 28018344 ER PT J AU Zhao, ZK Goldin, L Liu, SP Wu, L Zhou, WY Lou, H Yu, QC Tsang, SX Jiang, MM Li, FQ McMaster, M Li, Y Lin, XX Wang, ZF Xu, LQ Marti, G Li, GB Wu, K Yeager, M Yang, HM Xu, X Chanock, SJ Li, B Hou, Y Caporaso, N Dean, M AF Zhao, Zhikun Goldin, Lynn Liu, Shiping Wu, Liang Zhou, Weiyin Lou, Hong Yu, Qichao Tsang, Shirley X. Jiang, Miaomiao Li, Fuqiang McMaster, MaryLou Li, Yang Lin, Xinxin Wang, Zhifeng Xu, Liqin Marti, Gerald Li, Guibo Wu, Kui Yeager, Meredith Yang, Huanming Xu, Xun Chanock, Stephen J. Li, Bo Hou, Yong Caporaso, Neil Dean, Michael TI Evolution of multiple cell clones over a 29-year period of a CLL patient SO NATURE COMMUNICATIONS LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; NON-HODGKIN-LYMPHOMA; SINGLE-CELL; EXPRESSION ANALYSIS; BIOLOGIC AGENTS; SEQUENCING DATA; R-PACKAGE; GENOME; CANCER; GENE AB Chronic lymphocytic leukaemia (CLL) is a frequent B-cell malignancy, characterized by recurrent somatic chromosome alterations and a low level of point mutations. Here we present single-nucleotide polymorphism microarray analyses of a single CLL patient over 29 years of observation and treatment, and transcriptome and whole-genome sequencing at selected time points. We identify chromosome alterations 13q14 -, 6q - and 12q+ in early cell clones, elimination of clonal populations following therapy, and subsequent appearance of a clone containing trisomy 12 and chromosome 10 copy-neutral loss of heterogeneity that marks a major population dominant at death. Serial single-cell RNA sequencing reveals an expression pattern with high FOS, JUN and KLF4 at disease acceleration, which resolves following therapy, but reoccurs following relapse and death. Transcriptome evolution indicates complex changes in expression occur over time. In conclusion, CLL can evolve gradually during indolent phases, and undergo rapid changes following therapy. C1 [Zhao, Zhikun; Liu, Shiping; Wu, Liang; Yu, Qichao; Jiang, Miaomiao; Li, Fuqiang; Li, Yang; Lin, Xinxin; Wang, Zhifeng; Xu, Liqin; Li, Guibo; Wu, Kui; Yang, Huanming; Xu, Xun; Li, Bo; Hou, Yong; Dean, Michael] BGI Shenzhen, Shenzhen 518083, Peoples R China. [Zhao, Zhikun] Southeast Univ, State Key Lab Bioelect, Nanjing 210096, Jiangsu, Peoples R China. [Zhao, Zhikun; Jiang, Miaomiao] Southeast Univ, Sch Biol Sci & Med Engn, Nanjing 210096, Jiangsu, Peoples R China. [Goldin, Lynn; McMaster, MaryLou; Chanock, Stephen J.; Caporaso, Neil; Dean, Michael] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Liu, Shiping] Sun Yat Sen Univ, Sch Life Sci, Guangzhou 510006, Guangdong, Peoples R China. [Zhou, Weiyin; Lou, Hong; Yeager, Meredith] NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Leidos Biomed Res Inc, Bethesda, MD 20892 USA. [Yu, Qichao] Univ Chinese Acad Sci, BGI Educ Ctr, Shenzhen 518083, Peoples R China. [Tsang, Shirley X.] Biomatrix, Bethesda, MD 20849 USA. [Marti, Gerald] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Li, Guibo; Wu, Kui; Hou, Yong] Univ Copenhagen, Dept Biol, DK-1599 Copenhagen, Denmark. [Yang, Huanming] James D Watson Inst Genome Sci, Hangzhou 310058, Zhejiang, Peoples R China. RP Li, B; Hou, Y; Dean, M (reprint author), BGI Shenzhen, Shenzhen 518083, Peoples R China.; Caporaso, N; Dean, M (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.; Hou, Y (reprint author), Univ Copenhagen, Dept Biol, DK-1599 Copenhagen, Denmark. EM libo@genomics.cn; houyong@genomics.cn; caporasn@mail.nih.gov; deanm@mail.nih.gov FU Shenzhen Science and Technology Program [CXZZ20150330171838997]; Shenzhen Municipal Government of China [ZDSYS20140509153457495]; Science, Technology and Innovation Committee of Shenzhen Municipality [JSGG20140702161347218]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We thank Rongchang Chen, Weijian Rao, Xiaolong Zhang, Jie Wang, Zhanlong Mei, Xinlan Zhou, Nannan Li, Xulian Shi and Fatima Abbassi for help on data analysis and discussion, Kathleen Noer and the CCR Flow Cytometry Core for cell sorting. This project was supported by grants of the Shenzhen Science and Technology Program (CXZZ20150330171838997), the Shenzhen Municipal Government of China (ZDSYS20140509153457495) and the Science, Technology and Innovation Committee of Shenzhen Municipality (JSGG20140702161347218). 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 US Government. NR 47 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 DEC 16 PY 2016 VL 7 AR 13765 DI 10.1038/ncomms13765 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EF4PX UT WOS:000390315600001 PM 27982015 ER PT J AU Singh, TP Zhang, HH Borek, I Wolf, P Hedrick, MN Singh, SP Kelsall, BL Clausen, BE Farber, JM AF Singh, Tej Pratap Zhang, Howard H. Borek, Izabela Wolf, Peter Hedrick, Michael N. Singh, Satya P. Kelsall, Brian L. Clausen, Bjorn E. Farber, Joshua M. TI Monocyte-derived inflammatory Langerhans cells and dermal dendritic cells mediate psoriasis-like inflammation SO NATURE COMMUNICATIONS LA English DT Article ID DELTA T-CELLS; CHEMOKINE RECEPTOR CCR6; SKIN INFLAMMATION; CUTTING EDGE; STEADY-STATE; EPIDERMAL HYPERPLASIA; PLAQUE-FORMATION; IN-VIVO; MICE; DISTINCT AB Dendritic cells (DCs) have been implicated in the pathogenesis of psoriasis but the roles for specific DC subsets are not well defined. Here we show that DCs are required for psoriasis-like changes in mouse skin induced by the local injection of IL-23. However, Flt3L-dependent DCs and resident Langerhans cells are dispensable for the inflammation. In epidermis and dermis, the critical DCs are TNF-producing and IL-1 beta-producing monocyte-derived DCs, including a population of inflammatory Langerhans cells. Depleting Ly6C(hi) blood monocytes reduces DC accumulation and the skin changes induced either by injecting IL-23 or by application of the TLR7 agonist imiquimod. Moreover, we find that IL-23-induced inflammation requires expression of CCR6 by DCs or their precursors, and that CCR6 mediates monocyte trafficking into inflamed skin. Collectively, our results imply that monocyte-derived cells are critical contributors to psoriasis through production of inflammatory cytokines that augment the activation of skin T cells. C1 [Singh, Tej Pratap; Zhang, Howard H.; Hedrick, Michael N.; Singh, Satya P.; Kelsall, Brian L.; Farber, Joshua M.] NIAID, Lab Mol Immunol, US Natl Inst Hlth, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Borek, Izabela] Med Univ Graz, Inst Pathophysiol & Immunol, A-8010 Graz, Austria. [Wolf, Peter] Med Univ Graz, Dept Dermatol, A-8036 Graz, Austria. [Clausen, Bjorn E.] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Mol Med, D-55131 Mainz, Germany. RP Farber, JM (reprint author), NIAID, Lab Mol Immunol, US Natl Inst Hlth, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jfarber@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; Austrian Science Fund FWF [W1241]; PhD program Molecular Fundamentals of Inflammation (DK-MOLIN) of the Medical University of Graz FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. Izabela Borek and Peter Wolf were supported through Austrian Science Fund FWF (W1241) and the PhD program Molecular Fundamentals of Inflammation (DK-MOLIN) of the Medical University of Graz. We thank Mark Udey, National Cancer Institute, for providing mice and advice; Vijay K. Kuchroo, Harvard Medical School, for providing mice; and Bishop Hague and other members of the Research Technologies Branch, NIAID, for their help with cell sorting. NR 69 TC 0 Z9 1 U1 10 U2 10 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 DEC 16 PY 2016 VL 7 AR 13581 DI 10.1038/ncomms13581 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE8CT UT WOS:000389853100001 PM 27982014 ER PT J AU Norrie, JL Li, Q Co, S Huang, BL Ding, D Uy, JC Ji, ZC Mackem, S Bedford, MT Galli, A Ji, HK Vokes, SA AF Norrie, Jacqueline L. Li, Qiang Co, Swanie Huang, Bau-Lin Ding, Ding Uy, Jann C. Ji, Zhicheng Mackem, Susan Bedford, Mark T. Galli, Antonella Ji, Hongkai Vokes, Steven A. TI PRMT5 is essential for the maintenance of chondrogenic progenitor cells in the limb bud SO DEVELOPMENT LA English DT Article DE BMP4; PRMT5; SOX9; Chondrogenesis; Limb development; Progenitor cells ID P38 MAP KINASE; APICAL ECTODERMAL RIDGE; HISTONE ARGININE METHYLATION; PHALANX-FORMING REGION; BRACHYDACTYLY TYPE A2; VERTEBRATE LIMB; CARTILAGE FORMATION; GENE-EXPRESSION; JOINT FORMATION; FGF SIGNALS AB During embryonic development, undifferentiated progenitor cells balance the generation of additional progenitor cells with differentiation. Within the developing limb, cartilage cells differentiate from mesodermal progenitors in an ordered process that results in the specification of the correct number of appropriately sized skeletal elements. The internal pathways by which these cells maintain an undifferentiated state while preserving their capacity to differentiate is unknown. Here, we report that the arginine methyltransferase PRMT5 has a crucial role in maintaining progenitor cells. Mouse embryonic buds lacking PRMT5 have severely truncated bones with wispy digits lacking joints. This novel phenotype is caused by widespread cell death that includes mesodermal progenitor cells that have begun to precociously differentiate into cartilage cells. We propose that PRMT5 maintains progenitor cells through its regulation of Bmp4. Intriguingly, adult and embryonic stem cells also require PRMT5 for maintaining pluripotency, suggesting that similar mechanisms might regulate lineage-restricted progenitor cells during organogenesis. C1 [Norrie, Jacqueline L.; Li, Qiang; Co, Swanie; Uy, Jann C.; Vokes, Steven A.] Univ Texas Austin, Dept Mol Biosci, 2500 Speedway Stop A4800, Austin, TX 78712 USA. [Huang, Bau-Lin; Mackem, Susan] NCI, CCR, Canc & Dev Biol Lab, Frederick, MD 21702 USA. [Ding, Ding; Ji, Zhicheng; Ji, Hongkai] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, 615 North Wolfe St,Room E3638, Baltimore, MD 21205 USA. [Bedford, Mark T.] MD Anderson Canc Ctr, Dept Epigenet & Mol Carcinogenesis, 1808 Pk Rd 1C POB 389, Smithville, TX 78957 USA. [Galli, Antonella] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. RP Vokes, SA (reprint author), Univ Texas Austin, Dept Mol Biosci, 2500 Speedway Stop A4800, Austin, TX 78712 USA. EM svokes@austin.utexas.edu FU National Institutes of Health [R01HD073151]; Cancer Prevention Research Institute of Texas [RP120343] FX This work was supported by the National Institutes of Health [R01HD073151 to S.A.V.] and Cancer Prevention Research Institute of Texas [# RP120343 to S.A.V.]. Deposited in PMC for release after 12 months. NR 102 TC 0 Z9 0 U1 3 U2 3 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD DEC 15 PY 2016 VL 143 IS 24 BP 4608 EP 4619 DI 10.1242/dev.140715 PG 12 WC Developmental Biology SC Developmental Biology GA EJ8DI UT WOS:000393454600006 PM 27827819 ER PT J AU Sima, J Piao, YL Chen, YH Schlessinger, D AF Sima, Jian Piao, Yulan Chen, Yaohui Schlessinger, David TI Molecular dynamics of Dkk4 modulates Wnt action and regulates meibomian gland development SO DEVELOPMENT LA English DT Article DE Dkk4; Proteolytic cleavage; Meibomian gland; Wnt; Eda; Lrp6; Mouse ID HAIR FOLLICLE DEVELOPMENT; KAPPA-B; SIGNALING INHIBITION; SKIN; ECTODYSPLASIN; MORPHOGENESIS; DICKKOPF-1; INDUCTION; RECEPTOR; DISEASE AB Secreted Dickkopf (Dkk) proteins are major Wnt pathway modulators during organ development. Dkk1 has been widely studied and acts as a general Wnt inhibitor. However, the molecular function of other Dkks remains largely unknown. Here, we show that Dkk4 selectively inhibits a subset of Wnts, but is further inactivated by proteolytic cleavage. Meibomian gland (MG) formation is employed as a model where Dkk4 and its Wnt targets are expressed. Skin-specific expression of Dkk4 arrests MG growth at early germ phase, which is similar to that observed in Eda-ablated Tabby mice. Consistent with transient Dkk4 action, intact Dkk4 inhibits MG extension but the cleaved form progressively increases during MG development with a concomitant upswing in Wnt activity. Furthermore, both Dkk4 and its receptor (and Wnt co-receptor) Lrp6 are direct Eda targets during MG induction. In cell and organotypic cultures, Dkk4 inhibition is eliminated by elevation of Lrp6. Also, Lrp6 upregulation restores MG formation in Tabby mice. Thus, the dynamic state of Dkk4 itself and its interaction with Lrp6 modulates Wnt function during MG development, with a novel limitation of Dkk4 action by proteolytic cleavage. C1 [Sima, Jian; Piao, Yulan; Chen, Yaohui; Schlessinger, David] NIA, Lab Genet & Genom, NIH, IRP, 251 Bayview Blvd,Room 10B014, Baltimore, MD 21224 USA. RP Sima, J; Schlessinger, D (reprint author), NIA, Lab Genet & Genom, NIH, IRP, 251 Bayview Blvd,Room 10B014, Baltimore, MD 21224 USA. EM simaj@mail.nih.gov; SchlessingerD@grc.nia.nih.gov FU Intramural Research Program of the National Institute on Aging, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. Deposited in PMC for release after 12 months. NR 42 TC 0 Z9 0 U1 1 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD DEC 15 PY 2016 VL 143 IS 24 BP 4723 EP 4735 DI 10.1242/dev.143909 PG 13 WC Developmental Biology SC Developmental Biology GA EJ8DI UT WOS:000393454600016 PM 27864382 ER PT J AU Mudd, JC Panigrahi, S Kyi, B Moon, SH Manion, MM Younes, SA Sieg, SF Funderburg, NT Zidar, DA Lederman, MM Freeman, ML AF Mudd, Joseph C. Panigrahi, Soumya Kyi, Benjamin Moon, So Hee Manion, Maura M. Younes, Souheil-Antoine Sieg, Scott F. Funderburg, Nicholas T. Zidar, David A. Lederman, Michael M. Freeman, Michael L. TI Inflammatory Function of CX3CR1(+) CD8(+) T Cells in Treated HIV Infection Is Modulated by Platelet Interactions SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE non-AIDS-related morbidities; CD8(+) T-cell expansion; atherosclerosis; platelets ID PROTEASE-ACTIVATED RECEPTORS; TRANSFORMING-GROWTH-FACTOR; CORONARY-ARTERY-DISEASE; DIFFERENTIAL EXPRESSION; ENDOTHELIAL DYSFUNCTION; ANTIRETROVIRAL THERAPY; COAGULATION; FRACTALKINE; LYMPHOCYTES; RESPONSES AB Increases in inflammation, coagulation, and CD8(+) T-cell numbers are associated with an elevated cardiovascular disease (CVD) risk in human immunodeficiency virus (HIV)-infected antiretroviral therapy (ART) recipients. Circulating memory CD8(+) T cells that express the vascular endothelium-homing receptor CX3CR1 (fractalkine receptor) are enriched in HIV-infected ART recipients. Thrombin-activated receptor (PAR-1) expression is increased in HIV-infected ART recipients and is particularly elevated on CX3CR1(+) CD8(+) T cells, suggesting that these cells could interact with coagulation elements. Indeed, thrombin directly enhanced T-cell receptor-mediated interferon. production by purified CD8(+) T cells but was attenuated by thrombin-induced release of transforming growth factor beta by platelets. We have therefore identified a population of circulating memory CD8(+) T cells in HIV infection that may home to endothelium, can be activated by clot-forming elements, and are susceptible to platelet-mediated regulation. Complex interactions between inflammatory elements and coagulation at endothelial surfaces may play an important role in CVD risk in HIV-infected ART recipients. C1 [Mudd, Joseph C.; Panigrahi, Soumya; Kyi, Benjamin; Moon, So Hee; Manion, Maura M.; Younes, Souheil-Antoine; Sieg, Scott F.; Lederman, Michael M.; Freeman, Michael L.] Case Western Reserve Univ, Univ Hosp Cleveland, Med Ctr, Div Infect Dis & HIV Med,Dept Med,Ctr AIDS Res, Cleveland, OH 44106 USA. [Mudd, Joseph C.; Manion, Maura M.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Funderburg, Nicholas T.] Ohio State Univ, Sch Hlth & Rehabil Sci, Div Med Lab Sci, Columbus, OH 43210 USA. [Zidar, David A.] Univ Hosp Cleveland, Med Ctr, Harrington Heart & Vasc Inst, Cleveland, OH 44106 USA. RP Freeman, ML (reprint author), Case Western Reserve Univ, Sch Med, 2109 Adelbert Rd BRB 1048B, Cleveland, OH 44106 USA. EM mlf62@case.edu FU NIH [T32AI089474, R56HL126563, P01AI076174, UM1AI069501]; Richard J. Fasenmyer Foundation; Center for AIDS Research at Case Western Reserve University [P30AI036219] FX This work was supported by the NIH (grants T32AI089474 [to J. C. M.], R56HL126563 [to N. T. F.], and P01AI076174 and UM1AI069501 [to M. M. L.]), the Richard J. Fasenmyer Foundation, and the Center for AIDS Research at Case Western Reserve University (grant P30AI036219; developmental awards to D. A. Z. and M. L. F.). NR 49 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 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD DEC 15 PY 2016 VL 214 IS 12 BP 1808 EP 1816 DI 10.1093/infdis/jiw463 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EJ3RT UT WOS:000393130000006 PM 27703039 ER PT J AU Alkaitis, MS Wang, HH Ikeda, AK Rowley, CA MacCormick, IJC Chertow, JH Billker, O Suffredini, AF Roberts, DJ Taylor, TE Seydel, KB Ackerman, HC AF Alkaitis, Matthew S. Wang, Honghui Ikeda, Allison K. Rowley, Carol A. MacCormick, Ian J. C. Chertow, Jessica H. Billker, Oliver Suffredini, Anthony F. Roberts, David J. Taylor, Terrie E. Seydel, Karl B. Ackerman, Hans C. TI Decreased Rate of Plasma Arginine Appearance in Murine Malaria May Explain Hypoargininemia in Children With Cerebral Malaria SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE metabolism; host response; plasmodium; nitric oxide; endothelium; urea cycle ID NITRIC-OXIDE BIOAVAILABILITY; UNDERIVATIZED AMINO-ACIDS; VON-WILLEBRAND-FACTOR; FALCIPARUM-MALARIA; PLASMODIUM-FALCIPARUM; IN-VIVO; MICROCIRCULATORY DYSFUNCTION; CITRULLINE SYNTHESIS; MALAWIAN CHILDREN; PARASITE AB Background. Plasmodium infection depletes arginine, the substrate for nitric oxide synthesis, and impairs endothelium-dependent vasodilation. Increased conversion of arginine to ornithine by parasites or host arginase is a proposed mechanism of arginine depletion. Methods. We used high-performance liquid chromatography to measure plasma arginine, ornithine, and citrulline levels in Malawian children with cerebral malaria and in mice infected with Plasmodium berghei ANKA with or without the arginase gene. Heavy isotope-labeled tracers measured by quadrupole time-of-flight liquid chromatography-mass spectrometry were used to quantify the in vivo rate of appearance and interconversion of plasma arginine, ornithine, and citrulline in infected mice. Results. Children with cerebral malaria and P. berghei-infected mice demonstrated depletion of plasma arginine, ornithine, and citrulline. Knock out of Plasmodium arginase did not alter arginine depletion in infected mice. Metabolic tracer analysis demonstrated that plasma arginase flux was unchanged by P. berghei infection. Instead, infected mice exhibited decreased rates of plasma arginine, ornithine, and citrulline appearance and decreased conversion of plasma citrulline to arginine. Notably, plasma arginine use by nitric oxide synthase was decreased in infected mice. Conclusions. Simultaneous arginine and ornithine depletion in malaria parasite-infected children cannot be fully explained by plasma arginase activity. Our mouse model studies suggest that plasma arginine depletion is driven primarily by a decreased rate of appearance. C1 [Alkaitis, Matthew S.; Ikeda, Allison K.; Rowley, Carol A.; Chertow, Jessica H.; Ackerman, Hans C.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Wang, Honghui; Suffredini, Anthony F.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Taylor, Terrie E.; Seydel, Karl B.] Mississippi State Univ, E Lansing, MI USA. [Alkaitis, Matthew S.; Roberts, David J.] Univ Oxford, John Radcliffe Hosp, Radcliffe Dept Med, Headington, England. [MacCormick, Ian J. C.] Univ Liverpool, Dept Eye & Vis Sci, Liverpool L69 3BX, Merseyside, England. [MacCormick, Ian J. C.] Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh EH8 9YL, Midlothian, Scotland. [Billker, Oliver] Wellcome Trust Sanger Inst, Hinxton, England. [Roberts, David J.] John Radcliffe Hosp, Natl Hlth Serv Blood & Transplant, Oxford, England. [MacCormick, Ian J. C.] Malawi Liverpool Wellcome Trust Clin Res Programm, Blantyre, Malawi. [Seydel, Karl B.] Blantyre Malaria Project, Blantyre, Malawi. [Alkaitis, Matthew S.] Harvard Med Sch, Boston, MA USA. [Ikeda, Allison K.] Emory Univ, Sch Med, Atlanta, GA USA. [Rowley, Carol A.] Univ Virginia, Sch Med, Charlottesville, VA 22908 USA. [Chertow, Jessica H.; Ackerman, Hans C.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Ackerman, HC (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA.; Ackerman, HC (reprint author), NHLBI, Physiol Sect, Sickle Cell Branch, Bldg 10,Rm 6N240, Bethesda, MD 20814 USA. EM hans.ackerman@nih.gov OI Billker, Oliver/0000-0003-1716-168X FU National Institute of Allergy and Infectious Diseases Division of Intramural Research; National Institutes of Health Oxford-Cambridge Scholars Program; National Institute of General Medical Sciences [T32GM007753]; Wellcome Trust [WT098051]; European Virtual Institute of Malaria Research; Research and Development, NHS Blood and Transplant, United Kingdom; Oxford Biomedical Research Centre, United Kingdom National Institute of Health Research FX This work was supported by the National Institute of Allergy and Infectious Diseases Division of Intramural Research (to H. C. A.); the National Institutes of Health Oxford-Cambridge Scholars Program (to M. S. A.); the National Institute of General Medical Sciences (award T32GM007753 to M. S. A.); the Wellcome Trust (grant WT098051 to O. B.); the European Virtual Institute of Malaria Research (to D. J. R.); Research and Development, NHS Blood and Transplant, United Kingdom (to D. J. R.); and the Oxford Biomedical Research Centre, United Kingdom National Institute of Health Research (to D. J. R.). NR 49 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 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD DEC 15 PY 2016 VL 214 IS 12 BP 1840 EP 1849 DI 10.1093/infdis/jiw452 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EJ3RT UT WOS:000393130000011 PM 27923948 ER PT J AU Hom, EK Duprez, DA Jacobs, DR Bluemke, DA Brumback, LC Polak, JF Peralta, CA Greenland, P Magzamen, SL Lima, JAC Redheuil, A Herrington, DM Stein, JH Vaidya, D Ouyang, P Kaufman, JD AF Hom, Elizabeth K. Duprez, Daniel A. Jacobs, David R., Jr. Bluemke, David A. Brumback, Lyndia C. Polak, Joseph F. Peralta, Carmen A. Greenland, Philip Magzamen, Sheryl L. Lima, Joao A. C. Redheuil, Alban Herrington, David M. Stein, James H. Vaidya, Dhananjay Ouyang, Pamela Kaufman, Joel D. TI Comparing Arterial Function Parameters for the Prediction of Coronary Heart Disease Events The Multi-Ethnic Study of Atherosclerosis (MESA) SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE arteries; coronary disease; vascular stiffness ID ALL-CAUSE MORTALITY; AORTIC DISTENSIBILITY; CARDIOVASCULAR-DISEASE; STIFFNESS; RISK; MODELS; HOORN AB Arterial dysfunction has been linked to decline in cardiac function and increased risk of cardiovascular disease events. We calculated the value of arterial function, measured at baseline (2000-2002), in predicting time to first coronary heart disease (CHD) event (median follow-up, 10.2 years) among participants in the MultiEthnic Study of Atherosclerosis (MESA). Measures included the following: C-1 and C-2, derived from diastolic pulse contour analysis from the radial artery blood pressure waveform obtained by tonometry (n = 6,336); carotid distensibility and Young's elastic modulus at the carotid artery, derived from carotid artery ultrasonography (n = 6,531 and 6,528); and aortic distensibility, measured using cardiac magnetic resonance imaging (n = 3,677). After adjustment, the hazard ratio for a CHD event per standard-deviation increment in arterial function was 0.97 (95% confidence interval (CI): 0.86, 1.10) for C1, 0.73 (95% CI: 0.63, 0.86) for C-2, 0.98 (95% CI: 0.86, 1.11) for carotid distensibility, 0.99 (95% CI: 0.90, 1.09) for Young's modulus, and 0.90 (95% CI: 0.74, 1.10) for aortic distensibility. We examined the area under the receiver operating characteristic curve for the model with full adjustment plus the addition of each measure individually. C-2 provided additional discrimination for the prediction of CHD (area under the curve = 0.736 vs. 0.743; P = 0.04). Lower C-2 was associated with a higher risk of future CHD events. C1 [Hom, Elizabeth K.; Kaufman, Joel D.] Univ Washington, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98195 USA. [Hom, Elizabeth K.; Kaufman, Joel D.] Univ Washington, Sch Publ Hlth, Dept Environm & Occupat Hlth Sci, Seattle, WA 98195 USA. [Duprez, Daniel A.] Univ Minnesota, Dept Med, Sch Med, Box 736 UMHC, Minneapolis, MN 55455 USA. [Jacobs, David R., Jr.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Bluemke, David A.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Brumback, Lyndia C.] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Polak, Joseph F.] Tufts Univ, Sch Med, Dept Radiol, Tufts Med Ctr, Boston, MA 02111 USA. [Peralta, Carmen A.] Univ Calif San Francisco, Sch Med, Dept Med, San Francisco, CA 94143 USA. [Greenland, Philip] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Greenland, Philip] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Magzamen, Sheryl L.] Colorado State Univ, Coll Vet Med & Biomed Sci, Dept Environm & Radiol Hlth Sci, Ft Collins, CO 80523 USA. [Lima, Joao A. C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Lima, Joao A. C.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [Redheuil, Alban] Univ Paris 06, Sorbonne Univ, La Pitie Salpetriere, Cardiovasc Imaging, Paris, France. [Redheuil, Alban] INSERM, UMRS 1146, Lab Imagerie Biomed, Inst Cardiometabol & Nutr,Unite Mixte Rech 7371, Paris, France. [Herrington, David M.] Wake Forest Univ, Sch Med, Dept Cardiol, Winston Salem, NC 27109 USA. [Stein, James H.] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI USA. [Vaidya, Dhananjay; Ouyang, Pamela] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Kaufman, Joel D.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. RP Hom, EK (reprint author), Univ Washington, Dept Environm & Occupat Hlth Sci, Sch Publ Hlth, Box 354695,4225 Roosevelt Way NE,Suite 302, Seattle, WA 98105 USA. EM ehom@uw.edu FU National Heart, Lung, and Blood Institute [HSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, R01-HL-098382]; Environmental Protection Agency [RD831697]; National Institute of Environmental Health Sciences [P50ES015915, T32ES015459, K24ES013195] FX MESA was supported by the National Heart, Lung, and Blood Institute (contracts HSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and R01-HL-098382). This work was also supported in part by the Environmental Protection Agency (award RD831697) and the National Institute of Environmental Health Sciences (grants P50ES015915, T32ES015459, and K24ES013195). This publication was developed under a STAR research assistance agreement awarded by the Environmental Protection Agency (award RD831697). This publication was supported by the National Institute of Environmental Health Sciences (grants P50ES015915, T32ES015459, and K24ES013195). NR 20 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 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD DEC 15 PY 2016 VL 184 IS 12 BP 894 EP 901 DI 10.1093/aje/kww113 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EI8AF UT WOS:000392725700006 PM 27923782 ER PT J AU Cookson, MR AF Cookson, Mark R. TI Cellular functions of LRRK2 implicate vesicular trafficking pathways in Parkinson's disease SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article ID REPEAT KINASE 2; LOCOMOTOR DEFICITS; ALPHA-SYNUCLEIN; MUTATIONS; AUTOPHAGY; MICE; LOCALIZATION; MICROTUBULES; ENDOCYTOSIS; GOLGI AB Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene, associated with Parkinson's disease, have been shown to affect intracellular trafficking pathways in a variety of cells and organisms. An emerging theme is that LRRK2 can bind to multiple membranous structures in cells, and several recent studies have suggested that the Rab family of small GTPases might be important in controlling the recruitment of LRRK2 to specific cellular compartments. Once localized to membranes, LRRK2 then influences downstream events, evidenced by changes in the autophagy-lysosome pathway. Here, I will discuss available evidence that supports or challenges this outline, with a specific emphasis on those aspects of LRRK2 function that have been controversial or remain to be fully clarified. C1 [Cookson, Mark R.] NIA, Cell Biol & Gene Express Sect, Neurogenet Lab, NIH, Bldg 35,Room 1A116,MSC3707,35 Convent Dr, Bethesda, MD 20892 USA. RP Cookson, MR (reprint author), NIA, Cell Biol & Gene Express Sect, Neurogenet Lab, NIH, Bldg 35,Room 1A116,MSC3707,35 Convent Dr, Bethesda, MD 20892 USA. EM cookson@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute on Aging FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 52 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 0300-5127 EI 1470-8752 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD DEC 15 PY 2016 VL 44 BP 1603 EP 1610 DI 10.1042/BST20160228 PN 6 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EI8BX UT WOS:000392730800004 PM 27913668 ER PT J AU Nixon-Abell, J Berwick, DC Harvey, K AF Nixon-Abell, Jonathon Berwick, Daniel C. Harvey, Kirsten TI L'RRK de Triomphe: a solution for LRRK2 GTPase activity? SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article ID REPEAT KINASE 2; DISEASE-ASSOCIATED MUTATIONS; FAMILIAL PARKINSONS-DISEASE; NEURONAL TOXICITY; RISK-FACTOR; DOMAIN; PROTEIN; BINDING; AUTOPHOSPHORYLATION; PHOSPHORYLATION AB Leucine-rich repeat kinase 2 (LRRK2) is a central protein in the pathogenesis of Parkinson's disease (PD), yet its normal function has proved stubbornly hard to elucidate. Even though it remains unclear how pathogenic mutations affect LRRK2 to cause PD, recent findings provide increasing cause for optimism. We summarise here the developing consensus over the effect of pathogenic mutations in the Ras of complex proteins and C-terminal of Roc domains on LRRK2 GTPase activity. This body of work has been greatly reinforced by our own study of the protective R1398H variant contained within the LRRK2 GTPase domain. Collectively, data point towards the pathogenicity of GTP-bound LRRK2 and strengthen a working model for LRRK2 GTPase function as a GTPase activated by dimerisation. Together with the identification of the protective R1398H variant as a valuable control for pathogenic mutations, we have no doubt that these triumphs for the LRRK2 field will accelerate research towards resolving LRRK2 function and towards new treatments for PD. C1 [Nixon-Abell, Jonathon; Harvey, Kirsten] UCL, Sch Pharm, Dept Pharmacol, 29-39 Brunswick Sq, London WC1N 1AX, England. [Nixon-Abell, Jonathon] NINDS, Neurogenet Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Berwick, Daniel C.] Open Univ, Dept Life Hlth & Chem Sci, Milton Keynes MK7 6AA, Bucks, England. RP Harvey, K (reprint author), UCL, Sch Pharm, Dept Pharmacol, 29-39 Brunswick Sq, London WC1N 1AX, England.; Berwick, DC (reprint author), Open Univ, Dept Life Hlth & Chem Sci, Milton Keynes MK7 6AA, Bucks, England. EM daniel.berwick@open.ac.uk; kirsten.harvey@ucl.ac.uk OI Nixon-Abell, Jonathon/0000-0003-4169-0012 FU [R1398H] FX We thank Simone Granno, Vicky Spain, and Craig Blackstone for their work on the R1398H project, and to acknowledge the valuable contributions of other members of the Kirsten Harvey laboratory, past and present, and of our collaborators in the LRRK2 field. NR 57 TC 0 Z9 0 U1 2 U2 2 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0300-5127 EI 1470-8752 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD DEC 15 PY 2016 VL 44 BP 1625 EP 1634 DI 10.1042/BST20160240 PN 6 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EI8BX UT WOS:000392730800007 PM 27913671 ER PT J AU Zhang, Y Xu, H AF Zhang, Yi Xu, Hong TI Translational regulation of mitochondrial biogenesis SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article ID RNA-BINDING PROTEIN; MESSENGER-RNA; YEAST MITOCHONDRIA; OUTER-MEMBRANE; GENE-EXPRESSION; DNA; IMPORT; PARKIN; LOCALIZATION; METABOLISM AB Mitochondria are generated by the expression of genes on both nuclear and mitochondrial genome. Mitochondrial biogenesis is highly plastic in response to cellular energy demand, developmental signals and environmental stimuli. Mechanistic target of rapamycin (mTOR) pathway regulates mitochondrial biogenesis to co-ordinate energy homeostasis with cell growth. The local translation of mitochondrial proteins on the outer membrane facilitates their efficient import and thereby allows prodigious mitochondrial biogenesis during rapid cell growth and proliferation. We postulate that the local translation may also allow cells to promote mitochondrial biogenesis selectively based on the fitness of individual organelle. MDI-Larp complex promotes the biogenesis of healthy mitochondria and thereby is essential for the selective transmission of healthy mitochondria. On the other hand, PTEN-induced putative kinase 1 (PINK1)-Pakin activates protein synthesis on damaged mitochondria to maintain the organelle homeostasis and activity. We also summarize some recent progress on miRNAs' regulation on mitochondrial biogenesis. C1 [Zhang, Yi; Xu, Hong] NHLBI, NIH, Bethesda, MD 20892 USA. RP Xu, H (reprint author), NHLBI, NIH, Bethesda, MD 20892 USA. EM hong.xu@nih.gov FU National Heart, Lung and Blood Institute FX The work in authors' laboratory is supported by the intramural program at National Heart, Lung and Blood Institute. NR 65 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 0300-5127 EI 1470-8752 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD DEC 15 PY 2016 VL 44 BP 1717 EP 1724 DI 10.1042/BST20160071C PN 6 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EI8BX UT WOS:000392730800018 PM 27913682 ER PT J AU Martinez, AF Abe, Y Hong, S Molyneux, K Yarnell, D Lohr, H Driever, W Acosta, MT Arcos-Burgos, M Muenke, M AF Martinez, Ariel F. Abe, Yu Hong, Sungkook Molyneux, Kevin Yarnell, David Loehr, Heiko Driever, Wolfgang Acosta, Maria T. Arcos-Burgos, Mauricio Muenke, Maximilian TI An Ultraconserved Brain-Specific Enhancer Within ADGRL3 (LPHN3) Underpins Attention-Deficit/Hyperactivity Disorder Susceptibility SO BIOLOGICAL PSYCHIATRY LA English DT Article DE ADGRL3; ADHD; Cis-acting regulatory element; Enhancer; Evolutionary conserved regions; Genetics; Latrophilin; LPHN3; Zebrafish ID DEFICIT HYPERACTIVITY DISORDER; SUBSTANCE USE DISORDERS; TRANSPORTER CODING VARIANT; HUMAN GENOME; ADHD; GENE; NEURONS; BINDING; CELLS; YY1 AB BACKGROUND: Genetic factors predispose individuals to attention-deficit/hyperactivity disorder (ADHD). Previous studies have reported linkage and association to ADHD of gene variants within ADGRL3. In this study, we functionally analyzed noncoding variants in this gene as likely pathological contributors. METHODS: In silico, in vitro, and in vivo approaches were used to identify and characterize evolutionary conserved elements within the ADGRL3 linkage region (similar to 207 Kb). Family-based genetic analyses of 838 individuals (372 affected and 466 unaffected patients) identified ADHD-associated single nucleotide polymorphisms harbored in some of these conserved elements. Luciferase assays and zebrafish green fluorescent protein transgenesis tested conserved elements for transcriptional enhancer activity. Electromobility shift assays were used to verify transcription factor-binding disruption by ADHD risk alleles. RESULTS: An ultraconserved element was discovered (evolutionary conserved region 47) that functions as a transcriptional enhancer. A three-variant ADHD risk haplotype in evolutionary conserved region 47, formed by rs17226398, rs56038622, and rs2271338, reduced enhancer activity by 40% in neuroblastoma and astrocytoma cells (p(Bonferroni) < .0001). This enhancer also drove green fluorescent protein expression in the zebrafish brain in a tissue-specific manner, sharing aspects of endogenous ADGRL3 expression. The rs2271338 risk allele disrupts binding of YY1 transcription factor, an important factor in the development and function of the central nervous system. Expression quantitative trait loci analysis of postmortem human brain tissues revealed an association between rs2271338 and reduced ADGRL3 expression in the thalamus. CONCLUSIONS: These results uncover the first functional evidence of common noncoding variants with potential implications for the pathology of ADHD. C1 [Martinez, Ariel F.; Abe, Yu; Hong, Sungkook; Molyneux, Kevin; Yarnell, David; Acosta, Maria T.; Arcos-Burgos, Mauricio; Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, 35 Convent Dr,Room 1B-203, Bethesda, MD 20892 USA. [Loehr, Heiko; Driever, Wolfgang] Univ Freiburg, Inst Biol 1, Freiburg, Germany. [Arcos-Burgos, Mauricio] Australian Natl Univ, John Curtin Sch Med Res, Genome Biol Dept, Canberra, ACT, Australia. [Loehr, Heiko] Univ Cologne, Inst Dev Biol, Cologne, Germany. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, 35 Convent Dr,Room 1B-203, Bethesda, MD 20892 USA. EM mamuenke@mail.nih.gov FU Intramural NIH HHS [Z01 HG000175-08, Z99 HG999999] NR 90 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 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD DEC 15 PY 2016 VL 80 IS 12 BP 943 EP 954 DI 10.1016/j.biopsych.2016.06.026 PG 12 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EI8JZ UT WOS:000392754000010 PM 27692237 ER PT J AU Little, RF McShane, LM AF Little, Richard F. McShane, Lisa M. TI Measure for measure: minimal residual disease in CLL SO BLOOD LA English DT Editorial Material ID CHRONIC LYMPHOCYTIC-LEUKEMIA; END-POINT; THERAPY; TRIAL C1 [Little, Richard F.; McShane, Lisa M.] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 10 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 DEC 15 PY 2016 VL 128 IS 24 BP 2747 EP 2748 DI 10.1182/blood-2016-11-745323 PG 2 WC Hematology SC Hematology GA EI7CC UT WOS:000392653900001 PM 27979863 ER PT J AU Stringaris, K Marin, D Barrett, AJ Hills, R Sobieski, C Cao, K Saltarrelli, JG Daher, M Shaim, H Smith, N Linch, D Gale, R Allen, C Sekine, T Mehta, R Champlin, R Shpall, EJ Kantarjian, H Garcia-Manero, G Rezvani, K AF Stringaris, Kate Marin, David Barrett, A. John Hills, Robert Sobieski, Catherine Cao, Kai Saltarrelli, Jerome G. Daher, May Shaim, Hila Smith, Nathaniel Linch, David Gale, Rosemary Allen, Christopher Sekine, Takuya Mehta, Rohtesh Champlin, Richard Shpall, Elizabeth J. Kantarjian, Hagop Garcia-Manero, Guillermo Rezvani, Katayoun TI KIR gene haplotype: an independent predictor of clinical outcome in MDS patients SO BLOOD LA English DT Article ID NATURAL-KILLER-CELLS; ACUTE MYELOGENOUS LEUKEMIA; RECEPTOR GENES; TRANSPLANTATION; RISK; RELAPSE; SURVIVAL; DONORS; AML AB Myelodysplastic syndromes (MDSs) are a group of hematopoietic disorders affecting the myeloid lineage, characterized by cytopenias and clonal evolution to acute myeloid leukemia (AML). We hypothesized that natural killer (NK) cells and their activating killer immunoglobulin-like receptors (aKIRs) influence the immune surveillance and clinical outcome of patients with MDSs. Here, we first examined the distribution of aKIR genes and haplotype in 2 independent cohorts of MDS and AML patients. The median number of aKIR genes was lower in MDS patients than healthy controls (2 vs 3 genes; P=.001), and lower in patients with secondary AML(progressed from MDSs) compared with de novo AML patients (2 vs 3; P=.008) and healthy controls (2 vs 3; P=.006). In a multivariate analysis, the presence of KIR haplotype A (characterized by low aKIR content 0-1) independently predicted a higher risk of conversion to AML (relative risk [RR] with 95% confidence interval [CI], 2.67 [1.13-6.71]; P=.02) and worse adjusted progression-free survival (RR with 95% CI, 2.96 [1.59-5.52]; P=.001) and overall survival (2.25 [1.17-4.31]; P=.02), compared with KIR haplotype B(multiple aKIR genes). These novel findings may help to identify MDS patients with a high risk of disease progression who would likely benefit from adoptive NK-cell therapy. C1 [Stringaris, Kate] Imperial Coll London, Hammersmith Hosp, Dept Haematol, London, England. [Marin, David; Sobieski, Catherine; Cao, Kai; Saltarrelli, Jerome G.; Daher, May; Shaim, Hila; Smith, Nathaniel; Sekine, Takuya; Mehta, Rohtesh; Champlin, Richard; Shpall, Elizabeth J.; Rezvani, Katayoun] MD Anderson Canc Ctr, Stem Cell Transplantat & Cellular Therapy, 1515 Holcombe Blvd, Houston, TX 77004 USA. [Barrett, A. John] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Hills, Robert] Cardiff Univ, Sch Med, Ctr Trials Res, Cardiff, S Glam, Wales. [Linch, David; Gale, Rosemary; Allen, Christopher] UCL, UCL Canc Inst, Dept Haematol, London, England. [Kantarjian, Hagop; Garcia-Manero, Guillermo] MD Anderson Canc Ctr, Leukemia Dept, Houston, TX USA. EM krezvani@mdanderson.org FU MD Anderson Cancer Center Leukemia Specialized Program of Research Excellence grant from National Institutes of Health, National Cancer Institute [CA 100632] FX This work was supported in part by MD Anderson Cancer Center Leukemia Specialized Program of Research Excellence grant CA 100632 from the National Institutes of Health, National Cancer Institute and the generous philanthropic contributions to The University of Texas MD Anderson Moon Shots Program. NR 23 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 DEC 15 PY 2016 VL 128 IS 24 BP 2819 EP 2823 DI 10.1182/blood-2016-05-713099 PG 5 WC Hematology SC Hematology GA EI7CC UT WOS:000392653900014 PM 27760759 ER PT J AU Rasmussen, C Ariey, F Fairhurst, RM Ringwald, P Menard, D AF Rasmussen, Charlotte Ariey, Frederic Fairhurst, Rick M. Ringwald, Pascal Menard, Didier TI Role of K13 Mutations in Artemisinin-Based Combination Therapy SO CLINICAL INFECTIOUS DISEASES LA English DT Letter ID PLASMODIUM-FALCIPARUM MALARIA; DIHYDROARTEMISININ-PIPERAQUINE; PARASITE CLEARANCE; MYANMAR BORDER; EFFICACY; SUSCEPTIBILITY; ARTESUNATE; VIETNAM C1 [Rasmussen, Charlotte; Ringwald, Pascal] WHO, Global Malaria Programme, Geneva, Switzerland. [Ariey, Frederic] Univ Paris 05, Serv Parasitol Mycol, Hop Cochin, Paris, France. [Ariey, Frederic] Univ Paris 05, Inst Cochin, INSERM, U1016,UMR8104,CNRS,UMR S8104, Paris, France. [Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Menard, Didier] Malaria Mol Epidemiol Unit, Phnom Penh, Cambodia. [Menard, Didier] Inst Pasteur, Phnom Penh, Cambodia. [Menard, Didier] Inst Pasteur, Malaria Translat Res Unit, Paris, France. RP Ringwald, P (reprint author), WHO, Global Malaria Programme DER, 20 Ave Appia, CH-1200 Geneva, Switzerland. EM elseak@who.int FU National Institute of Allergy and Infectious Diseases, NIH FX R. M. F. is supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. C. R. and P. R. are staff members of the WHO, and R. M. F. is a staff member of the NIH. 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 DEC 15 PY 2016 VL 63 IS 12 DI 10.1093/cid/ciw641 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA EI7WW UT WOS:000392716100029 ER PT J AU Babic, A Bao, Y Qian, ZR Yuan, C Giovannucci, EL Aschard, H Kraft, P Amundadottir, LT Stolzenberg-Solo-mon, R Morales-Oyarvide, V Ng, K Stampfer, MJ Ogino, S Buring, JE Sesso, HD Gaziano, JM Rifai, N Pollak, MN Anderson, ML Cochrane, BB Luo, JH Manson, JE Fuchs, CS Wolpin, BM AF Babic, Ana Bao, Ying Qian, Zhi Rong Yuan, Chen Giovannucci, Edward L. Aschard, Hugues Kraft, Peter Amundadottir, Laufey T. Stolzenberg-Solo-mon, Rachael Morales-Oyarvide, Vicente Ng, Kimmie Stampfer, Meir J. Ogino, Shuji Buring, Julie E. Sesso, Howard D. Gaziano, John Michael Rifai, Nader Pollak, Michael N. Anderson, Matthew L. Cochrane, Barbara B. Luo, Juhua Manson, JoAnn E. Fuchs, Charles S. Wolpin, Brian M. TI Pancreatic Cancer Risk Associated with Prediagnostic Plasma Levels of Leptin and Leptin Receptor Genetic Polymorphisms SO CANCER RESEARCH LA English DT Article ID GENOME-WIDE ASSOCIATION; C-REACTIVE PROTEIN; BODY-MASS INDEX; INSULIN-RESISTANCE; CIRCULATING LEPTIN; PHYSICAL-ACTIVITY; BREAST-CANCER; WOMENS HEALTH; OBESITY; ADIPONECTIN AB Leptin is an adipokine involved in regulating energy balance, which has been identified as a potential biologic link in the development of obesity-associated cancers, such as pancreatic cancer. In this prospective, nested case-control study of 470 cases and 1,094 controls from five U.S. cohorts, we used conditional logistic regression to evaluate pancreatic cancer risk by prediagnostic plasma leptin, adjusting for race/ethnicity, diabetes, body mass index, physical activity, plasma C-peptide, adiponectin, and 25-hydroxyvitamin D. Because of known differences in leptin levels by gender, analyses were conducted separately for men and women. We also evaluated associations between 32 tagging SNPs in the leptin receptor (LEPR) gene and pancreatic cancer risk. Leptin levels were higher in female versus male control participants (median, 20.8 vs. 6.7 ng/mL; P < 0.0001). Among men, plasma leptin was positively associated with pancreatic cancer risk and those in the top quintile had a multivariable-adjusted OR of 3.02 [ 95% confidence interval (CI), 1.27-7.16; P-trend = 0.02] compared with men in the bottom quintile. Among women, circulating leptin was not associated with pancreatic cancer risk (P-trend = 0.21). Results were similar across cohorts (P-heterogeneity = 0.88 for two male cohorts and 0.35 for three female cohorts). In genetic analyses, rs10493380 in LEPR was associated with increased pancreatic cancer risk among women, with an OR per minor allele of 1.54 (95% CI, 1.18-2.02; multiple hypothesis-corrected P = 0.03). NoSNPs were significantly associated with risk in men. In conclusion, higher prediagnostic levels of plasmaleptin were associated with an elevated risk of pancreatic cancer among men, but not among women. (C)2016 AACR. C1 [Babic, Ana; Qian, Zhi Rong; Yuan, Chen; Morales-Oyarvide, Vicente; Ng, Kimmie; Ogino, Shuji; Fuchs, Charles S.; Wolpin, Brian M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Bao, Ying; Giovannucci, Edward L.; Stampfer, Meir J.; Manson, JoAnn E.; Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Bao, Ying; Giovannucci, Edward L.; Stampfer, Meir J.; Buring, Julie E.; Sesso, Howard D.; Gaziano, John Michael; Manson, JoAnn E.; Fuchs, Charles S.] Harvard Med Sch, Boston, MA USA. [Giovannucci, Edward L.; Aschard, Hugues; Kraft, Peter; Stampfer, Meir J.; Sesso, Howard D.; Manson, JoAnn E.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Giovannucci, Edward L.; Stampfer, Meir J.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Kraft, Peter] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Amundadottir, Laufey T.] NCI, Lab Translat Gen, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Stolzenberg-Solo-mon, Rachael] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Div MPE Mol Pathol Epidemiol, 75 Francis St, Boston, MA 02115 USA. [Buring, Julie E.; Sesso, Howard D.; Gaziano, John Michael] Brigham & Womens Hosp, Dept Med, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Buring, Julie E.] Harvard Med Sch, Dept Ambulatory Care & Prevent, Boston, MA USA. [Gaziano, John Michael] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA USA. [Rifai, Nader] Childrens Hosp Boston, Dept Lab Med, Boston, MA USA. [Pollak, Michael N.; Manson, JoAnn E.] McGill Univ, Fac Med, Dept Oncol, Canc Prevent Res Unit, Montreal, PQ, Canada. [Anderson, Matthew L.] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Cochrane, Barbara B.] Univ Washington, Sch Nursing, Seattle, WA 98195 USA. [Luo, Juhua] West Virginia Univ, Dept Community Med, Morgantown, WV USA. RP Wolpin, BM (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM bwolpin@partners.org FU NIH [UM1 CA167552, UM1 CA186107, P01 CA87969, R01 CA49449, CA97193, CA34944, CA40360, HL26490, HL34595, KL2 TR001100, U54 CA155626, P30 DK046200, K07 CA148894, R01 CA124908, P50 CA127003]; National Heart, Lung, and Blood Institute, NIH, U.S. Department of Health and Human Services [HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, HHSN268201600004C]; NIH (Bethesda, MD) [CA047988, HL043851, HL080467, HL099355, UM1 CA182913]; NCI [R35 CA197735]; Robert T. and Judith B. Hale Fund for Pancreatic Cancer; Perry S. Levy Fund for Gastrointestinal Cancer Research; Pappas Family Research Fund for Pancreatic Cancer; NIH/NCI [U01 CA210171]; Department of Defense [CA130288]; Lustgarten Foundation; Pancreatic Cancer Action Network; Noble Effort Fund; Peter R. Leavitt Family Fund; Wexler Family Fund; Promises for Purple FX HPFS is supported by NIH grant UM1 CA167552. NHS is supported by NIH grants UM1 CA186107, P01 CA87969, and R01 CA49449. PHS is supported by NIH grants CA97193, CA34944, CA40360, HL26490, and HL34595. The WHI program is funded by the National Heart, Lung, and Blood Institute, NIH, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. The WHS is supported by grants CA047988, HL043851, HL080467, HL099355, and UM1 CA182913 from the NIH (Bethesda, MD).; Additional support from NIH KL2 TR001100, NIH U54 CA155626, and NIH P30 DK046200 was provided to Y. Bao; NIH K07 CA148894 to K. Ng; from NCI R35 CA197735 to S. Ogino; from the Robert T. and Judith B. Hale Fund for Pancreatic Cancer, Perry S. Levy Fund for Gastrointestinal Cancer Research, Pappas Family Research Fund for Pancreatic Cancer, NIH R01 CA124908, and NIH P50 CA127003 to C.S. Fuchs; and from NIH/NCI U01 CA210171, Department of Defense CA130288, Lustgarten Foundation, Pancreatic Cancer Action Network, Noble Effort Fund, Peter R. Leavitt Family Fund, Wexler Family Fund, and Promises for Purple to B. M. Wolpin. NR 50 TC 1 Z9 1 U1 6 U2 6 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 DEC 15 PY 2016 VL 76 IS 24 BP 7160 EP 7167 DI 10.1158/0008-5472.CAN-16-1699 PG 8 WC Oncology SC Oncology GA EH0RE UT WOS:000391470600010 PM 27780823 ER PT J AU Steeg, PS Zimmer, A Gril, B AF Steeg, Patricia S. Zimmer, Alexandra Gril, Brunilde TI Therapeutics for Brain Metastases, v3 SO CLINICAL CANCER RESEARCH LA English DT Editorial Material ID BREAST-CANCER; PERMEABILITY C1 [Steeg, Patricia S.; Zimmer, Alexandra; Gril, Brunilde] NCI, Womens Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Steeg, PS (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM steegp@mail.nih.gov FU Intramural Program of the NCI; DOD BCRP [W81XWH-06-2-0033] FX This work is supported by the Intramural Program of the NCI and grant W81XWH-06-2-0033 from the DOD BCRP. NR 12 TC 0 Z9 0 U1 4 U2 4 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 DEC 15 PY 2016 VL 22 IS 24 BP 5953 EP 5955 DI 10.1158/1078-0432.CCR-16-2035 PG 3 WC Oncology SC Oncology GA EH0RW UT WOS:000391472400001 PM 27803066 ER PT J AU Wang, J Yang, SH He, PJ Schetter, AJ Gaedcke, J Ghadimi, BM Ried, T Yfantis, HG Lee, DH Gaida, MM Hanna, N Alexander, HR Hussain, SP AF Wang, Jian Yang, Shouhui He, Peijun Schetter, Aaron J. Gaedcke, Jochen Ghadimi, B. Michael Ried, Thomas Yfantis, Harris G. Lee, Dong H. Gaida, Matthias M. Hanna, Nader Alexander, H. Richard Hussain, S. Perwez TI Endothelial Nitric Oxide Synthase Traffic Inducer (NOSTRIN) is a Negative Regulator of Disease Aggressiveness in Pancreatic Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID DUCTAL ADENOCARCINOMA; ENOS ACTIVATION; EXPRESSION; SIGNATURE; MIR-200 AB Purpose: Pancreatic ductal adenocarcinoma (PDAC) is refractory to available treatments. Delineating critical pathways, responsible for disease aggressiveness and therapeutic resistance, may identify effective therapeutic targets. We aimed to identify key pathways contributing to disease aggressiveness by comparing gene expression profiles of tumors from early-stage PDAC cases with extremely poor survival (<= 7 months) and those surviving 2 years or more following surgical resection. Experimental Design: Gene expression profiling was performed in tumors in a test cohort of PDAC (N = 50), which included short (<= 7 months, N = 11) and long surviving (>= 2 years, N = 14) patients, using affymetrix GeneChip Human 1.0 ST array. Key genes associated with disease aggressiveness were identified, using Cox regression, Kaplan-Meier, and pathway analyses with validations in independent cohorts for mechanistic and functional analyses. Results: Gene expression profiling identified 1,820 differentially expressed genes between short and long survival groups with inflammatory gene network ranking first. Lower expression of endothelial nitric oxide synthase traffic inducer (NOSTRIN) was associated with worst survival indicating its potential inhibitory role in disease progression. NOSTRIN overexpression suppressed migration and invasion of pancreatic cancer cells and enhanced sensitivity to chemotherapeutic drug gemcitabine. NOSTRIN inhibited production of nitric oxide (NO) by suppressing the activation of endothelial nitric oxide synthase (eNOS). Furthermore, miR-221, bound to the 3'UTR of NOSTRIN and suppressed its expression, and an increased miR-221 expression associated with poor survival in PDAC. Conclusions: Our findings showed that NOSTRIN is a potential negative regulator of disease aggressiveness, which may be targeted for designing improved treatment strategy in PDAC. (C)2016 AACR. C1 [Wang, Jian; Yang, Shouhui; He, Peijun; Hussain, S. Perwez] NCI, Pancreat Canc Unit, Ctr Canc Res, Bethesda, MD 20892 USA. [Wang, Jian; Yang, Shouhui; He, Peijun; Schetter, Aaron J.; Hussain, S. Perwez] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bldg 37, Bethesda, MD 20892 USA. [Gaedcke, Jochen; Ghadimi, B. Michael] Univ Med Ctr Gottingen, Dept Gen Visceral & Pediat Surg, Gottingen, Germany. [Ried, Thomas] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Yfantis, Harris G.; Lee, Dong H.] Baltimore Vet Affairs Med Ctr, Pathol & Lab Med, Baltimore, MD USA. [Gaida, Matthias M.] Univ Heidelberg Hosp, Inst Pathol, Heidelberg, Germany. [Hanna, Nader; Alexander, H. Richard] Univ Maryland, Sch Med, Div Surg Oncol, Baltimore, MD 21201 USA. RP Hussain, SP (reprint author), NIH, Pancreat Canc Unit, Human Carcinogenesis Lab, NCI, Bldg 37 Room 3044B,37 Convent Dr, Bethesda, MD 20892 USA. EM hussainp@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, NCI, NIH FX This work was supported by the Intramural Research Program of the Center for Cancer Research, NCI, NIH. NR 35 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 DEC 15 PY 2016 VL 22 IS 24 BP 5992 EP 6001 DI 10.1158/1078-0432.CCR-16-0511 PG 10 WC Oncology SC Oncology GA EH0RW UT WOS:000391472400007 PM 27401251 ER PT J AU Morrow, JJ Mendoza, A Koyen, A Lizardo, MM Ren, L Waybright, TJ Hansen, RJ Gustafson, DL Zhou, M Fan, TM Scacheri, PC Khanna, C AF Morrow, James J. Mendoza, Arnulfo Koyen, Allyson Lizardo, Michael M. Ren, Ling Waybright, Timothy J. Hansen, Ryan J. Gustafson, Daniel L. Zhou, Ming Fan, Timothy M. Scacheri, Peter C. Khanna, Chand TI mTOR Inhibition Mitigates Enhanced mRNA Translation Associated with the Metastatic Phenotype of Osteosarcoma Cells In Vivo SO CLINICAL CANCER RESEARCH LA English DT Article ID MAMMALIAN TARGET; PHASE-II; RAPAMYCIN; PROGRESSION; INITIATION; PATHWAY; RIDAFOROLIMUS; PROTEINS; FEATURES; SARCOMAS AB Purpose: To successfully metastasize, tumor cells must respond appropriately to biological stressors encountered during metastatic progression. We sought to test the hypothesis that enhanced efficiency of mRNA translation during periods of metastatic stress is required for metastatic competence of osteosarcoma and that this metastasis-specific adaptation is amenable to therapeutic intervention. Experimental Design: We employ novel reporter and proteomic systems that enable tracking of mRNA translation efficiency and output in metastatic osteosarcoma cells as they colonize the lungs. We test the potential to target mRNA translation as an antimetastatic therapeutic strategy through pharmacokinetic studies and preclinical assessment of the prototypic mTOR inhibitor, rapamycin, across multiple models of metastasis. Results: Metastatic osteosarcoma cells translate mRNA more efficiently than nonmetastatic cells during critical stressful periods of metastatic colonization of the lung. Rapamycin inhibits translational output during periods of metastatic stress, mitigates lung colonization, and prolongs survival. mTOR-inhibiting exposures of rapamycin are achievable in mice using treatment schedules that correspond to human doses well below the MTDs defined in human patients, and as such are very likely to be tolerated over long exposures alone and in combination with other agents. Conclusions: Metastatic competence of osteosarcoma cells is dependent on efficient mRNA translation during stressful periods of metastatic progression, and the mTOR inhibitor, rapamycin, can mitigate this translation and inhibit metastasis in vivo. Our data suggest that mTOR pathway inhibitors should be reconsidered in the clinic using rationally designed dosing schedules and clinical metrics related to metastatic progression. (C)2016 AACR. C1 [Morrow, James J.] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. [Morrow, James J.; Scacheri, Peter C.] Case Western Reserve Univ, Dept Genet & Genome Sci, Cleveland, OH 44106 USA. [Morrow, James J.; Mendoza, Arnulfo; Koyen, Allyson; Lizardo, Michael M.; Ren, Ling; Khanna, Chand] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Waybright, Timothy J.; Zhou, Ming] Leidos Biomed Res Inc, Canc Res Technol Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Hansen, Ryan J.; Gustafson, Daniel L.] Colorado State Univ, Flint Anim Canc Ctr, Ft Collins, CO 80523 USA. [Hansen, Ryan J.; Gustafson, Daniel L.] Univ Colorado, Ctr Canc, Pharmacol Shared Resource, Anschutz Med Campus, Aurora, CO USA. [Fan, Timothy M.] Univ Illinois, Coll Vet Med, Dept Vet Clin Med, Urbana, IL 61801 USA. [Scacheri, Peter C.] Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. RP Khanna, C (reprint author), Ethos Vet Hlth, 20 Cabot Rd, Woburn, MA 01801 USA.; Khanna, C (reprint author), Ethos Discovery, 4926 Wisconsin Ave NW, Washington, DC 20016 USA. EM ckhanna@ethosvet.com FU NIH [CA186633, GM007250]; NIH Intramural Visiting Fellow Program [15335, R01CA160356, 1R01CA193677, P30CA046934]; NIH Intramural Research Program FX This work was supported by funding from the NIH CA186633 (J.J. Morrow); GM007250 (J.J. Morrow); NIH Intramural Visiting Fellow Program #15335 (M.M. Lizardo), R01CA160356 (P.C. Scacheri); 1R01CA193677 (P.C. Scacheri); P30CA046934 (R.J. Hansen and D.L. Gustafson); and the NIH Intramural Research Program (C. Khanna). NR 33 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 DEC 15 PY 2016 VL 22 IS 24 BP 6129 EP 6141 DI 10.1158/1078-0432.CCR-16-0326 PG 13 WC Oncology SC Oncology GA EH0RW UT WOS:000391472400021 PM 27342399 ER PT J AU Hamilton, DH Griner, LM Keller, JM Hu, X Southall, N Marugan, J David, JM Ferrer, M Palena, C AF Hamilton, Duane H. Griner, Lesley Mathews Keller, Jonathan M. Hu, Xin Southall, Noel Marugan, Juan David, Justin M. Ferrer, Marc Palena, Claudia TI Targeting Estrogen Receptor Signaling with Fulvestrant Enhances Immune and Chemotherapy-Mediated Cytotoxicity of Human Lung Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; HORMONE REPLACEMENT THERAPY; TRANSCRIPTION FACTOR; AUTOPHAGY INDUCTION; CARCINOMA; SURVIVAL; CELLS; WOMEN; RESISTANCE; BREAST AB Purpose: The conversion of tumor cells from an epithelial to a mesenchymal-like phenotype, via a process designated as the epithelial-mesenchymal transition (EMT), is known to mediate tumor resistance to a variety of cell death inducers, including cytotoxic effector immune cells. The goal of this study was to identify and potentially repurpose FDA-approved compounds capable of reducing mesenchymal features of human lung carcinoma cells, which could be used in combination with immunotherapies or chemotherapeutic strategies to improve clinical responses. Experimental Design: In the current report, we have utilized a quantitative high-throughput screening (qHTS) of a pharmaceutical collection of more than 2,000 compounds to identify clinically approved drugs capable of augmenting the sensitivity of mesenchymal-like, lung cancer cells to immune-and chemotherapy-mediated lysis, both in vitro and in vivo. Results: The estrogen receptor antagonist fulvestrant was shown to reduce mesenchymal features of lung carcinoma cells, resulting in tumor sensitization to the cytotoxic effect of antigen-specific T cells, natural killer (NK) effector cells, and chemotherapy both in vivo and in vitro. Conclusions: To our knowledge, this is the first report defining a potential role for estrogenic signaling in promoting tumor resistance to immune-mediated cytotoxicity and chemotherapy in lung cancer. Our data demonstrate a robust association between the acquisition of mesenchymal attributes, therapeutic resistance of lung carcinoma cells, and the expression of estrogen receptor 1 (ESR1), supporting further investigations on the role of estrogen signaling in lung cancer progression via the induction of EMT. (C)2016 AACR. C1 [Hamilton, Duane H.; Palena, Claudia] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. [Griner, Lesley Mathews; Keller, Jonathan M.; Hu, Xin; Southall, Noel; Marugan, Juan; David, Justin M.; Ferrer, Marc] NIH, Natl Ctr Adv Translat Sci, Rockville, MD USA. RP Palena, C (reprint author), NCI, NIH, 10 Ctr Dr,Room 8B14, Bethesda, MD 20892 USA. EM palenac@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute; National Center for Advancing Translational Sciences, NIH FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, and the National Center for Advancing Translational Sciences, NIH. NR 39 TC 1 Z9 1 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 DEC 15 PY 2016 VL 22 IS 24 BP 6204 EP 6216 DI 10.1158/1078-0432.CCR-15-3059 PG 13 WC Oncology SC Oncology GA EH0RW UT WOS:000391472400027 PM 27267852 ER PT J AU Barr, VA Sherman, E Yi, J Akpan, I Rouquette-Jazdanian, AK Samelson, LE AF Barr, Valarie A. Sherman, Eilon Yi, Jason Akpan, Itoro Rouquette-Jazdanian, Alexandre K. Samelson, Lawrence E. TI Development of nanoscale structure in LAT-based signaling complexes SO JOURNAL OF CELL SCIENCE LA English DT Article DE Photoactivated localization microscopy; T cell activation; Signaling complex; Microcluster; Single-molecule localization microscopy; Nanostructure ID T-CELL-RECEPTOR; PHOTOACTIVATED LOCALIZATION MICROSCOPY; IMMUNOLOGICAL SYNAPSE FORMATION; ANTIGEN RECEPTOR; ACTIN CYTOSKELETON; SUPERRESOLUTION MICROSCOPY; MULTIPOINT BINDING; FLUORESCENT-PROBES; ADAPTER PROTEIN; LIPID RAFTS AB The adapter molecule linker for activation of T cells (LAT) plays a crucial role in forming signaling complexes induced by stimulation of the T cell receptor (TCR). These multi-molecular complexes are dynamic structures that activate highly regulated signaling pathways. Previously, we have demonstrated nanoscale structure in LAT-based complexes where the adapter SLP-76 (also known as LCP2) localizes to the periphery of LAT clusters. In this study, we show that initially LAT and SLP-76 are randomly dispersed throughout the clusters that form upon TCR engagement. The segregation of LAT and SLP-76 develops near the end of the spreading process. The local concentration of LAT also increases at the same time. Both changes require TCR activation and an intact actin cytoskeleton. These results demonstrate that the nanoscale organization of LAT-based signaling complexes is dynamic and indicates that different kinds of LAT-based complexes appear at different times during T cell activation. C1 [Barr, Valarie A.; Yi, Jason; Akpan, Itoro; Rouquette-Jazdanian, Alexandre K.; Samelson, Lawrence E.] NCI, Cellular & Mol Biol Lab, CCR, NIH, Bethesda, MD 20892 USA. [Sherman, Eilon] Hebrew Univ Jerusalem, Racah Inst Phys, IL-91904 Jerusalem, Israel. RP Samelson, LE (reprint author), NCI, Cellular & Mol Biol Lab, CCR, NIH, Bethesda, MD 20892 USA. EM samelsonl@helix.nih.gov OI ROUQUETTE-JAZDANIAN, Alexandre K./0000-0003-2646-0040 FU Intramural Research Programs of the National Cancer Institute (The Center for Cancer Research) FX This research was supported by the Intramural Research Programs of the National Cancer Institute (The Center for Cancer Research). Deposited in PMC for release after 12 months. NR 71 TC 0 Z9 0 U1 2 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 EI 1477-9137 J9 J CELL SCI JI J. Cell Sci. PD DEC 15 PY 2016 VL 129 IS 24 BP 4548 EP 4562 DI 10.1242/jcs.194886 PG 15 WC Cell Biology SC Cell Biology GA EG5SD UT WOS:000391103700011 PM 27875277 ER PT J AU Charette, MF Oh, YS Maric-Bilkan, C Scott, LL Wu, CC Eblen, M Pearson, K Tolunay, HE Galis, ZS AF Charette, Marc F. Oh, Young S. Maric-Bilkan, Christine Scott, Lindsey L. Wu, Charles C. Eblen, Matthew Pearson, Katrina Tolunay, H. Eser Galis, Zorina S. TI Shifting Demographics among Research Project Grant Awardees at the National Heart, Lung, and Blood Institute (NHLBI) SO PLOS ONE LA English DT Article AB The present study was initiated because of concerns expressed by NHLBI-funded midcareer investigators regarding perceived difficulties in the renewal of their grant awards. This led us to ask: "Are mid-career investigators experiencing disproportionate difficulties in the advancement of their professional careers?" Our portfolio analysis indicates that there has been a significant and evolving shift in the demographics of research project grant (RPG) awardees at NHLBI. In 1998, mid-career (ages 41-55) investigators constituted approximately 60% of all investigators with the remaining 40% being equally divided between early-stage (ages 24-40) investigators and established (ages 56 to 70 and older) investigators. However, since 1998, the proportion of established RPG awardees has been increasing in a slowly progressive and strikingly linear fashion. At the same time the proportion of early-stage awardees fell precipitously until 2006 and then stabilized. During the same period, the proportion of mid-career awardees, which had been relatively stable through 2006, began to fall significantly. In examining potential causes of these demographic shifts we have identified certain inherent properties within the RPG award system that appear to promote an increasingly more established awardee population and a persistent decrease in the proportion of mid-career investigators. A collateral result of these demographic shifts, when combined with level or declining funding, is a significant reduction in the number of RPG awards received by NHLBI mid-career investigators and a corresponding decrease in the number of independent research laboratories. C1 [Charette, Marc F.; Oh, Young S.; Maric-Bilkan, Christine; Tolunay, H. Eser; Galis, Zorina S.] NHLBI, Vasc Biol & Hypertens Branch, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. [Scott, Lindsey L.; Wu, Charles C.; Pearson, Katrina] NIH, Stat Anal & Reporting Branch, Off Planning Anal & Commun, Off Extramural Res, Bldg 10, Bethesda, MD 20892 USA. [Eblen, Matthew] Ctr Dis Control & Prevent, Off Publ Hlth Sci Serv, Atlanta, GA USA. RP Charette, MF (reprint author), NHLBI, Vasc Biol & Hypertens Branch, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. EM marc.charette@nih.gov NR 8 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 DEC 15 PY 2016 VL 11 IS 12 AR e0168511 DI 10.1371/journal.pone.0168511 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG7HN UT WOS:000391217400115 PM 27978544 ER PT J AU Riley, CL Dao, C Kenaston, MA Muto, L Kohno, S Nowinski, SM Solmonson, AD Pfeiffer, M Sack, MN Lu, ZP Fiermonte, G Sprague, JE Mills, EM AF Riley, Christopher L. Dao, Christine Kenaston, M. Alexander Muto, Luigina Kohno, Shohei Nowinski, Sara M. Solmonson, Ashley D. Pfeiffer, Matthew Sack, Michael N. Lu, Zhongping Fiermonte, Giuseppe Sprague, Jon E. Mills, Edward M. TI The complementary and divergent roles of uncoupling proteins 1 and 3 in thermoregulation SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article DE brown adipose tissue; LPS; methamphetamine; skeletal muscle; sympathomimetic; thermogenesis; uncoupling protein ID SKELETAL-MUSCLE MITOCHONDRIA; BROWN-FAT MITOCHONDRIA; INDUCED THERMOGENESIS; PROTON CONDUCTANCE; UCP1-ABLATED MICE; THYROID-HORMONE; COLD TOLERANCE; ACID; UCP3; 3,4-METHYLENEDIOXYMETHAMPHETAMINE AB Both uncoupling protein 1 (UCP1) and UCP3 are important for mammalian thermoregulation. UCP1 and UCP3 in brown adipose tissue mediate early and late phases of sympathomimetic thermogenesis, respectively. Lipopolysaccharide thermogenesis requires skeletal muscle UCP3 but not UCP1. Acute noradrenaline-induced hyperthermia requires UCP1 but not UCP3. Loss of both UCP1 and UCP3 accelerate the loss of body temperature compared to UCP1KO alone during acute cold exposure. AbstractUncoupling protein 1 (UCP1) is the established mediator of brown adipose tissue-dependent thermogenesis. In contrast, the role of UCP3, expressed in both skeletal muscle and brown adipose tissue, in thermoregulatory physiology is less well understood. Here, we show that mice lacking UCP3 (UCP3KO) have impaired sympathomimetic (methamphetamine) and completely abrogated lipopolysaccharide (LPS) thermogenesis, but a normal response to noradrenaline. By comparison, UCP1 knockout (UCP1KO) mice exhibit blunted methamphetamine and fully inhibited noradrenaline thermogenesis, but an increased febrile response to LPS. We further establish that mice lacking both UCP1 and 3 (UCPDK) fail to show methamphetamine-induced hyperthermia, and have a markedly accelerated loss of body temperature and survival after cold exposure compared to UCP1KO mice. Finally, we show that skeletal muscle-specific human UCP3 expression is able to significantly rescue LPS, but not sympathomimetic thermogenesis blunted in UCP3KO mice. These studies identify UCP3 as an important mediator of physiological thermogenesis and support a renewed focus on targeting UCP3 in metabolic physiology. Both uncoupling protein 1 (UCP1) and UCP3 are important for mammalian thermoregulation. UCP1 and UCP3 in brown adipose tissue mediate early and late phases of sympathomimetic thermogenesis, respectively. Lipopolysaccharide thermogenesis requires skeletal muscle UCP3 but not UCP1. Acute noradrenaline-induced hyperthermia requires UCP1 but not UCP3. Loss of both UCP1 and UCP3 accelerate the loss of body temperature compared to UCP1KO alone during acute cold exposure. C1 [Riley, Christopher L.; Solmonson, Ashley D.] Univ Texas Austin, Dept Mol Biosci, Coll Nat Sci, Austin, TX 78712 USA. [Dao, Christine; Kenaston, M. Alexander; Kohno, Shohei; Solmonson, Ashley D.; Pfeiffer, Matthew; Mills, Edward M.] Univ Texas Austin, Div Pharm & Toxicol, Coll Pharm, Austin, TX 78712 USA. [Muto, Luigina] Univ Calabria, Dept Pharm Hlth & Nutr Sci, Cosenza, Italy. [Nowinski, Sara M.] Univ Utah, Dept Biochem, Salt Lake City, UT 84112 USA. [Sack, Michael N.] NHLBI, Lab Mitochondrial Biol & Metab, NIH, Bethesda, MD 20892 USA. [Lu, Zhongping] George Washington Univ, Cardiovasc & Pulm Branch, Washington, DC 20422 USA. [Lu, Zhongping] George Washington Univ, Dept Biochem & Mol Med, Washington, DC 20422 USA. [Lu, Zhongping] Vet Affairs Med Ctr, Washington, DC 20422 USA. [Fiermonte, Giuseppe] Univ Bari, Dept Biosci Biotechnol & Biopharmaceut, I-70125 Bari, Italy. [Fiermonte, Giuseppe] Univ Bari, Ctr Excellence Comparat Genom, I-70125 Bari, Italy. [Sprague, Jon E.] Bowling Green State Univ, Ohio Attorney Gen Ctr Future Forens Sci, Bowling Green, OH 43403 USA. RP Mills, EM (reprint author), Univ Texas Austin, Div Pharm & Toxicol, Coll Pharm, Austin, TX 78712 USA. EM tedmills@austin.utexas.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [5R01DK089224-05] FX National Institute of Diabetes and Digestive and Kidney Diseases 5R01DK089224-05. NR 40 TC 3 Z9 3 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 EI 1469-7793 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD DEC 15 PY 2016 VL 594 IS 24 BP 7455 EP 7464 DI 10.1113/JP272971 PG 10 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA EF9LX UT WOS:000390652800030 PM 27647490 ER PT J AU Chengalroyen, MD Beukes, GM Gordhan, BG Streicher, EM Churchyard, G Hafner, R Warren, R Otwombe, K Martinson, N Kana, BD AF Chengalroyen, Melissa D. Beukes, Germar M. Gordhan, Bhavna G. Streicher, Elizabeth M. Churchyard, Gavin Hafner, Richard Warren, Robin Otwombe, Kennedy Martinson, Neil Kana, Bavesh D. TI Detection and Quantification of Differentially Culturable Tubercle Bacteria in Sputum from Patients with Tuberculosis SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE tuberculosis; resuscitation-promoting factor's; HIV; culturability; limiting dilution assay ID RESUSCITATION-PROMOTING FACTORS; MYCOBACTERIUM-TUBERCULOSIS; GROWTH; POPULATIONS; DORMANCY; DRUGS AB Rationale: Recent studies suggest that baseline tuberculous sputum comprises a mixture of routinely culturable and differentially culturable tubercle bacteria (DCTB). The latter seems to be drug tolerant and dependent on resuscitation-promoting factors (Rpfs). Objectives: To further explore this, we assessed sputum from patients with tuberculosis for DCTB and studied the impact of exogenous culture filtrate (CF) supplementation ex vivo. Methods: Sputum samples from adults with tuberculosis and HIV-1 and adults with no HIV-1 were used for most probable number (MPN) assays" supplemented with CF and Rpf-deficient CF, to detect CF-dependent and Rpf-independent DCTB, respectively. Measurements and Main Results: In 110 individuals, 19.1% harbored CF-dependent DCTB and no Rpf-independent DCTB. Furthermore, 11.8% yielded Rpf-independent DCTB with no CF dependent DCTB. In addition, 53.6% displayed both CF-dependent and Rpf-independent DCTB, 1.8% carried CF-independent DCTB, and 13.6% had no DCTB. Sputum from individuals without HIV-1 yielded higher CF-supplemented MPN counts compared with counterparts with HIV-1. Furthermore, individuals with HIV-1 with CD4 counts greater than 200 cells/mm(3) displayed higher CF supplemented MPN counts compared with participants with HIV-1 with CD4 counts less than 200 cells/mm(3). CF supplementation allowed for detection of mycobacteria in 34 patients with no culturable bacteria on solid media. Additionally, the use of CF enhanced detection of sputum smear-negative individuals. Conclusions: These observations demonstrate a novel Rpf-independent DCTB population in sputum and reveal that reduced host immunity is associated with lower prevalence of CF-responsive bacteria. Quantification of DCTB in standard TB diagnosis would be beneficial because these organisms provide a putative biomarker to monitor treatment response and risk of disease recurrence. C1 [Chengalroyen, Melissa D.; Beukes, Germar M.; Gordhan, Bhavna G.; Martinson, Neil; Kana, Bavesh D.] Univ Witwatersrand, Dept Sci & Technol, Natl Res Fdn, Ctr Excellence Biomed TB Res,Sch Pathol,Fac Hlth, POB 1038, ZA-2000 Johannesburg, South Africa. [Chengalroyen, Melissa D.; Beukes, Germar M.; Gordhan, Bhavna G.; Martinson, Neil; Kana, Bavesh D.] Natl Hlth Lab Serv, POB 1038, ZA-2000 Johannesburg, South Africa. [Streicher, Elizabeth M.; Warren, Robin] Univ Stellenbosch, Fac Med & Hlth Sci, Div Mol Biol & Human Genet, Med Res Council,Ctr TB Res, Stellenbosch, South Africa. [Churchyard, Gavin] Aurum Inst, Johannesburg, South Africa. [Hafner, Richard] NIAID, TB Clin Res Team, Div Aids, NIH,Dept Hlth & Human Serv, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Otwombe, Kennedy; Martinson, Neil] Univ Witwatersrand, Fac Hlth Sci, Perinatal HIV Res Unit, Johannesburg, South Africa. [Martinson, Neil] Johns Hopkins Univ, Ctr TB Res, Baltimore, MD USA. RP Kana, BD (reprint author), Univ Witwatersrand, Dept Sci & Technol, Natl Res Fdn, Ctr Excellence Biomed TB Res,Sch Pathol,Fac Hlth, POB 1038, ZA-2000 Johannesburg, South Africa.; Kana, BD (reprint author), Natl Hlth Lab Serv, POB 1038, ZA-2000 Johannesburg, South Africa. EM bavesh.kana@nhls.ac.za FU National Institutes of Health [U01 AI069453-07]; National Research Foundation of South Africa; South African Medical Research Council; Centre for Aids Prevention Research in South Africa; Howard Hughes Medical Institute FX Supported by the National Institutes of Health (U01 AI069453-07), National Research Foundation of South Africa, South African Medical Research Council, Centre for Aids Prevention Research in South Africa, and the Howard Hughes Medical Institute. NR 23 TC 1 Z9 1 U1 4 U2 4 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 DEC 15 PY 2016 VL 194 IS 12 BP 1532 EP 1540 DI 10.1164/rccm.201604-0769OC PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EF2VP UT WOS:000390184000017 PM 27387272 ER PT J AU Melander, RJ Liu, HB Stephens, MD Bewley, CA Melander, C AF Melander, Roberta J. Liu, Hong-bing Stephens, Matthew D. Bewley, Carole A. Melander, Christian TI Marine sponge alkaloids as a source of anti-bacterial adjuvants SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Marine sponge; Pyrrole-imidazole alkaloid; Biofilm; Antibiotic; Adjuvant ID PYRROLE-IMIDAZOLE ALKALOIDS; PSEUDOMONAS-AERUGINOSA BIOFILMS; RESISTANT STAPHYLOCOCCUS-AUREUS; SMALL-MOLECULE SUPPRESSION; OROIDIN LIBRARY; ACINETOBACTER-BAUMANNII; ANTIBIOFILM ACTIVITY; BACTERIAL BIOFILMS; 2-AMINOIMIDAZOLE; INHIBITION AB Novel approaches that do not rely upon developing microbicidal compounds are sorely needed to combat multidrug resistant (MDR) bacteria. The potential of marine secondary metabolites to serve as a source of non-traditional anti-bacterial agents is demonstrated by showing that pyrrole-imidazole alkaloids inhibit biofilm formation and suppress antibiotic resistance. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Melander, Roberta J.; Stephens, Matthew D.; Melander, Christian] North Carolina State Univ, Dept Chem, Raleigh, NC 27695 USA. [Liu, Hong-bing; Bewley, Carole A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Melander, C (reprint author), North Carolina State Univ, Dept Chem, Raleigh, NC 27695 USA.; Bewley, CA (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM ccmeland@ncsu.edu FU NIH [GM055769, DE022350]; NIH Intramural Research Program (NIDDK) FX We thank the NIH (GM055769 and DE022350 to CM) and the NIH Intramural Research Program (NIDDK to CAB). NR 48 TC 0 Z9 0 U1 3 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD DEC 15 PY 2016 VL 26 IS 24 BP 5863 EP 5866 DI 10.1016/j.bmcl.2016.11.018 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA EE7GS UT WOS:000389784500005 PM 27876320 ER PT J AU Zhu, L Pickle, LW Pearson, JB AF Zhu, Li Pickle, Linda W. Pearson, James B., Jr. TI Confidence intervals for rate ratios between geographic units SO INTERNATIONAL JOURNAL OF HEALTH GEOGRAPHICS LA English DT Article DE Spatial autocorrelation; Rate ratio; Variance; Confidence intervals; Cancer statistics; Linked micromap plot ID CANCER; REGION; US AB Background: Ratios of age-adjusted rates between a set of geographic units and the overall area are of interest to the general public and to policy stakeholders. These ratios are correlated due to two reasons-the first being that each region is a component of the overall area and hence there is an overlap between them; and the second is that there is spatial autocorrelation between the regions. Existing methods in calculating the confidence intervals of rate ratios take into account the first source of correlation. This paper incorporates spatial autocorrelation, along with the correlation due to area overlap, into the rate ratio variance and confidence interval calculations. Results: The proposed method divides the rate ratio variances into three components, representing no correlation, overlap correlation, and spatial autocorrelation, respectively. Results applied to simulated and real cancer mortality and incidence data show that with increasing strength and scales in spatial autocorrelation, the proposed method leads to substantial improvements over the existing method. If the data do not show spatial autocorrelation, the proposed method performs as well as the existing method. Conclusions: The calculations are relatively easy to implement, and we recommend using this new method to calculate rate ratio confidence intervals in all cases. C1 [Zhu, Li] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, NIH, 9609 Med Ctr Dr,Suite 4E346, Rockville, MD 20850 USA. [Pickle, Linda W.; Pearson, James B., Jr.] StatNet Consulting LLC, Gaithersburg, MD 20882 USA. RP Zhu, L (reprint author), NCI, Surveillance Res Program, Div Canc Control & Populat Sci, NIH, 9609 Med Ctr Dr,Suite 4E346, Rockville, MD 20850 USA. EM li.zhu@nih.gov FU Statistical Methodology and Applications Branch of the National Cancer Institute [HHSN261201400193P] FX This work was partly supported by the Statistical Methodology and Applications Branch of the National Cancer Institute through a contract HHSN261201400193P. NR 17 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 1476-072X J9 INT J HEALTH GEOGR JI Int. J. Health Geogr. PD DEC 15 PY 2016 VL 15 AR 44 DI 10.1186/s12942-016-0073-5 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EF1UZ UT WOS:000390111700001 PM 27978838 ER PT J AU Gupta, N Singh, SS Stopfer, M AF Gupta, Nitin Singh, Swikriti Saran Stopfer, Mark TI Oscillatory integration windows in neurons SO NATURE COMMUNICATIONS LA English DT Article ID EVOKED NEURAL OSCILLATIONS; SUBTHRESHOLD OSCILLATIONS; OLFACTORY SYSTEM; FEEDFORWARD INHIBITION; ODOR REPRESENTATIONS; MUSHROOM BODIES; SPARSE; CORTEX; DROSOPHILA; INPUT AB Oscillatory synchrony among neurons occurs in many species and brain areas, and has been proposed to help neural circuits process information. One hypothesis states that oscillatory input creates cyclic integration windows: specific times in each oscillatory cycle when postsynaptic neurons become especially responsive to inputs. With paired local field potential (LFP) and intracellular recordings and controlled stimulus manipulations we directly test this idea in the locust olfactory system. We find that inputs arriving in Kenyon cells (KCs) sum most effectively in a preferred window of the oscillation cycle. With a computational model, we show that the non-uniform structure of noise in the membrane potential helps mediate this process. Further experiments performed in vivo demonstrate that integration windows can form in the absence of inhibition and at a broad range of oscillation frequencies. Our results reveal how a fundamental coincidence-detection mechanism in a neural circuit functions to decode temporally organized spiking. C1 [Gupta, Nitin; Stopfer, Mark] NICHHD, NIH, Bethesda, MD 20892 USA. [Gupta, Nitin; Singh, Swikriti Saran] Indian Inst Technol Kanpur, Dept Biol Sci & Bioengn, Kanpur 208016, Uttar Pradesh, India. RP Gupta, N; Stopfer, M (reprint author), NICHHD, NIH, Bethesda, MD 20892 USA.; Gupta, N (reprint author), Indian Inst Technol Kanpur, Dept Biol Sci & Bioengn, Kanpur 208016, Uttar Pradesh, India. EM guptan@iitk.ac.in; stopferm@mail.nih.gov OI Stopfer, Mark/0000-0001-9200-1884 FU NIH-NICHD; Department of Biotechnology in India [BT/08/IYBA/2014-8]; Intermediate Fellowship of the Wellcome Trust-DBT India Alliance [IA/I/15/2/502091] FX We thank Drs Maxim Bazhenov and Joby Joseph, and members of the Stopfer laboratory for helpful discussions, George Dold of the NIMH Instrumentation Core Facility for help with equipment, and Dr Kui Sun for her excellent animal care. This work was supported by an intramural grant from NIH-NICHD to M.S., and by the Department of Biotechnology in India (BT/08/IYBA/2014-8) and the Intermediate Fellowship of the Wellcome Trust-DBT India Alliance (IA/I/15/2/502091), to N.G. NR 41 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 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD DEC 15 PY 2016 VL 7 AR 13808 DI 10.1038/ncomms13808 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EF2RA UT WOS:000390170800001 PM 27976720 ER PT J AU Skalka, N Caspi, M Lahav-Ariel, L Loh, YP Hirschberg, K Rosin-Arbesfeld, R AF Skalka, N. Caspi, M. Lahav-Ariel, L. Loh, Y. P. Hirschberg, K. Rosin-Arbesfeld, R. TI Carboxypeptidase E (CPE) inhibits the secretion and activity of Wnt3a SO ONCOGENE LA English DT Article ID CELL-PROLIFERATION; COLORECTAL-CANCER; PATHWAY; STRESS; NEUROPROTECTION; EXPRESSION; ENDOCRINE; AUTOPHAGY; SURVIVAL; NEURONS AB The Wnt pathway has essential roles in cell proliferation, cell fate determination and tumorigenesis by regulating the expression of a wide range of target genes. As a core signaling cascade, the canonical Wnt pathway is regulated at different levels by numerous proteins. We have previously shown that carboxypeptidase E (CPE) is a novel regulator of the canonical Wnt signaling pathway. Here, we show that CPE and the Wnt3a ligand are co-secreted from cells. We show that although the C'-terminal Lys residue of Wnt3a is critical for its activity and is important for the effect of CPE on the Wnt pathway, CPE does not execute its effect by removing this Wnt3a residue. Interestingly, CPE through its N'-terminal sequence, forms aggregates with Wnt3a and possible endoplasmic reticulum (ER) stress leading to its loss of function. Together, our current results provide a mechanistic insight into the way CPE regulates the canonical Wnt signaling pathway. C1 [Skalka, N.; Caspi, M.; Lahav-Ariel, L.; Rosin-Arbesfeld, R.] Tel Aviv Univ, Sackler Sch Med, Dept Clin Microbiol & Immunol, IL-69978 Tel Aviv, Israel. [Loh, Y. P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Neurobiol, Program Dev Neurosci, NIH, Bethesda, MD USA. [Hirschberg, K.] Tel Aviv Univ, Sackler Sch Med, Dept Pathol, Tel Aviv, Israel. RP Rosin-Arbesfeld, R (reprint author), Tel Aviv Univ, Sackler Sch Med, Dept Clin Microbiol & Immunol, IL-69978 Tel Aviv, Israel. EM arina@post.tau.ac.il FU Rising Tide Foundation for Clinical Cancer Research; Gateway for Cancer Research Foundation; Israel Science Foundation [20120016] FX This work was supported by Rising Tide Foundation for Clinical Cancer Research, by the Gateway for Cancer Research Foundation and by the Israel Science Foundation (Grant no. 20120016). 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 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD DEC 15 PY 2016 VL 35 IS 50 BP 6416 EP 6428 DI 10.1038/onc.2016.173 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA EF3TP UT WOS:000390247600006 PM 27375026 ER PT J AU Sharma, P Kuehn, MR AF Sharma, P. Kuehn, M. R. TI SENP1-modulated sumoylation regulates retinoblastoma protein (RB) and Lamin A/C interaction and stabilization SO ONCOGENE LA English DT Article ID HUTCHINSON-GILFORD PROGERIA; TUMOR-SUPPRESSOR PROTEIN; A-TYPE LAMINS; MUSCULAR-DYSTROPHY; PROSTATE-CANCER; SUMO PROTEASES; NUCLEAR-BODIES; IN-VIVO; MUTATIONS; MECHANISMS AB The retinoblastoma tumor suppressor protein (RB) plays a critical role in cell proliferation and differentiation and its inactivation is a frequent underlying factor in tumorigenesis. While the regulation of RB function by phosphorylation is well studied, proteasome-mediated RB protein degradation is emerging as an important regulatory mechanism. Although our understanding of RB turnover is currently limited, there is evidence that the nuclear lamina filament protein Lamin A/C protects RB from proteasomal degradation. Here we show that SUMO1 conjugation of RB and Lamin A/C is modulated by the SUMO protease SENP1 and that sumoylation of both proteins is required for their interaction. Importantly, this SUMO1-dependent complex protects both RB and Lamin A/C from proteasomal turnover. C1 [Sharma, P.; Kuehn, M. R.] NCI, NIH, Frederick, MD 21701 USA. [Sharma, P.] NHGRI, Undiagnosed Dis Program, UDP Translat Lab, Rockville, MD USA. RP Kuehn, MR (reprint author), NCI, NIH, Frederick, MD 21701 USA. EM mkuehn@mail.nih.gov FU Intramural Research Program of the National Cancer Institute, National Institutes of Health FX We thank Stefano Campaner (IIT, Milan) for discussions, and Alessandra Mazzoni (AIRC, Milan), Shyam Sharan (NCI, Frederick), Sushil Rane (NIDDK, Bethesda) and Tom Misteli (NCI, Bethesda) for comments on the manuscript. This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 52 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 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD DEC 15 PY 2016 VL 35 IS 50 BP 6429 EP 6438 DI 10.1038/onc.2016.177 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA EF3TP UT WOS:000390247600007 PM 27270425 ER PT J AU Marzi, A Banadyga, L Haddock, E Thomas, T Shen, K Horne, EJ Scott, DP Feldmann, H Ebihara, H AF Marzi, Andrea Banadyga, Logan Haddock, Elaine Thomas, Tina Shen, Kui Horne, Eva J. Scott, Dana P. Feldmann, Heinz Ebihara, Hideki TI A hamster model for Marburg virus infection accurately recapitulates Marburg hemorrhagic fever SO SCIENTIFIC REPORTS LA English DT Article ID SYRIAN GOLDEN-HAMSTER; CYNOMOLGUS MACAQUES; NONHUMAN-PRIMATES; ANGOLA INFECTION; IMMUNE-RESPONSE; RHESUS MACAQUES; AEROSOL CHALLENGE; HOST RESPONSE; ANIMAL-MODELS; MOUSE MODEL AB Marburg virus (MARV), a close relative of Ebola virus, is the causative agent of a severe human disease known as Marburg hemorrhagic fever (MHF). No licensed vaccine or therapeutic exists to treat MHF, and MARV is therefore classified as a Tier 1 select agent and a category A bioterrorism agent. In order to develop countermeasures against this severe disease, animal models that accurately recapitulate human disease are required. Here we describe the development of a novel, uniformly lethal Syrian golden hamster model of MHF using a hamster-adapted MARV variant Angola. Remarkably, this model displayed almost all of the clinical features of MHF seen in humans and non-human primates, including coagulation abnormalities, hemorrhagic manifestations, petechial rash, and a severely dysregulated immune response. This MHF hamster model represents a powerful tool for further dissecting MARV pathogenesis and accelerating the development of effective medical countermeasures against human MHF. C1 [Marzi, Andrea; Banadyga, Logan; Haddock, Elaine; Thomas, Tina; Horne, Eva J.; Feldmann, Heinz; Ebihara, Hideki] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT 59840 USA. [Shen, Kui] NIAID, Bioinformat & Computat Biosci Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Scott, Dana P.] NIAID, Rocky Mt Vet Branch, Div Intramural Res, NIH, Hamilton, MT 59840 USA. [Ebihara, Hideki] Mayo Clin, Dept Mol Med, Rochester, MN 55905 USA. RP Marzi, A; Ebihara, H (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT 59840 USA.; Ebihara, H (reprint author), Mayo Clin, Dept Mol Med, Rochester, MN 55905 USA. EM marzia@niaid.nih.gov; ebiharah@niaid.nih.gov FU Division of Intramural Research, NIAID, NIH FX The authors thank the BSL4 animal care staff of the Rocky Mountain Veterinary Branch (NIH, NIAID) and Eric Dahlstrom, Sarah Anzick, Stacy Ricklefs, and Stephen Porcella of the RTS-Genomics unit at RML for their work sequencing HA-MARV. We also thank Ayato Takada (Hokkaido University, Sapporo, Japan) for supplying the anti-MARV nucleoprotein antibody. This work was funded by the Division of Intramural Research, NIAID, NIH. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the NIH. NR 54 TC 0 Z9 0 U1 13 U2 13 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 DEC 15 PY 2016 VL 6 AR 39214 DI 10.1038/srep39214 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EF4FE UT WOS:000390279400001 PM 27976688 ER PT J AU He, T Brocca-Cofano, E Policicchio, BB Sivanandham, R Gautam, R Raehtz, KD Xu, CL Pandrea, I Apetrei, C AF He, Tianyu Brocca-Cofano, Egidio Policicchio, Benjamin B. Sivanandham, Ranjit Gautam, Rajeev Raehtz, Kevin D. Xu, Cuiling Pandrea, Ivona Apetrei, Cristian TI Cutting Edge: T Regulatory Cell Depletion Reactivates Latent Simian Immunodeficiency Virus (SIV) in Controller Macaques While Boosting SIV-Specific T Lymphocytes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RHESUS MACAQUES; HIV-INFECTION; REPLICATION; SUPPRESSION; EXPRESSION; RESERVOIR; TISSUES AB T regulatory cells (Tregs) are critical in shaping the latent HIV/ SIV reservoir, as they are preferentially infected, reverse CD4(+) T cell activation status, and suppress CTL responses. To reactivate latent virus and boost cell-mediated immune responses, we performed in vivo Treg depletion with Ontak (denileukin diftitox) in two SIVsab-infected controller macaques. Ontak induced significant (> 75%) Treg depletion and major CD4(+) T cell activation, and only minimally depleted CD8(+) T cells. The overall ability of Tregs to control immune responses was significantly impaired despite their incomplete depletion, resulting in both reactivation of latent virus (virus rebound to 10 3 viral RNA copies/ ml plasma in the absence of antiretroviral therapy) and a significant boost of SIV-specific CD8(+) T cell frequency, with rapid clearance of reactivated virus. As none of the latency-reversing agents in development have such dual activity, our strategy holds great promise for cure research. C1 [He, Tianyu; Brocca-Cofano, Egidio; Policicchio, Benjamin B.; Sivanandham, Ranjit; Raehtz, Kevin D.; Xu, Cuiling; Pandrea, Ivona; Apetrei, Cristian] Univ Pittsburgh, Ctr Vaccine Res, 9044 Biomed Sci Tower 3,3501 Fifth Ave, Pittsburgh, PA 15261 USA. [He, Tianyu; Brocca-Cofano, Egidio; Sivanandham, Ranjit; Pandrea, Ivona] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15261 USA. [Policicchio, Benjamin B.; Pandrea, Ivona; Apetrei, Cristian] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Infect Dis & Microbiol, Pittsburgh, PA 15261 USA. [Gautam, Rajeev] NIAID, Mol Microbiol Lab, Viral Pathogenesis & Vaccine Sect, Bethesda, MD 20814 USA. [Raehtz, Kevin D.; Xu, Cuiling; Apetrei, Cristian] Univ Pittsburgh, Sch Med, Microbiol & Mol Genet, Pittsburgh, PA 15261 USA. RP Apetrei, C (reprint author), Univ Pittsburgh, Ctr Vaccine Res, 9044 Biomed Sci Tower 3,3501 Fifth Ave, Pittsburgh, PA 15261 USA. EM apetreic@pitt.edu OI Sivanandham, Ranjit/0000-0001-7431-8415 FU National Institutes of Health/National Center for Research Resources/National Heart, Lung and Blood Institute/National Institute of Allergy and Infectious Diseases [R01 AI119346, R01 RR025781, RO1 HL117715, RO1 AI104373]; National Institutes of Health Training Grant [T32AI065380] FX This work was supported by National Institutes of Health/National Center for Research Resources/National Heart, Lung and Blood Institute/National Institute of Allergy and Infectious Diseases Grants R01 AI119346 (to C.A.), R01 RR025781 (to C.A. and I.P.), RO1 HL117715 (to I.P.), and RO1 AI104373 (to B.B.P.), and National Institutes of Health Training Grant T32AI065380 (to K.D.R. and B.B.P.). NR 23 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 DEC 15 PY 2016 VL 197 IS 12 BP 4535 EP 4539 DI 10.4049/jimmunol.1601539 PG 5 WC Immunology SC Immunology GA EE5HG UT WOS:000389635900004 PM 27837106 ER PT J AU Tuero, I Venzon, D Robert-Guroff, M AF Tuero, Iskra Venzon, David Robert-Guroff, Marjorie TI Mucosal and Systemic gamma delta(+) T Cells Associated with Control of Simian Immunodeficiency Virus Infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FEMALE REPRODUCTIVE-TRACT; IMMUNE-RESPONSES; HIV-INFECTION; DISEASE PROGRESSION; ENVELOPE PROTEIN; RHESUS MACAQUES; MENSTRUAL-CYCLE; SEX-DIFFERENCES; GENITAL-TRACT; B-CELLS AB gamma delta T cells act as a first line of defense against invading pathogens. However, despite their abundance in mucosal tissue, little information is available about their functionality in this compartment in the context of HIV/SIV infection. In this study, we evaluated the frequency, phenotype, and functionality of V delta 1 and V delta 2 T cells from blood, rectum, and the female reproductive tract (FRT) of rhesus macaques to determine whether these cells contribute to control of SIV infection. No alteration in the peripheral V delta 1/V delta 2 ratio in SIV-infected macaques was observed. However, CD8(+) and CD4(+) CD8(+) V delta 1 T cells were expanded along with upregulation of NKG2D, CD107, and granzyme B, suggesting cytotoxic function. In contrast, V delta 2 T cells showed a reduced ability to produce the inflammatory cytokine IFN-gamma. In the FRT of SIV + macaques, V delta 1 and V delta 2 showed comparable levels across vaginal, ectocervical, and endocervical tissues; however, endocervical V delta 2 T cells showed higher inflammatory profiles than the two other regions. No sex difference was seen in the rectal V delta 1/V delta 2 ratio. Several peripheral V delta 1 and/or V delta 2 T cell subpopulations expressing IFN-gamma and/or NKG2D were positively correlated with decreased plasma viremia. Notably, V delta 2 CD8(+) T cells of the endocervix were negatively correlated with chronic viremia. Overall, our results suggest that a robust V delta 1 and V delta 2 T cell response in blood and the FRTof SIV-infected macaques contribute to control of viremia. C1 [Tuero, Iskra; Robert-Guroff, Marjorie] NCI, Immune Biol Retroviral Infect Sect, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Tuero, Iskra] Univ Peruana Cayetano Heredia, Lab Invest & Desarrollo, Fac Ciencias & Filosofia, Lima, Peru. RP Robert-Guroff, M (reprint author), NCI, Vaccine Branch, Ctr Canc Res, NIH, Bldg 41,Room D804,41 Medlars Dr,MSC5065, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 63 TC 0 Z9 0 U1 4 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2016 VL 197 IS 12 BP 4686 EP 4695 DI 10.4049/jimmunol.1600579 PG 10 WC Immunology SC Immunology GA EE5HG UT WOS:000389635900019 PM 27815422 ER PT J AU Califf, RM Robb, MA Bindman, AB Briggs, JP Collins, FS Conway, PH Coster, TS Cunningham, FE De Lew, N DeSalvo, KB Dymek, C Dzau, VJ Fleurence, RL Frank, RG Gaziano, M Kaufmann, P Lauer, M Marks, PW McGinnis, JM Richards, C Selby, JV Shulkin, DJ Shuren, J Slavitt, AM Smith, SR Washington, BV White, PJ Woodcock, J Woodson, J Sherman, RE AF Califf, Robert M. Robb, Melissa A. Bindman, Andrew B. Briggs, Josephine P. Collins, Francis S. Conway, Patrick H. Coster, Trinka S. Cunningham, Francesca E. De Lew, Nancy DeSalvo, Karen B. Dymek, Christine Dzau, Victor J. Fleurence, Rachael L. Frank, Richard G. Gaziano, Michael Kaufmann, Petra Lauer, Michael Marks, Peter W. McGinnis, J. Michael Richards, Chesley Selby, Joe V. Shulkin, David J. Shuren, Jeffrey Slavitt, Andrew M. Smith, Scott R. Washington, B. Vindell White, P. Jon Woodcock, Janet Woodson, Jonathan Sherman, Rachel E. TI Transforming Evidence Generation to Support Health and Health Care Decisions SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID TECHNOLOGY; GUIDELINES; SYSTEM C1 [Califf, Robert M.; Sherman, Rachel E.] US FDA, Off Commissioner, Silver Spring, MD USA. [Robb, Melissa A.; Sherman, Rachel E.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Marks, Peter W.] US FDA, Biol Evaluat & Res, Silver Spring, MD USA. [Shuren, Jeffrey] US FDA, Devices & Radiol Hlth, Silver Spring, MD USA. [Bindman, Andrew B.] Agcy Healthcare Res & Qual, Off Director, Rockville, MD USA. [Dymek, Christine] Agcy Healthcare Res & Qual, Ctr Evidence & Practice Improvement, Rockville, MD USA. [Briggs, Josephine P.] NIH, Natl Ctr Complementary & Integrat Hlth, Bldg 10, Bethesda, MD 20892 USA. [Collins, Francis S.] NIH, Off Director, Bldg 10, Bethesda, MD 20892 USA. [Kaufmann, Petra] NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Lauer, Michael] NIH, Off Extramural Res Act, Bldg 10, Bethesda, MD 20892 USA. [Conway, Patrick H.; Slavitt, Andrew M.] Ctr Medicare & Medicaid Serv, Baltimore, MD USA. [Coster, Trinka S.] US Army, Off Surg Gen Pharmacovigilance Ctr, Falls Church, VA USA. [Shulkin, David J.] Dept Vet Affairs, Off Secretary Hlth, Washington, DC USA. [De Lew, Nancy; DeSalvo, Karen B.] Off Assistant Secretary Planning & Evaluat, Off Hlth Policy, Washington, DC USA. [DeSalvo, Karen B.] Off Assistant Secretary Hlth, Washington, DC USA. [Washington, B. Vindell; White, P. Jon] Off Natl Coordinator Hlth Informat Technol, Washington, DC USA. [Dzau, Victor J.; McGinnis, J. Michael] Natl Acad Med, Dept Hlth & Human Serv, Washington, DC USA. [Fleurence, Rachael L.; Selby, Joe V.] Patient Centered Outcomes Res Inst, Washington, DC USA. [Cunningham, Francesca E.] Dept Vet Affairs, Ctr Medicat Safety, Hines, IL USA. [Frank, Richard G.] Harvard Univ, Dept Hlth Care Policy, Boston, MA 02115 USA. [McGinnis, J. Michael] Brigham & Womens Hosp, Div Aging, Mill Veteran Program, Vet Affairs Boston Healthcare Syst, Boston, MA 02115 USA. [McGinnis, J. Michael] Harvard Med Sch, Boston, MA USA. [Woodson, Jonathan] Boston Univ, Sch Med, Dept Surg, Boston, MA 02118 USA. [Richards, Chesley] Ctr Dis Control & Prevent, Off Publ Hlth Sci Serv, Atlanta, GA USA. RP Califf, RM (reprint author), US FDA, Off Commissioner, Silver Spring, MD USA. NR 13 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 DEC 15 PY 2016 VL 375 IS 24 BP 2395 EP 2400 DI 10.1056/NEJMsb1610128 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA EF0SO UT WOS:000390036500014 PM 27974039 ER PT J AU Hsu, CW Hsieh, JH Huang, RL Pijnenburg, D Khuc, T Hamm, J Zhao, JH Lynch, C van Beuningen, R Chang, XQ Houtman, R Xia, MH AF Hsu, Chia-Wen Hsieh, Jui-Hua Huang, Ruili Pijnenburg, Dirk Khuc, Thai Hamm, Jon Zhao, Jinghua Lynch, Caitlin van Beuningen, Rinie Chang, Xiaoqing Houtman, Rene Xia, Menghang TI Differential modulation of FXR activity by chlorophacinone and ivermectin analogs SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Farnesoid X receptor; Nuclear receptor; Ivermetin; Moxidectin; Chlorophacinone; Diphacinone; Tox21 ID FARNESOID-X-RECEPTOR; CONSTITUTIVE ANDROSTANE RECEPTOR; NUCLEAR RECEPTORS; DEFICIENCY; LIGAND; ROLES; DRUGS; MICE; IDENTIFICATION; CHOLESTEROL AB Chemicals that alter normal function of farnesoid X receptor (FXR) have been shown to affect the homeostasis of bile acids, glucose, and lipids. Several structural classes of environmental chemicals and drugs that modulated FXR transactivation were previously identified by quantitative high-throughput screening (qHTS) of the Tox21 10 K chemical collection. In the present study, we validated the FXR antagonist activity of selected structural classes, including avermectin anthelmintics, dihydropyridine calcium channel blockers, 1,3-indandione rodenticides, and pyrethroid pesticides, using in vitro assay and quantitative structural-activity relationship (QSAR) analysis approaches. (Z)-Guggulsterone, chlorophacinone, ivermectin, and their analogs were profiled for their ability to alter CDCA-mediated FXR binding using a panel of 154 coregulator motifs and to induce or inhibit transactivation and coactivator recruitment activities of constitutive androstane receptor (CAR), liver X receptor alpha (IXR alpha), or pregnane X receptor (PXR). Our results showed that chlorophacinone and ivermectin had distinct modes of action (MOA) in modulating FXR-coregulator interactions and compound selectivity against the four aforementioned functionally-relevant nuclear receptors. These findings collectively provide mechanistic in-sights regarding compound activities against FXR and possible explanations for in vivo toxicological observations of chlorophacinone, ivermectin, and their analogs. Published by Elsevier Inc. C1 [Hsu, Chia-Wen; Huang, Ruili; Khuc, Thai; Zhao, Jinghua; Lynch, Caitlin; Xia, Menghang] NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. [Hsieh, Jui-Hua] NIEHS, Natl Toxicol Program, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Pijnenburg, Dirk; van Beuningen, Rinie; Houtman, Rene] PamGene Int BV, Wolvenhoek 10, NL-5211 HH Shertogenbosch, Netherlands. [Chang, Xiaoqing] Integrated Lab Syst Inc, Morrisville, NC USA. RP Xia, MH (reprint author), NIH, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Bethesda, MD 20892 USA. EM mxia@mail.nih.gov FU U.S. Environmental Protection Agency [Y3-HG-7026-03]; National Institute of Environmental Health Sciences/Division of the National Toxicology Program [NTR 12003] FX This work was supported by the U.S. Environmental Protection Agency (Interagency Agreement #Y3-HG-7026-03) and the interagency agreement IAG #NTR 12003 from the National Institute of Environmental Health Sciences/Division of the National Toxicology Program to the National Center for Advancing Translational Sciences, National Institutes of Health. NR 25 TC 0 Z9 0 U1 6 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD DEC 15 PY 2016 VL 313 BP 138 EP 148 DI 10.1016/j.taap.2016.10.017 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EE8IK UT WOS:000389868700015 PM 27773686 ER PT J AU Gust, DA Soud, F Hardnett, FP Malotte, CK Rose, C Kebaabetswe, P Makgekgenene, L Henderson, F Paxton, L Segolodi, T Kilmarx, PH AF Gust, Deborah A. Soud, Fatma Hardnett, Felicia P. Malotte, Charles K. Rose, Charles Kebaabetswe, Poloko Makgekgenene, Lebogang Henderson, Faith Paxton, Lynn Segolodi, Tebogo Kilmarx, Peter H. TI Evaluation of Sexual Risk Behavior Among Study Participants in the TDF2 PrEP Study Among Heterosexual Adults in Botswana SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE clinical trial; tenofovir/emtricitabine; risk compensation; sexual risk behavior ID VACCINE EFFICACY TRIAL; SUB-SAHARAN AFRICA; HIV-INFECTION; PREEXPOSURE PROPHYLAXIS; ANTIRETROVIRAL PROPHYLAXIS; TRANSMITTED INFECTIONS; EDUCATIONAL-ATTAINMENT; MALE CIRCUMCISION; RANDOMIZED-TRIAL; DOUBLE-BLIND AB Objective: Among participants of a clinical trial to test the efficacy of tenofovir/emtricitabine in protecting heterosexual men and women living in Botswana from HIV infection, the aim was to determine (1) if sexual risk behavior, specifically condomless sex acts and number of sex partners, changed over time, (2) factors associated with condomless sex acts and number of sex partners, and (3) the effect of participant treatment arm perception on risk behavior to address the possibility of risk compensation. Methods: A longitudinal modeling of rates of risk behaviors was used to determine if the rate of condomless sex acts (#acts/person) and rate of sex partners (#partners/person) changed over time and which factors were associated with behavior change. Results: One thousand two hundred participants were analyzed over 1 year. There was a 25% decrease in the rate of sex partners among participants sexually active in the last 30 days. The rate of reported condomless sex acts was greater for males [rate ratio (RR) = 1.34; confidence interval (CI): 1.07 to 1.67] and participants whose sexual debut in years was <= 15 years of age (RR = 1.65; CI: 1.14 to 2.38) and 16-17 (RR = 1.68; CI: 1.22 to 2.31) compared with those >= 20 years. Rate of reported sex partners was greater for males (RR = 3.67; CI: 2.86 to 4.71) and participants whose age at sexual debut in years was <= 15 (RR = 2.92; CI: 2.01 to 4.22) and 16-17 (RR = 2.34; CI: 1.69 to 3.24) compared with those >= 20. There was no effect of participant treatment arm perception on risk behavior. Conclusions: Our study of preexposure prophylaxis to prevent HIV infection found no evidence of risk compensation which may have been due to participants' motivations to reduce their risk behaviors and risk-reduction counseling. C1 [Gust, Deborah A.; Soud, Fatma; Hardnett, Felicia P.; Rose, Charles; Henderson, Faith; Paxton, Lynn; Kilmarx, Peter H.] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Atlanta, GA USA. [Malotte, Charles K.] Calif State Univ Long Beach, Ctr Healthcare Innovat, Long Beach, CA 90840 USA. [Malotte, Charles K.] Calif State Univ Long Beach, Dept Hlth Sci, Long Beach, CA 90840 USA. [Kebaabetswe, Poloko; Makgekgenene, Lebogang] Univ Botswana, Dept Publ Hlth Med, Fac Med, Gaborone, Botswana. [Segolodi, Tebogo] CDC Botswana, Div Global HIV AIDS & TB, Gaborone, Botswana. [Kilmarx, Peter H.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. RP Gust, DA (reprint author), Clin Trials Team, Div HIV AIDS Prevent, 1600 Clifton Rd,MS E45, Atlanta, GA 30329 USA. EM dgust@cdc.gov FU Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention and the Division of AIDS, National Institutes of Health FX Supported by Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention and the Division of AIDS, National Institutes of Health. NR 52 TC 0 Z9 0 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD DEC 15 PY 2016 VL 73 IS 5 BP 556 EP 563 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA ED7LF UT WOS:000389045300013 PM 27509251 ER PT J AU Bien, SA Wojcik, GL Zubair, N Gignoux, CR Martin, AR Kocarnik, JM Martin, LW Buyske, S Haessler, J Walker, RW Cheng, I Graff, M Xia, L Franceschini, N Matise, T James, R Hindorff, L Le Marchand, L North, KE Haiman, CA Peters, U Loos, RJF Kooperberg, CL Bustamante, CD Kenny, EE Carlson, CS AF Bien, Stephanie A. Wojcik, Genevieve L. Zubair, Niha Gignoux, Christopher R. Martin, Alicia R. Kocarnik, Jonathan M. Martin, Lisa W. Buyske, Steven Haessler, Jeffrey Walker, Ryan W. Cheng, Iona Graff, Mariaelisa Xia, Lucy Franceschini, Nora Matise, Tara James, Regina Hindorff, Lucia Le Marchand, Loic North, Kari E. Haiman, Christopher A. Peters, Ulrike Loos, Ruth J. F. Kooperberg, Charles L. Bustamante, Carlos D. Kenny, Eimear E. Carlson, Christopher S. CA PAGE Study TI Strategies for Enriching Variant Coverage in Candidate Disease Loci on a Multiethnic Genotyping Array SO PLOS ONE LA English DT Article ID SPLICING EFFICIENCY; DIVERSE POPULATIONS; POLYMORPHISM; GENE; PROTEIN; DESIGN; MDR1; SNP AB Investigating genetic architecture of complex traits in ancestrally diverse populations is imperative to understand the etiology of disease. However, the current paucity of genetic research in people of African and Latin American ancestry, Hispanic and indigenous peoples in the United States is likely to exacerbate existing health disparities for many common diseases. The Population Architecture using Genomics and Epidemiology, Phase II (PAGE II), Study was initiated in 2013 by the National Human Genome Research Institute to expand our understanding of complex trait loci in ethnically diverse and well characterized study populations. To meet this goal, the Multi-Ethnic Genotyping Array (MEGA) was designed to substantially improve fine-mapping and functional discovery by increasing variant coverage across multiple ethnicities at known loci for metabolic, cardiovascular, renal, inflammatory, anthropometric, and a variety of lifestyle traits. Studying the frequency distribution of clinically relevant mutations, putative risk alleles, and known functional variants across multiple populations will provide important insight into the genetic architecture of complex diseases and facilitate the discovery of novel, sometimes population-specific, disease associations. DNA samples from 51,650 self-identified African ancestry (17,328), Hispanic/Latino (22,379), Asian/Pacific Islander (8,640), and American Indian (653) and an additional 2,650 participants of either South Asian or European ancestry, and other reference panels have been genotyped on MEGA by PAGE II. MEGA was designed as a new resource for studying ancestrally diverse populations. Here, we describe the methodology for selecting trait-specific content for use in multi-ethnic populations and how enriching MEGA for this content may contribute to deeper biological understanding of the genetic etiology of complex disease. C1 [Bien, Stephanie A.; Zubair, Niha; Kocarnik, Jonathan M.; Haessler, Jeffrey; Peters, Ulrike; Kooperberg, Charles L.; Carlson, Christopher S.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Wojcik, Genevieve L.; Gignoux, Christopher R.; Martin, Alicia R.; Bustamante, Carlos D.] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Martin, Lisa W.] George Washington Univ, Sch Med & Hlth Sci, Div Cardiol, Washington, DC 20052 USA. [Buyske, Steven; Matise, Tara] Rutgers State Univ, Dept Genet, Sch Arts & Sci, Piscataway, NJ USA. [Walker, Ryan W.; Loos, Ruth J. F.; Kenny, Eimear E.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Walker, Ryan W.; Loos, Ruth J. F.; Kenny, Eimear E.] Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA. [Cheng, Iona] Canc Prevent Inst Calif, Fremont, CA USA. [Graff, Mariaelisa; Franceschini, Nora; North, Kari E.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Xia, Lucy; Haiman, Christopher A.] Univ Southern Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [James, Regina] NICHHD, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Hindorff, Lucia] NHGRI, Div Genom Med, NIH, Bethesda, MD 20892 USA. [Le Marchand, Loic] Univ Hawaii, Dept Epidemiol Program, Ctr Canc, Honolulu, HI 96822 USA. [Peters, Ulrike; Carlson, Christopher S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. RP Carlson, CS (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. EM sbien@fredhutch.org; ccarlson@fredhutch.org OI Kocarnik, Jonathan/0000-0001-8084-1608; Buyske, Steven/0000-0001-8539-5416; Bien, Stephanie/0000-0002-8713-4583; Martin, Alicia/0000-0003-0241-3522 FU National Human Genome Research Institute (NHGRI); National Institutes of Health [U01HG004803, U01HG004802, U01HG004790, U01HG004801]; NHGRI PAGE II program [U01HG004802]; National Cancer Institute [R37CA54281, R01 CA63, P01CA33619, U01CA136792, U01CA98758]; NHGRI PAGE program [U01HG004803, U01HG004790]; National Heart, Lung, and Blood Institute (NHLBI); US Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; NHLBI [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-45134, N01-HC-05187, N01-HC-45205, N01-HC-85079]; National Institute of Neurological Disorders and Stroke; National Center for Research Resources [M01-RR00425]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; National Center on Minority Health and Health Disparities; National Institute on Deafness and Other Communication Disorders; National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases; Office of Dietary Supplements; Andrea and Charles Bronfman Philantropies; [N01-HC-85086]; [N01-HC-35129]; [N01-HC-15103]; [N01 HC-55222]; [N01-HC-75150]; [N01-HC-45133]; [U01HL080295]; [R01 HL087652]; [N01-HC65233]; [N01-HC65234]; [N01-HC65235]; [N01-HC65236]; [N01-HC65237]; [U01 HL65520]; [U01 HL41642]; [U01 HL41652]; [U01 HL41654]; [U01 HL65521] FX The Population Architecture using Genomics and Epidemiology (PAGE) Study is a collaboration between the Multi-Ethnic Cohort Study (MEC), the Women's Health Initiative (WHI), the Institute for Personalized Medicine at the Icahn School of Medicine at Mount Sinai (ISMMS) and the Genetic Epidemiology of Causal Variants Across the Life Course (CALiCo) consortium, which comprises the Atherosclerosis Risk in Communities (ARIC) Study, the Coronary Artery Risk Development in Young Adults (CARDIA) Study, the Cardiovascular Health Study (CHS), the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), and the Strong Heart Study (SHS). A complete list of members of the PAGE consortium can be found at [http://www.pagestudy.org]. PAGE II is funded by the National Human Genome Research Institute (NHGRI) and is supported by National Institutes of Health grants U01HG004803 (CALiCo), U01HG004802 (MEC), U01HG004790 (WHI), and U01HG004801 (Coordinating Center). Characterization of epidemiological architecture in the Multiethnic Cohort Study is funded through the NHGRI PAGE II program (grant U01HG004802). The Multiethnic Cohort Study is funded by the National Cancer Institute (grants R37CA54281, R01 CA63, P01CA33619, U01CA136792, and U01CA98758). Funding for the study of the epidemiology of putative genetic variants in the WHI is provided through the NHGRI PAGE program (grant U01HG004790). The WHI is funded by the National Heart, Lung, and Blood Institute (NHLBI) and the US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. (The authors thank the WHI investigators and staff for their dedication). A full listing of WHI investigators can be found at [http://www.whiscience.org/publications/WHI_investigators_shortlist.pdf] . Funding for the CALiCo consortium was provided through the NHGRI PAGE program (grant U01HG004803). The ARIC Study is carried out as a collaborative study supported by NHLBI contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022. The CARDIA Study is supported by the following NHLBI contracts: N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-45134, N01-HC-05187, and N01-HC-45205. The Cardiovascular Health Study is supported by contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01-HC-15103, N01 HC-55222, N01-HC-75150, and N01-HC-45133 and grants U01HL080295 and R01 HL087652 from the NHLBI, with an additional contribution from the National Institute of Neurological Disorders and Stroke. Genome-wide association study DNA handling and genotyping in the Cardiovascular Health Study was supported in part by National Center for Research Resources grant M01-RR00425 to the Cedars-Sinai General Clinical Research Center genotyping core and by National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The HCHS/SOL is supported by NHLBI contracts N01-HC65233, N01-HC65234, N01-HC65235, N01-HC65236, and N01-HC65237.; The following institutes/centers/offices contribute to the HCHS/SOL through a transfer of funds to the NHLBI: the National Center on Minority Health and Health Disparities, the National Institute on Deafness and Other Communication Disorders, the National Institute of Dental and Craniofacial Research, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the Office of Dietary Supplements. The Strong Heart Study is supported by NHLBI grants U01 HL65520, U01 HL41642, U01 HL41652, U01 HL41654, and U01 HL65521. (The opinions expressed in this paper are those of the author(s) and do not necessarily reflect the views of the Indian Health Service). Funding for the BioMe Biobank program is supported by the Andrea and Charles Bronfman Philantropies. We thank the participants in the BioMe Biobank for their invaluable contribution to biomedical research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 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 DEC 14 PY 2016 VL 11 IS 12 AR e0167758 DI 10.1371/journal.pone.0167758 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EI8KC UT WOS:000392754300044 PM 27973554 ER PT J AU Konig, MF Abusleme, L Reinholdt, J Palmer, RJ Teles, RP Sampson, K Rosen, A Nigrovic, PA Sokolove, J Giles, JT Moutsopoulos, NM Andrade, F AF Konig, Maximilian F. Abusleme, Loreto Reinholdt, Jesper Palmer, Robert J. Teles, Ricardo P. Sampson, Kevon Rosen, Antony Nigrovic, Peter A. Sokolove, Jeremy Giles, Jon T. Moutsopoulos, Niki M. Andrade, Felipe TI Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID NEUTROPHIL EXTRACELLULAR TRAPS; LEUKOTOXIC JP2 CLONE; EPSTEIN-BARR-VIRUS; ACTINOBACILLUS-ACTINOMYCETEMCOMITANS; CITRULLINATED PROTEIN; SUBGINGIVAL PLAQUE; PEPTIDYLARGININE DEIMINASE; SYNOVIAL-FLUID; ANTIBODIES; PORPHYROMONAS AB A bacterial etiology of rheumatoid arthritis (RA) has been suspected since the beginnings of modern germ theory. Recent studies implicate mucosal surfaces as sites of disease initiation. The common occurrence of periodontal dysbiosis in RA suggests that oral pathogens may trigger the production of disease-specific autoantibodies and arthritis in susceptible individuals. We used mass spectrometry to define the microbial composition and antigenic repertoire of gingival crevicular fluid in patients with periodontal disease and healthy controls. Periodontitis was characterized by the presence of citrullinated autoantigens that are primary immune targets in RA. The citrullinome in periodontitis mirrored patterns of hypercitrullination observed in the rheumatoid joint, implicating this mucosal site in RA pathogenesis. Proteomic signatures of several microbial species were detected in hypercitrullinated periodontitis samples. Among these, Aggregatibacter actinomycetemcomitans (Aa), but not other candidate pathogens, induced hypercitrullination in host neutrophils. We identified the pore-forming toxin leukotoxin A (LtxA) as the molecular mechanism by which Aa triggers dysregulated activation of citrullinating enzymes in neutrophils, mimicking mem-branolytic pathways that sustain autoantigen citrullination in the RA joint. Moreover, LtxA induced changes in neutrophil morphology mimicking extracellular trap formation, thereby releasing the hypercitrullinated cargo. Exposure to leukotoxic Aa strains was confirmed in patients with RA and was associated with both anticitrullinated protein antibodies and rheumatoid factor. The effect of human lymphocyte antigen-DRB1 shared epitope alleles on autoantibody positivity was limited to RA patients who were exposed to Aa. These studies identify the periodontal pathogen Aa as a candidate bacterial trigger of autoimmunity in RA. C1 [Konig, Maximilian F.; Sampson, Kevon; Rosen, Antony; Andrade, Felipe] Johns Hopkins Univ, Div Rheumatol, Sch Med, Baltimore, MD 21224 USA. [Abusleme, Loreto; Palmer, Robert J.; Moutsopoulos, Niki M.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Reinholdt, Jesper] Aarhus Univ, Dept Biomed, DK-8000 Aarhus C, Denmark. [Teles, Ricardo P.] Univ North Carolina Chapel Hill, Sch Dent, Dept Periodontol, Chapel Hill, NC 27599 USA. [Teles, Ricardo P.] Forsyth Inst, Dept Appl Oral Sci, Cambridge, MA 02142 USA. [Nigrovic, Peter A.] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, 75 Francis St, Boston, MA 02115 USA. [Nigrovic, Peter A.] Boston Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Sokolove, Jeremy] Stanford Univ, Div Rheumatol & Immunol, Sch Med, Stanford, CA 94305 USA. [Giles, Jon T.] Columbia Univ, Coll Phys & Surg, Div Rheumatol, New York, NY 10032 USA. [Konig, Maximilian F.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Andrade, F (reprint author), Johns Hopkins Univ, Div Rheumatol, Sch Med, Baltimore, MD 21224 USA. EM andrade@jhmi.edu FU Jerome L. Greene Foundation; Donald B. and Dorothy L. Stabler Foundation; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)/NIH grant [R01AR069569]; Intramural Research Program of the NIDCR/NIH; NIH/NIDCR grant [R37 DE12354]; NIDCR/NIH grant [DE021127-01]; Fundacion Bechara; Rheumatology Research Foundation; NIAMS/NIH [AR050026-01] FX F.A. was supported by the Jerome L. Greene Foundation, the Donald B. and Dorothy L. Stabler Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)/NIH grant R01AR069569. N.M.M. and R.J.P. were supported by the Intramural Research Program of the NIDCR/NIH. A.R. was supported by NIH/NIDCR grant R37 DE12354. R.P.T. was supported by NIDCR/NIH grant DE021127-01. P.A.N. was supported by the Fundacion Bechara. J.S. was supported by the Rheumatology Research Foundation. ESCAPE RA was supported by NIAMS/NIH AR050026-01. NR 64 TC 1 Z9 1 U1 3 U2 3 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 DEC 14 PY 2016 VL 8 IS 369 AR 369ra176 DI 10.1126/scitranslmed.aaj1921 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EG5UL UT WOS:000391110000002 PM 27974664 ER PT J AU Zengeya, TT Garlick, JM Kulkarni, RA Miley, M Roberts, AM Yang, YF Crooks, DR Sourbier, C Linehan, WM Meier, JL AF Zengeya, Thomas T. Garlick, Julie M. Kulkarni, Rhushikesh A. Miley, Mikayla Roberts, Allison M. Yang, Youfeng Crooks, Daniel R. Sourbier, Carole Linehan, W. Marston Meier, Jordan L. TI Co-opting a Bioorthogonal Reaction for Oncometabolite Detection SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID PHOTOCLICK CHEMISTRY; FUMARATE HYDRATASE; IN-VIVO; LIVING CELLS; CANCER; PROTEIN; FH; FUNCTIONALIZATION; MUTATIONS; CARCINOMA AB Dysregulated metabolism is a hallmark of many diseases, including cancer. Methods to fluorescently detect metabolites have the potential to enable new approaches to cancer detection and imaging. However, fluorescent sensing methods for naturally occurring cellular metabolites are relatively unexplored. Here we report the development of a chemical approach to detect the oncometabolite fumarate. Our strategy exploits a known bioorthogonal reaction, the 1,3-dipolar cycloaddition of nitrileimines and electron-poor olefins, to detect fumarate via fluorescent pyrazoline cycloadduct formation. We demonstrate hydrazonyl chlorides serve as readily accessible nitrileimine precursors, whose reactivity and spectral properties can be tuned to enable detection of fumarate and other dipolarophile metabolites. Finally, we show this reaction can be used to detect enzyme activity changes caused by mutations in fumarate hydratase, which underlie the familial cancer predisposition syndrome hereditary leiomyomatosis and renal cell cancer. Our studies define a novel intersection of bioorthogonal chemistry and metabolite reactivity that may be harnessed to enable biological profiling, imaging, and diagnostic applications. C1 [Zengeya, Thomas T.; Garlick, Julie M.; Kulkarni, Rhushikesh A.; Miley, Mikayla; Roberts, Allison M.; Meier, Jordan L.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. [Yang, Youfeng; Crooks, Daniel R.; Sourbier, Carole; Linehan, W. Marston] NCI, Urol Oncol Branch, Bethesda, MD 20817 USA. RP Meier, JL (reprint author), NCI, Biol Chem Lab, Frederick, MD 21702 USA. EM jordan.meier@nih.gov FU Intramural Research Program of the NIH, National Cancer Institute [ZIA BC011488-02] FX We thank Dr. Martin Schnermann (NCI) and Dr. Rolf Swenson (Intramural Probe Development Center, NHLBI) for helpful discussions. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute (ZIA BC011488-02). NR 31 TC 0 Z9 0 U1 21 U2 21 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD DEC 14 PY 2016 VL 138 IS 49 BP 15813 EP 15816 DI 10.1021/jacs.6b09706 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA EE9RB UT WOS:000389962800005 PM 27960310 ER PT J AU Schakner, ZA Buhnerkempe, MG Tennis, MJ Stansell, RJ van der Leeuw, BK Lloyd-Smith, JO Blumstein, DT AF Schakner, Zachary A. Buhnerkempe, Michael G. Tennis, Mathew J. Stansell, Robert J. van der Leeuw, Bjorn K. Lloyd-Smith, James O. Blumstein, Daniel T. TI Epidemiological models to control the spread of information in marine mammals SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE human - wildlife conflict; social transmission; culling; salmon conservation; social learning; network-based diffusion ID TUBERCULOSIS; TRANSMISSION; NETWORKS AB Socially transmitted wildlife behaviours that create human-wildlife conflict are an emerging problem for conservation efforts, but also provide a unique opportunity to apply principles of infectious disease control to wildlife management. As an example, California sea lions (Zalophus californianus) have learned to exploit concentrations of migratory adult salmonids below the fish ladders at Bonneville Dam, impeding endangered salmonid recovery. Proliferation of this foraging behaviour in the sea lion population has resulted in a controversial culling programme of individual sea lions at the dam, but the impact of such culling remains unclear. To evaluate the effectiveness of current and alternative culling strategies, we used network-based diffusion analysis on a long-term dataset to demonstrate that social transmission is implicated in the increase in dam-foraging behaviour and then studied different culling strategies within an epidemiological model of the behavioural transmission data. We show that current levels of lethal control have substantially reduced the rate of social transmission, but failed to effectively reduce overall sea lion recruitment. Earlier implementation of culling could have substantially reduced the extent of behavioural transmission and, ultimately, resulted in fewer animals being culled. Epidemiological analyses offer a promising tool to understand and control socially transmissible behaviours. C1 [Schakner, Zachary A.; Buhnerkempe, Michael G.; Lloyd-Smith, James O.; Blumstein, Daniel T.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. [Buhnerkempe, Michael G.; Lloyd-Smith, James O.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Tennis, Mathew J.] Pacific States Marine Fisheries Commiss, 2001 Marine Dr,Room 120, Astoria, OR 97103 USA. [Stansell, Robert J.; van der Leeuw, Bjorn K.] US Army Corps Engineers, Fisheries Field Unit, POB 150, Cascade Locks, OR 97014 USA. RP Schakner, ZA; Buhnerkempe, MG (reprint author), Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA.; Buhnerkempe, MG (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM zschakner@ucla.edu; Michael.buhnerkempe@gmail.com RI Lloyd-Smith, James/K-4080-2012; OI Lloyd-Smith, James/0000-0001-7941-502X; Blumstein, Daniel/0000-0001-5793-9244; schakner, zachary/0000-0002-8325-3526 FU National Science Foundation Graduate Research Fellowship; Research and Policy for Infectious Disease Dynamics (RAPIDD) programme of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; NSF [OCE-1335657] FX Z.A.S. was supported by a National Science Foundation Graduate Research Fellowship, M.G.B and J.O.L-S. are supported by the Research and Policy for Infectious Disease Dynamics (RAPIDD) programme of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health and the NSF(OCE-1335657), and D.T.B. is currently supported by the NSF. NR 23 TC 0 Z9 0 U1 8 U2 8 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8452 EI 1471-2954 J9 P ROY SOC B-BIOL SCI JI Proc. R. Soc. B-Biol. Sci. PD DEC 14 PY 2016 VL 283 IS 1844 AR 20162037 DI 10.1098/rspb.2016.2037 PG 9 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA EF5XW UT WOS:000390404200020 ER PT J AU Chu, FF Esworthy, RS Doroshow, JH Shen, BH AF Chu, Fong-Fong Esworthy, R. Steven Doroshow, James H. Shen, Binghui TI NADPH oxidase-1 deficiency offers little protection in Salmonella typhimurium-induced typhlitis in mice SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Knockout mouse; NADPH Oxidase-1; Salmonella typhimurium; Goblet cells; Reactive oxygen species ID EPITHELIAL-CELLS; COLITIS; NOX1; SUSCEPTIBILITY; INFLAMMATION; INFECTION; PATHOGEN; DISEASE; HOST AB AIM To test whether Nox1 plays a role in typhlitis induced by Salmonella enterica serovar Typhimurium (S. Tm) in a mouse model. METHODS Eight-week-old male wild-type (WT) and Nox1 knockout (KO) C57BL6/J (B6) mice were administered metronidazole water for 4 d to make them susceptible to S. Tm infection by the oral route. The mice were given plain water and administered with 4 different doses of S. Tm by oral gavage. The mice were followed for another 4 d. From the time of the metronidazole application, the mice were observed twice daily and weighed daily. The ileum, cecum and colon were removed for sampling at the fourth day post-inoculation. Portions of all three tissues were fixed for histology and placed in RNAlater for mRNA/cDNA preparation and quantitative real-time PCR. The contents of the cecum were recovered for estimation of S. Tm CFU. RESULTS We found Nox1-knockout (Nox1-KO) mice were not more sensitive to S. Tm colonization and infection than WT B6 mice. This conclusion is based on the following observations: (1) S. Tm-infection induced similar weight loss in Nox1-KO mice compared to WT mice; (2) the same S. Tm CFU was recovered from the cecal content of Nox1-KO and WT mice regardless of the inoculation dose, except the lowest inoculation dose (2 x 10(6) CFU) for which the Nox1-KO had one-log lower CFU than WT mice; (3) there is no difference in cecal pathology between WT and Nox1-KO groups; and (4) there are no S. Tm infection-induced changes in gene expression levels (IL-1b, TNF-alpha, and Duox2) between WT and Nox1-KO groups. The Alpi gene expression was more suppressed by S. Tm treatment in WT than the Nox1-KO cecum. CONCLUSION Nox1 does not protect mice from S. Tm colonization. Nox1-KO provides a very minor protective effect against S. Tm infection. Using NOX1-specific inhibitors for colitis therapy should not increase risks in bacterial infection. C1 [Chu, Fong-Fong] Henan Univ Sci & Technol, Dept Gastroenterol & Hepatol, Affiliated Hosp 1, Luoyang 471003, Henan Province, Peoples R China. [Chu, Fong-Fong] Henan Univ Sci & Technol, Coll Clin Med, Luoyang 471003, Henan Province, Peoples R China. [Chu, Fong-Fong; Esworthy, R. Steven; Shen, Binghui] City Hope Natl Med Ctr, Beckman Res Inst, Dept Canc Genet & Epigenet, 1450 E Duarte Rd, Duarte, CA 91010 USA. [Doroshow, James H.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Doroshow, James H.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Chu, FF (reprint author), City Hope Natl Med Ctr, Beckman Res Inst, Dept Canc Genet & Epigenet, 1450 E Duarte Rd, Duarte, CA 91010 USA. EM fchu@coh.org FU National Cancer Institute (NCI) [HHSN261200800001E]; National Cancer Institute of the National Institutes of Health [P30CA033572] FX Supported by Federal funds from the National Cancer Institute (NCI) under Contract, No. HHSN261200800001E (to Chu FF); Research reported in this publication included work performed in the Animal Resources Center Core supported by the National Cancer Institute of the National Institutes of Health under award No. P30CA033572. NR 24 TC 0 Z9 0 U1 3 U2 3 PU BAISHIDENG PUBLISHING GROUP INC PI PLEASANTON PA 8226 REGENCY DR, PLEASANTON, CA 94588 USA SN 1007-9327 EI 2219-2840 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD DEC 14 PY 2016 VL 22 IS 46 BP 10158 EP 10165 DI 10.3748/wjg.v22.i46.10158 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EF2XY UT WOS:000390190100010 PM 28028364 ER PT J AU Payne, JM Barton, B Ullrich, NJ Cantor, A Hearps, SJC Cutter, G Rosser, T Walsh, KS Gioia, GA Wolters, PL Tonsgard, J Schorry, E Viskochil, D Klesse, L Fisher, M Gutmann, DH Silva, AJ Hunter, SJ Rey-Casserly, C Cantor, NL Byars, AW Stavinoha, PL Ackerson, JD Armstrong, CL Isenberg, J O'Neil, SH Packer, RJ Korf, B Acosta, MT North, KN AF Payne, Jonathan M. Barton, Belinda Ullrich, Nicole J. Cantor, Alan Hearps, Stephen J. C. Cutter, Gary Rosser, Tena Walsh, Karin S. Gioia, Gerard A. Wolters, Pamela L. Tonsgard, James Schorry, Elizabeth Viskochil, David Klesse, Laura Fisher, Michael Gutmann, David H. Silva, Alcino J. Hunter, Scott J. Rey-Casserly, Celiane Cantor, Nancy L. Byars, Anna W. Stavinoha, Peter L. Ackerson, Joseph D. Armstrong, Carol L. Isenberg, Jill O'Neil, Sharon H. Packer, Roger J. Korf, Bruce Acosta, Maria T. North, Kathryn N. CA NF Clinical Trials Consortium TI Randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1 SO NEUROLOGY LA English DT Article ID COGNITIVE DEFICITS; CONTROLLED-TRIAL; SIMVASTATIN; INHIBITION AB Objective: To assess the efficacy of lovastatin on visuospatial learning and attention for treating cognitive and behavioral deficits in children with neurofibromatosis type 1 (NF1). Methods: A multicenter, international, randomized, double-blind, placebo-controlled trial was conducted between July 2009 and May 2014 as part of the NF Clinical Trials Consortium. Children with NF1 aged 8-15 yearswere screened for visuospatial learning or attention deficits (n = 272); 146 children demonstrated deficits at baseline and were randomly assigned to lovastatin (n = 74; 40 mg/d) or placebo (n = 70). Treatment was administered once daily for 16 weeks. Primary outcomes were total errors on the Cambridge Neuropsychological Test Automated Battery Paired Associate Learning task (visuospatial learning) and the Score subtest from the Test of Everyday Attention for Children (sustained attention). Secondary outcomes measured executive function, attention, visuospatial skills, behavior, and quality of life. Primary analyses were performed on the intention-to-treat population. Results: Lovastatin had no significant effect on primary outcomes after 16 weeks of treatment: visuospatial learning (Cohen d = -0.15, 95% confidence interval -0.47 to 0.18) or sustained attention (Cohen d = 0.19, 95% confidence interval -0.14 to 0.53). Lovastatin was well tolerated, with no increase in reported adverse events compared to placebo. Conclusions: Lovastatin administered once daily for 16 weeks did not improve visuospatial learning or attention in children with NF1 and is not recommended for amelioration of cognitive deficits in this population. ClinicalTrials.gov identifier: This study was registered at ClinicalTrials.gov (NCT00853580) and Australian New Zealand Clinical Trials Registry (ACTRN12607000560493). Classification of evidence: This study provides Class I evidence that for children with NF1, lovastatin does not improve visuospatial learning or attention deficits. C1 [Payne, Jonathan M.; Hearps, Stephen J. C.; North, Kathryn N.] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic, Australia. [Payne, Jonathan M.; North, Kathryn N.] Univ Melbourne, Dept Paediat, Fac Med Dent & Hlth Sci, Melbourne, Vic, Australia. [Barton, Belinda] Childrens Hosp, Educ Res Inst, Westmead, NSW, Australia. [Barton, Belinda] Univ Sydney, Discipline Paediat & Child Hlth, Sydney, NSW, Australia. [Ullrich, Nicole J.; Rey-Casserly, Celiane] Boston Childrens Hosp, Dept Neurol, Boston, MA USA. [Cantor, Alan] Univ Alabama Birmingham, Dept Preventat Med, Birmingham, AL USA. [Cutter, Gary] Univ Alabama Birmingham, Sch Publ Hlth, Birmingham, AL 35294 USA. [Ackerson, Joseph D.] Univ Alabama Birmingham, Dept Psychol, Birmingham, AL 35294 USA. [Korf, Bruce] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA. [Rosser, Tena; O'Neil, Sharon H.] Childrens Hosp Los Angeles, Dept Neurol, Los Angeles, CA 90027 USA. [Walsh, Karin S.; Gioia, Gerard A.; Packer, Roger J.; Acosta, Maria T.] Childrens Natl Hlth Syst, Ctr Neurosci & Behav Med, Washington, DC USA. [Wolters, Pamela L.] NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Tonsgard, James; Hunter, Scott J.] Univ Chicago Med, Comer Childrens Hosp, Div Neurol, Chicago, IL 60637 USA. [Schorry, Elizabeth] Cincinnati Childrens Hosp Med Ctr, Human Genet, Cincinnati, OH 45229 USA. [Byars, Anna W.] Cincinnati Childrens Hosp Med Ctr, Div Neurol, Cincinnati, OH 45229 USA. [Viskochil, David] Univ Utah, Dept Genet, Salt Lake City, UT USA. [Klesse, Laura] Univ Texas Southwestern Med Ctr Dallas, Dept Pediat, Dallas, TX USA. [Fisher, Michael; Armstrong, Carol L.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Gutmann, David H.; Isenberg, Jill] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Silva, Alcino J.] Univ Calif Los Angeles, Gonda Neurosci & Genet Ctr, Los Angeles, CA 90024 USA. [Cantor, Nancy L.] Primary Childrens Med Ctr, Salt Lake City, UT USA. [Stavinoha, Peter L.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP North, KN (reprint author), Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic, Australia.; North, KN (reprint author), Univ Melbourne, Dept Paediat, Fac Med Dent & Hlth Sci, Melbourne, Vic, Australia. EM kathryn.north@mcri.edu.au FU US Army Medical Research and Materiel Command, Office of the Congressionally Directed Medical Research Programs, Department of Defense Neurofibromatosis Research Program [W81XWH-05-1-0615] FX This work was supported by the US Army Medical Research and Materiel Command, Office of the Congressionally Directed Medical Research Programs, Department of Defense Neurofibromatosis Research Program, grant W81XWH-05-1-0615. The funding source reviewed and approved the protocol. It had no role in the conception and design of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The work was also partially funded by Sally Gottesman and Rachel B. Tiven. NR 26 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 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD DEC 13 PY 2016 VL 87 IS 24 BP 2575 EP 2584 DI 10.1212/WNL.0000000000003435 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA EI1NN UT WOS:000392244200018 PM 27956565 ER PT J AU Ahmed, R Roger, L del Amo, PC Miners, KL Jones, RE Boelen, L Fali, T Elemans, M Zhang, Y Appay, V Baird, DM Asquith, B Price, DA Macallan, DC Ladell, K AF Ahmed, Raya Roger, Laureline del Amo, Pedro Costa Miners, Kelly L. Jones, Rhiannon E. Boelen, Lies Fali, Tinhinane Elemans, Marjet Zhang, Yan Appay, Victor Baird, Duncan M. Asquith, Becca Price, David A. Macallan, Derek C. Ladell, Kristin TI Human Stem Cell-like Memory T Cells Are Maintained in a State of Dynamic Flux SO CELL REPORTS LA English DT Article ID HIV DISEASE; PROLIFERATION; DIVISION; DIVERSIFICATION; DIFFERENTIATION; INFECTION; TURNOVER; WATER; DNA AB Adaptive immunity requires the generation of memory T cells from naive precursors selected in the thymus. The key intermediaries in this process are stem cell-like memory T (T-SCM) cells, multipotent progenitors that can both self-renew and replenish more differentiated subsets of memory T cells. In theory, antigen specificity within the T-SCM pool may be imprinted statically as a function of largely dormant cells and/or retained dynamically by more transitory subpopulations. To explore the origins of immunological memory, we measured the turnover of T-SCM cells in vivo using stable isotope labeling with heavy water. The data indicate that T-SCM cells in both young and elderly subjects are maintained by ongoing proliferation. In line with this finding, T-SCM cells displayed limited telomere length erosion coupled with high expression levels of active telomerase and Ki67. Collectively, these observations show that T-SCM cells exist in a state of perpetual flux throughout the human lifespan. C1 [Ahmed, Raya; Zhang, Yan; Macallan, Derek C.] St Georges Univ London, Inst Infect & Immun, London SW17 0RE, England. [Roger, Laureline; Miners, Kelly L.; Price, David A.; Ladell, Kristin] Cardiff Univ, Sch Med, Div Infect & Immun, Heath Pk, Cardiff CF14 4XN, S Glam, Wales. [del Amo, Pedro Costa; Boelen, Lies; Elemans, Marjet; Asquith, Becca] St Marys Hosp, Imperial Coll London, Dept Med, London W2 1PG, England. [Jones, Rhiannon E.; Baird, Duncan M.] Cardiff Univ, Sch Med, Div Canc & Genet, Heath Pk, Cardiff CF14 4XN, S Glam, Wales. [Fali, Tinhinane; Appay, Victor] UPMC Univ Paris 06, Sorbonne Univ, CIMI Paris, F-75013 Paris, France. [Fali, Tinhinane; Appay, Victor] CIMI Paris, INSERM U1135, F-75013 Paris, France. [Price, David A.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Macallan, Derek C.] St Georges Univ Hosp Natl Hlth Serv Fdn Trust, Blackshaw Rd, London SW17 0QT, England. RP Macallan, DC (reprint author), St Georges Univ London, Inst Infect & Immun, London SW17 0RE, England.; Price, DA; Ladell, K (reprint author), Cardiff Univ, Sch Med, Div Infect & Immun, Heath Pk, Cardiff CF14 4XN, S Glam, Wales.; Price, DA (reprint author), NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA.; Macallan, DC (reprint author), St Georges Univ Hosp Natl Hlth Serv Fdn Trust, Blackshaw Rd, London SW17 0QT, England. EM priced6@cardiff.ac.uk; macallan@sgul.ac.uk; ladellk@gmail.com RI Baird, Duncan/C-9671-2011 OI Baird, Duncan/0000-0001-8408-5467 FU Wellcome Trust [093053/Z/10/Z]; Medical Research Council [G1001052]; Cancer Research UK [C17199/A18246] FX This work was funded by the Wellcome Trust (Grant 093053/Z/10/Z), the Medical Research Council (Grant G1001052), and Cancer Research UK (Grant C17199/A18246). B.A. and D.A.P. are Wellcome Trust Investigators. The authors extend their profound thanks to all study participants. NR 32 TC 0 Z9 0 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD DEC 13 PY 2016 VL 17 IS 11 BP 2811 EP 2818 DI 10.1016/j.celrep.2016.11.037 PG 8 WC Cell Biology SC Cell Biology GA EG2SP UT WOS:000390894700002 PM 27974195 ER PT J AU Syed, KS He, XM Tillo, D Wang, J Durell, SR Vinson, C AF Syed, Khund Sayeed He, Ximiao Tillo, Desiree Wang, Jun Durell, Stewart R. Vinson, Charles TI 5-Methylcytosine (5mC) and 5-Hydroxymethylcytosine (5hmC) Enhance the DNA Binding of CREB1 to the C/EBP Half-Site Tetranucleotide GCAA SO BIOCHEMISTRY LA English DT Article ID AMP RESPONSE ELEMENT; ZIPPER COILED-COIL; VERTICAL-BAR-GTG; TRANSCRIPTION FACTORS; MEMORY FORMATION; DIMERIZATION SPECIFICITY; CG DINUCLEOTIDE; CPG METHYLATION; PROTEIN-BINDING; MAMMALIAN DNA AB In human and mouse stem cells and brain, 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) can occur outside of CG dinucleotides. Using protein binding microarrays (PBMs) containing 60-mer DNA probes, we evaluated the effect of 5mC and 5hmC on one DNA strand on the double-stranded DNA binding of the mouse B-ZIP transcription factors (TFs) CREB1, ATF1, and JUND. 5mC inhibited binding of CREB1 to the canonical CRE half-site IGTCA but enhanced binding to the C/EBP half-site IGCAA. 5hmC inhibited binding of CREB1 to all 8-mers except TGAT vertical bar GCAA, where binding is enhanced. We observed similar DNA binding patterns with ATF1, a closely related B-ZIP domain. In contrast, both 5mC and ShmC inhibited binding of JUND. These results identify new DNA sequences that are well-bound by CREB1 and ATF1 only when they contain 5mC or 5hmC. Analysis of two X-ray structures examines the consequences of 5mC and 5hmC on DNA binding by CREB and FOSIJUN. C1 [Syed, Khund Sayeed; He, Ximiao; Tillo, Desiree; Wang, Jun; Vinson, Charles] NCI, Lab Metab, NIH, Room 3128,Bldg 37, Bethesda, MD 20892 USA. [Durell, Stewart R.] NCI, Cell Biol Lab, NIH, Room 3128,Bldg 37, Bethesda, MD 20892 USA. RP Vinson, C (reprint author), NCI, Lab Metab, NIH, Room 3128,Bldg 37, Bethesda, MD 20892 USA. EM vinsonc@mail.nih.gov FU National Cancer Institute, National Institutes of Health FX This work is supported by intramural research grants from the National Cancer Institute, National Institutes of Health. NR 54 TC 0 Z9 0 U1 8 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD DEC 13 PY 2016 VL 55 IS 49 BP 6940 EP 6948 DI 10.1021/acs.biochem.6b00796 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EE8HN UT WOS:000389866400019 PM 27951657 ER PT J AU Lewis, RJ Calis, KA DeMets, DL AF Lewis, Roger J. Calis, Karim A. DeMets, David L. TI Enhancing the Scientific Integrity and Safety of Clinical Trials Recommendations for Data Monitoring Committees SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Lewis, Roger J.] Harbor UCLA Med Ctr, Dept Emergency Med, 1000 W Carson St,Bldg D9, Torrance, CA 90509 USA. [Lewis, Roger J.] Berry Consultants LLC, Austin, TX USA. [Calis, Karim A.] US FDA, Ctr Drug Evaluat & Res, Off Med Policy, Silver Spring, MD USA. [Calis, Karim A.] NICHHD, NIH, Bethesda, MD 20892 USA. [DeMets, David L.] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI 53706 USA. RP Lewis, RJ (reprint author), Harbor UCLA Med Ctr, Dept Emergency Med, 1000 W Carson St,Bldg D9, Torrance, CA 90509 USA. EM roger@emedharbor.edu FU FDA HHS [R18 FD005292, U19 FD003800] NR 1 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 DEC 13 PY 2016 VL 316 IS 22 BP 2359 EP 2360 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA EE8OE UT WOS:000389884600013 PM 27960001 ER PT J AU Lessing, D Dial, TO Wei, CY Payer, B Carrette, LLG Kesner, B Szanto, A Jadhav, A Maloney, DJ Simeonov, A Theriault, J Hasaka, T Bedalov, A Bartolomei, MS Lee, JT AF Lessing, Derek Dial, Thomas O. Wei, Chunyao Payer, Bernhard Carrette, Lieselot L. G. Kesner, Barry Szanto, Attila Jadhav, Ajit Maloney, David J. Simeonov, Anton Theriault, Jimmy Hasaka, Thomas Bedalov, Antonio Bartolomei, Marisa S. Lee, Jeannie T. TI A high-throughput small molecule screen identifies synergism between DNA methylation and Aurora kinase pathways for X reactivation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE X reactivation; high-throughput screen; small molecules; Aurora kinase; DNA methyltransferase ID EARLY MOUSE EMBRYOS; CHROMOSOME INACTIVATION; INHIBITOR SELECTIVITY; DOSAGE COMPENSATION; XIST RNA; TSIX RNA; IN-VIVO; CELLS; GENE; DIFFERENTIATION AB X-chromosome inactivation is a mechanism of dosage compensation in which one of the two X chromosomes in female mammals is transcriptionally silenced. Once established, silencing of the inactive X (Xi) is robust and difficult to reverse pharmacologically. However, the Xi is a reservoir of > 1,000 functional genes that could be potentially tapped to treat X-linked disease. To identify compounds that could reactivate the Xi, here we screened similar to 367,000 small molecules in an automated high-content screen using an Xi-linked GFP reporter in mouse fibroblasts. Given the robust nature of silencing, we sensitized the screen by "priming" cells with the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (5azadC). Compounds that elicited GFP activity include VX680, MLN8237, and 5azadC, which are known to target the Aurora kinase and DNA methylation pathways. We demonstrate that the combinations of VX680 and 5azadC, as well as MLN8237 and 5azadC, synergistically up-regulate genes on the Xi. Thus, our work identifies a synergism between the DNA methylation and Aurora kinase pathways as being one of interest for possible pharmacological reactivation of the Xi. C1 [Lessing, Derek; Dial, Thomas O.; Wei, Chunyao; Carrette, Lieselot L. G.; Kesner, Barry; Szanto, Attila; Lee, Jeannie T.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Lessing, Derek; Dial, Thomas O.; Wei, Chunyao; Carrette, Lieselot L. G.; Kesner, Barry; Szanto, Attila; Lee, Jeannie T.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Lessing, Derek; Dial, Thomas O.; Wei, Chunyao; Carrette, Lieselot L. G.; Kesner, Barry; Szanto, Attila; Lee, Jeannie T.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Payer, Bernhard] Ctr Genom Regulat, Barcelona 08003, Spain. [Carrette, Lieselot L. G.] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium. [Jadhav, Ajit; Maloney, David J.; Simeonov, Anton] Natl Ctr Adv Translat Sci, Div Preclin Innovat, NIH, Rockville, MD 20850 USA. [Theriault, Jimmy; Hasaka, Thomas] Broad Inst, Cambridge, MA 02142 USA. [Bedalov, Antonio] Fred Hutchinson Canc Res Ctr, Clin Res Div, Seattle, WA 98109 USA. [Bartolomei, Marisa S.] Univ Penn, Sch Med, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA. RP Lee, JT (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA.; Lee, JT (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.; Lee, JT (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. EM lee@molbio.mgh.harvard.edu OI Payer, Bernhard/0000-0002-4694-2082 FU Molecular Libraries Program [1 U54 HG005032-01]; Rett Syndrome Research Trust; NIH [R03-MH097478, R01-DA36895]; National Center for Research Resources Grant [1S10RR023440-01]; Human Frontier Science Program; Charles King Postdoctoral Fellowships; Fund for Scientific Research-Flanders; Belgian American Educational Foundation; Plateforme pour l'Education et le Talent; National Center for Advancing Translational Sciences; Molecular Libraries Initiative of the NIH Roadmap for Medical Research [U54MH084681] FX We thank D. Dombkowski for assistance with FACS (Massachusetts General Hospital Pathology Flow Cytometry Core), H. Sunwoo for Xist probes and FISH advice, Y. Jeon for control fibroblasts, P. Shinn and D. van Leer for assistance with compound management, and Stuart L. Schreiber and Nicola Tolliday for support as part of the Molecular Libraries Program (1 U54 HG005032-01). We acknowledge the following funding: the Rett Syndrome Research Trust (J.T.L., M.S.B., and A.B.), NIH Grants R03-MH097478 and R01-DA36895 (to J.T.L.), National Center for Research Resources Grant 1S10RR023440-01, the Human Frontier Science Program (B.P.), Charles King Postdoctoral Fellowships (to B.P.), the Fund for Scientific Research-Flanders, and the Belgian American Educational Foundation and Plateforme pour l'Education et le Talent (L.L.G.C.). A.J., D.J.M., and A. Simeonov were supported by the National Center for Advancing Translational Sciences and the Molecular Libraries Initiative of the NIH Roadmap for Medical Research (U54MH084681). J.T.L. is an Investigator of the Howard Hughes Medical Institute. NR 47 TC 1 Z9 1 U1 8 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 13 PY 2016 VL 113 IS 50 BP 14366 EP 14371 DI 10.1073/pnas.1617597113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE6CQ UT WOS:000389696700063 PM 28182563 ER PT J AU Schumann, G Liu, CY O'Reilly, P Gao, H Song, P Xu, B Ruggeri, B Amin, N Jia, T Preis, S Lepe, MS Akira, S Barbieri, C Baumeister, S Cauchi, S Clarke, TK Enroth, S Fischer, K Hallfors, J Harris, SE Hieber, S Hofer, E Hottenga, JJ Johansson, A Joshi, P Kaartinen, N Laitinen, J Lemaitre, R Loukola, A Luan, J Lyytikainen, LP Mangino, M Manichaikul, A Mbarek, H Milaneschi, Y Moayyeri, A Mukamal, K Nelson, C Nettleton, J Partinen, E Rawal, R Robino, A Rose, L Sala, C Satoh, T Schmidt, R Schrautz, K Scott, R Smith, AV Starr, JM Teumer, A Trompet, S Uitterlinden, AG Venturini, C Vergnaud, AC Verweij, N Vitart, V Vuckovic, D Wedenoja, J Yengo, L Yu, B Zhang, W Zhao, JH Boomsma, DI Chambers, J Chasman, DI Daniela, T de Geus, E Deary, I Eriksson, JG Esko, T Eulenburg, V Franco, OH Froguel, P Gieger, C Grabe, HJ Gudnason, V Gyllensten, U Harris, TB Hartikainen, AL Heath, AC Hocking, L Hofman, A Huth, C Jarvelin, MR Jukema, JW Kaprio, J Kooner, JS Kutalik, Z Lahti, J Langenberg, C Lehtimaki, T Liu, Y Madden, PAF Martin, N Morrison, A Penninx, B Pirastu, N Psaty, B Raitakari, O Ridker, P Rose, R Rotter, JI Samani, NJ Schmidt, H Spector, TD Stott, D Strachan, D Tzoulaki, I van der Harst, P van Duijn, CM Marques-Vidal, P Vollenweider, P Wareham, NJ Whitfield, JB Wilson, J Wolffenbuttel, B Bakalkin, G Evangelou, E Liu, Y Rice, KM Desrivieres, S Kliewer, SA Mangelsdorf, DJ Muller, CP Levy, D Elliott, P AF Schumann, Gunter Liu, Chunyu O'Reilly, Paul Gao, He Song, Parkyong Xu, Bing Ruggeri, Barbara Amin, Najaf Jia, Tianye Preis, Sarah Lepe, Marcelo Segura Akira, Shizuo Barbieri, Caterina Baumeister, Sebastian Cauchi, Stephane Clarke, Toni-Kim Enroth, Stefan Fischer, Krista Hallfors, Jenni Harris, Sarah E. Hieber, Saskia Hofer, Edith Hottenga, Jouke-Jan Johansson, Asa Joshi, PeterK. Kaartinen, Niina Laitinen, Jaana Lemaitre, Rozenn Loukola, Anu Luan, Jian'an Lyytikainen, Leo-Pekka Mangino, Massimo Manichaikul, Ani Mbarek, Hamdi Milaneschi, Yuri Moayyeri, Alireza Mukamal, Kenneth Nelson, Christopher Nettleton, Jennifer Partinen, Eemil Rawal, Rajesh Robino, Antonietta Rose, Lynda Sala, Cinzia Satoh, Takashi Schmidt, Reinhold Schrautz, Katharina Scott, Robert Smith, Albert Vernon Starr, John M. Teumer, Alexander Trompet, Stella Uitterlinden, Andre G. Venturini, Cristina Vergnaud, Anne-Claire Verweij, Niek Vitart, Veronique Vuckovic, Dragana Wedenoja, Juho Yengo, Loic Yu, Bing Zhang, Weihua Zhao, Jing Hua Boomsma, Dorret I. Chambers, John Chasman, Daniel I. Daniela, Toniolo de Geus, Eco Deary, Ian Eriksson, Johan G. Esko, Tonu Eulenburg, Volker Franco, Oscar H. Froguel, Philippe Gieger, Christian Grabe, Hans J. Gudnason, Vilmundur Gyllensten, Ulf Harris, Tamara B. Hartikainen, Anna-Liisa Heath, Andrew C. Hocking, Lynne Hofman, Albert Huth, Cornelia Jarvelin, Marjo-Riitta Jukema, J. Wouter Kaprio, Jaakko Kooner, Jaspal S. Kutalik, Zoltan Lahti, Jari Langenberg, Claudia Lehtimaki, Terho Liu, Yongmei Madden, Pamela A. F. Martin, Nicholas Morrison, Alanna Penninx, Brenda Pirastu, Nicola Psaty, Bruce Raitakari, Olli Ridker, Paul Rose, Richard Rotter, Jerome I. Samani, Nilesh J. Schmidt, Helena Spector, Tim D. Stott, David Strachan, David Tzoulaki, Ioanna van der Harst, Pim van Duijn, Cornelia M. Marques-Vidal, Pedro Vollenweider, Peter Wareham, Nicholas J. Whitfield, John B. Wilson, James Wolffenbuttel, Bruce Bakalkin, Georgy Evangelou, Evangelos Liu, Yun Rice, Kenneth M. Desrivieres, Sylvane Kliewer, Steven A. Mangelsdorf, David J. Muller, Christian P. Levy, Daniel Elliott, Paul TI KLB is associated with alcohol drinking, and its gene product beta-Klotho is necessary for FGF21 regulation of alcohol preference SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE alcohol consumption; human; beta-Klotho; FGF21; mouse model ID GENOME-WIDE ASSOCIATION; CONSUMPTION; DISEASE; ACTIVATION; DEPENDENCE; SWEET; LIVER; HEART; MICE AB Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified beta-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 x 10(-12)). beta-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific beta-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption. C1 [Schumann, Gunter; O'Reilly, Paul; Xu, Bing; Ruggeri, Barbara; Jia, Tianye; Desrivieres, Sylvane] Kings Coll London, MRC, Inst Psychiat Psychol & Neurosci, Social Genet & Dev Psychiat Ctr, London SE5 8AF, England. [Liu, Chunyu; Levy, Daniel] Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. [Liu, Chunyu; Levy, Daniel] NHLBI, Populat Sci Branch, Div Intramural Res, Bethesda, MD 20824 USA. [Liu, Chunyu; Preis, Sarah] Boston Univ, Sch Publ, Dept Biostat, Boston, MA 02118 USA. [Gao, He; Lepe, Marcelo Segura; Moayyeri, Alireza; Vergnaud, Anne-Claire; Zhang, Weihua; Chambers, John; Jarvelin, Marjo-Riitta; Tzoulaki, Ioanna; Evangelou, Evangelos; Elliott, Paul] Imperial Coll London, Dept Epidemiol & Biostat, Sch Publ Hlth, London W2 1PG, England. [Gao, He; Tzoulaki, Ioanna; Elliott, Paul] Imperial Coll London, MRC, Publ Hlth England Ctr Environm & Hlth, London W2 1PG, England. [Song, Parkyong; Kliewer, Steven A.; Mangelsdorf, David J.] Univ Texas Southwestern Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Song, Parkyong; Mangelsdorf, David J.] Univ Texas Southwestern Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA. [Amin, Najaf; van Duijn, Cornelia M.] Erasmus MC, Genet Epidemiol Unit, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Lepe, Marcelo Segura] Bayer Pharma AG, Sect Bioinformat, D-13342 Berlin, Germany. [Akira, Shizuo; Satoh, Takashi] Osaka Univ, World Premier Int Immunol Frontier Res Ctr, Microbial Dis Res Inst, Lab Host Def, Osaka 5650871, Japan. [Barbieri, Caterina; Sala, Cinzia; Daniela, Toniolo] San Raffaele Res Inst, Div Genet & Cell Biol, I-20132 Milan, Italy. [Baumeister, Sebastian; Teumer, Alexander] Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany. [Baumeister, Sebastian] Univ Regensburg, Dept Epidemiol & Prevent Med, D-93053 Regensburg, Germany. [Cauchi, Stephane; Yengo, Loic; Froguel, Philippe] Univ Lille 2, European Genom Inst Diabet, Lille Pasteur Inst, CNRS,UMR 8199, F-59000 Lille, France. [Clarke, Toni-Kim] Univ Edinburgh, Div Psychiat, Edinburgh EH10 5HF, Midlothian, Scotland. [Enroth, Stefan; Johansson, Asa; Gyllensten, Ulf] Uppsala Univ, Sci Life Lab, Dept Immunol Genet & Pathol, S-75108 Uppsala, Sweden. [Fischer, Krista; Esko, Tonu] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia. [Hallfors, Jenni; Loukola, Anu; Kaprio, Jaakko] Univ Helsinki, Inst Mol Med, Helsinki 00290, Finland. [Harris, Sarah E.; Starr, John M.; Deary, Ian] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Harris, Sarah E.] Univ Edinburgh, Ctr Genom & Expt Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Hieber, Saskia; Muller, Christian P.] Friedrich Alexander Univ Erlangen Nuremberg, Dept Psychiat & Psychotherapy, D-91054 Erlangen, Germany. [Hofer, Edith; Schmidt, Reinhold] Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, A-8036 Graz, Austria. [Hofer, Edith] Med Univ Graz, Inst Med Informat Stat & Documentat, A-8036 Graz, Austria. [Hottenga, Jouke-Jan; Mbarek, Hamdi; Boomsma, Dorret I.; de Geus, Eco] Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands. [Hottenga, Jouke-Jan; Mbarek, Hamdi; Boomsma, Dorret I.; de Geus, Eco] EMGO Inst Hlth & Care Res, NL-1081 BT Amsterdam, Netherlands. [Joshi, PeterK.; Schrautz, Katharina; Pirastu, Nicola; Wilson, James] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland. [Kaartinen, Niina; Eriksson, Johan G.; Kaprio, Jaakko] Natl Inst Hlth & Welf, Helsinki 00271, Finland. [Laitinen, Jaana] Finnish Inst Occupat Hlth, Quantified Employee Unit, Helsinki 00250, Finland. [Lemaitre, Rozenn; Psaty, Bruce] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. [Loukola, Anu; Wedenoja, Juho; Kaprio, Jaakko] Univ Helsinki, Dept Publ Hlth, FIN-00014 Helsinki, Finland. [Luan, Jian'an; Langenberg, Claudia] Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit,Inst Metab Sci, Cambridge CB2 0QQ, England. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Univ Tampere, Sch Med, Tampere 33520, Finland. [Mangino, Massimo; Venturini, Cristina; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Mangino, Massimo] Guys & St Thomas Fdn Trust, Natl Inst Hlth Res, Biomed Res Ctr, London SE1 9RT, England. [Manichaikul, Ani] Univ Virginia, Ctr Publ Hlth Genom, Dept Publ Hlth Sci, Charlottesville, VA 22903 USA. [Manichaikul, Ani] Univ Virginia, Biostat Sect, Dept Publ Hlth Sci, Charlottesville, VA 22903 USA. [Milaneschi, Yuri; Penninx, Brenda] Vrije Univ Amsterdam, Inst Hlth & Care Res EMGO, Inst Hlth & Care Res, Dept Psychiat,Univ Med Ctr,Geestelijke Gezondheid, NL-1081 HL Amsterdam, Netherlands. [Milaneschi, Yuri; Penninx, Brenda] Vrije Univ Amsterdam, Neurosci Campus Amsterdam, Univ Med Ctr, Geestelijke Gezondheids Zorg GGZ InGeest, NL-1081 HL Amsterdam, Netherlands. [Moayyeri, Alireza] UCL, Inst Hlth Informat, London NW1 2DA, England. [Moayyeri, Alireza] UCL, Inst Hlth Informat, Farr Inst Hlth Informat Res, London NW1 2DA, England. [Mukamal, Kenneth] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Mukamal, Kenneth; Chasman, Daniel I.; Ridker, Paul] Harvard Med Sch, Boston, MA 02215 USA. [Nelson, Christopher; Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England. [Nelson, Christopher; Samani, Nilesh J.] Glenfield Hosp, Natl Inst Hlth Res, Leicester Cardiovasc Biomed Res Unit, Leicester LE3 9QP, Leics, England. [Nettleton, Jennifer] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol Human Genet & Environm Sci, Houston, TX 77225 USA. [Partinen, Eemil] Univ Tartu, Fac Med, EE-50411 Tartu, Estonia. [Rawal, Rajesh; Gieger, Christian] Helmholtz Zentrum Munchen, Dept Mol Epidemiol, Inst Epidemiol 2, D-85764 Neuherberg, Germany. [Robino, Antonietta] Ist Ricovero & Cura Carattere Sci IRCCS Burlo Gar, Inst Maternal & Child Hlth, I-34137 Trieste, Italy. [Rose, Lynda; Chasman, Daniel I.; Ridker, Paul] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. [Scott, Robert; Zhao, Jing Hua; Wareham, Nicholas J.] Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit, Cambridge CB2 0QQ, England. [Smith, Albert Vernon; Gudnason, Vilmundur] Iceland Heart Assoc, Res Inst, IS-201 Kopavogur, Iceland. [Starr, John M.] Univ Edinburgh, Alzheimer Scotland Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland. [Teumer, Alexander] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, D-17475 Greifswald, Germany. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 RC Leiden, Netherlands. [Trompet, Stella] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, NL-2300 RC Leiden, Netherlands. [Uitterlinden, Andre G.; Jarvelin, Marjo-Riitta] Erasmus MC, Dept Internal Med, NL-3015 CN Rotterdam, Netherlands. [Uitterlinden, Andre G.; Franco, Oscar H.; Hofman, Albert] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Verweij, Niek; van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 RB Groningen, Netherlands. [Vitart, Veronique; Wilson, James] Univ Edinburgh, Western Gen Hosp, MRC, Human Genet Unit,Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Vuckovic, Dragana; Pirastu, Nicola] Univ Trieste, Dept Med Sci, I-34149 Trieste, Italy. [Yu, Bing; Morrison, Alanna] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Houston, TX 77225 USA. [Yu, Bing] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol, Houston, TX 77225 USA. [Zhang, Weihua; Chambers, John; Kooner, Jaspal S.] Ealing Gen Hosp, Dept Cardiol, Southall UB1 3HW, Middx, England. [Chambers, John; Kooner, Jaspal S.] Imperial Coll Healthcare Natl Hlth Serv Trust, London W12 0HS, England. [Deary, Ian] Univ Edinburgh, Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, FIN-00014 Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, FIN-00014 Helsinki, Finland. [Eriksson, Johan G.; Lahti, Jari] Publ Hlth Res, Folkhalsan Res Ctr, Helsinki 00290, Finland. [Eriksson, Johan G.] Vasa Cent Hosp, Vaasa 65130, Finland. [Eulenburg, Volker] Friedrich Alexander Univ Erlangen Nuremberg, Inst Biochem & Mol Med, D-91054 Erlangen, Germany. [Froguel, Philippe] Imperial Coll London, Dept Genom Common Dis, Sch Publ Hlth, London W12 0HR, England. [Grabe, Hans J.] Univ Med Greifswald, Dept Psychiat & Psychotherapy, D-17475 Greifswald, Germany. [Gudnason, Vilmundur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Harris, Tamara B.] NIA, NIH, Bethesda, MD 20892 USA. [Hartikainen, Anna-Liisa] Oulu Univ Hosp, Dept Obstet & Gynecol, Oulu 90029, Finland. [Hartikainen, Anna-Liisa] Univ Oulu, MRC, Oulu 90014, Finland. [Hartikainen, Anna-Liisa; Jarvelin, Marjo-Riitta] Oulu Univ Hosp, Unit Primary Care, Oulu 90220, Finland. [Heath, Andrew C.; Madden, Pamela A. F.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Hocking, Lynne] Univ Aberdeen, Inst Med Sci, Aberdeen AB25 2ZD, Scotland. [Huth, Cornelia] German Res Ctr Environm Hlth GmbH, Inst Epidemiol 2, Helmholtz Zentrum Munchen, D-85764 Neuherberg, Germany. [Jarvelin, Marjo-Riitta] Univ Oulu, Fac Med, Ctr Life Course Epidemiol, FI-90014 Oulu, Finland. [Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, FI-90014 Oulu, Finland. [Kooner, Jaspal S.] Imperial Coll London, Hammersmith Hosp, Natl Heart & Lung Inst, Fac Med,Cardiovasc Sci, London W12 0NN, England. [Kutalik, Zoltan] Ctr Hosp Univ Vaudoise, Inst Social & Prevent Med, CH-1010 Lausanne, Switzerland. [Lahti, Jari] Univ Helsinki, Coll Adv Studies, FIN-00014 Helsinki, Finland. [Lahti, Jari] Univ Helsinki, Inst Behav Sci, FIN-00014 Helsinki, Finland. [Liu, Yongmei] Wake Forest Sch Med, Wake Forest Sch Med, Dept Epidemiol & Prevent, Publ Hlth Sci, Winston Salem, NC 27157 USA. [Martin, Nicholas; Whitfield, John B.] Queensland Inst Med Res, Berghofer Med Res Inst, Genet Epidemiol, Brisbane, Qld 4029, Australia. [Psaty, Bruce] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA 98101 USA. [Raitakari, Olli] Univ Turku, Dept Clin Physiol & Nucl Med, Turku Univ Hosp, FIN-20520 Turku, Finland. [Raitakari, Olli] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FIN-20520 Turku, Finland. [Rose, Richard] Indiana Univ, Dept Psychol & Brain Sci, Bloomington, IN 47405 USA. [Rotter, Jerome I.] Univ Calif Los Angeles, Los Angeles Biomed Res Inst Harbor, Med Ctr, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Schmidt, Helena] Med Univ Graz, Inst Mol Biol & Biochem, Ctr Mol Med, A-8010 Graz, Austria. [Stott, David] Univ Glasgow, Inst Cardiovasc & Med Sci, Fac Med, Glasgow G31 2ER, Lanark, Scotland. [Strachan, David] St Georges Univ London, Populat Hlth Res Inst, London SW17 0RE, England. [Tzoulaki, Ioanna; Evangelou, Evangelos] Univ Ioannina, Dept Hyg & Epidemiol, Med Sch, GR-45110 Ioannina, Greece. [van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands. [van der Harst, Pim] Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Interuniv Cardiol Inst Netherlands, NL-3511 GC Utrecht, Netherlands. [Marques-Vidal, Pedro; Vollenweider, Peter] Univ Lausanne Hosp, Dept Med, Internal Med, CH-1011 Lausanne, Switzerland. [Wolffenbuttel, Bruce] Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, NL-9700 RB Groningen, Netherlands. [Bakalkin, Georgy] Uppsala Univ, Div Biol Res Drug Dependence, Dept Pharmaceut, Biosci, NL-75124 Uppsala, Netherlands. [Liu, Yun] Minist Educ, Key Lab Metab & Mol Med, Shanghai 200032, Peoples R China. [Liu, Yun] Fudan Univ, Shanghai Med Coll, Dept Biochem & Mol Biol, Shanghai 200032, Peoples R China. [Rice, Kenneth M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Kliewer, Steven A.] Univ Texas Southwestern Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA. RP Schumann, G (reprint author), Kings Coll London, MRC, Inst Psychiat Psychol & Neurosci, Social Genet & Dev Psychiat Ctr, London SE5 8AF, England.; Elliott, P (reprint author), Imperial Coll London, Dept Epidemiol & Biostat, Sch Publ Hlth, London W2 1PG, England.; Elliott, P (reprint author), Imperial Coll London, MRC, Publ Hlth England Ctr Environm & Hlth, London W2 1PG, England.; Mangelsdorf, DJ (reprint author), Univ Texas Southwestern Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA.; Mangelsdorf, DJ (reprint author), Univ Texas Southwestern Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA. EM gunter.schumann@kcl.ac.uk; davo.mango@utsouthwestern.edu; p.elliott@imperial.ac.uk RI Verweij, Niek/A-4499-2017; Colaus, PsyColaus/K-6607-2013; Akira, Shizuo/C-3134-2009; Yengo, Loic/D-2692-2017; Eulenburg, Volker/B-7263-2013; OI Yengo, Loic/0000-0002-4272-9305; Eulenburg, Volker/0000-0002-4878-5746; Loukola, Anu-Maria/0000-0003-0542-5967; Wedenoja, Juho/0000-0002-6155-0378; Kaprio, Jaakko/0000-0002-3716-2455; Lahti, Jari/0000-0002-4310-5297 FU Medical Research Council-UK Medical Bioinformatics Partnership Programme [MR/L01632X/1] FX Funding sources and acknowledgments for contributing authors and consortia can be found in SI Appendix. Part of this work used computing resources provided by Medical Research Council-funded UK Medical Bioinformatics Partnership Programme MR/L01632X/1. NR 26 TC 0 Z9 0 U1 13 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 13 PY 2016 VL 113 IS 50 BP 14372 EP 14377 DI 10.1073/pnas.1611243113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE6CQ UT WOS:000389696700064 PM 27911795 ER PT J AU Urs, NM Gee, SM Pack, TF McCorvy, JD Evron, T Snyder, JC Yang, XB Rodriguiz, RM Borrelli, E Wetsel, WC Jin, J Roth, BL O'Donnell, P Caron, MG AF Urs, Nikhil M. Gee, Steven M. Pack, Thomas F. McCorvy, John D. Evron, Tama Snyder, Joshua C. Yang, Xiaobao Rodriguiz, Ramona M. Borrelli, Emiliana Wetsel, William C. Jin, Jian Roth, Bryan L. O'Donnell, Patricio Caron, Marc G. TI Distinct cortical and striatal actions of a beta-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE arrestin; antipsychotics; biased signaling; dopamine D2R; fast-spiking interneurons ID MEDIAL PREFRONTAL CORTEX; PROTEIN-COUPLED RECEPTORS; MEDIUM SPINY NEURONS; BASAL GANGLIA; BETA(2)-ADRENERGIC RECEPTOR; FUNCTIONAL SELECTIVITY; CLATHRIN ADAPTER; LITHIUM ACTION; SCHIZOPHRENIA; MICE AB The current dopamine (DA) hypothesis of schizophrenia postulates striatal hyperdopaminergia and cortical hypodopaminergia. Although partial agonists at DA D2 receptors (D2Rs), like aripiprazole, were developed to simultaneously target both phenomena, they do not effectively improve cortical dysfunction. In this study, we investigate the potential for newly developed beta-arrestin2 (beta arr2)-biased D2R partial agonists to simultaneously target hyper-and hypodopaminergia. Using neuron-specific beta arr2-KO mice, we show that the antipsychotic-like effects of a beta arr2-biased D2R ligand are driven through both striatal antagonism and cortical agonism of D2R-beta arr2 signaling. Furthermore, beta arr2-biased D2R agonism enhances firing of cortical fast-spiking interneurons. This enhanced cortical agonism of the biased ligand can be attributed to a lack of G-protein signaling and elevated expression of beta arr2 and G protein-coupled receptor (GPCR) kinase 2 in the cortex versus the striatum. Therefore, we propose that beta arr2-biased D2R ligands that exert region-selective actions could provide a path to develop more effective antipsychotic therapies. C1 [Urs, Nikhil M.; Pack, Thomas F.; Evron, Tama; Snyder, Joshua C.; Wetsel, William C.; Caron, Marc G.] Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. [Gee, Steven M.; O'Donnell, Patricio] Pfizer Inc, Neurosci & Pain Res Unit, Cambridge, MA 02139 USA. [McCorvy, John D.; Roth, Bryan L.] Univ North Carolina Chapel Hill, Dept Pharmacol, Sch Med, Chapel Hill, NC 27514 USA. [McCorvy, John D.; Roth, Bryan L.] Univ North Carolina Chapel Hill, Div Chem Biol & Med Chem, Sch Med, Chapel Hill, NC 27514 USA. [McCorvy, John D.; Roth, Bryan L.] Univ North Carolina Chapel Hill, NIMH, Sch Med, Psychoact Drug Screening Program, Chapel Hill, NC 27514 USA. [Yang, Xiaobao; Jin, Jian] Icahn Sch Med Mt Sinai, Dept Struct & Chem Biol, New York, NY 10029 USA. [Yang, Xiaobao; Jin, Jian] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA. [Yang, Xiaobao; Jin, Jian] Icahn Sch Med Mt Sinai, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA. [Rodriguiz, Ramona M.; Wetsel, William C.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. [Borrelli, Emiliana] Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92697 USA. [Wetsel, William C.; Caron, Marc G.] Duke Univ, Med Ctr, Dept Med & Neurobiol, Durham, NC 27710 USA. RP Caron, MG (reprint author), Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA.; Caron, MG (reprint author), Duke Univ, Med Ctr, Dept Med & Neurobiol, Durham, NC 27710 USA. EM marc.caron@dm.duke.edu FU NIH [5R37-MH-073853, 5U-19-MH-082441]; Sidney R. Baer Jr. Foundation; Pall Family Foundation; Ruth K. Broad Biomedical Research Foundation; National Cancer Institute (NCI) Clinical Oncology Research Career Development Program [NCI 5K12-CA100639-10]; Institutional Development Award (IDeA) Centers of Biomedical Research Excellence (COBRE) Program of NIH/National Institute of General Medical Sciences [P30 GM103328]; Cuyahoga County Medical Examiner's Office FX We thank Xiuqin Zhang and Benjamin Phillips for maintenance of the mouse colony. Antibodies to beta arr2 for Western blot analyses (A2CT) and beta arr2-specific IHC antibody were generous gifts from Dr. Robert Lefkowitz (Duke University) and Dr. Jeff Benovic (Thomas Jefferson University), respectively. Human postmortem brain samples were obtained from Dr. Craig Stockmeier (Postmortem Brain Core, University of Mississippi Medical Center). We also acknowledge the assistance of Dr. James C. Overholser, Dr. George Jurjus, and Lesa Dieter in psychiatric assessments and Gouri Mahajan in tissue preparation. This work was supported, in part, by NIH Grants 5R37-MH-073853 and 5U-19-MH-082441. Support from the Sidney R. Baer Jr. Foundation (N.M.U.) and the Pall Family Foundation (M.G.C.) for parts of this work is also greatly appreciated. This study was also supported by an award from the Ruth K. Broad Biomedical Research Foundation (T.F.P.) and the National Cancer Institute (NCI) Clinical Oncology Research Career Development Program NCI 5K12-CA100639-10 (to J.C.S.). Some of the behavioral experiments were conducted with equipment and software purchased with a North Carolina Biotechnology Center grant. The Postmortem Brain core is supported by Institutional Development Award (IDeA) Centers of Biomedical Research Excellence (COBRE) Program of NIH/National Institute of General Medical Sciences Grant P30 GM103328. We acknowledge the support of the Cuyahoga County Medical Examiner's Office. NR 95 TC 1 Z9 1 U1 12 U2 12 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 DEC 13 PY 2016 VL 113 IS 50 BP E8178 EP E8186 DI 10.1073/pnas.1614347113 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE6CQ UT WOS:000389696700021 PM 27911814 ER PT J AU Yuan, J Cha, J Deng, WB Bartos, A Sun, XF Ho, HYH Borg, JP Yamaguchi, TP Yang, YZ Dey, SK AF Yuan, Jia Cha, Jeeyeon Deng, Wenbo Bartos, Amanda Sun, Xiaofei Ho, Hsin-Yi Henry Borg, Jean-Paul Yamaguchi, Terry P. Yang, Yingzi Dey, Sudhansu K. TI Planar cell polarity signaling in the uterus directs appropriate positioning of the crypt for embryo implantation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE PCP; Vangl2; embryo implantation; uterus; crypt ID PROTEIN ASSEMBLIES; WNT/BETA-CATENIN; TUBE DEFECTS; WNT; MICE; MORPHOGENESIS; PATHWAYS; VANGL2; GROWTH; PHOSPHORYLATION AB Blastocyst implantation is a complex process requiring coordination of a dynamic sequence of embryo-uterine interactions. Blood vessels enter the uterus from the mesometrium, demarcating the uterus into mesometrial (M) and antimesometrial (AM) domains. Implantation occurs along the uterine longitudinal axis within specialized implantation chambers (crypts) that originate within the evaginations directed from the primary lumen toward the AM domain. The morphological orientation of crypts in rodent uteri was recognized more than a century ago, but the mechanism remained unknown. Here we provide evidence that planar cell polarity (PCP) signaling orchestrates directed epithelial evaginations to form crypts for implantation in mice. Uterine deletion of Vang-like protein 2, but not Vang-like protein 1, conferred aberrant PCP signaling, misdirected epithelial evaginations, defective crypt formation, and blastocyst attachment, leading to severely compromised pregnancy outcomes. The study reveals a previously unrecognized role for PCP in executing spatial cues for crypt formation and implantation. Because PCP is an evolutionarily conserved phenomenon, our study is likely to inspire implantation studies of this signaling pathway in humans and other species. C1 [Yuan, Jia; Cha, Jeeyeon; Deng, Wenbo; Bartos, Amanda; Sun, Xiaofei; Dey, Sudhansu K.] Cincinnati Childrens Hosp Med Ctr, Div Reprod Sci, Cincinnati, OH 45229 USA. [Ho, Hsin-Yi Henry] Univ Calif Davis, Dept Cell Biol & Human Anat, Davis, CA 95616 USA. [Borg, Jean-Paul] Aix Marseille Univ, Ctr Rech Cancerol Marseille, UM105, F-3284 Marseille, France. [Borg, Jean-Paul] Cell Polar Cell Signalling & Canc Equipe Labellis, INSERM, U1068, CNRS,UMR7258, F-13009 Marseille, France. [Yamaguchi, Terry P.] NCI, Canc & Dev Biol Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Yang, Yingzi] Harvard Sch Dent Med, Dept Dev Biol, Boston, MA 02115 USA. [Cha, Jeeyeon] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA. RP Dey, SK (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Reprod Sci, Cincinnati, OH 45229 USA. EM sk.dey@cchmc.org FU NIH [R01HD068524, DA006668, P01CA77839]; March of Dimes; University of Cincinnati Medical Scientist Training Program [F30AG040858] FX We thank Katie A. Gerhardt for efficient editing and preparation of the manuscript; Yingju Li for help in some histological sectioning; Alexandra Tavenier for help in genotyping; Elaine Fuchs (Rockefeller University) and Ed Laufer (Columbia University) for kindly providing the Celsr1 and pSmad1/5/8 antibodies, respectively; and Matt Kofron for support with confocal imaging at the Cincinnati Children's Nikon Center of Excellence in Imaging and Services. This work was supported in part by NIH Grants R01HD068524, DA006668, and P01CA77839 and by grants from the March of Dimes (to S.K.D.). J.C. was the recipient of National Research Service Fellow Award F30AG040858 of the University of Cincinnati Medical Scientist Training Program. NR 67 TC 0 Z9 0 U1 1 U2 1 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 DEC 13 PY 2016 VL 113 IS 50 BP E8079 EP E8088 DI 10.1073/pnas.1614946113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE6CQ UT WOS:000389696700010 PM 27911818 ER PT J AU Jin, H St Hilaire, C Huang, YT Yang, D Dmitrieva, NI Negro, A Schwartzbeck, R Liu, YTY Yu, Z Walts, A Davaine, JM Lee, DY Donahue, D Hsu, KS Chen, J Cheng, T Gahl, W Chen, GB Boehm, M AF Jin, Hui St Hilaire, Cynthia Huang, Yuting Yang, Dan Dmitrieva, Natalia I. Negro, Alejandra Schwartzbeck, Robin Liu, Yangtengyu Yu, Zhen Walts, Avram Davaine, Jean-Michel Lee, Duck-Yeon Donahue, Danielle Hsu, Kevin S. Chen, Jessica Cheng, Tao Gahl, William Chen, Guibin Boehm, Manfred TI Increased activity of TNAP compensates for reduced adenosine production and promotes ectopic calcification in the genetic disease ACDC SO SCIENCE SIGNALING LA English DT Article ID PLURIPOTENT STEM-CELLS; GENERALIZED ARTERIAL CALCIFICATION; NONSPECIFIC ALKALINE-PHOSPHATASE; HUMAN EMBRYONIC STEM; VASCULAR CALCIFICATION; NT5E MUTATIONS; STROMAL CELLS; MICE; DIFFERENTIATION; MINERALIZATION AB ACDC (arterial calcification due to deficiency of CD73) is an autosomal recessive disease resulting from loss-offunction mutations in NT5E, which encodes CD73, a 5'-ectonucleotidase that converts extracellular adenosine monophosphate to adenosine. ACDC patients display progressive calcification of lower extremity arteries, causing limb ischemia. Tissue-nonspecific alkaline phosphatase (TNAP), which converts pyrophosphate (PPi) to inorganic phosphate (Pi), and extracellular purine metabolism play important roles in other inherited forms of vascular calcification. Compared to cells from healthy subjects, induced pluripotent stem cell-derived mesenchymal stromal cells (iMSCs) from ACDC patients displayed accelerated calcification and increased TNAP activity when cultured under conditions that promote osteogenesis. TNAP activity generated adenosine in iMSCs derived from ACDC patients but not in iMSCs from control subjects, which have CD73. In response to osteogenic stimulation, ACDC patient-derived iMSCs had decreased amounts of the TNAP substrate PPi, an inhibitor of extracellular matrix calcification, and exhibited increased activation of AKT, mechanistic target of rapamycin (mTOR), and the 70-kDa ribosomal protein S6 kinase (p70S6K), a pathway that promotes calcification. In vivo, teratomas derived from ACDC patient cells showed extensive calcification and increased TNAP activity. Treating mice bearing these teratomas with an A2b adenosine receptor agonist, the mTOR inhibitor rapamycin, or the bisphosphonate etidronate reduced calcification. These results show that an increase of TNAP activity in ACDC contributes to ectopic calcification by disrupting the extracellular balance of PPi and Pi and identify potential therapeutic targets for ACDC. C1 [Jin, Hui; St Hilaire, Cynthia; Huang, Yuting; Yang, Dan; Dmitrieva, Natalia I.; Negro, Alejandra; Schwartzbeck, Robin; Liu, Yangtengyu; Yu, Zhen; Walts, Avram; Davaine, Jean-Michel; Lee, Duck-Yeon; Donahue, Danielle; Hsu, Kevin S.; Chen, Jessica; Gahl, William; Chen, Guibin; Boehm, Manfred] NHLBI, Ctr Mol Med, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. [Lee, Duck-Yeon] NHLBI, Biochem Facil, NIH, Bethesda, MD 20892 USA. [Donahue, Danielle] NINDS, Mouse Imaging Facil, NIH, Bethesda, MD 20892 USA. [Hsu, Kevin S.; Gahl, William] NHGRI, Med Genet Branch, NIH, Bldg 10,Room 10C103, Bethesda, MD 20892 USA. [Jin, Hui; Cheng, Tao] Chinese Acad Med Sci, Inst Hematol, State Key Lab Expt Hematol, Tianjin 300020, Peoples R China. [Jin, Hui; Cheng, Tao] Chinese Acad Med Sci, Blood Dis Hosp, Tianjin 300020, Peoples R China. [Jin, Hui; Cheng, Tao] Peking Union Med Coll, Tianjin 300020, Peoples R China. [St Hilaire, Cynthia] Univ Pittsburgh, Sch Med, Div Cardiol, BST 1744,200 Lothrop St, Pittsburgh, PA 15261 USA. [St Hilaire, Cynthia] Univ Pittsburgh, Sch Med, Vasc Med Inst, BST 1744,200 Lothrop St, Pittsburgh, PA 15261 USA. [Huang, Yuting] Childrens Res Inst, Childrens Natl Hlth Syst, Ctr Canc & Immunol Res, 111 Michigan Ave NW, Washington, DC 20010 USA. [Davaine, Jean-Michel] CHU Pitie Salpetriere, CH Pontoise, Dept Vasc Surg, 6 Ave lIle De France, F-95300 Pontoise, France. RP Chen, GB; Boehm, M (reprint author), NHLBI, Ctr Mol Med, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM chengb@nhlbi.nih.gov; boehmm@nhlbi.nih.gov RI Ma, Yuchi/D-2690-2017; OI St. Hilaire, Cynthia/0000-0003-1871-6915 FU Intramural Research Program of the NHLBI [K22 HL117917]; Ministry of Science and Technology of China [2016ZY05002341, 2011CB964800, 2013CB966902]; National Natural Science Foundation of China [81421002] FX This study was supported by the Intramural Research Program of the NHLBI (M.B.) and K22 HL117917 (C.S.H.), Ministry of Science and Technology of China (2016ZY05002341, 2011CB964800, and 2013CB966902), and the National Natural Science Foundation of China (81421002). NR 52 TC 0 Z9 0 U1 5 U2 5 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD DEC 13 PY 2016 VL 9 IS 458 AR ra121 DI 10.1126/scisignal.aaf9109 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EE5LL UT WOS:000389648900001 PM 27965423 ER PT J AU Ligthart, S Marzi, C Aslibekyan, S Mendelson, MM Conneely, KN Tanaka, T Colicino, E Waite, LL Joehanes, R Guan, WH Brody, JA Elks, C Marioni, R Jhun, MA Agha, G Bressler, J Ward-Caviness, CK Chen, BH Huan, TX Bakulski, K Salfati, EL Wahl, S Schramm, K Sha, J Hernandez, DG Just, AC Smith, JA Sotoodehnia, N Pilling, LC Pankow, JS Tsao, PS Liu, CY Zhao, W Guarrera, S Michopoulos, VJ Smith, AK Peters, MJ Melzer, D Vokonas, P Fornage, M Prokisch, H Bis, JC Chu, AY Herder, C Grallert, H Yao, C Shah, S McRae, AF Lin, HH Horvath, S Fallin, D Hofman, A Wareham, NJ Wiggins, KL Feinberg, AP Starr, JM Visscher, PM Murabito, JM Kardia, SLR Absher, DM Binder, EB Singleton, AB Bandinelli, S Peters, A Waldenberger, M Matullo, G Schwartz, JD Demerath, EW Uitterlinden, AG van Meurs, JBJ Franco, OH Chen, YDI Levy, D Turner, ST Deary, IJ Ressler, KJ Dupuis, J Ferrucci, L Ong, KK Assimes, TL Boerwinkle, E Koenig, W Arnett, DK Baccarelli, AA Benjamin, EJ Dehghan, A AF Ligthart, Symen Marzi, Carola Aslibekyan, Stella Mendelson, Michael M. Conneely, Karen N. Tanaka, Toshiko Colicino, Elena Waite, Lindsay L. Joehanes, Roby Guan, Weihua Brody, Jennifer A. Elks, Cathy Marioni, Riccardo Jhun, Min A. Agha, Golareh Bressler, Jan Ward-Caviness, Cavin K. Chen, Brian H. Huan, Tianxiao Bakulski, Kelly Salfati, Elias L. Wahl, Simon Schramm, Katharina Sha, Jin Hernandez, Dena G. Just, Allan C. Smith, Jennifer A. Sotoodehnia, Nona Pilling, Luke C. Pankow, James S. Tsao, Phil S. Liu, Chunyu Zhao, Wei Guarrera, Simonetta Michopoulos, Vasiliki J. Smith, Alicia K. Peters, Marjolein J. Melzer, David Vokonas, Pantel Fornage, Myriam Prokisch, Holger Bis, Joshua C. Chu, Audrey Y. Herder, Christian Grallert, Harald Yao, Chen Shah, Sonia McRae, Allan F. Lin, Honghuang Horvath, Steve Fallin, Daniele Hofman, Albert Wareham, Nicholas J. Wiggins, Kerri L. Feinberg, Andrew P. Starr, John M. Visscher, Peter M. Murabito, Joanne M. Kardia, Sharon L. R. Absher, Devin M. Binder, Elisabeth B. Singleton, Andrew B. Bandinelli, Stefania Peters, Annette Waldenberger, Melanie Matullo, Giuseppe Schwartz, Joel D. Demerath, Ellen W. Uitterlinden, Andre G. van Meurs, Joyce B. J. Franco, Oscar H. Chen, Yii-Der Ida Levy, Daniel Turner, Stephen T. Deary, Ian J. Ressler, Kerry J. Dupuis, Josee Ferrucci, Luigi Ong, Ken K. Assimes, Themistocles L. Boerwinkle, Eric Koenig, Wolfgang Arnett, Donna K. Baccarelli, Andrea A. Benjamin, Emelia J. Dehghan, Abbas CA WHI-EMPC Invest Giovanni Fiorito CHARGE Epigenetics Coronary Heart TI DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases SO GENOME BIOLOGY LA English DT Article DE Inflammation; DNA methylation; Epigenome-wide association study; C-reactive protein; Body mass index; Diabetes; Coronary heart disease ID WIDE ASSOCIATION; ATHEROSCLEROSIS AB Background: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation. Results: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 x 10(-7)) in the discovery panel of European ancestry and replicated (P < 2.29 x 10(-4)) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 x 10(-5)), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 x 10(-3)), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58x 10(-5)). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R-2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants. Conclusion: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation. C1 [Ligthart, Symen; Hofman, Albert; Franco, Oscar H.; Dehghan, Abbas] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Marzi, Carola; Wahl, Simon; Grallert, Harald; Waldenberger, Melanie] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Inst Epidemiol 2, Neuherber, Germany. [Marzi, Carola; Wahl, Simon; Grallert, Harald] German Ctr Diabet Res DZD eV, Munich, Germany. [Aslibekyan, Stella; Sha, Jin] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Mendelson, Michael M.; Murabito, Joanne M.; Levy, Daniel; Benjamin, Emelia J.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Mendelson, Michael M.] Boston Childrens Hosp, Dept Cardiol, Boston, MA USA. [Mendelson, Michael M.; Huan, Tianxiao; Liu, Chunyu; Chu, Audrey Y.; Yao, Chen; Levy, Daniel; Dehghan, Abbas] NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA. [Conneely, Karen N.] Emory Univ, Dept Human Genet, Sch Med, Atlanta, GA 30322 USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Colicino, Elena; Agha, Golareh; Just, Allan C.; Baccarelli, Andrea A.; Dehghan, Abbas] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Waite, Lindsay L.; Absher, Devin M.] HudsonAlpha Inst Biotechnol, Huntsville, AL USA. [Joehanes, Roby] Harvard Med Sch, Hebrew SeniorLife, Boston, MA USA. [Guan, Weihua] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. [Brody, Jennifer A.; Sotoodehnia, Nona; Bis, Joshua C.; Wiggins, Kerri L.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA. [Elks, Cathy; Wareham, Nicholas J.; Ong, Ken K.] Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England. [Marioni, Riccardo; Starr, John M.; Visscher, Peter M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Marioni, Riccardo; Starr, John M.; Deary, Ian J.; Dehghan, Abbas] Univ Edinburgh, Med Genet Sect, Ctr Genom & Expt Med, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Marioni, Riccardo; Shah, Sonia; McRae, Allan F.; Visscher, Peter M.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Jhun, Min A.; Smith, Jennifer A.; Zhao, Wei; Kardia, Sharon L. R.; Dehghan, Abbas] Univ Michigan, Dept Epidemiol, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Bressler, Jan; Fornage, Myriam; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Houston, TX 77030 USA. [Ward-Caviness, Cavin K.; Peters, Annette] Helmholtz Zentrum Munchen, Inst Epidemiol 2, German Res Ctr Environm Hlth, Neuherber, Germany. [Chen, Brian H.] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Bakulski, Kelly; Fallin, Daniele; Feinberg, Andrew P.] Johns Hopkins Univ, Ctr Epigenet, Sch Med, Baltimore, MD USA. [Salfati, Elias L.] Stanford Univ, Dept Med, Div Cardiovasc Med, Sch Med, Stanford, CA 94305 USA. [Guarrera, Simonetta; Matullo, Giuseppe] Human Genet Fdn, Turin, Italy. [Guarrera, Simonetta; Matullo, Giuseppe; WHI-EMPC Invest Giovanni Fiorito] Univ Turin, Dept Med Sci, Turin, Italy. [Schramm, Katharina; Prokisch, Holger] German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Inst Human Genet, Neuherberg, Germany. [Schramm, Katharina; Prokisch, Holger] Tech Univ Munich, Inst Human Genet, Munich, Germany. [Hernandez, Dena G.; Singleton, Andrew B.] NIA, Lab Neurogenet, Bethesda, MD 20892 USA. [Pilling, Luke C.; Melzer, David] Univ Exeter, Epidemiol & Publ Hlth, Sch Med, Exeter, Devon, England. [Pankow, James S.; Demerath, Ellen W.] Univ Minnesota, Div Epidemiol & Community Hlth, Sch Publ Hlth, Minneapolis, MN USA. [Tsao, Phil S.] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Tsao, Phil S.] VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Liu, Chunyu; Lin, Honghuang; Dupuis, Josee] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02118 USA. [Michopoulos, Vasiliki J.; Smith, Alicia K.; Binder, Elisabeth B.; Ressler, Kerry J.] Emory Univ, Dept Psychiat & Behav Sci, Sch Med, Atlanta, GA 30322 USA. [Peters, Marjolein J.; Uitterlinden, Andre G.; van Meurs, Joyce B. J.] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Vokonas, Pantel] VA Boston Healthcare Syst, Boston, MA USA. [Vokonas, Pantel] Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Vokonas, Pantel] Boston Univ, Sch Med, Boston, MA 02215 USA. [Herder, Christian] Univ Dusseldorf, Leibniz Ctr Diabet Res Heinrich Heine, Inst Clin Diabetol, German Diabet Ctr, Dusseldorf, Germany. [Herder, Christian] German Ctr Diabet Res DZD eV, Munich, Germany. [Shah, Sonia; McRae, Allan F.; Visscher, Peter M.] Univ Queensland, Translat Res Inst, Diamantina Inst, Brisbane, Qld, Australia. [Horvath, Steve] Univ Calif Los Angeles, Dept Human Genet, Gonda Res Ctr, David Geffen Sch Med, Los Angeles, CA USA. [Hofman, Albert] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Binder, Elisabeth B.] Max Planck Inst Psychiat, Munich, Germany. [Bandinelli, Stefania] ASF, Geriatr Unit, Florence, Italy. [Schwartz, Joel D.] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth & Epidemiol, Boston, MA USA. [Chen, Yii-Der Ida] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Turner, Stephen T.] Mayo Clin, Div Nephrol & Hypertens, Rochester, MN USA. [Ressler, Kerry J.] McLean Hosp, Div Depress & Anxiety Disorders, Belmont, MA 02178 USA. [Ressler, Kerry J.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Assimes, Themistocles L.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Koenig, Wolfgang] Univ Ulm, Dept Internal Med Cardiol 2, Med Ctr, Ulm, Germany. [Koenig, Wolfgang] Tech Univ Munich, Deutsches Herzzentrum Munchen, Munich, Germany. [Koenig, Wolfgang] DZHK German Ctr Cardiovasc Res, Munich Heart Alliance, Munich, Germany. [Arnett, Donna K.] Univ Kentucky, Coll Publ Hlth, Lexington, KY USA. [Benjamin, Emelia J.] Boston Univ, Dept Epidemiol, Sch Publ Hlth, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Boston, MA 02215 USA. [Benjamin, Emelia J.] NHLBIs Framingham Heart Study, Boston, MA USA. [Dehghan, Abbas] Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Biostat & Epidemiol, London, England. RP Dehghan, A (reprint author), Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. EM a.dehghan@erasmusmc.nl RI Shah, Sonia/N-7547-2013; Grallert, Harald/B-3424-2013; OI Shah, Sonia/0000-0001-5860-4526; Just, Allan/0000-0003-4312-5957; Pankow, James/0000-0001-7076-483X FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; National Institutes of Health (NIH) through the American Recovery and Reinvestment Act (ARRA) [5RC2HL102419]; NHLBI [R01HL105756, HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, R01HL087652, R01HL092111, R01HL103612, R01HL111089, R01HL116747, R01HL120393]; National Institute on Aging (NIA) [R01AG023629]; Laughlin Family; Alpha Phi Foundation; Locke Charitable Foundation; National Center for Advancing Translational Sciences, CTSI grant [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]; Medical Research Council (MRC) [G9502233, G0401527]; Cancer Research UK [C864/A8257]; MRC Cambridge initiative in metabolomic science [MR/L00002/1]; MRC programme [MC_UU_12015/1, MC_UU_12015/2]; U.S. NIH [N01-HC-25195, HHSN268201500001I]; Division of Intramural Research, NHLBI, NIH; Director's Challenge Award, NIH; Division of Intramural Research, NHLBI; Center for Information Technology, NIH, Bethesda, MD; Tommy Kaplan Fund, Boston Children's Hospital; NHLBI of the NIH [HL054457, HL100185, HL119443]; NIH [R01HL104135]; National Institute of Mental Health [MH096764, MH071537]; Emory and Grady Memorial Hospital General Clinical Research Center; Max Planck Society; Behrens-Weise Foundation, NIH National Centers for Research Resources [M01RR00039]; National Center for Advancing Translational Sciences of the NIH [UL1TR000454]; Helmholtz Zentrum Munchen - German Research Center for Environmental Health - German Federal Ministry of Education and Research (BMBF); State of Bavaria; Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ; European Union [603288, HEALTH-F2-2013-602736]; BMBF e:Med project: e:AtheroSysMed - Systems medicine of myocardial infarction and stroke; BMBF; German National Genome Research Network (NGFNplus) [01GS0834]; University of Ulm; U.S. National Institute of Environmental Health Sciences (NIEHS) [R01ES015172, R01ES021733]; Cooperative Studies Program/ERIC, US Department of Veterans Affairs; US Department of Agriculture, Agricultural Research Service [53-K06-510]; Genetic Laboratory of the Department of Internal Medicine; Erasmus MC; Netherlands Organization for Scientific Research (NWO) [184021007]; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; [1RO1 HL64753]; [R01 HL076784]; [1R01 AG028321]; [1P50HL120163] FX The Atherosclerosis Risk in Communities (ARIC) study is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Funding support for "Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium" was provided by the National Institutes of Health (NIH) through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419).; CHS: Infrastructure for the CHARGE Consortium is supported in part by the NHLBI grant R01HL105756. The CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL092111, R01HL105756, R01HL103612, R01HL111089, R01HL116747, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA) as well as the Laughlin Family, Alpha Phi Foundation, and Locke Charitable Foundation. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.; EPIC-Norfolk is supported by programme grants from the Medical Research Council (MRC) (G9502233; G0401527) and Cancer Research UK (C864/A8257). The generation and management of the Illumina 450 K methylation array data in this cohort is supported through the MRC Cambridge initiative in metabolomic science (MR/L00002/1). CEE, KKO, and NJW are supported by MRC programme grants (MC_UU_12015/1 and MC_UU_12015/2). FHS is funded by the U.S. NIH contract N01-HC-25195 and HHSN268201500001I. The laboratory work for this investigation was funded by the Division of Intramural Research, NHLBI, NIH, and by a Director's Challenge Award, NIH (DL). The analytical component of this project was funded by the Division of Intramural Research, NHLBI, and the Center for Information Technology, NIH, Bethesda, MD. This study utilized the computational resources of the Biowulf system at the NIH, Bethesda, MD (https://hpc.nih.gov/docs/user_guides.html). MMM is partly supported by the Tommy Kaplan Fund, Boston Children's Hospital. EJB was supported by 1RO1 HL64753, R01 HL076784, 1R01 AG028321, and 1P50HL120163. Support for the Genetic Epidemiology Network of Arteriopathy (GENOA) was provided by the NHLBI (HL054457, HL100185, and HL119443) of the NIH. GOLDN is supported by NIH grant R01HL104135.; Methylation and expression work for GTP was primarily supported by the National Institute of Mental Health (MH096764 and MH071537 to KJR). Support was also received from Emory and Grady Memorial Hospital General Clinical Research Center, the Max Planck Society, the Behrens-Weise Foundation, NIH National Centers for Research Resources (M01RR00039), and the National Center for Advancing Translational Sciences of the NIH (UL1TR000454).; The KORA study was initiated and financed by the Helmholtz Zentrum Munchen - German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ. The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 603288 (SysVasc) and HEALTH-F2-2013-602736 (PAIN-OMICS) and BMBF e:Med project: e:AtheroSysMed - Systems medicine of myocardial infarction and stroke. Furthermore, this study was supported in part by a grant from the BMBF to the German Center for Diabetes Research (DZD). In addition, part of this work was financed by the German National Genome Research Network (NGFNplus, project no. 01GS0834) and through additional funds from the University of Ulm.; The present work on the US Department of Veterans Affairs (VA) Normative Aging Study has been supported by funding from the U.S. National Institute of Environmental Health Sciences (NIEHS) (R01ES015172, R01ES021733). The VA Normative Aging Study is supported by the Cooperative Studies Program/ERIC, US Department of Veterans Affairs, and is a research component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC). Additional support to the VA Normative Aging Study was provided by the US Department of Agriculture, Agricultural Research Service (contract 53-K06-510). The views expressed in this paper are those of the authors and do not necessarily represent the views of the US Department of Veterans Affairs.; The generation and management of the Illumina 450 K methylation array data (EWAS data) for the Rotterdam Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands. The EWAS data were funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by the Netherlands Organization for Scientific Research (NWO; project number 184021007). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. NR 29 TC 1 Z9 1 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1474-760X J9 GENOME BIOL JI Genome Biol. PD DEC 12 PY 2016 VL 17 AR 255 DI 10.1186/s13059-016-1119-5 PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA EF3BI UT WOS:000390199000001 PM 27955697 ER PT J AU Balansky, R Ganchev, G Iltcheva, M Nikolov, M La Maestra, S Micale, RT Steele, VE De Flora, S AF Balansky, Roumen Ganchev, Gancho Iltcheva, Marietta Nikolov, Manasi La Maestra, S. Micale, Rosanna T. Steele, Vernon E. De Flora, Silvio TI Interactions between ethanol and cigarette smoke in a mouse lung carcinogenesis model SO TOXICOLOGY LA English DT Article DE Cigarette smoke; Ethanol; Lung tumors; Histopathological alterations; Cytogenetic damage ID N-ACETYLCYSTEINE; TOBACCO-SMOKE; RAT-LIVER; ALCOHOL-CONSUMPTION; OXIDATIVE STRESS; NEONATAL MICE; EXPOSED MICE; DNA-ADDUCTS; CANCER; MODULATION AB Both ethanol and cigarette smoke are classified as human carcinogens. They can synergize, especially in tissues of the upper aerodigestive tract that are targeted by both agents. The main objective of the present study was to evaluate the individual and combined effects of ethanol and smoke in the respiratory tract, either following transplacental exposure and/or postnatal exposure. We designed two consecutive studies in mouse models by exposing Swiss H mice to oral ethanol and/or inhaled mainstream cigarette smoke for up to 4 months, at various prenatal and postnatal life stages. Clastogenic effects and histopathological alterations were evaluated after 4 and 8 months, respectively. Ethanol was per se devoid of clastogenic effects in mouse peripheral blood erythrocytes. However, especially in mice exposed both transplacentally throughout pregnancy and in the postnatal life, ethanol administration was associated not only with liver damage but also with pro-angiogenetic effects in the lung by stimulating the proliferation of blood vessels. In addition, these mice developed pulmonary emphysema, alveolar epithelial hyperplasias, microadenomas, and benign tumors. On the other hand, ethanol interfered in the lung carcinogenesis process resulting from the concomitant exposure of mice to smoke. In fact, ethanol significantly attenuated some smoke-related preneoplastic and neoplastic lesions in the respiratory tract, such as alveolar epithelial hyperplasia, microadenomas, and even malignant tumors. In addition, ethanol attenuated cigarette smoke clastogenicity. In conclusion, preclinical studies provide evidence that, in spite of its pulmonary toxicity, ethanol may mitigate some noxious effects of cigarette smoke in the respiratory tract. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Balansky, Roumen; Ganchev, Gancho; Iltcheva, Marietta; Nikolov, Manasi] Natl Oncol Ctr, Str Plovdivsko Pole 6, Sofia 1756, Bulgaria. [Balansky, Roumen; La Maestra, S.; Micale, Rosanna T.; De Flora, Silvio] Univ Genoa, Dept Hlth Sci, Via A Pastore 1, I-16132 Genoa, Italy. [Steele, Vernon E.] NCI, Chemoprevent Agent Dev Res Grp, Div Canc Prevent, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. RP De Flora, S (reprint author), Univ Genoa, Dept Hlth Sci, Via A Pastore 1, I-16132 Genoa, Italy. EM rubalansky@sbaloncology.bg; drganchoganchev@abv.bg; mariettailtcheva@yahoo.com; mdn@mail.bg; lamaestra78@yahoo.it; rosannamicale@yahoo.it; steelev@mail.nih.gov; sdf@unige.it FU Bulgarian Ministry of Education and Science (National Research Fund); Hasumi International Research Foundation - Bulgaria; U.S. National Cancer Institute [N01-CN53301] FX This work was supported by the Bulgarian Ministry of Education and Science (National Research Fund); the Hasumi International Research Foundation - Bulgaria; and the U.S. National Cancer Institute (grant N01-CN53301). NR 49 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD DEC 12 PY 2016 VL 373 BP 54 EP 62 DI 10.1016/j.tox.2016.11.008 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EF9DS UT WOS:000390631500005 PM 27840117 ER PT J AU Stark, GV Sivko, GS VanRaden, M Schiffer, J Taylor, KL Hewitt, JA Quinn, CP Nuzum, EO AF Stark, G. V. Sivko, G. S. VanRaden, M. Schiffer, J. Taylor, K. L. Hewitt, J. A. Quinn, C. P. Nuzum, E. O. TI Cross-species prediction of human survival probabilities for accelerated anthrax vaccine absorbed (AVA) regimens and the potential for vaccine and antibiotic dose sparing SO VACCINE LA English DT Article DE Anthrax; Bacillus anthracis; Correlate of protection; Bootstrap; Logistic regression; Cross-species prediction ID POSTEXPOSURE PROPHYLAXIS; INTRAMUSCULAR INJECTION; INHALATIONAL ANTHRAX; RHESUS MACAQUES; PROTECTION; EFFICACY; MODEL; IMMUNOGENICITY; CORRELATE; SCHEDULE AB Anthrax vaccine adsorbed (AVA, BioThrax) was recently approved by the Food and Drug Administration (FDA) for a post-exposure prophylaxis (PEP) indication in adults 18-65 years of age. The schedule is three doses administered subcutaneous (SC) at 2-week intervals (0, 2, and 4 weeks), in conjunction with a 60-day course of antimicrobials. The Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) developed an animal model to support assessment of a shortened antimicrobial PEP duration following Bacillus anthracis exposure. A nonhuman primate (NHP) study was completed to evaluate the efficacy of a two dose anthrax vaccine absorbed (AVA) schedule (0, 2 weeks) aerosol challenged with high levels of B. anthracis spores at week 4 the time point at which humans would receive the third vaccination of the approved PEP schedule. Here we use logistic regression models to combine the survival data from the NHP study along with serum anthrax lethal toxin neutralizing activity (TNA) and anti-PA IgG measured by enzyme linked immunosorbent assay (ELISA) data to perform a cross-species analysis to estimate survival probabilities in vaccinated human populations at this time interval (week 4 of the PEP schedule). The bridging analysis demonstrated that high levels of NHP protection also yield high predicted probability of human survival just 2 weeks after the second dose of vaccine with the full or half antigen dose regimen. The absolute difference in probability of human survival between the full and half antigen dose was estimated to be at most approximately 20%, indicating that more investigation of the half-antigen dose for vaccine dose sparing strategies may be warranted. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Stark, G. V.; Sivko, G. S.] Battelle Mem Inst, 505 King Ave, Columbus, OH 43201 USA. [VanRaden, M.; Taylor, K. L.; Hewitt, J. A.; Nuzum, E. O.] NIAID, Div Microbiol & Infect Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Schiffer, J.; Quinn, C. P.] Ctr Dis Control & Prevent, Atlanta, GA 30329 USA. RP Stark, GV (reprint author), 505 King Ave, Columbus, OH 43201 USA. EM starkg@battelle.org FU NIAID NIH HHS [HHSN272201200003I] NR 18 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD DEC 12 PY 2016 VL 34 IS 51 BP 6512 EP 6517 DI 10.1016/j.vaccine.2016.06.041 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EF7JO UT WOS:000390506100008 PM 27558619 ER PT J AU Sivko, GS Stark, GV Tordoff, KP Taylor, KL Glaze, E VanRaden, M Schiffer, JM Hewitt, JA Quinn, CP Nuzum, EO AF Sivko, G. S. Stark, G. V. Tordoff, K. P. Taylor, K. L. Glaze, E. VanRaden, M. Schiffer, J. M. Hewitt, J. A. Quinn, C. P. Nuzum, E. O. TI Evaluation of early immune response-survival relationship in cynomolgus macaques after Anthrax Vaccine Adsorbed vaccination and Bacillus anthracis spore challenge SO VACCINE LA English DT Article DE BioThrax; Anthrax; Bacillus anthracis; Correlates of protection ID EXPERIMENTAL INHALATIONAL ANTHRAX; POSTEXPOSURE PROPHYLAXIS; INTRAMUSCULAR INJECTION; PROTECTIVE ANTIGEN; RHESUS MACAQUES; ANTIBODIES; IMMUNOGENICITY; PATHOGENESIS; SCHEDULE; SAFETY AB Anthrax Vaccine Adsorbed (AVA, BioThrax) is approved by the US Food and Drug Administration for post-exposure prophylaxis (PEP) of anthrax in adults. The PEP schedule is 3 subcutaneous (SC) doses (0, 14 and 28 days), in conjunction with a 60 day course of antimicrobials. The objectives of this study were to understand the onset of protection from AVA PEP vaccination and to assess the potential for shortening the duration of antimicrobial treatment (http://www.phe.gov/Preparednessimcm/phemce/Documents/2014-phemce-sip.pdf). We determined the efficacy against inhalation anthrax in nonhuman primates (NHP) of the first two doses of the PEP schedule by infectious challenge at the time scheduled for receipt of the third PEP dose (Day 28). Forty-eight cynomolgus macaques were randomized to five groups and vaccinated with serial dilutions of AVA on Days 0 and 14. NHP were exposed to Bacillus anthracis Ames spores on Day 28 (target dose 200 LD50 equivalents). Anti-protective antigen (PA) IgG and toxin neutralizing antibody (TNA) responses to vaccination and in post-challenge survivors were determined. Post-challenge blood and selected tissue samples were assessed for B. anthracis at necropsy or end of study (Day 56). Pre-challenge humoral immune responses correlated with survival, which ranged from 24 to 100% survival depending on vaccination group. Surviving, vaccinated animals had elevated anti-PA IgG and TNA levels for the duration of the study, were abacteremic, exhibited no apparent signs of infection, and had no gross or microscopic lesions. However, survivors had residual spores in lung tissues. We conclude that the first two doses of the PEP schedule provide high levels of protection by the scheduled timing of the third dose. These data may also support consideration of a shorter duration PEP antimicrobial regimen. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Sivko, G. S.; Stark, G. V.; Tordoff, K. P.] Battelle Mem Inst, 505 King Ave, Columbus, OH 43201 USA. [Taylor, K. L.; Glaze, E.; VanRaden, M.; Hewitt, J. A.; Nuzum, E. O.] NIAID, Div Microbiol & Infect Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Schiffer, J. M.; Quinn, C. P.] Ctr Dis Control & Prevent, Atlanta, GA 30329 USA. RP Sivko, GS (reprint author), 505 King Ave, Columbus, OH 43201 USA. EM sivkog@battelle.org FU National Institute of Allergy and Infectious Disease (NIAID) [HHSN272201200003I/HHSN27200002] FX This study was supported by National Institute of Allergy and Infectious Disease (NIAID) under Contract HHSN272201200003I/HHSN27200002. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institutes of Health (NIH) or Centers for Disease Control and Prevention. NR 25 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD DEC 12 PY 2016 VL 34 IS 51 BP 6518 EP 6528 DI 10.1016/j.vaccine.2016.04.048 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EF7JO UT WOS:000390506100009 PM 27155494 ER PT J AU Condit, RC Williamson, AL Sheets, R Seligman, SJ Monath, TP Excler, JL Gurwith, M Bok, K Robertson, JS Kim, D Hendry, RM Singh, V Mac, LM Chen, RT AF Condit, Richard C. Williamson, Anna-Lise Sheets, Rebecca Seligman, Stephen J. Monath, Thomas P. Excler, Jean-Louis Gurwith, Marc Bok, Karin Robertson, James S. Kim, Denny Hendry, R. Michael Singh, Vidisha Mac, Lisa M. Chen, Robert T. CA Brighton Collaboration Viral TI Unique safety issues associated with virus-vectored vaccines: Potential for and theoretical consequences of recombination with wild type virus strains SO VACCINE LA English DT Article DE Live viral vaccines; Vaccines; Vaccine safety; Potential for recombination; Virus recombination; Vaccine manufacturing; Brighton Collaboration ID VESICULAR STOMATITIS-VIRUS; NEWCASTLE-DISEASE VIRUS; FLAVIVIRUS VACCINES; RNA RECOMBINATION; CLINICAL DEVELOPMENT; ATTENUATED VACCINES; NONHUMAN-PRIMATES; DENGUE VIRUS; FEVER VIRUS; LIVE AB In 2003 and 2013, the World Health Organization convened informal consultations on characterization and quality aspects of vaccines based on live virus vectors. In the resulting reports, one of several issues raised for future study was the potential for recombination of virus-vectored vaccines with wild type pathogenic virus strains. This paper presents an assessment of this issue formulated by the Brighton Collaboration. To provide an appropriate context for understanding the potential for recombination of virus-vectored vaccines, we review briefly the current status of virus-vectored vaccines, mechanisms of recombination between viruses, experience with recombination involving live attenuated vaccines in the field, and concerns raised previously in the literature regarding recombination of virus-vectored vaccines with wild type virus strains. We then present a discussion of the major variables that could influence recombination between a virus-vectored vaccine and circulating wild type virus and the consequences of such recombination, including intrinsic recombination properties of the parent virus used as a vector; sequence relatedness of vector and wild virus; virus host range, pathogenesis and transmission; replication competency of vector in target host; mechanism of vector attenuation; additional factors potentially affecting virulence; and circulation of multiple recombinant vectors in the same target population. Finally, we present some guiding principles for vector design and testing intended to anticipate and mitigate the potential for and consequences of recombination of virus-vectored vaccines with wild type pathogenic virus strains. (C) 2016 Published by Elsevier Ltd. C1 [Condit, Richard C.] Univ Florida, Dept Mol Genet & Microbiol, Gainesville, FL 32610 USA. [Williamson, Anna-Lise] Univ Cape Town, Inst Infect Dis & Mol Med, Cape Town, South Africa. [Williamson, Anna-Lise] Natl Hlth Lab Serv, Cape Town, South Africa. [Sheets, Rebecca] NIAID, NIH, Bethesda, MD 20893 USA. [Seligman, Stephen J.] New York Med Coll, Dept Microbiol & Immunol, Valhalla, NY 10595 USA. [Seligman, Stephen J.] Rockefeller Univ, St Giles Lab Human Genet Infect Dis, New York, NY 10065 USA. [Monath, Thomas P.] Kleiner Perkins Caufield & Byers, Menlo Pk, CA 94025 USA. [Excler, Jean-Louis] US Mil HIV Res Program MHRP, Bethesda, MD 20817 USA. [Excler, Jean-Louis] Int AIDS Vaccine Initiat, New York, NY 10004 USA. [Gurwith, Marc] PaxVax Inc, 900 Vet Blvd,Ste 500, San Diego, CA 92121 USA. [Bok, Karin] US Dept HHS, Natl Vaccine Program Off, OASH, Washington, DC 20201 USA. [Robertson, James S.] Natl Inst Biol Stand & Controls, Potters Bar EN6 3QG, Herts, England. [Kim, Denny] Takeda Vaccines Inc, One Takeda Pkwy, Deerfield, IL 60015 USA. [Hendry, R. Michael; Singh, Vidisha; Mac, Lisa M.; Chen, Robert T.] Ctr Dis Control & Prevent CDC, Natl Ctr HIV AIDS Viral Hepatitis STD & TB Preven, Div HIV AIDS Prevent, Atlanta, GA 30333 USA. [Monath, Thomas P.] NewLink Genet Corp, BioProtect Syst, Ames, IA 50010 USA. RP Singh, V (reprint author), Ctr Dis Control & Prevent CDC, Natl Ctr HIV AIDS Viral Hepatitis STD & TB Preven, Div HIV AIDS Prevent, Atlanta, GA 30333 USA. EM brightoncollaborationv3swg@gmail.com FU Intramural CDC HHS [CC999999] NR 78 TC 0 Z9 0 U1 8 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD DEC 12 PY 2016 VL 34 IS 51 BP 6610 EP 6616 DI 10.1016/j.vaccine.2016.04.060 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EF7JO UT WOS:000390506100018 PM 27346303 ER PT J AU Klug, B Robertson, JS Condit, RC Seligman, SJ Laderoute, MP Sheets, R Williamson, AL Gurwith, M Kochhar, S Chapman, L Carbery, B Mac, LM Chen, RT AF Klug, Bettina Robertson, James S. Condit, Richard C. Seligman, Stephen J. Laderoute, Marian P. Sheets, Rebecca Williamson, Anna-Lise Gurwith, Marc Kochhar, Sonali Chapman, Louisa Carbery, Baevin Mac, Lisa M. Chen, Robert T. CA Brighton Collaboration Viral TI Adventitious agents and live viral vectored vaccines: Considerations for archiving samples of biological materials for retrospective analysis SO VACCINE LA English DT Article DE Live viral vaccines; Vaccines; Adventitious agents; Traceability; Sample archiving; Vaccine manufacturing; Vaccine safety; Brighton Collaboration ID REVERSE-TRANSCRIPTASE ACTIVITY; PORCINE CIRCOVIRUS TYPE-1; AVIAN-LEUKOSIS VIRUS; UNITED-STATES-ARMY; 1942 EPIDEMIC; FOLLOW-UP; MEASLES; SV40; SIMIAN-VIRUS-40; RETROVIRUSES AB Vaccines are one of the most effective public health medicinal products with an excellent safety record. As vaccines are produced using biological materials, there is a need to safeguard against potential contamination with adventitious agents. Adventitious agents could be inadvertently introduced into a vaccine through starting materials used for production. Therefore, extensive testing has been recommended at specific stages of vaccine manufacture to demonstrate the absence of adventitious agents. Additionally, the incorporation of viral clearance steps in the manufacturing process can aid in reducing the risk of adventitious agent contamination. However, for live viral vaccines, aside from possible purification of the virus or vector, extensive adventitious agent clearance may not be feasible. In the event that an adventitious agent is detected in a vaccine, it is important to determine its origin, evaluate its potential for human infection and pathology, and discern which batches of vaccine may have been affected in order to take risk mitigation action. To achieve this, it is necessary to have archived samples of the vaccine and ancillary components, ideally from developmental through to current batches, as well as samples of the biological materials used in the manufacture of the vaccine, since these are the most likely sources of an adventitious agent. The need for formal guidance on such vaccine sample archiving has been recognized but not fulfilled. We summarize in this paper several prior major cases of vaccine contamination with adventitious agents and provide points for consideration on sample archiving of live recombinant viral vector vaccines for use in humans. (C) 2016 Published by Elsevier Ltd. C1 [Klug, Bettina] Paul Ehrlich Inst, Div Immunol, D-63225 Langen, Germany. [Condit, Richard C.] Univ Florida, Dept Mol Genet & Microbiol, Gainesville, FL 32610 USA. [Seligman, Stephen J.] New York Med Coll, Dept Microbiol & Immunol, Valhalla, NY 10595 USA. [Laderoute, Marian P.] Immune Syst Management Inc, Ottawa, ON K1S 5R5, Canada. [Williamson, Anna-Lise] Univ Cape Town, Inst Infect Dis & Mol Med, Cape Town, South Africa. [Williamson, Anna-Lise] Natl Hlth Lab Serv, Cape Town, South Africa. [Gurwith, Marc] PaxVax, Redwood City, CA 94063 USA. [Kochhar, Sonali] Global Healthcare Consulting, New Delhi, India. [Robertson, James S.] Natl Inst Biol Stand & Controls, Potters Bar EN6 3QG, Herts, England. [Laderoute, Marian P.] Publ Hlth Agcy Canada, Blood Safety Contribut Program, Ottawa, ON K1A 0K9, Canada. [Sheets, Rebecca] NIAID, NIH, Bethesda, MD 20893 USA. RP Klug, B (reprint author), Paul Ehrlich Inst, Div Immunol, D-63225 Langen, Germany. EM rtc1@cdc.gov FU Intramural CDC HHS [CC999999] NR 71 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 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD DEC 12 PY 2016 VL 34 IS 51 BP 6617 EP 6625 DI 10.1016/j.vaccine.2016.02.015 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EF7JO UT WOS:000390506100019 PM 27317264 ER PT J AU Mishra, S Peterson, K Yin, LL Berger, A Fan, JG Wistow, G AF Mishra, Sanghamitra Peterson, Katherine Yin, Lili Berger, Alan Fan, Jianguo Wistow, Graeme TI Accumulation of cholesterol and increased demand for zinc in serum-deprived RPE cells SO MOLECULAR VISION LA English DT Article ID RETINAL-PIGMENT EPITHELIUM; LOW-DENSITY LIPOPROTEIN; MACULAR DEGENERATION; OXIDATIVE STRESS; GENE-EXPRESSION; FINGER PROTEIN; BRUCH MEMBRANE; DISEASE; BINDING; TISSUE AB Purpose: Having observed that confluent ARPE-19 cells (derived from human RPE) survive well in high-glucose serum-free medium (SFM) without further feeding for several days, we investigated the expression profile of RPE cells under the same conditions. Methods: Expression profiles were examined with microarray and quantitative PCR (qPCR) analyses, followed by western blot analysis of key regulated proteins. The effects of low-density lipoprotein (LDL) and zinc supplementation were examined with qPCR. Immunofluorescence was used to localize the LDL receptor and to examine LDL uptake. Cellular cholesterol levels were measured with filipin binding. Expression patterns in primary fetal RPE cells were compared using qPCR. Results: Microarray analyses of gene expression in ARPE-19, confirmed with qPCR, showed upregulation of lipid and cholesterol biosynthesis pathways in SFM. At the protein level, the cholesterol synthesis control factor SRBEF2 was activated, and other key lipid synthesis proteins increased. Supplementation of SFM with LDL reversed the upregulation of lipid and cholesterol synthesis genes, but not of cholesterol transport genes. The LDL receptor relocated to the plasma membrane, and LDL uptake was activated by day 5-7 in SFM, suggesting increased demand for cholesterol. Confluent ARPE-19 cells in SFM accumulated intracellular cholesterol, compared with cells supplemented with serum, over 7 days. Over the same time course in SFM, the expression of metallothioneins decreased while the major zinc transporter was upregulated, consistent with a parallel increase in demand for zinc. Supplementation with zinc reversed expression changes for metallothionein genes, but not for other zinc-related genes. Similar patterns of regulation were also seen in primary fetal human RPE cells in SFM. Conclusions: ARPE-19 cells respond to serum deprivation and starvation with upregulation of the lipid and cholesterol pathways, accumulation of intracellular cholesterol, and increased demand for zinc. Similar trends are seen in primary fetal RPE cells. Cholesterol accumulation basal to RPE is a prominent feature of age-related macular degeneration (AMD), while dietary zinc is protective. It is conceivable that accumulating defects in Bruch's membrane and dysfunction of the choriocapillaris could impede transport between RPE and vasculature in AMD. Thus, this pattern of response to serum deprivation in RPE-derived cells may have relevance for some aspects of the progression of AMD. C1 [Mishra, Sanghamitra; Peterson, Katherine; Yin, Lili; Fan, Jianguo; Wistow, Graeme] NEI, Sect Mol Struct & Funct Genom, NIH, Bldg 6 Room 106, Bethesda, MD 20892 USA. [Berger, Alan] Johns Hopkins Univ, Sch Med, Lowe Family Genom Core, Baltimore, MD USA. RP Wistow, G (reprint author), NEI, Sect Mol Struct & Funct Genom, NIH, Bldg 6 Room 106, Bethesda, MD 20892 USA. EM graeme@helix.nih.gov FU Intramural Program of the National Eye Institute, National Institutes of Health USA FX We thank Drs. Chun Gao and Maria Campos of NEI for expert help with microscopy and Dr. Cynthia Jaworski for helpful comments. We thank the laboratory of Dr. Sheldon Miller for human primary cells. This work was performed with support from the Intramural Program of the National Eye Institute, National Institutes of Health USA. NR 68 TC 0 Z9 0 U1 0 U2 0 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD DEC 10 PY 2016 VL 22 BP 1387 EP 1404 PG 18 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA EK4PJ UT WOS:000393908800001 PM 28003730 ER PT J AU Suto, N Laque, A De Ness, GL Wagner, GE Watry, D Kerr, T Koya, E Mayford, MR Hope, BT Weiss, F AF Suto, Nobuyoshi Laque, Amanda De Ness, Genna L. Wagner, Grant E. Watry, Debbie Kerr, Tony Koya, Eisuke Mayford, Mark R. Hope, Bruce T. Weiss, Friedbert TI Distinct memory engrams in the infralimbic cortex of rats control opposing environmental actions on a learned behavior SO ELIFE LA English DT Article ID MEDIAL PREFRONTAL CORTEX; NEURONAL ENSEMBLES; ALCOHOL-SEEKING; COCAINE-SEEKING; EXTINCTION; FEAR; INHIBITION; CIRCUITS; REWARD AB Conflicting evidence exists regarding the role of infralimbic cortex (IL) in the environmental control of appetitive behavior. Inhibition of IL, irrespective of its intrinsic neural activity, attenuates not only the ability of environmental cues predictive of reward availability to promote reward seeking, but also the ability of environmental cues predictive of reward omission to suppress this behavior. Here we report that such bidirectional behavioral modulation in rats is mediated by functionally distinct units of neurons (neural ensembles) that are concurrently localized within the same IL brain area but selectively reactive to different environmental cues. Ensemble specific neural activity is thought to function as a memory engram representing a learned association between environment and behavior. Our findings establish the causal evidence for the concurrent existence of two distinct engrams within a single brain site, each mediating opposing environmental actions on a learned behavior. C1 [Suto, Nobuyoshi; Laque, Amanda; De Ness, Genna L.; Wagner, Grant E.; Watry, Debbie; Kerr, Tony; Weiss, Friedbert] Scripps Res Inst, Dept Mol & Cellular Neurosci, La Jolla, CA 92037 USA. [Koya, Eisuke] Univ Sussex, Sch Psychol, Sussex Neurosci, Brighton, E Sussex, England. [Mayford, Mark R.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Hope, Bruce T.] NIDA, Behav Neurosci Branch, NIH, Intramural Res Program, Baltimore, MD 21224 USA. RP Suto, N; Weiss, F (reprint author), Scripps Res Inst, Dept Mol & Cellular Neurosci, La Jolla, CA 92037 USA.; Hope, BT (reprint author), NIDA, Behav Neurosci Branch, NIH, Intramural Res Program, Baltimore, MD 21224 USA. EM nsuto@scripps.edu; bhope@intra.nida.nih.gov; bweiss@scripps.edu RI Hope, Bruce/A-9223-2010 OI Hope, Bruce/0000-0001-5804-7061 FU National Institute on Drug Abuse [R21DA033533, R01DA037294, ZIADA000467]; National Institute on Alcohol Abuse and Alcoholism [R01AA023183, R01AA021549] FX National Institute on Drug Abuse R21DA033533 Nobuyoshi Suto; National Institute on Alcohol Abuse and Alcoholism R01AA023183 Nobuyoshi Suto; National Institute on Drug Abuse R01DA037294 Nobuyoshi Suto; National Institute on Drug Abuse ZIADA000467 Bruce T Hope; National Institute on Alcohol Abuse and Alcoholism R01AA021549 Friedbert Weiss; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 28 TC 0 Z9 0 U1 2 U2 2 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD DEC 10 PY 2016 VL 5 AR e21920 DI 10.7554/eLife.21920 PG 12 WC Biology SC Life Sciences & Biomedicine - Other Topics GA EH9WQ UT WOS:000392122800001 ER PT J AU Hashimoto, K Simmons, AN Kajino-Sakamoto, R Tsuji, Y Ninomiya-Tsuji, J AF Hashimoto, Kazunori Simmons, Alicia N. Kajino-Sakamoto, Rie Tsuji, Yoshiaki Ninomiya-Tsuji, Jun TI TAK1 Regulates the Nrf2 Antioxidant System Through Modulating p62/SQSTM1 SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article DE intestine; TAK1; Nrf2; Keap1; p62/SQSTM ID TRANSCRIPTION FACTOR NRF2; NF-KAPPA-B; SELECTIVE AUTOPHAGY; OXIDATIVE STRESS; CELL-DEATH; KEAP1-NRF2 PATHWAY; SIGNALING PATHWAY; CYSTEINE RESIDUES; ACTIVATE NRF2; KINASE TAK1 AB Aims: Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) is the master transcriptional regulator of antioxidant gene expression. On increased oxidative stress, an adaptor for Nrf2 degradation, Kelch-like ECH-associated protein 1 (Keap1), is directly modulated by oxidants in the cytoplasm, which results in stabilization and activation of Nrf2. Nrf2 is also constitutively active, to some extent, in the absence of exogenous oxidative stress. We have previously demonstrated that intestinal epithelium-specific TGF-beta-activated kinase 1 (TAK1) deletion downregulates the level of Nrf2 protein, resulting in an increase of reactive oxygen species (ROS) in a mouse model. We aim at determining the mechanism by which TAK1 modulates the level of Nrf2. Results: We found that TAK1 upregulated serine 351 phosphorylation of an autophagic adaptor protein, p62/Sequestosome-1 (SQSTM1), which facilitates interaction between p62/SQSTM1 and Keap1 and subsequent Keap1 degradation. This, ultimately, causes increased Nrf2. Tak1 deficiency reduced the phosphorylation of p62/SQSTM1, resulting in decreased steady-state levels of Nrf2 along with increased Keap1. We also found that this regulation is independent of the canonical redox-mediated Nrf2 activation mechanism. In Tak1-deficient intestinal epithelium, a synthetic phenolic electrophile, butylated hydroxyanisole still effectively upregulated Nrf2 and reduced ROS. Innovation: Our results identify for the first time that TAK1 is a modulator of p62/SQSTM1-dependent Keap1 degradation and maintains the steady state-level of Nrf2. Conclusion: TAK1 regulates Nrf2 through modulation of Keap-p62/SQSTM1 interaction. This regulation is important for homeostatic antioxidant protection in the intestinal epithelium. C1 [Hashimoto, Kazunori; Simmons, Alicia N.; Kajino-Sakamoto, Rie; Tsuji, Yoshiaki; Ninomiya-Tsuji, Jun] North Carolina State Univ, Dept Biol Sci, Raleigh, NC 27695 USA. [Simmons, Alicia N.] NIEHS, Lab Signal Transduct, POB 12233, Res Triangle Pk, NC 27709 USA. [Kajino-Sakamoto, Rie] Aichi Canc Ctr, Res Inst, Div Mol Pathol, Nagoya, Aichi, Japan. RP Ninomiya-Tsuji, J (reprint author), North Carolina State Univ, Dept Biol Sci, Raleigh, NC 27695 USA. EM jun_tsuji@ncsu.edu OI Wellman, Dr. Alicia S./0000-0003-2754-5580 FU National Institutes of Health [GM068812, GM112986, GM088392] FX The authors thank Dr. Yue Xiong for Keap1 expression vector, Dr. Shizuo Akira for Tak1flox/flox mice, Dr. Robine for villin. CreERT2 mice, and North Carolina State University Biological Resources Facility for animal care. This work was supported by the National Institutes of Health Grants GM068812 and GM112986 (to J.N-T.), and GM088392 (to Y.T). NR 56 TC 1 Z9 1 U1 4 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD DEC 10 PY 2016 VL 25 IS 17 BP 953 EP 964 DI 10.1089/ars.2016.6663 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA EF6DM UT WOS:000390421000003 PM 27245349 ER PT J AU Bennet, L Stenkula, K Cushman, SW Brismar, K AF Bennet, Louise Stenkula, Karin Cushman, Samuel W. Brismar, Kerstin TI BMI and waist circumference cut-offs for corresponding levels of insulin sensitivity in a Middle Eastern immigrant versus a native Swedish population - the MEDIM population based study SO BMC PUBLIC HEALTH LA English DT Article DE Insulin sensitivity; Immigrants; Body mass index; Abdominal obesity ID DIABETES RISK; ETHNIC-DIFFERENCES; BETA-CELL; CUT POINTS; OBESITY; PREVALENCE; RESISTANCE; AMERICANS; DISEASE; GLUCOSE AB Background: The aim of this study was to identify corresponding body mass index (BMI) and waist circumference cut-offs for equivalent levels of insulin sensitivity in a Middle Eastern immigrant population compared with native Swedes. Methods: Citizens of Malmo, Sweden aged 30 to 75 years, who were born in Iraq or Sweden, were in 2010-2012 invited to participate in a health examination including anthropometrics, oral glucose tolerance test, fasting samples and interviews concerning sociodemographic factors and lifestyle behaviours. Results: In total, 1176 individuals born in Iraq and 688 born in Sweden, without previously diagnosed type 2 diabetes, participated in the study. In normal weight participants (BMI < 25 kg/m(2)), 21.2% of Iraqis vs 9.3% of Swedes were insulin resistant. Corresponding figures in participants without abdominal obesity (waist circumference, men < 94 cm, women < 80 cm) were 28.2% of Iraqis vs 9.4% of Swedes. The age-adjusted insulin sensitivity index (ISI) for obese Swedes (BMI 30 kg/m(2)) corresponded in Iraqi men with BMI of 28.5 kg/m(2), and in Iraqi women with BMI of 27.5 kg/m(2). The ISI level in abdominally obese Swedes corresponded with waist circumference cut-offs of 84.0 cm and 71.0 cm in Iraqi men and women, respectively. In men only, larger waist circumference (P-interaction = 0.026) presented a stronger association with impaired ISI in Iraqis as compared to Swedes. Conclusions: Our data shows that the impact of BMI and waist circumference on ISI is ethnic- and gender-specific, indicating a disturbed fat metabolism in Iraqi males in particular. Our data suggests that 10 cm lower cut-off values for abdominal obesity, than is currently recommended by major organisations, should be considered when estimating diabetes risk in Middle Eastern populations. C1 [Bennet, Louise] Lund Univ, Dept Clin Sci, Lund, Sweden. [Bennet, Louise] Lund Univ, Skane Univ Hosp, Dept Family Med, Lund, Sweden. [Stenkula, Karin] Lund Univ, Glucose Transport & Prot Trafficking, Lund, Sweden. [Cushman, Samuel W.] NIDDK, NIH, Bethesda, MD 20892 USA. [Brismar, Kerstin] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Brismar, Kerstin] Karolinska Univ Hosp, Stockholm, Sweden. [Bennet, Louise] Skane Univ Hosp, Clin Res Ctr, Ctr Primary Hlth Care Res, Malmo, Sweden. RP Bennet, L (reprint author), Lund Univ, Dept Clin Sci, Lund, Sweden.; Bennet, L (reprint author), Lund Univ, Skane Univ Hosp, Dept Family Med, Lund, Sweden.; Bennet, L (reprint author), Skane Univ Hosp, Clin Res Ctr, Ctr Primary Hlth Care Res, Malmo, Sweden. EM Louise.Bennet@med.lu.se FU Lund University (ALF) [20101641, 20101837, 162641]; Region Skane [226661, 121811]; Swedish Society of Medicine (SLS) [97081, 176831]; Crafoord Foundation [20110719]; Swedish Research Council [349-2008-6589, 2009-1039, 825-2010-5983] FX This study was funded by grants from Lund University (ALF grants 20101641, 20101837, and 162641), Region Skane (226661 and 121811), the Swedish Society of Medicine (SLS 97081 and 176831), the Crafoord Foundation (20110719), and the Swedish Research Council (Linne grant to LUDC 349-2008-6589, Exodiab 2009-1039, and ANDIS 825-2010-5983). 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 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD DEC 9 PY 2016 VL 16 AR 1242 DI 10.1186/s12889-016-3892-1 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EF7BS UT WOS:000390485700004 PM 27938404 ER PT J AU Yang, YK Yang, C Chan, WP Wang, ZQ Deibel, KE Pomerantz, JL AF Yang, Yong-Kang Yang, Chao Chan, Waipan Wang, Zhaoquan Deibel, Katelynn E. Pomerantz, Joel L. TI Molecular Determinants of Scaffold-induced Linear Ubiquitinylation of B Cell Lymphoma/Leukemia 10 (Bcl10) during T Cell Receptor and Oncogenic Caspase Recruitment Domain-containing Protein 11 (CARD11) Signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NF-KAPPA-B; CHAIN ASSEMBLY COMPLEX; RESPONSIVE INHIBITORY DOMAIN; COMBINED IMMUNODEFICIENCY; POLYUBIQUITIN CHAINS; REPRESSIVE ELEMENTS; IMMUNE-RESPONSES; LYMPHOMA-CELLS; MALT1 CLEAVES; MICE LACKING AB The activation of NF-kappa B downstream of T cell receptor (TCR) engagement is a key signaling step required for normal lymphocyte function during the adaptive immune response. During TCR signaling, the adaptor protein Bcl10 is inducibly recruited to the CARD11 scaffold protein as part of a multicomponent complex that induces I kappa B kinase (IKK) activity and NF-kappa B activation. Here, we show that a consequence of this recruitment is the TCR-induced conjugation of Bcl10 with linear-linked polyubiquitin chains to generate the signaling intermediate Lin(Ub)(n)-Bcl10, which is required for the association of Bcl10 with the NEMO subunit of the IKK complex. The TCR-induced generation of Lin(Ub)(n)-Bcl10 requires Bcl10 lysines 17, 31, and 63, CARD11, MALT1, and the HOIP subunit of the linear ubiquitin chain assembly complex (LUBAC) but not the HOIP accessory protein SHARPIN. CARD11 promotes signal-induced Lin(Ub)(n)-Bcl10 generation by co-recruiting Bcl10 with HOIP, thereby bringing substrate to enzyme. The CARD11-HOIP interaction is rendered TCR-inducible by the four autoinhibitory repressive elements in the CARD11 inhibitory domain and involves the CARD11 coiled-coil domain and two independent regions of HOIP. Interestingly, oncogenic CARD11 variants associated with diffuse large B cell lymphoma spontaneously induce Lin(Ub)(n)-Bcl10 production to extents that correlate with their abilities to activate NF-kappa B and with their enhanced abilities to bind HOIP and Bcl10. Our results define molecular determinants that control the production of Lin(Ub)(n)-Bcl10, an important signaling intermediate in TCR and oncogenic CARD11 signaling. C1 Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Inst Cell Engn, Baltimore, MD 21205 USA. [Chan, Waipan] NIAID, NIH, Lab Syst Biol, Lymphocyte Biol Sect, Bethesda, MD 20892 USA. RP Pomerantz, JL (reprint author), Johns Hopkins Univ, Sch Med, Dept Biol Chem, Inst Cell Engn, Miller Res Bldg,Rm 607,733 N Broadway, Baltimore, MD 21205 USA. EM joel.pomerantz@jhmi.edu FU Quest for Cures Grant from the Leukemia and Lymphoma Society [0793-14]; National Institutes of Health [RO1CA177600]; Johns Hopkins University Institute for Cell Engineering; Leukemia and Lymphoma Society FX This work was supported in part by Quest for Cures Grant 0793-14 from the Leukemia and Lymphoma Society, Grant RO1CA177600 from the National Institutes of Health, and funds from The Johns Hopkins University Institute for Cell Engineering. 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.; Recipient of a Leukemia and Lymphoma Society Fellow Award. NR 58 TC 0 Z9 0 U1 2 U2 2 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 DEC 9 PY 2016 VL 291 IS 50 BP 25921 EP 25936 DI 10.1074/jbc.M116.754028 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EF5BH UT WOS:000390345200015 PM 27777308 ER PT J AU Chen, I Chau, G Wang, J Clarke, W Marzinke, MA Cummings, V Breaud, A Laeyendecker, O Fields, SD Griffith, S Scott, HM Shoptaw, S del Rio, C Magnus, M Mannheimer, S Tieu, HV Wheeler, DP Mayer, KH Koblin, BA Eshleman, SH AF Chen, Iris Chau, Gordon Wang, Jing Clarke, William Marzinke, Mark A. Cummings, Vanessa Breaud, Autumn Laeyendecker, Oliver Fields, Sheldon D. Griffith, Sam Scott, Hyman M. Shoptaw, Steven del Rio, Carlos Magnus, Manya Mannheimer, Sharon Hong-Van Tieu Wheeler, Darrell P. Mayer, Kenneth H. Koblin, Beryl A. Eshleman, Susan H. TI Analysis of HIV Diversity in HIV-Infected Black Men Who Have Sex with Men (HPTN 061) SO PLOS ONE LA English DT Article ID RESOLUTION MELTING ASSAY; GENETIC DIVERSITY; SEQUENCE DIVERSITY; ENV; EVOLUTION; VIREMIA; GAG AB Background HIV populations often diversify in response to selective pressures, such as the immune response and antiretroviral drug use. We analyzed HIV diversity in Black men who have sex with men who were enrolled in the HIV Prevention Trials Network 061 study. Methods A high resolution melting (HRM) diversity assay was used to measure diversity in six regions of the HIV genome: two in gag, one in pot, and three in env. HIV diversity was analyzed for 146 men who were HIV infected at study enrollment, including three with acute infection and 13 with recent infection (identified using a multi-assay algorithm), and for 21 men who seroconverted during the study. HIV diversification was analyzed in a paired analysis for 62 HIV-infected men using plasma samples from the enrollment and 12-month (end of study) visits. Results Men with acute or recent infection at enrollment and seroconverters had lower median HRM scores (lower HIV diversity) than men with non-recent infection in all six regions analyzed. In univariate analyses, younger age, higher CD4 cell count, and HIV drug resistance were associated with lower median HRM scores in multiple regions; ARV drug detection was marginally associated with lower diversity in the po/region. In multivariate analysis, acute or recent infection (all six regions) and HIV drug resistance (both gag regions) were associated with lower median HRM scores. Diversification in the pol region over 12 months was greater for men with acute or recent infection, higher CD4 cell count, and lower HIV viral load at study enrollment. Conclusions HIV diversity was significantly associated with duration of HIV infection, and lower gag diversity was observed in men who had HIV drug resistance. HIV po/diversification was more pronounced in men with acute or recent infection, higher CD4 cell count, and lower HIV viral load. C1 [Chen, Iris; Clarke, William; Marzinke, Mark A.; Cummings, Vanessa; Breaud, Autumn; Eshleman, Susan H.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Chau, Gordon; Wang, Jing] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA. [Laeyendecker, Oliver] NIAID, Immunoregulat Lab, NIA, Baltimore, MD USA. [Laeyendecker, Oliver] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Fields, Sheldon D.] Charles R Drew Univ Med & Sci, Mervyn M Dymally Sch Nursing, 1621 E 120th St, Los Angeles, CA 90059 USA. [Griffith, Sam] Sci Facilitat Dept, FHI 360, Durham, NC USA. [Scott, Hyman M.] Bridge HIV, San Francisco Dept Publ Hlth, San Francisco, CA USA. [Shoptaw, Steven] Univ Calif Los Angeles, Dept Family Med, Los Angeles, CA USA. [del Rio, Carlos] Emory Univ, Rollins Sch Publ Hlth, Dept Global Hlth, Atlanta, GA 30322 USA. [Magnus, Manya] George Washington Univ, Dept Epidemiol & Biostat, Milken Inst Sch Publ Hlth, Washington, DC USA. [Mannheimer, Sharon] Columbia Univ, Dept Med, Harlem Hosp, Mailman Sch Publ Hlth, New York, NY USA. [Hong-Van Tieu; Koblin, Beryl A.] New York Blood Ctr, Lindsley F Kimball Res Inst, Lab Infect Dis Prevent, New York, NY 10021 USA. [Wheeler, Darrell P.] SUNY Albany, Sch Social Welf, Albany, NY 12222 USA. [Mayer, Kenneth H.] Fenway Hlth, Fenway Inst, Boston, MA USA. [Mayer, Kenneth H.] Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA 02215 USA. [Mayer, Kenneth H.] Harvard Med Sch, Dept Med, Boston, MA USA. RP Eshleman, SH (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. EM seshlem@jhmi.edu RI del Rio, Carlos/B-3763-2012 OI del Rio, Carlos/0000-0002-0153-3517 FU National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Child Health and Human Development (NICH/HD); National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH), Office of AIDS Research, National Institutes of Health (NIH), Department of Health and Human Services [UM1-A1068613, R01-A1095068]; Division of Intramural Research, NIAID FX The HIV Prevention Trials Network (HPTN) is funded by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Child Health and Human Development (NICH/HD), National Institute of Drug Abuse (NIDA) and the National Institute of Mental Health (NIMH), Office of AIDS Research, National Institutes of Health (NIH), Department of Health and Human Services (UM1-A1068613), and R01-A1095068 (Eshleman). Additional support was provided by the Division of Intramural Research, NIAID. 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 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 DEC 9 PY 2016 VL 11 IS 12 AR e0167629 DI 10.1371/journal.pone.0167629 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE4PU UT WOS:000389587100134 PM 27936098 ER PT J AU Hobbs, CV Gabriel, EE Kamthunzi, P Tegha, G Tauzie, J Petzold, E Barlow-Mosha, L Chi, BH Li, YH Ilmet, T Kirmse, B Neal, J Parikh, S Deygoo, N Philippe, PJ Mofenson, L Prescott, W Chen, JY Musoke, P Palumbo, P Duffy, PE Borkowsky, W AF Hobbs, Charlotte V. Gabriel, Erin E. Kamthunzi, Portia Tegha, Gerald Tauzie, Jean Petzold, Elizabeth Barlow-Mosha, Linda Chi, Benjamin H. Li, Yonghua Ilmet, Tiina Kirmse, Brian Neal, Jillian Parikh, Sunil Deygoo, Nagamah Philippe, Patrick Jean Mofenson, Lynne Prescott, William Chen, Jingyang Musoke, Philippa Palumbo, Paul Duffy, Patrick E. Borkowsky, William CA P1068s Study Team TI Malaria in HIV-Infected Children Receiving HIV Protease-Inhibitor-Compared with Non-Nucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy, IMPAACT P1068s, Substudy to P1060 SO PLOS ONE LA English DT Article ID PLASMODIUM-FALCIPARUM; UGANDAN CHILDREN; CLINICAL-TRIALS; EXPOSURE; BLOOD; TRANSMISSION; PREVENTION; NEVIRAPINE; LOPINAVIR; AGENTS AB Background HIV and malaria geographically overlap. HIV protease inhibitors kill malaria parasites in vitro and in vivo, but further evaluation in clinical studies is needed. Methods Thirty-one children from Malawi aged 4-62 months were followed every 3 months and at intercurrent illness visits for <= 47 months (September 2009-December 2011). We compared malaria incidence (CCM, or positive BS with malaria symptoms) in children initiated on HIV antiretroviral therapy (ART) with zidovudine, lamivudine, and either nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor, or lopinavir-ritonavir (LPV-rtv), a protease inhibitor. Results We found an association between increased time to recurrent positive BS, but not CCM, when anti-malarial treatment and LPV-rtv based ART were used concurrently and when accounting for a LPV-rtv and antimalarial treatment interaction (adjusted HR 0.39; 95% CI (0.17,0.89); p = 0.03). Conclusions LPV-rtv in combination with malaria treatment was associated with lower risk of recurrent positive BS, but not CCM, in HIV-infected children. Larger, randomized studies are needed to confirm these findings which may permit ART optimization for malaria-endemic settings. C1 [Hobbs, Charlotte V.; Neal, Jillian; Chen, Jingyang; Duffy, Patrick E.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD 20852 USA. [Hobbs, Charlotte V.; Li, Yonghua; Ilmet, Tiina; Deygoo, Nagamah; Borkowsky, William] NYU, Sch Med, Div Infect Dis & Immunol, Dept Pediat, New York, NY 10003 USA. [Hobbs, Charlotte V.] Batson Childrens Hosp, Dept Pediat, Div Infect Dis, Jackson, MS 39216 USA. [Hobbs, Charlotte V.] Univ Mississippi, Med Ctr, Dept Microbiol, Jackson, MS 39216 USA. [Gabriel, Erin E.] NIAID, Biostat Res Branch, NIH, Rockville, MD USA. [Kamthunzi, Portia; Tegha, Gerald; Tauzie, Jean] Univ North Carolina Chapel Hill, Lilongwe Project, Kamuzu Cent Hosp, Lilongwe, Malawi. [Petzold, Elizabeth] Duke Clin Res Inst, Durham, NC USA. [Barlow-Mosha, Linda; Musoke, Philippa] Johns Hopkins Univ Res Collaborat, Makerere Univ, Kampala, Uganda. [Chi, Benjamin H.] Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC USA. [Ilmet, Tiina] Weill Cornell Med, Cornell Clin Trials Unit, New York, NY USA. [Kirmse, Brian] Univ Mississippi, Med Ctr, Batson Childrens Hosp, Dept Pediat,Div Med Genet, Jackson, MS 39216 USA. [Parikh, Sunil] Yale Sch Publ Hlth, New Haven, CT USA. [Parikh, Sunil] Yale Sch Med, New Haven, CT USA. [Philippe, Patrick Jean] Div Henry M Jackson Fdn Adv Mil Med Inc, HJF DAIDS, Bethesda, MD USA. [Philippe, Patrick Jean] NIAID, DHHS, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Mofenson, Lynne] Elizabeth Glaser Pediat AIDS Fdn, Washington, DC USA. [Prescott, William] HYDAS World Hlth Inc, Hummelstown, PA USA. [Chen, Jingyang] Univ Washington, Seattle Childrens Res Inst, Ben Towne Ctr Childhood Canc Res, Seattle, WA 98195 USA. [Chen, Jingyang] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Musoke, Philippa] Makerere Univ, Dept Pediat & Child Hlth, Kampala, Uganda. [Palumbo, Paul] Geisel Sch Med Dartmouth, Div Infect Dis & Int Hlth, Lebanon, NH USA. RP Hobbs, CV (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD 20852 USA.; Hobbs, CV (reprint author), NYU, Sch Med, Div Infect Dis & Immunol, Dept Pediat, New York, NY 10003 USA.; Hobbs, CV (reprint author), Batson Childrens Hosp, Dept Pediat, Div Infect Dis, Jackson, MS 39216 USA.; Hobbs, CV (reprint author), Univ Mississippi, Med Ctr, Dept Microbiol, Jackson, MS 39216 USA. EM chobbs@umc.edu FU National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) [UM1AI068632, UM1AI068616, UM1AI106716]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH) FX Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) [Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC) and UM1AI106716 (IMPAACT LC)], with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH). We thank the children, parents, and guardians who participated in this study, and the clinical study team for their efforts in this study. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 0 Z9 0 U1 5 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 9 PY 2016 VL 11 IS 12 AR e0165140 DI 10.1371/journal.pone.016514 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE4PU UT WOS:000389587100010 PM 27936233 ER PT J AU Su, D Wang, XT Campbell, MR Porter, DK Pittman, GS Bennett, BD Wan, M Englert, NA Crowl, CL Gimple, RN Adamski, KN Huang, ZQ Murphy, SK Bell, DA AF Su, Dan Wang, Xuting Campbell, Michelle R. Porter, Devin K. Pittman, Gary S. Bennett, Brian D. Wan, Ma Englert, Neal A. Crowl, Christopher L. Gimple, Ryan N. Adamski, Kelly N. Huang, Zhiqing Murphy, Susan K. Bell, Douglas A. TI Distinct Epigenetic Effects of Tobacco Smoking in Whole Blood and among Leukocyte Subtypes SO PLOS ONE LA English DT Article ID HYDROCARBON RECEPTOR REPRESSOR; DNA METHYLATION DATA; CIGARETTE-SMOKING; HUMAN GENOME; IMMUNE-SYSTEM; SMOKERS; EXPRESSION; FREQUENCY; CANCER; MTSS1 AB Tobacco smoke exposure dramatically alters DNA methylation in blood cells and may mediate smoking-associated complex diseases through effects on immune cell function. However, knowledge of smoking effects in specific leukocyte subtypes is limited. To better characterize smoking-associated methylation changes in whole blood and leukocyte subtypes, we used Illumina 450K arrays and Reduced Representation Bisulfite Sequencing (RRBS) to assess genome-wide DNA methylation. Differential methylation analysis in whole blood DNA from 172 smokers and 81 nonsmokers revealed 738 CpGs, including 616 previously unreported CpGs, genome-wide significantly associated with current smoking (p < 1.2x10(-7), Bonferroni correction). Several CpGs (MTSS1, NKX6-2, BTG2) were associated with smoking duration among heavy smokers (>22 cigarettes/day, n = 86) which might relate to long-term heavy-smoking pathology. In purified leukocyte subtypes from an independent group of 20 smokers and 14 nonsmokers we further examined methylation and gene expression for selected genes among CD14+ monocytes, CD15+ granulocytes, CD19 + B cells, and CD2+ T cells. In 10 smokers and 10 nonsmokers we used RRBS to fine map differential methylation in CD4+ T cells, CD8+ T cells, CD14+, CD15+, CD19+, and CD56+ natural killer cells. Distinct cell-type differences in smoking-associated methylation and gene expression were identified. AHRR (cg05575921), ALPPL2 (cg21566642), GFI1 (cg09935388), IER3 (cg06126421) and F2RL3 (cg03636183) showed a distinct pattern of significant smoking-associated methylation differences across cell types: granulocytes> monocytes >> B cells. In contrast GPR15 (cg19859270) was highly significant in T and B cells and ITGAL (cg09099830) significant only in T cells. Numerous other CpGs displayed distinctive cell-type responses to tobacco smoke exposure that were not apparent in whole blood DNA. Assessing the overlap between these CpG sites and differential methylated regions (DMRs) with RRBS in 6 cell types, we confirmed cell-type specificity in the context of DMRs. We identified new CpGs associated with current smoking, pack-years, duration, and revealed unique profiles of smoking-associated DNA methylation and gene expression among immune cell types, providing potential clues to hematopoietic lineage-specific effects in disease etiology. C1 [Su, Dan; Wang, Xuting; Campbell, Michelle R.; Porter, Devin K.; Pittman, Gary S.; Wan, Ma; Englert, Neal A.; Crowl, Christopher L.; Gimple, Ryan N.; Adamski, Kelly N.; Bell, Douglas A.] NIEHS, Environm Genom Grp, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Bennett, Brian D.] NIEHS, Integrated Bioinformat, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Huang, Zhiqing; Murphy, Susan K.] Duke Univ, Sch Med, Durham, NC 27708 USA. RP Bell, DA (reprint author), NIEHS, Environm Genom Grp, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM BELL1@niehs.nih.gov OI Wang, Xuting/0000-0001-6781-8008; Gimple, Ryan/0000-0002-7189-3243 FU Intramural Research Program of National Institute of Environmental Health Sciences-National Institutes of Health [Z01-ES100475]; NIH/FDA Intramural Center for Tobacco Research; NIEHS Clinical Research Unit and Hematology Core FX Work was funded by the Intramural Research Program of National Institute of Environmental Health Sciences-National Institutes of Health (Z01-ES100475) (www.niehs.nih.gov) and a grant from NIH/FDA Intramural Center for Tobacco Research (https://prevention.nih.gov/tobacco-regulatory-science-program) to D.A.B. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We thank the NIEHS Clinical Research Unit and Hematology Core for support and the NIEHS Molecular Genetics Core, NIH Intramural Sequencing Center, and NCI DCEG Center for Genomics Research for methylation analysis. NR 55 TC 0 Z9 0 U1 8 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 9 PY 2016 VL 11 IS 12 AR e0166486 DI 10.1371/journal.pone.0166486 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE4PU UT WOS:000389587100029 PM 27935972 ER PT J AU Haskins, N Mumo, A Brown, PH Tuchman, M Morizono, H Caldovic, L AF Haskins, N. Mumo, A. Brown, P. H. Tuchman, M. Morizono, H. Caldovic, L. TI Effect of arginine on oligomerization and stability of N-acetylglutamate synthase SO Scientific Reports LA English DT Article ID CARBAMOYL-PHOSPHATE SYNTHETASE; RAT-LIVER MITOCHONDRIA; L-GLUTAMATE SYNTHASE; PURIFICATION; EVOLUTION; ULTRACENTRIFUGATION; BIOSYNTHESIS; ASSOCIATION; MECHANISMS; INHIBITOR AB N-acetylglutamate synthase (NAGS; E.C.2.3.1.1) catalyzes the formation of N-acetylglutamate (NAG) from acetyl coenzyme A and glutamate. In microorganisms and plants, NAG is the first intermediate of the L-arginine biosynthesis; in animals, NAG is an allosteric activator of carbamylphosphate synthetase I and III. In some bacteria bifunctional N-acetylglutamate synthase-kinase (NAGS-K) catalyzes the first two steps of L-arginine biosynthesis. L-arginine inhibits NAGS in bacteria, fungi, and plants and activates NAGS in mammals. L-arginine increased thermal stability of the NAGS-K from Maricaulis maris (MmNAGS-K) while it destabilized the NAGS-K from Xanthomonas campestris (XcNAGS-K). Analytical gel chromatography and ultracentrifugation indicated tetrameric structure of the MmMNAGS-K in the presence and absence of L-arginine and a tetramer-octamer equilibrium that shifted towards tetramers upon binding of L-arginine for the XcNAGS-K. Analytical gel chromatography of mouse NAGS (mNAGS) indicated either different oligomerization states that are in moderate to slow exchange with each other or deviation from the spherical shape of the mNAGS protein. The partition coefficient of the mNAGS increased in the presence of L-arginine suggesting smaller hydrodynamic radius due to change in either conformation or oligomerization. Different effects of L-arginine on oligomerization of NAGS may have implications for efforts to determine the three-dimensional structure of mammalian NAGS. C1 [Haskins, N.; Tuchman, M.; Morizono, H.; Caldovic, L.] Childrens Natl Med Ctr, Ctr Genet Med Res, Washington, DC 20010 USA. [Mumo, A.] Amer Acad Otolaryngol Head & Neck Surg Fdn, Alexandria, VA USA. [Brown, P. H.] NIGMS, NIH, Bethesda, MD USA. RP Caldovic, L (reprint author), Childrens Natl Med Ctr, Ctr Genet Med Res, Washington, DC 20010 USA. EM lcaldovic@cnmcresearch.org FU National Institutes of Health [R01DK064913]; Intramural Research Programs of the National Institute for Biomedical Imaging and Bioengineering, National Institutes of Health FX This work was supported by Public Health Service Grant R01DK064913 from the National Institutes of Health. Dr. Patrick H Brown was supported by the Intramural Research Programs of the National Institute for Biomedical Imaging and Bioengineering, National Institutes of Health. NR 45 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 2045-2322 J9 SCI REP-UK JI Sci Rep PD DEC 9 PY 2016 VL 6 AR 38711 DI 10.1038/srep38711 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE3ZY UT WOS:000389542500001 PM 27934952 ER PT J AU Paulukat, C Gilleaudeau, GJ Chernyavskiy, P Frei, R AF Paulukat, Cora Gilleaudeau, Geoffrey J. Chernyavskiy, Pavel Frei, Robert TI The Cr-isotope signature of surface seawater - A global perspective SO CHEMICAL GEOLOGY LA English DT Article DE Chromium isotopes; Chromium cycling; Global distribution; Seawater; Redox proxies ID CHROMIUM ISOTOPES; HEXAVALENT CHROMIUM; CR(VI) REDUCTION; NATURAL-WATERS; BALTIC SEA; FRACTIONATION; SPECIATION; CARBONATES; OCEAN; OXYGENATION AB This study presents chromium-isotope data (expressed as delta Cr-53) and chromium concentrations (Cr) of surface seawater (0-2 m depth) from a variety of locations worldwide. In addition to samples from the open ocean (Arctic, Southern, Pacific, and Atlantic Oceans), samples were analysed from areas with more restricted water exchange rates (the Mediterranean Sea, Oresund, and Baltic Sea). The data indicate a heterogeneous distribution of delta Cr-53 in seawater with a total range from +0.13%o to +1.24 parts per thousand. The data are in agreement with a previous study, which focused on depth profiles, suggesting that seawater heterogeneity in delta Cr-53 and Cr concentration can be explained using a single fractionation factor for Cr-reduction (epsilon = -0.79 +/- 0.06 parts per thousand 2SD). In basins with limited water exchange with the open ocean, however, local factors seem to control the Cr-isotope composition. (C) 2016 Elsevier B.V. All rights reserved. C1 [Paulukat, Cora; Gilleaudeau, Geoffrey J.; Frei, Robert] Univ Copenhagen, Geol Sect, Dept Geosci & Nat Resource Management, Oster Voldgade 10, DK-1350 Copenhagen, Denmark. [Paulukat, Cora; Frei, Robert] Univ Copenhagen, NordCEE, Nord Ctr Earth Evolut, DK-1168 Copenhagen, Denmark. [Paulukat, Cora] ALS Scandinavia AB, Aurorum 10, S-97775 Lulea, Sweden. [Gilleaudeau, Geoffrey J.] Arizona State Univ, Sch Earth & Space Explorat, Tempe, AZ USA. [Chernyavskiy, Pavel] NCI, Biostat Radiat Epidemiol Branch, NIH, Rockville, MD USA. RP Paulukat, C (reprint author), Univ Copenhagen, Geol Sect, Dept Geosci & Nat Resource Management, Oster Voldgade 10, DK-1350 Copenhagen, Denmark. EM cora.paulukat@gmail.com FU Danish Agency for Science, Technology and Innovation [11-103378]; Danish National Research Foundation's center of excellence NordCEE (DNRF) [DNRF53]; Carlsberg Foundation [CF14-0115]; NASA Postdoctoral Program FX Financial support through the Danish Agency for Science, Technology and Innovation grant number 11-103378 to RF and through the Danish National Research Foundation's center of excellence NordCEE (DNRF grant number DNRF53) is highly appreciated. G.J.G. thanks the Carlsberg Foundation (grant number CF14-0115) and the NASA Postdoctoral Program. NR 41 TC 1 Z9 1 U1 8 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-2541 EI 1878-5999 J9 CHEM GEOL JI Chem. Geol. PD DEC 9 PY 2016 VL 444 BP 101 EP 109 DI 10.1016/j.chemgeo.2016.10.004 PG 9 WC Geochemistry & Geophysics SC Geochemistry & Geophysics GA ED3VO UT WOS:000388776800009 ER PT J AU Chu, HY McKenna, MM Krump, NA Zheng, SL Mendelsohn, L Thein, SL Garrett, LJ Bodine, DM Low, PS AF Chu, Haiyan McKenna, Mary M. Krump, Nathan A. Zheng, Suilan Mendelsohn, Laurel Thein, Swee Lay Garrett, Lisa J. Bodine, David M. Low, Philip S. TI Reversible binding of hemoglobin to band 3 constitutes the molecular switch that mediates O-2 regulation of erythrocyte properties SO BLOOD LA English DT Article ID OXYGEN-INDUCED REGULATION; BLOOD-CELL MEMBRANE; CYTOPLASMIC DOMAIN; RED-CELL; NITRIC-OXIDE; VASCULAR-TONE; ATP RELEASE; NA+/K+ PUMP; PROTEIN; DEOXYHEMOGLOBIN AB Functional studies have shown that the oxygenation state of the erythrocyte regulates many important pathways, including glucose metabolism, membrane mechanical stability, and cellular adenosine triphosphate (ATP) release. Deoxyhemoglobin (deoxyHb), but not oxyhemoglobin, binds avidly and reversibly to band 3, the major erythrocyte membrane protein. Because band 3 associates with multiple metabolic, solute transport, signal transduction, and structural proteins, the hypothesis naturally arises that the O-2-dependent regulation of erythrocyte properties might be mediated by the reversible association of deoxyHb with band 3. To explore whether the band 3-deoxyHb interaction constitutes a "molecular switch" for regulating erythrocyte biology, we have generated transgenic mice with mutations in the deoxyHb-binding domain of band 3. One strain of mouse contains a "humanized" band 3 in which the N-terminal 45 residues of mouse band 3 are replaced by the homologous sequence from human band 3, including the normal human band 3 deoxyHb-binding site. The second mouse contains the same substitution as the first, except the deoxyHb site on band 3 (residues 12-23) has been deleted. Comparison of these animals with wild-type mice demonstrates that the following erythrocyte properties are controlled by the O-2-dependent association of hemoglobin with band 3: (1) assembly of a glycolytic enzyme complex on the erythrocyte membrane which is associated with a shift in glucose metabolism between the pentose phosphate pathway and glycolysis, (2) interaction of ankyrin with band 3 and the concomitant regulation of erythrocyte membrane stability, and (3) release of ATP from the red cell which has been linked to vasodilation. C1 [Chu, Haiyan; Zheng, Suilan; Low, Philip S.] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [McKenna, Mary M.; Krump, Nathan A.; Bodine, David M.] NHGRI, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. [Mendelsohn, Laurel; Thein, Swee Lay] NHLBI, Sickle Cell Branch, Bldg 10, Bethesda, MD 20892 USA. [Garrett, Lisa J.] NHGRI, Embryon Stem Cell & Transgen Mouse Core Facil, NIH, Bethesda, MD 20892 USA. EM tedyaz@mail.nih.gov; plow@purdue.edu FU National Institutes of Health, National Institute of General Medical Sciences [GM24417-36]; National Institutes of Health intramural funds FX This work was supported by National Institutes of Health, National Institute of General Medical Sciences grant GM24417-36 (P.S.L.) and National Institutes of Health intramural funds (D.M.B., S.L.T.). NR 66 TC 1 Z9 1 U1 4 U2 4 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 DEC 8 PY 2016 VL 128 IS 23 BP 2708 EP 2716 DI 10.1182/blood2016-01-692079 PG 9 WC Hematology SC Hematology GA EI7BO UT WOS:000392652300019 PM 27688804 ER PT J AU Wen, WQ Shu, XO Guo, XY Cai, QY Long, JR Bolla, MK Michailidou, K Dennis, J Wang, Q Gao, YT Zheng, Y Dunning, AM Garcia-Closas, M Brennan, P Chen, ST Choi, JY Hartman, M Ito, H Lophatananon, A Matsuo, K Miao, H Muir, K Sangrajrang, S Shen, CY Teo, SH Tseng, CC Wu, AH Yip, CH Simard, J Pharoah, PDP Hall, P Kang, DH Xiang, YB Easton, DF Zheng, W AF Wen, Wanqing Shu, Xiao-ou Guo, Xingyi Cai, Qiuyin Long, Jirong Bolla, Manjeet K. Michailidou, Kyriaki Dennis, Joe Wang, Qin Gao, Yu-Tang Zheng, Ying Dunning, Alison M. Garcia-Closas, Montserrat Brennan, Paul Chen, Shou-Tung Choi, Ji-Yeob Hartman, Mikael Ito, Hidemi Lophatananon, Artitaya Matsuo, Keitaro Miao, Hui Muir, Kenneth Sangrajrang, Suleeporn Shen, Chen-Yang Teo, Soo H. Tseng, Chiu-chen Wu, Anna H. Yip, Cheng Har Simard, Jacques Pharoah, Paul D. P. Hall, Per Kang, Daehee Xiang, Yongbing Easton, Douglas F. Zheng, Wei TI Prediction of breast cancer risk based on common genetic variants in women of East Asian ancestry SO BREAST CANCER RESEARCH LA English DT Article DE Breast cancer risk; Prediction model; Methodology for SNP data analysis; Statistical methods in genetics ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI AB Background: Approximately 100 common breast cancer susceptibility alleles have been identified in genome-wide association studies (GWAS). The utility of these variants in breast cancer risk prediction models has not been evaluated adequately in women of Asian ancestry. Methods: We evaluated 88 breast cancer risk variants that were identified previously by GWAS in 11,760 cases and 11,612 controls of Asian ancestry. SNPs confirmed to be associated with breast cancer risk in Asian women were used to construct a polygenic risk score (PRS). The relative and absolute risks of breast cancer by the PRS percentiles were estimated based on the PRS distribution, and were used to stratify women into different levels of breast cancer risk. Results: We confirmed significant associations with breast cancer risk for SNPs in 44 of the 78 previously reported loci at P < 0.05. Compared with women in the middle quintile of the PRS, women in the top 1% group had a 2.70-fold elevated risk of breast cancer (95% CI: 2.15-3.40). The risk prediction model with the PRS had an area under the receiver operating characteristic curve of 0.606. The lifetime risk of breast cancer for Shanghai Chinese women in the lowest and highest 1% of the PRS was 1.35% and 10.06%, respectively. Conclusion: Approximately one-half of GWAS-identified breast cancer risk variants can be directly replicated in East Asian women. Collectively, common genetic variants are important predictors for breast cancer risk. Using common genetic variants for breast cancer could help identify women at high risk of breast cancer. C1 [Wen, Wanqing; Shu, Xiao-ou; Guo, Xingyi; Cai, Qiuyin; Long, Jirong; Zheng, Wei] Vanderbilt Univ, Sch Med, Dept Med, Div Epidemiol, Nashville, TN 37212 USA. [Bolla, Manjeet K.; Michailidou, Kyriaki; Dennis, Joe; Wang, Qin; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Gao, Yu-Tang; Xiang, Yongbing] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Zheng, Ying] Shanghai Municipal Ctr Dis Control & Prevent, Shanghai, Peoples R China. [Dunning, Alison M.; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, London, England. [Garcia-Closas, Montserrat] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Brennan, Paul] Int Agcy Res Canc, Lyon, France. [Chen, Shou-Tung] Changhua Christian Hosp, Dept Surg, Changhua, Taiwan. [Choi, Ji-Yeob] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea. [Choi, Ji-Yeob] Seoul Natl Univ, Res Inst, Seoul, South Korea. [Hartman, Mikael; Miao, Hui] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. [Hartman, Mikael] Natl Univ Hlth Syst, Dept Surg, Singapore, Singapore. [Ito, Hidemi] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi, Japan. [Lophatananon, Artitaya; Muir, Kenneth] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry, W Midlands, England. [Matsuo, Keitaro] Aichi Canc Ctr Res Inst, Div Mol Biol, Nagoya, Aichi, Japan. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Sangrajrang, Suleeporn] Natl Canc Inst, Bangkok, Thailand. [Shen, Chen-Yang] China Med Univ, Sch Publ Hlth, Taichung, Taiwan. [Shen, Chen-Yang] Acad Sinica, Taiwan Biobank, Inst Biomed Sci, Taipei, Taiwan. [Teo, Soo H.] Canc Res Initiat Fdn, Subang Jaya, Selangor, Malaysia. [Teo, Soo H.; Yip, Cheng Har] Univ Malaya, Canc Res Inst, Canc Res Unit, Med Ctr, Kuala Lumpur, Malaysia. [Tseng, Chiu-chen; Wu, Anna H.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Simard, Jacques] Univ Laval, Ctr Hosp Univ Quebec Res Ctr, Genom Ctr, Quebec City, PQ, Canada. [Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Wen, Wanqing] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA. [Wen, Wanqing] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA. RP Wen, WQ (reprint author), Vanderbilt Univ, Sch Med, Dept Med, Div Epidemiol, Nashville, TN 37212 USA.; Wen, WQ (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA.; Wen, WQ (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA. EM wanqing.wen@vanderbilt.edu RI Yip, Cheng-Har/B-1909-2010 FU US National Institutes of Health [R01CA124558, R01CA148667, R37CA070867, R01CA118229, R01CA092585, R01CA064277, R01CA122756, R01CA137013]; US Department of Defense Idea Awards [BC011118, BC050791]; Ingram Professorship and Research Reward funds; Cancer Research UK [C1287/A10118, C1287/A12014, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565]; European Community [223175, HEALTH-F2-2009-223175]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR); Breast Cancer Research Foundation; Ovarian Cancer Research Fund; Breast Cancer Research Trust, UK; Ministry of Education, Science, Sports, Culture and Technology of Japan; Japan Agency for Medical Research and development (AMED) [15ck0106177h0001]; Ministry Health, Labour and Welfare of Japan; National Cancer Center Research and Development Fund; California Breast Cancer Research Program [1RB-0287, 3 PB-0102, 5 PB-0018, 10 PB-0098]; California Department of Health; National Cancer Institute's Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program [N01CN25403]; Malaysian Ministry of Science, Technology and Innovation (MOSTI); Malaysian Ministry of Higher Education [UM.C/HIR/MOHE/06]; Cancer Research Initiatives Foundation (CARIF); Biomedical Research Council, Singapore [BMRC08/1/35/19/550]; National Medical Research Council, Singapore [NMRC/CG/SERI/2010]; BRL (Basic Research Laboratory) program through the National Research Foundation of Korea - Ministry of Education, Science and Technology [2012-0000347]; NUS start-up Grant; National University Cancer Institute Singapore (NCIS) Centre Grant; NMRC Clinician Scientist Award; Biomedical Research Council [05/1/21/19/425]; National Cancer Institute Thailand; Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan; National Institutes of Health [CA128978]; Komen Foundation FX The work conducted for this project at Vanderbilt University (SBCGS, SGWAS, SGWAS_stage2) was supported in part by US National Institutes of Health grants (R01CA124558, R01CA148667, R37CA070867, R01CA118229, R01CA092585, R01CA064277, R01CA122756, R01CA137013), US Department of Defense Idea Awards (BC011118, BC050791), and Ingram Professorship and Research Reward funds. The BCAC was funded by Cancer Research UK (C1287/A10118, C1287/A12014) and by the European Community's Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065, 1U19 CA148112-the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The ACP study was funded by the Breast Cancer Research Trust, UK. The HERPACC was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, Culture and Technology of Japan, by the Practical Research for Innovative Cancer Control (15ck0106177h0001) from Japan Agency for Medical Research and development (AMED), by a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from Ministry Health, Labour and Welfare of Japan, by Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan, and National Cancer Center Research and Development Fund. The LAABC was supported by grants (1RB-0287, 3 PB-0102, 5 PB-0018, 10 PB-0098) from the California Breast Cancer Research Program. Incident breast cancer cases were collected by the USC Cancer Surveillance Program (CSP) which is supported under subcontract by the California Department of Health. The CSP is also part of the National Cancer Institute's Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program, under contract number N01CN25403. The MYBRCA was funded by research grants from the Malaysian Ministry of Science, Technology and Innovation (MOSTI), Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06), and Cancer Research Initiatives Foundation (CARIF). Additional controls were recruited by the Singapore Eye Research Institute, which was supported by a grant from the Biomedical Research Council (BMRC08/1/35/19/550), Singapore and the National Medical Research Council, Singapore (NMRC/CG/SERI/2010). The SEBCS was supported by the BRL (Basic Research Laboratory) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012-0000347). The SGBCS was funded by the NUS start-up Grant, the National University Cancer Institute Singapore (NCIS) Centre Grant, and the NMRC Clinician Scientist Award. Additional controls were recruited by the Singapore Consortium of Cohort Studies-Multi-ethnic cohort (SCCS-MEC), which was funded by the Biomedical Research Council (grant number: 05/1/21/19/425). The TBCS was funded by The National Cancer Institute Thailand.; The TWBCS was supported by the Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan. No funder had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. NR 25 TC 0 Z9 0 U1 3 U2 3 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 DEC 8 PY 2016 VL 18 AR 124 DI 10.1186/s13058-016-0786-1 PG 8 WC Oncology SC Oncology GA EH1DB UT WOS:000391502700001 PM 27931260 ER PT J AU Chen, X McCorvy, JD Fischer, MG Butler, KV Shen, YD Roth, BL Jin, J AF Chen, Xin McCorvy, John D. Fischer, Matthew G. Butler, Kyle V. Shen, Yudao Roth, Bryan L. Jin, Jian TI Discovery of G Protein-Biased D2 Dopamine Receptor Partial Agonists SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID FUNCTIONAL SELECTIVITY; SCHIZOPHRENIA; PHARMACOLOGY; DRUG; ANTIPSYCHOTICS; DISORDERS; LIGANDS; ARIPIPRAZOLE; RECRUITMENT; ACTIVATION AB Biased ligands (also known as functionally selective ligands) of G protein-coupled receptors are valuable tools for dissecting the roles of G protein-dependent and independent signaling pathways in health and disease. Biased ligands have also been increasingly pursued by the biomedical community as promising therapeutics with improved efficacy and reduced side effects compared with unbiased ligands. We previously discovered first-in-class,beta-arrestin-biased agonists of dopamine D2 receptor (D2R) by extensively exploring multiple regions of aripiprazole, a balanced D2R agonist. In our continuing efforts to identify biased agonists of D2R, we unexpectedly discovered a G protein-biased agonist of D2R, compound 1, which is the first G protein-biased D2R agonist from the aripiprazole scaffold. We designed and synthesized novel analogues to explore two regions of 1 and conducted structure functional selectivity relationship (SFSR) studies. Here we report the discovery of 1, findings from our SFSR studies, and characterization of novel G protein-biased D2R agonists. C1 [Chen, Xin; Fischer, Matthew G.; Butler, Kyle V.; Shen, Yudao; Jin, Jian] Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, 1425 Madison Ave, New York, NY 10029 USA. [Chen, Xin; Fischer, Matthew G.; Butler, Kyle V.; Shen, Yudao; Jin, Jian] Icahn Sch Med Mt Sinai, Dept Oncol Sci, 1425 Madison Ave, New York, NY 10029 USA. [McCorvy, John D.; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. [McCorvy, John D.; Roth, Bryan L.] Univ N Carolina, NIMH, Psychoact Drug Screening Program, Sch Med, Chapel Hill, NC 27599 USA. RP Jin, J (reprint author), Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, 1425 Madison Ave, New York, NY 10029 USA.; Jin, J (reprint author), Icahn Sch Med Mt Sinai, Dept Oncol Sci, 1425 Madison Ave, New York, NY 10029 USA.; Roth, BL (reprint author), Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA.; Roth, BL (reprint author), Univ N Carolina, NIMH, Psychoact Drug Screening Program, Sch Med, Chapel Hill, NC 27599 USA. EM bryan_roth@med.unc.edu; jian.jin@mssm.edu FU National Institutes of Health [U19MH082441] FX The research described here was supported by the grant U19MH082441 (to J.J. and B.L.R.) from the National Institutes of Health. NR 51 TC 1 Z9 1 U1 11 U2 11 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 DEC 8 PY 2016 VL 59 IS 23 BP 10601 EP 10618 DI 10.1021/acs.jmedchem.6b01208 PG 18 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA EE5DB UT WOS:000389623900016 PM 27805392 ER PT J AU Almaliti, J Al-Hamashi, AA Negmeldin, AT Hanigan, CL Perera, L Pflum, MKH Casero, RA Tillekeratne, LMV AF Almaliti, Jehad Al-Hamashi, Ayad A. Negmeldin, Ahmed T. Hanigan, Christin L. Perera, Lalith Pflum, Mary Kay H. Casero, Robert A., Jr. Tillekeratne, L. M. Viranga TI Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring: Development of a More Selective and Highly Potent Analogue SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HISTONE DEACETYLASE INHIBITORS; HDAC ISOFORM SELECTIVITY; BIOLOGICAL EVALUATION; RHEUMATOID-ARTHRITIS; CANCER; RECOGNITION; EXPRESSION; DISORDERS; DISCOVERY; THERAPY AB A number of analogues of the marine-derived histone deacetylase inhibitor largazole incorporating major structural changes in the depsipeptide ring were synthesized. Replacing the thiazole-thiazoline fragment of largazole with a bipyridine group gave analogue 7 with potent cell growth inhibitory activity and an activity profile similar to that of largazole, suggesting that conformational change accompanying switching hybridization from sp(3) to sp(2) at C-7 is well tolerated. Analogue 7 was more class I selective compared to largazole, with at least 464-fold selectivity for class I HDAC proteins over class II HDAC6 compared to a 22-fold selectivity observed with largazole. To our knowledge 7 represents the first example of a potent and highly cytotoxic largazole analogue not containing a thiazoline ring. The elimination of a chiral center derived from the unnatural amino acid R-a-methylcysteine makes the molecule more amenable to chemical synthesis, and coupled with its increased class I selectivity, 7 could serve as a new lead compound for developing selective largazole analogues. C1 [Almaliti, Jehad; Al-Hamashi, Ayad A.; Tillekeratne, L. M. Viranga] Univ Toledo, Dept Med & Biol Chem, Coll Pharm & Pharmaceut Sci, 2801 W Bancroft St, Toledo, OH 43606 USA. [Almaliti, Jehad] Univ Jordan, Dept Pharmaceut Sci, Fac Pharm, Amman 11942, Jordan. [Negmeldin, Ahmed T.; Pflum, Mary Kay H.] Wayne State Univ, Dept Chem, 5101 Cass Ave, Detroit, MI 48202 USA. [Hanigan, Christin L.; Casero, Robert A., Jr.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Bunting Blaustein Canc Res Bldg 1,Room 551, Baltimore, MD 21231 USA. [Perera, Lalith] Natl Inst Environm Hlth Sci, Lab Struct Biol, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Tillekeratne, LMV (reprint author), Univ Toledo, Dept Med & Biol Chem, Coll Pharm & Pharmaceut Sci, 2801 W Bancroft St, Toledo, OH 43606 USA. EM ltillek@utnet.utoledo.edu OI Negmeldin, Ahmed/0000-0003-3399-3435 FU National Institutes of Health, National Institute of Environmental Health Sciences [Z01-ES043010]; NIH [CA051085] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences Grant Z01-ES043010 (to L.P.), and NIH Grant CA051085 (to R.A.C.). NR 54 TC 0 Z9 0 U1 5 U2 5 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 DEC 8 PY 2016 VL 59 IS 23 BP 10642 EP 10660 DI 10.1021/acs.jmedchem.6b01271 PG 19 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA EE5DB UT WOS:000389623900019 PM 27809521 ER PT J AU Cao, J Slack, RD Bakare, OM Burzynski, C Rais, R Slusher, BS Kopajtic, T Bonifazi, A Ellenberger, MP Yano, H He, Y Bi, GH Xi, ZX Loland, CJ Newman, AH AF Cao, Jianjing Slack, Rachel D. Bakare, Oluyomi M. Burzynski, Caitlin Rais, Rana Slusher, Barbara S. Kopajtic, Theresa Bonifazi, Alessandro Ellenberger, Michael P. Yano, Hideaki He, Yi Bi, Guo-Hua Xi, Zheng-Xiong Loland, Claus J. Newman, Amy Hauck TI Novel and High Affinity 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical Dopamine Transporter Inhibitors SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ABUSE THERAPEUTIC AGENTS; COCAINE-ABUSE; SIGMA-RECEPTORS; GBR 12935; MONOAMINE TRANSPORTERS; REUPTAKE INHIBITORS; BINDING-SITES; DOUBLE-BLIND; LIGANDS; DERIVATIVES AB The development of pharmacotherapeutic treatments of psychostimulant abuse has remained a challenge, despite significant efforts made toward relevant mechanistic targets, such as the dopamine transporter (DAT). The atypical DAT inhibitors have received attention due to their promising pharmacological profiles in animal models of cocaine and methamphetamine abuse. Herein, we report a series of modafinil analogues that have an atypical DAT inhibitor profile. We extended SAR by chemically manipulating the oxidation states of the sulfoxide and the amide functional groups, halogenating the phenyl rings, and/or functionalizing the terminal nitrogen with substituted piperazines, resulting in several novel leads such as 11b, which demonstrated high DAT affinity (K-i = 2.5 nM) and selectivity without producing concomitant locomotor stimulation in mice, as compared to cocaine. These results are consistent with an atypical DAT inhibitor profile and suggest that 11b may be a potential lead for development as a psychostimulant abuse medication. C1 [Cao, Jianjing; Slack, Rachel D.; Bakare, Oluyomi M.; Burzynski, Caitlin; Bonifazi, Alessandro; Ellenberger, Michael P.; Yano, Hideaki; He, Yi; Bi, Guo-Hua; Xi, Zheng-Xiong; Newman, Amy Hauck] NIDA, Mol Targets & Medicat Discovery Branch, Intramural Res Program, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. [Burzynski, Caitlin; Rais, Rana; Slusher, Barbara S.] Johns Hopkins Univ, Sch Med, Dept Neurol, Johns Hopkins Drug Discovery, 855 N Wolfe St, Baltimore, MD 21205 USA. [Kopajtic, Theresa] NIDA, Psychobiol Sect, Mol Neuropsychiat Branch, Intramural Res Program,NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. [Loland, Claus J.] Univ Copenhagen, Mol Neuropharmacol & Genet Lab, Fac Hlth & Med Sci, Dept Neurosci & Pharmacol, DK-2200 Copenhagen, Denmark. RP Newman, AH (reprint author), NIDA, Mol Targets & Medicat Discovery Branch, Intramural Res Program, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM anewman@intra.nida.nih.gov FU National Institute on Drug Abuse; Lundbeck Foundation; Danish Council for Independent Research FX Support for this research was provided to A.H.N., J.C., R.D.S., O.M.B., C.B., T.K., A.B., M.P.E., H.Y., Y.H., G.-H.B., and Z.-X.X. by the National Institute on Drug Abuse, Intramural Research Program. C.J.L. is supported by the Lundbeck Foundation and the Danish Council for Independent Research Sapere Aude programme. NR 58 TC 0 Z9 0 U1 3 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD DEC 8 PY 2016 VL 59 IS 23 BP 10676 EP 10691 DI 10.1021/acs.jmedchem.6b01373 PG 16 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA EE5DB UT WOS:000389623900021 PM 27933960 ER PT J AU Koonin, EV Krupovic, M AF Koonin, Eugene V. Krupovic, Mart TI A parasite's parasite saves host's neighbours SO NATURE LA English DT Editorial Material ID GIANT VIRUSES; VIROPHAGE; EVOLUTION; IMMUNITY AB Viruses can be attacked by parasitic viruses, which compete with them for cellular resources. It emerges that one such parasitic virus can defend a host-cell population from a viral attack. SEE LETTER p. 288 C1 [Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. [Krupovic, Mart] Inst Pasteur, Dept Microbiol, F-75015 Paris, France. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM koonin@ncbi.nlm.nih.gov NR 15 TC 0 Z9 0 U1 14 U2 14 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 DEC 8 PY 2016 VL 540 IS 7632 BP 204 EP 205 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE4CF UT WOS:000389548700041 PM 27929010 ER PT J AU Jha, JK Chattoraj, DK AF Jha, Jyoti K. Chattoraj, Dhruba K. TI Inactivation of Individual SeqA Binding Sites of the E. coli Origin Reveals Robustness of Replication Initiation Synchrony SO PLOS ONE LA English DT Article ID CELL-CYCLE INITIATION; SINGLE-STRANDED-DNA; ESCHERICHIA-COLI; GATC SITES; COORDINATED REPLICATION; CHROMOSOME-REPLICATION; PRE-RC; PROTEIN; SEQUESTRATION; SEQUENCES AB The Escherichia coli origin of replication, oriC, comprises mostly binding sites of two proteins: DnaA, a positive regulator, and SeqA, a negative regulator. SeqA, although not essential, is required for timely initiation, and during rapid growth, synchronous initiation from multiple origins. Unlike DnaA, details of SeqA binding to oriC are limited. Here we have determined that SeqA binds to all its sites tested (9/11) and with variable efficiency. Titration of DnaA alters SeqA binding to two sites, both of which have overlapping DnaA sites. The altered SeqA binding, however, does not affect initiation synchrony. Synchrony is also unaffected when individual SeqA sites are mutated. An apparent exception was one mutant where the mutation also changed an overlapping DnaA site. In this mutant, the observed asynchrony could be from altered DnaA binding, as selectively mutating this SeqA site did not cause asynchrony. These results reveal robust initiation synchrony against alterations of individual SeqA binding sites. The redundancy apparently ensures SeqA function in controlling replication in E. coli. C1 [Jha, Jyoti K.; Chattoraj, Dhruba K.] NCI, Lab Biochem & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Chattoraj, DK (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, NCI, NIH FX This work was funded by the Intramural Research Program of the Center for Cancer Research, NCI, NIH. NR 45 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 DEC 8 PY 2016 VL 11 IS 12 AR e0166722 DI 10.1371/journal.pone.0166722 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE4OA UT WOS:000389580900014 PM 27930658 ER PT J AU Murphy, N Falk, RT Messinger, DB Pollak, M Xue, XN Lin, J Sgueglia, R Strickler, HD Gaudet, MM Gunter, MJ AF Murphy, Neil Falk, Roni T. Messinger, Diana B. Pollak, Michael Xue, Xiaonan Lin, Juan Sgueglia, Robin Strickler, Howard D. Gaudet, Mia M. Gunter, Marc J. TI Influence of Fasting Status and Sample Preparation on Metabolic Biomarker Measurements in Postmenopausal Women SO PLOS ONE LA English DT Article ID GROWTH-FACTOR-I; SERUM C-PEPTIDE; COLORECTAL-CANCER; BREAST-CANCER; PLASMA ADIPONECTIN; DIABETES-MELLITUS; HEALTHY-SUBJECTS; BINDING-PROTEIN; RISK; INSULIN AB Background Epidemiologic data linking metabolic markers-such as insulin, insulin-like growth factors (IGFs)-and adipose tissue-derived factors with cancer are inconsistent. Between-study differences in blood collection protocols, in particular participant's fasting status, may influence measurements. Methods We investigated the impact of fasting status and blood sample processing time on components of the insulin/IGF axis and in adipokines in a controlled feeding study of 45 healthy postmenopausal-women aged 50-75 years. Fasting blood samples were drawn (T0), after which subjects ate a standardized breakfast; subsequent blood draws were made at 1 hour (T1), 3 hours (T3), and 6 hours (T6) after breakfast. Serum samples were assayed for insulin, C-peptide, total-and free-IGF-I, IGF-binding protein [BP]-1 and -3, total and high molecular weight (HMW)-adiponectin, retinol binding protein-4, plasminogen activator inhibitor (PAI)-1, and resistin. Results Insulin and C-peptide levels followed similar postprandial trajectories; intra-class correlation coefficients [ICC] for insulin = 0.75, (95% CI: 0.64-0.97) and C-peptide (ICC = 0.66, 95% CI: 0.54-0.77) were similarly correlated in fasting (Spearman correlation, r = 0.78, 95% CI: 0.64-0.88) and postprandial states (T1, r = 0.77 (95% CI: 0.62-0.87); T3, r = 0.78 (95% CI: 0.63-0.87); T6, r = 0.77 (95% CI: 0.61-0.87)). Free-IGF-I and IGFBP-1 levels were also affected by fasting status, whereas total-IGF-I and IGFBP-3 levels remained unchanged. Levels of adipokines were largely insensitive to fasting status and blood sample processing delays. Conclusion Several components of the insulin/IGF axis were significantly impacted by fasting state and in particular, C-peptide levels were substantially altered postprandially and in a similar manner to insulin. C1 [Murphy, Neil] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Murphy, Neil; Gunter, Marc J.] Int Agcy Res Canc, Lyon, France. [Falk, Roni T.] NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, Bethesda, MD 20892 USA. [Messinger, Diana B.] Rockefeller Univ Hosp, 1230 York Ave, New York, NY 10021 USA. [Pollak, Michael] McGill Univ, Dept Oncol, Montreal, PQ, Canada. [Xue, Xiaonan; Lin, Juan; Sgueglia, Robin; Strickler, Howard D.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Gaudet, Mia M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA USA. RP Murphy, N (reprint author), Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.; Murphy, N (reprint author), Int Agcy Res Canc, Lyon, France. EM murphyn@iarc.fr RI Murphy, Neil/E-1189-2017 OI Murphy, Neil/0000-0003-3347-8249 FU National Center for Advancing Translational Sciences (NCATS), National Institutes of Health [UL1RR024143]; National Cancer Institute [R03CA143956-01]; ICTR Einstein-Montefiore CTSA [UL1TR001073]; Diabetes Research Center [DK020541]; [8 UL1 TR000043] FX The study population were recruited at the Center for Clinical and Translational Science (CCTS) at the Rockefeller University Hospital (New York, NY) using funds Grant # 8 UL1 TR000043. Supported in part by grant # UL1RR024143 from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health. The funds for the measurement of adipokines were obtained from the National Cancer Institute (R03CA143956-01). Robin Sgueglia is supported by the ICTR Einstein-Montefiore CTSA (UL1TR001073) and the Diabetes Research Center (DK020541). NR 23 TC 0 Z9 0 U1 8 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 8 PY 2016 VL 11 IS 12 AR e0167832 DI 10.1371/journal.pone.0167832 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE4OA UT WOS:000389580900048 PM 27930694 ER PT J AU Tran, E Robbins, PF Lu, YC Prickett, TD Gartner, JJ Jia, L Pasetto, A Zheng, ZL Ray, S Groh, EM Kriley, IR Rosenberg, SA AF Tran, Eric Robbins, Paul F. Lu, Yong-Chen Prickett, Todd D. Gartner, Jared J. Jia, Li Pasetto, Anna Zheng, Zhili Ray, Satyajit Groh, Eric M. Kriley, Isaac R. Rosenberg, Steven A. TI T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID METASTATIC MELANOMA; CTLA-4 BLOCKADE; SEQUENCING DATA; PD-1 BLOCKADE; HUMAN TUMORS; IDENTIFICATION; LYMPHOCYTES; PATIENT; IMMUNOTHERAPY; SENSITIVITY AB We identified a polyclonal CD8+ T-cell response against mutant KRAS G12D in tumor-infiltrating lymphocytes obtained from a patient with metastatic colorectal cancer. We observed objective regression of all seven lung metastases after the infusion of approximately 1.11x10(11) HLA-C*08: 02-restricted tumor-infiltrating lymphocytes that were composed of four different T-cell clonotypes that specifically targeted KRAS G12D. However, one of these lesions had progressed on evaluation 9 months after therapy. The lesion was resected and found to have lost the chromosome 6 haplotype encoding the HLA-C*08: 02 class I major histocompatibility complex (MHC) molecule. The loss of expression of this molecule provided a direct mechanism of tumor immune evasion. Thus, the infusion of CD8+ cells targeting mutant KRAS mediated effective antitumor immunotherapy against a cancer that expressed mutant KRAS G12D and HLA-C*08: 02. C1 [Tran, Eric; Robbins, Paul F.; Lu, Yong-Chen; Prickett, Todd D.; Gartner, Jared J.; Jia, Li; Pasetto, Anna; Zheng, Zhili; Ray, Satyajit; Groh, Eric M.; Kriley, Isaac R.; Rosenberg, Steven A.] NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, 10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM sar@nih.gov FU Center for Cancer Research Intramural Research Program of the National Cancer Institute FX Supported by the Center for Cancer Research Intramural Research Program of the National Cancer Institute. NR 24 TC 13 Z9 14 U1 20 U2 20 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 DEC 8 PY 2016 VL 375 IS 23 BP 2255 EP 2262 DI 10.1056/NEJMoa1609279 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA EE0ZQ UT WOS:000389310000008 PM 27959684 ER PT J AU Morrison, AC Fu, YP O'Donnell, CJ AF Morrison, Alanna C. Fu, Yi-Ping O'Donnell, Christopher J. CA Cohorts Heart Aging Res Genomic Ep Subclinical Atherosclerosis CHD Wo TI Variants in ANGPTL4 and the Risk of Coronary Artery Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Morrison, Alanna C.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Fu, Yi-Ping] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] Boston Vet Adm Healthcare Syst, Boston, MA USA. RP Morrison, AC (reprint author), Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. EM alanna.c.morrison@uth.tmc.edu NR 6 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 DEC 8 PY 2016 VL 375 IS 23 BP 2303 EP 2303 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA EE0ZQ UT WOS:000389310000020 PM 27959691 ER PT J AU Fagin, JA Wells, SA AF Fagin, James A. Wells, Samuel A., Jr. TI Biologic and Clinical Perspectives on Thyroid Cancer REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Fagin, James A.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Wells, Samuel A., Jr.] NCI, Bethesda, MD 20892 USA. RP Wells, SA (reprint author), NCI, Bethesda, MD 20892 USA. EM wellss@mail.nih.gov NR 4 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 DEC 8 PY 2016 VL 375 IS 23 BP 2307 EP 2307 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA EE0ZQ UT WOS:000389310000027 PM 27959677 ER PT J AU Goh, JOS Su, YS Tang, YJ McCarrey, AC Tereshchenko, A Elkins, W Resnick, SM AF Goh, Joshua O. S. Su, Yu-Shiang Tang, Yong-Jheng McCarrey, Anna C. Tereshchenko, Alexander Elkins, Wendy Resnick, Susan M. TI Frontal, Striatal, and Medial Temporal Sensitivity to Value Distinguishes Risk-Taking from Risk-Aversive Older Adults during Decision Making SO JOURNAL OF NEUROSCIENCE LA English DT Article DE aging; decision making; fMRI; individual differences; older adults; reward system ID AGE-RELATED-CHANGES; PREFRONTAL CORTEX; INDIVIDUAL-DIFFERENCES; ALZHEIMERS-DISEASE; NUCLEUS-ACCUMBENS; NEURAL BASIS; HUMAN-BRAIN; REWARD; DOPAMINE; MEMORY AB Aging compromises the frontal, striatal, and medial temporal areas of the reward system, impeding accurate value representation and feedback processing critical for decision making. However, substantial variability characterizes age-related effects on the brain so that some older individuals evince clear neurocognitive declines whereas others are spared. Moreover, the functional correlates of normative individual differences in older-adult value-based decision making remain unclear. We performed a functional magnetic resonance imaging study in 173 human older adults during a lottery choice task in which costly to more desirable stakes were depicted using low to high expected values (EVs) of points. Across trials that varied in EVs, participants decided to accept or decline the offered stakes to maximize total accumulated points. We found that greater age was associated with less optimal decisions, accepting stakes when losses were likely and declining stakes when gains were likely, and was associated with increased frontal activity for costlier stakes. Critically, risk preferences varied substantially across older adults and neural sensitivity to EVs in the frontal, striatal, and medial temporal areas dissociated risk-aversive from risk-taking individuals. Specifically, risk-averters increased neural responses to increasing EVs as stakes became more desirable, whereas risk-takers increased neural responses with decreasing EV as stakes became more costly. Risk preference also modulated striatal responses during feedback with risk-takers showing more positive responses to gains compared with risk-averters. Our findings highlight the frontal, striatal, and medial temporal areas as key neural loci in which individual differences differentially affect value-based decision-making ability in older adults. C1 [Goh, Joshua O. S.; Su, Yu-Shiang; Tang, Yong-Jheng] Natl Taiwan Univ, Coll Med, Grad Inst Brain & Mind Sci, 1 Ren Ai Rd,Sect 1,RM 1554, Taipei 10051, Taiwan. [Goh, Joshua O. S.] Natl Taiwan Univ, Neurobiol & Cognit Sci Ctr, Taipei 10617, Taiwan. [Goh, Joshua O. S.] Natl Taiwan Univ, Dept Psychol, Taipei 10617, Taiwan. [Goh, Joshua O. S.; McCarrey, Anna C.; Tereshchenko, Alexander; Elkins, Wendy; Resnick, Susan M.] NIA, Lab Behav Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. RP Goh, JOS (reprint author), Natl Taiwan Univ, Coll Med, Grad Inst Brain & Mind Sci, 1 Ren Ai Rd,Sect 1,RM 1554, Taipei 10051, Taiwan. EM joshuagoh@ntu.edu.tw OI GOH, JOSHUA/0000-0001-7808-5452 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health; National Science Council, Taiwan [102-2410-H-002-004]; Ministry of Science and Technology, Taiwan [103-2410-H-002-082] FX This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health; by the National Science Council, Taiwan, Grant #102-2410-H-002-004; and by the Ministry of Science and Technology, Taiwan, Grant #103-2410-H-002-082. We also thank Anne M. Farrell and Brian J. White for their conceptual input. NR 47 TC 1 Z9 1 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD DEC 7 PY 2016 VL 36 IS 49 BP 12498 EP 12509 DI 10.1523/JNEUROSCI.1386-16.2016 PG 12 WC Neurosciences SC Neurosciences & Neurology GA EG6GB UT WOS:000391141500018 PM 27927964 ER PT J AU Wu, XS Lee, SH Sheng, JS Zhang, Z Zhao, WD Wang, DS Jin, YH Charnay, P Ervasti, JM Wu, LG AF Wu, Xin-Sheng Lee, Sung Hoon Sheng, Jiansong Zhang, Zhen Zhao, Wei-Dong Wang, Dongsheng Jin, Yinghui Charnay, Patrick Ervasti, James M. Wu, Ling-Gang TI Actin Is Crucial for All Kinetically Distinguishable Forms of Endocytosis at Synapses SO NEURON LA English DT Article ID CLATHRIN-MEDIATED ENDOCYTOSIS; RETINAL BIPOLAR CELLS; SYNAPTIC VESICLES; PRESYNAPTIC TERMINALS; SLOW ENDOCYTOSIS; NERVE-TERMINALS; HELD SYNAPSE; POLYMERIZATION; CYTOSKELETON; EXPRESSION AB Mechanical force is needed to mediate endocytosis. Whether actin, the most abundant force-generating molecule, is essential for endocytosis is highly controversial in mammalian cells, particularly synapses, likely due to the use of actin blockers, the efficiency and specificity of which are often unclear in the studied cell. Here we addressed this issue using a knockout approach combined with measurements of membrane capacitance and fission pore conductance, imaging of vesicular protein endocytosis, and electron microscopy. We found that two actin isoforms, beta- and gamma-actin, are crucial for slow, rapid, bulk, and overshoot endocytosis at large calyx-type synapses, and for slow endocytosis and bulk endocytosis at small hippocampal synapses. Polymerized actin provides mechanical force to form endocytic pits. Actin also facilitates replenishment of the readily releasable vesicle pool, likely via endocytic clearance of active zones. We conclude that polymerized actin provides mechanical force essential for all kinetically distinguishable forms of endocytosis at synapses. C1 [Wu, Xin-Sheng; Lee, Sung Hoon; Sheng, Jiansong; Zhang, Zhen; Zhao, Wei-Dong; Wang, Dongsheng; Jin, Yinghui; Wu, Ling-Gang] NINDS, 35 Convent Dr, Bethesda, MD 20892 USA. [Charnay, Patrick] PSL Res Univ, Ecole Normale Super, CNRS, Inserm,Inst Biol,Ecole Normale Super, F-75005 Paris, France. [Ervasti, James M.] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. [Zhang, Zhen] US FDA, Off Genet Drugs, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. RP Sheng, JS; Zhang, Z; Wu, LG (reprint author), NINDS, 35 Convent Dr, Bethesda, MD 20892 USA.; Zhang, Z (reprint author), US FDA, Off Genet Drugs, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM shengjs@gmail.com; zhen0806@gmail.com; wul@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke; Korea Research Institute of Bioscience and Biotechnology FX This work was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program, and a fellowship program from Korea Research Institute of Bioscience and Biotechnology. We thank Dr. Yongling Zhu (Northwestern University) for providing synaptophysin-pHluorin2X plasmid, Drs. Zhiping Pang and Thomas C. Sudhof for the gift of the L309 plasmid, and Dr. Ralf Schneggenburger (EPFL) for shipping krox20Cre mice. NR 50 TC 1 Z9 1 U1 4 U2 4 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 DEC 7 PY 2016 VL 92 IS 5 BP 1020 EP 1035 DI 10.1016/j.neuron.2016.10.014 PG 16 WC Neurosciences SC Neurosciences & Neurology GA EG7VJ UT WOS:000391264200014 PM 27840001 ER PT J AU Li, Y Dharkar, P Han, TH Serpe, M Lee, CH Mayer, ML AF Li, Yan Dharkar, Poorva Han, Tae-Hee Serpe, Mihaela Lee, Chi-Hon Mayer, Mark L. TI Novel Functional Properties of Drosophila CNS Glutamate Receptors SO NEURON LA English DT Article ID LIGAND-BINDING CORE; LOCUST MUSCLE-FIBERS; CRYSTAL-STRUCTURES; COMPETITIVE ANTAGONISTS; NEUROMUSCULAR-JUNCTION; NMDA RECEPTORS; NERVOUS-SYSTEM; AMPA RECEPTORS; AMINO-ACIDS; KAINATE AB Phylogenetic analysis reveals AMPA, kainate, and NMDA receptor families in insect genomes, suggesting conserved functional properties corresponding to their vertebrate counterparts. However, heterologous expression of the Drosophila kainate receptor DKaiR1D and the AMPA receptor DGluR1A revealed novel ligand selectivity at odds with the classification used for vertebrate glutamate receptor ion channels (iGluRs). DKaiR1D forms a rapidly activating and desensitizing receptor that is inhibited by both NMDA and the NMDA receptor antagonist AP5; crystallization of the KaiR1D ligand-binding domain reveals that these ligands stabilize open cleft conformations, explaining their action as antagonists. Surprisingly, the AMPA receptor DGluR1A shows weak activation by its namesake agonist AMPA and also by quisqualate. Crystallization of the DGluR1A ligand-binding domain reveals amino acid exchanges that interfere with binding of these ligands. The unexpected ligand-binding profiles of insect iGluRs allows classical tools to be used in novel approaches for the study of synaptic regulation. C1 [Li, Yan; Han, Tae-Hee; Serpe, Mihaela; Lee, Chi-Hon] NICHD, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. [Dharkar, Poorva; Mayer, Mark L.] NICHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Lee, CH (reprint author), NICHD, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA.; Mayer, ML (reprint author), NICHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. EM leechih@mail.nih.gov; mayerm@mail.nih.gov FU U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; NICHD, NIH, and DHHS [Z01-HD008776, Z01-HD000707-31] FX We thank Carla Glasser, Chun-Yuan Ting, and Bo Shi for technical support and Rich Grey for performing the phylogenetic analysis. Synchrotron diffraction data were collected by the Southeast Regional Collaborative Access Team (SER-CAT) 22-ID beamline at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. W-31-109-Eng-38. This work was supported by the intramural research program of NICHD, NIH, and DHHS (Z01-HD008776 to C.-H.L. and Z01-HD000707-31 to M.L.M). NR 62 TC 0 Z9 0 U1 4 U2 4 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 DEC 7 PY 2016 VL 92 IS 5 BP 1036 EP 1048 DI 10.1016/j.neuron.2016.10.058 PG 13 WC Neurosciences SC Neurosciences & Neurology GA EG7VJ UT WOS:000391264200015 PM 27889096 ER PT J AU Yarmolinsky, DA Peng, YQ Pogorzala, LA Rutlin, M Hoon, MA Zuker, CS AF Yarmolinsky, David A. Peng, Yueqing Pogorzala, Leah A. Rutlin, Michael Hoon, Mark A. Zuker, Charles S. TI Coding and Plasticity in the Mammalian Thermosensory System SO NEURON LA English DT Article ID CAPSAICIN-RECEPTOR; ION-CHANNEL; CELLULAR BASIS; COLD RECEPTOR; TRP CHANNELS; NOXIOUS HEAT; PAIN; SENSITIVITY; ACTIVATION; SENSATION AB Perception of the thermal environment begins with the activation of peripheral thermosensory neurons innervating the body surface. To understand how temperature is represented in vivo, we used genetically encoded calcium indicators to measure temperature-evoked responses in hundreds of neurons across the trigeminal ganglion. Our results show how warm, hot, and cold stimuli are represented by distinct population responses, uncover unique functional classes of thermosensory neurons mediating heat and cold sensing, and reveal the molecular logic for peripheral warmth sensing. Next, we examined how the peripheral somatosensory system is functionally reorganized to produce altered perception of the thermal environment after injury. We identify fundamental transformations in sensory coding, including the silencing and recruitment of large ensembles of neurons, providing a cellular basis for perceptual changes in temperature sensing, including heat hypersensitivity, persistence of heat perception, cold hyperalgesia, and cold analgesia. C1 [Yarmolinsky, David A.; Peng, Yueqing; Rutlin, Michael; Zuker, Charles S.] Columbia Univ, Howard Hughes Med Inst, Columbia Coll Phys & Surg, New York, NY 10032 USA. [Yarmolinsky, David A.; Peng, Yueqing; Rutlin, Michael; Zuker, Charles S.] Columbia Univ, Dept Biochem & Mol Biophys, Columbia Coll Phys & Surg, New York, NY 10032 USA. [Yarmolinsky, David A.; Peng, Yueqing; Rutlin, Michael; Zuker, Charles S.] Columbia Univ, Dept Neurosci, Columbia Coll Phys & Surg, New York, NY 10032 USA. [Pogorzala, Leah A.; Hoon, Mark A.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Zuker, CS (reprint author), Columbia Univ, Howard Hughes Med Inst, Columbia Coll Phys & Surg, New York, NY 10032 USA.; Zuker, CS (reprint author), Columbia Univ, Dept Biochem & Mol Biophys, Columbia Coll Phys & Surg, New York, NY 10032 USA.; Zuker, CS (reprint author), Columbia Univ, Dept Neurosci, Columbia Coll Phys & Surg, New York, NY 10032 USA. EM cz2195@columbia.edu FU Thomson Family Foundation Initiative in Chemotherapy Induced Peripheral Neuropathy and Sensory Neuroscience; NIDCR FX We particularly thank Youmei Wu and Nick Ryba for the generous gift of Rosa-GCaMP5, and the NIDCR and Janelia Farm Transgenic Core Services for TrpM8-Cre TrpA1-DTR-Cre animals. We thank Nick Ryba for comments and valuable insights and Marco Gallio, Kristin Scott, and members of C.S.Z.'s lab for helpful comments and suggestions. This work was funded in part by support from the Thomson Family Foundation Initiative in Chemotherapy Induced Peripheral Neuropathy and Sensory Neuroscience and the intramural program at NIDCR (L.A.P. and M.A.H.). C.S.Z. is an investigator of the HHMI and a senior fellow at the Janelia Farm Research Campus. NR 42 TC 0 Z9 0 U1 4 U2 4 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 DEC 7 PY 2016 VL 92 IS 5 BP 1079 EP 1092 DI 10.1016/j.neuron.2016.10.021 PG 14 WC Neurosciences SC Neurosciences & Neurology GA EG7VJ UT WOS:000391264200018 PM 27840000 ER PT J AU Xu, XW Zhang, K Zhao, L Li, C Bu, WH Shen, YQ Gu, ZY Chang, B Zheng, CY Lin, CT Sun, HC Yang, B AF Xu, Xiaowei Zhang, Kai Zhao, Liang Li, Chen Bu, Wenhuan Shen, Yuqin Gu, Zhongyi Chang, Bei Zheng, Changyu Lin, Chongtao Sun, Hongchen Yang, Bai TI Aspirin-Based Carbon Dots, a Good Biocompatibility of Material Applied for Bioimaging and Anti-Inflammation SO ACS APPLIED MATERIALS & INTERFACES LA English DT Article DE aspirin; carbon dots; bioimaging; anti-inflammation; biocompatibility ID GRAPHENE QUANTUM DOTS; ONE-POT SYNTHESIS; SIGNAL-TRANSDUCTION; FACILE SYNTHESIS; SALICYLIC-ACID; MACROPHAGES; NANOPARTICLES; FLUORESCENCE; MECHANISM; CANCER AB The emerging photoluminescent carbon-based nanomaterials are promising in various fields besides cell imaging and carrier transport. Carbon nanomaterials with specific biological functions, however, are rarely investigated. Aspirin is a very common anti-inflammatory medication to relieve aches and pains. In this study, we have tried to create a carbon nanoparticle with aspirin, and we expect that this new carbon nanoparticle will have both anti-inflammatory and fluorescent biomarker functions. Fluorescent aspirin-based carbon dots (FACDs) were synthesized by condensing aspirin and hydrazine through a one-step microwave-assisted method. Imaging data demonstrated that FACDs efficiently entered into human cervical carcinoma and mouse monocyte macrophage cells in vitro with low cell toxicity. Results from quantitative polymerase chain reaction and histological analysis indicated that FACDs possessed effective anti-inflammatory effects in vitro and in vivo compared to aspirin only. Hematology, serum biochemistry, and histology results suggested that FACDs also had no significant toxicity in vivo. Our results clearly demonstrate that FACDs have dual functions, cellular imaging/bioimaging and anti-inflammation, and suggest that FACDs have great potential in future clinical applications. C1 [Xu, Xiaowei; Zhao, Liang; Bu, Wenhuan; Chang, Bei; Sun, Hongchen] Jilin Univ, Sch & Hosp Stomatol, Dept Oral Pathol, Changchun 130021, Peoples R China. [Xu, Xiaowei; Shen, Yuqin; Gu, Zhongyi; Lin, Chongtao] Jilin Univ, Sch & Hosp Stomatol, Dept Periodontol, Changchun 130021, Peoples R China. [Xu, Xiaowei; Sun, Hongchen] Jilin Univ, Jilin Prov Key Lab Tooth Dev & Bone Remodeling, Changchun 130021, Peoples R China. [Xu, Xiaowei; Zhang, Kai; Sun, Hongchen; Yang, Bai] Jilin Univ, Coll Chem, State Key Lab Supramol Struct & Mat, Changchun 130012, Peoples R China. [Li, Chen] Jilin Univ, Sch & Hosp Stomatol, Dept Oral Med, Changchun 130021, Peoples R China. [Zheng, Changyu] Natl Inst Dent & Craniofacial Res, Natl Inst Hlth, Mol Physiol & Therapeut Branch, Bethesda, MD 20892 USA. RP Sun, HC (reprint author), Jilin Univ, Sch & Hosp Stomatol, Dept Oral Pathol, Changchun 130021, Peoples R China.; Lin, CT (reprint author), Jilin Univ, Sch & Hosp Stomatol, Dept Periodontol, Changchun 130021, Peoples R China.; Sun, HC (reprint author), Jilin Univ, Jilin Prov Key Lab Tooth Dev & Bone Remodeling, Changchun 130021, Peoples R China.; Sun, HC; Yang, B (reprint author), Jilin Univ, Coll Chem, State Key Lab Supramol Struct & Mat, Changchun 130012, Peoples R China. EM linct@jlu.edu.cn; hcsun@jlu.edu.cn; yangoffice@jlu.edu.cn FU National Key Research and Development Program of China [2016YFC1102800]; Natural Science Foundation of China [81320108011, 81600879, 81371153, 81500820, 81400488] FX We would like to thank Cindy Clark and Brigit S. Sullivan, NIH Library Editing Service, for reviewing and editing the manuscript. This work was supported by grants from the National Key Research and Development Program of China 2016YFC1102800, and the Natural Science Foundation of China (81320108011, 81600879, 81371153, 81500820, and 81400488). NR 56 TC 1 Z9 1 U1 46 U2 46 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1944-8244 J9 ACS APPL MATER INTER JI ACS Appl. Mater. Interfaces PD DEC 7 PY 2016 VL 8 IS 48 BP 32706 EP 32716 DI 10.1021/acsami.6b12252 PG 11 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA EE5DH UT WOS:000389624600011 PM 27934165 ER PT J AU Krumm, BE Lee, S Bhattacharya, S Botos, I White, CF Du, HJ Vaidehi, N Grisshammer, R AF Krumm, Brian E. Lee, Sangbae Bhattacharya, Supriyo Botos, Istvan White, Courtney F. Du, Haijuan Vaidehi, Nagarajan Grisshammer, Reinhard TI Structure and dynamics of a constitutively active neurotensin receptor SO SCIENTIFIC REPORTS LA English DT Article ID PROTEIN-COUPLED RECEPTORS; BETA(2)-ADRENERGIC RECEPTOR; MEMBRANE-PROTEINS; FUNCTIONAL EXPRESSION; CRYSTAL-STRUCTURE; ACTIVATION; INSIGHTS; GPCR; RHODOPSIN; ANTAGONISTS AB Many G protein-coupled receptors show constitutive activity, resulting in the production of a second messenger in the absence of an agonist; and naturally occurring constitutively active mutations in receptors have been implicated in diseases. To gain insight into mechanistic aspects of constitutive activity, we report here the 3.3 angstrom crystal structure of a constitutively active, agonist-bound neurotensin receptor (NTSR1) and molecular dynamics simulations of agonist-occupied and ligand-free receptor. Comparison with the structure of a NTSR1 variant that has little constitutive activity reveals uncoupling of the ligand-binding domain from conserved connector residues, that effect conformational changes during GPCR activation. Furthermore, molecular dynamics simulations show strong contacts between connector residue side chains and increased flexibility at the intracellular receptor face as features that coincide with robust signalling in cells. The loss of correlation between the binding pocket and conserved connector residues, combined with altered receptor dynamics, possibly explains the reduced neurotensin efficacy in the constitutively active NTSR1 and a facilitated initial engagement with G protein in the absence of agonist. C1 [Krumm, Brian E.; White, Courtney F.; Du, Haijuan; Grisshammer, Reinhard] NINDS, Membrane Prot Struct Funct Unit, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Lee, Sangbae; Bhattacharya, Supriyo; Vaidehi, Nagarajan] City Hope Natl Med Ctr, Beckman Res Inst, Dept Mol Immunol, 1500 E Duarte Rd, Duarte, CA 91010 USA. [Botos, Istvan] NIDDK, Lab Mol Biol, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Krumm, Brian E.] Univ N Carolina, Sch Med, Pharmacol, Chapel Hill, NC USA. RP Grisshammer, R (reprint author), NINDS, Membrane Prot Struct Funct Unit, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. EM rkgriss@helix.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke; National Institute of Diabetes and Digestive and Kidney Diseases; NIH [R01-GM097261]; National Cancer Institute [ACB-12002]; National Institute of General Medical Sciences [AGM-12006]; DOE Office of Science [DE-AC02-06CH11357]; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]; DOE Office of Biological and Environmental Research; National Institutes of Health, National Institute of General Medical Sciences [P41GM103393] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke (B.E.K., C.F.W., H.D., R.G.) and National Institute of Diabetes and Digestive and Kidney Diseases (I.B.). The MD simulations work presented in this paper was supported by the NIH R01-GM097261 grant (N.V.). We thank the staff at the General Medicine and Cancer Institute's Collaborative Access Team (GM/CA-CAT) beamline at the Advanced Photon Source, Argonne National Laboratory; and personnel at the Stanford Synchrotron Radiation Lightsource, beamline 12-2, for their assistance during data acquisition. GM/CA at APS has been funded in whole or in part with Federal funds from the National Cancer Institute (ACB-12002) and the National Institute of General Medical Sciences (AGM-12006). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393). We thank Di Xia and Lothar Esser (NCI) for review of the x-ray data and coordinates; David Sibley, Lani Chun, Ben Free and Amy Moritz (NINDS) for use of the Flex Station; and Jaroslawna Meister (NIDDK) for providing HEK293 cells. NR 63 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 2045-2322 J9 SCI REP-UK JI Sci Rep PD DEC 7 PY 2016 VL 6 AR 38564 DI 10.1038/srep38564 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE3VJ UT WOS:000389527400001 PM 27924846 ER PT J AU Rogozin, IB Lada, AG Goncearenco, A Green, MR De, S Nudelman, G Panchenko, AR Koonin, EV Pavlov, YI AF Rogozin, Igor B. Lada, Artem G. Goncearenco, Alexander Green, Michael R. De, Subhajyoti Nudelman, German Panchenko, Anna R. Koonin, Eugene V. Pavlov, Youri I. TI Activation induced deaminase mutational signature overlaps with CpG methylation sites in follicular lymphoma and other cancers SO SCIENTIFIC REPORTS LA English DT Article ID INDUCED CYTIDINE DEAMINASE; SINGLE-STRANDED-DNA; SOMATIC MUTATIONS; ANTIBODY DIVERSIFICATION; IMMUNOGLOBULIN GENES; CYTOSINE DEAMINATION; POLYMERASE-ETA; BREAST-CANCER; IN-VIVO; AID AB Follicular lymphoma (FL) is an uncurable cancer characterized by progressive severity of relapses. We analyzed sequence context specificity of mutations in the B cells from a large cohort of FL patients. We revealed substantial excess of mutations within a novel hybrid nucleotide motif: the signature of somatic hypermutation (SHM) enzyme, Activation Induced Deaminase (AID), which overlaps the CpG methylation site. This finding implies that in FL the SHM machinery acts at genomic sites containing methylated cytosine. We identified the prevalence of this hybrid mutational signature in many other types of human cancer, suggesting that AID-mediated, CpG-methylation dependent mutagenesis is a common feature of tumorigenesis. C1 [Rogozin, Igor B.; Goncearenco, Alexander; Koonin, Eugene V.] Natl Inst Hlth, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD USA. [Rogozin, Igor B.] Novosibirsk State Univ, Novosibirsk, Russia. [Lada, Artem G.; Pavlov, Youri I.] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE USA. [Lada, Artem G.] Univ Calif, Dept Microbiol & Mol Genet, Davis, CA USA. [De, Subhajyoti] Rutgers State Univ, Rutgers Canc Inst New Jersey, New Brunswick, NJ USA. [Nudelman, German] Icahn Sch Med, Dept Neurol & Syst Biol Ctr, Mount Sinai, NY USA. [Pavlov, Youri I.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Biochem & Mol Biol, Omaha, NE USA. RP Rogozin, IB (reprint author), Natl Inst Hlth, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD USA.; Rogozin, IB (reprint author), Novosibirsk State Univ, Novosibirsk, Russia.; Pavlov, YI (reprint author), Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE USA.; Pavlov, YI (reprint author), Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Biochem & Mol Biol, Omaha, NE USA. EM rogozin@ncbi.nlm.nih.gov; ypavlov@unmc.edu RI Goncearenco, Alexander/M-3946-2015 OI Goncearenco, Alexander/0000-0002-9738-7146 FU Buffett Cancer Center; St. Petersburg State University [1.38.426.2015]; US Department of Health and Human Services FX AGL was supported by Buffett Cancer Center Pilot grant and in part by Research Grant of St. Petersburg State University #1.38.426.2015 to YIP. IBR, ARP, AG and EVK are supported by the intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). NR 57 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 2045-2322 J9 SCI REP-UK JI Sci Rep PD DEC 7 PY 2016 VL 6 AR 38133 DI 10.1038/srep38133 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE6AM UT WOS:000389690700001 PM 27924834 ER PT J AU Zhao, N Han, D Liu, HC Li, Y Wong, SW Cao, ZY Xu, J Zhang, XW Cai, T Wang, YX Feng, HL AF Zhao, Na Han, Dong Liu, Haochen Li, Yue Wong, Sing-Wai Cao, Zhengyi Xu, Jian Zhang, Xiaowei Cai, Tao Wang, Yixiang Feng, Hailan TI Senescence: novel insight into DLX3 mutations leading to enhanced bone formation in Tricho-Dento-Osseous syndrome SO SCIENTIFIC REPORTS LA English DT Article ID MESENCHYMAL STEM-CELLS; DISTAL-LESS 3; IN-VIVO; OSTEOBLAST DIFFERENTIATION; QUANTITATIVE PCR; TELOMERE LENGTH; GENES; HOMEOSTASIS; ACTIVATION; EXPRESSION AB The homeodomain transcription factor distal-less homeobox 3 gene (DLX3) is required for hair, tooth and skeletal development. DLX3 mutations have been found to be responsible for Tricho-Dento-Osseous (TDO) syndrome, characterized by kinky hair, thin-pitted enamel and increased bone density. Here we show that the DLX3 mutation (c.533 A>G; Q178R) attenuates osteogenic potential and senescence of bone mesenchymal stem cells (BMSCs) isolated from a TDO patient, providing a molecular explanation for abnormal increased bone density. Both DLX3 mutations (c.533 A>G and c.571_574delGGGG) delayed cellular senescence when they were introduced into pre-osteoblastic cells MC3T3-E1. Furthermore, the attenuated skeletal aging and bone loss in DLX3 (Q178R) transgenic mice not only reconfirmed that DLX3 mutation (Q178R) delayed cellular senescence, but also prevented aging-mediated bone loss. Taken together, these results indicate that DLX3 mutations act as a loss of function in senescence. The delayed senescence of BMSCs leads to increased bone formation by compensating decreased osteogenic potentials with more generations and extended functional lifespan. Our findings in the rare human genetic disease unravel a novel mechanism of DLX3 involving the senescence regulation of bone formation. C1 [Zhao, Na; Han, Dong; Liu, Haochen; Li, Yue; Wong, Sing-Wai; Feng, Hailan] Peking Univ, Sch & Hosp Stomatol, Dept Prosthodont, Beijing, Peoples R China. [Wong, Sing-Wai] Univ N Carolina, Sch Dens, Oral Biol Curriculum, Chapel Hill, NC USA. [Cao, Zhengyi; Zhang, Xiaowei] Peking Univ, Dept Biochem & Mol Biol, Hlth Sci Ctr, Beijing, Peoples R China. [Xu, Jian] Henan Polytech Univ, Sch Phys & Elect Informat, Jiaozuo, Peoples R China. [Cai, Tao] Wenzhou Med Univ, Inst Genom Med, Wenzhou, Peoples R China. [Cai, Tao] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Wang, Yixiang] Peking Univ, Sch & Hosp Stomatol, Cent Lab, Beijing, Peoples R China. RP Feng, HL (reprint author), Peking Univ, Sch & Hosp Stomatol, Dept Prosthodont, Beijing, Peoples R China.; Wang, YX (reprint author), Peking Univ, Sch & Hosp Stomatol, Cent Lab, Beijing, Peoples R China. EM kqwangyx@bjmu.edu.cn; kqfenghl@bjmu.edu.cn FU National Natural Science Foundation of China [81570961]; Natural Science Foundation of Beijing Municipality [7092113]; National Key Health Research Project Foundation of China during the 11th Five-Year Plan Period [2006BAI05A07]; Capital Medical Developing Foundation [2007-1005]; Beijing Natural Science Foundation Grant [5162013]; National Institute of Dental and Craniofacial Research [R90DE022527] FX This work was supported by grants from the National Natural Science Foundation of China (81570961), the Natural Science Foundation of Beijing Municipality (7092113), the National Key Health Research Project Foundation of China during the 11th Five-Year Plan Period (2006BAI05A07), the Capital Medical Developing Foundation (2007-1005), the Beijing Natural Science Foundation Grant (5162013) and National Institute of Dental and Craniofacial Research (R90DE022527). We are grateful to the TDO patient and the normal healthy donors and for participating in this study. NR 50 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 2045-2322 J9 SCI REP-UK JI Sci Rep PD DEC 7 PY 2016 VL 6 AR 38680 DI 10.1038/srep38680 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE6UZ UT WOS:000389749500001 PM 27924851 ER PT J AU Strickland, M Stanley, AM Wang, GS Botos, I Schwieters, CD Buchanan, SK Peterkofsky, A Tjandra, N AF Strickland, Madeleine Stanley, Ann Marie Wang, Guangshun Botos, Istvan Schwieters, Charles D. Buchanan, Susan K. Peterkofsky, Alan Tjandra, Nico TI Structure of the NPr:EINNtr Complex: Mechanism for Specificity in Paralogous Phosphotransferase Systems SO STRUCTURE LA English DT Article ID MOLECULAR-STRUCTURE DETERMINATION; RESIDUAL DIPOLAR COUPLINGS; N-TERMINAL DOMAIN; ESCHERICHIA-COLI; ENZYME I; DEPHOSPHORYLATED NPR; XPLOR-NIH; PROTEIN; NMR; MACROMOLECULES AB Paralogous enzymes arise from gene duplication events that confer a novel function, although it is unclear how cross-reaction between the original and duplicate protein interaction network is minimized. We investigated HPr: EIsugar and NPr: EINtr, the initial complexes of paralogous phosphorylation cascades involved in sugar import and nitrogen regulation in bacteria, respectively. Although the HPr: EIsugar interaction has been well characterized, involving multiple complexes and transient interactions, the exact nature of the NPr: EINtr complex was unknown. We set out to identify the key features of the interaction by performing binding assays and elucidating the structure of NPr in complex with the phosphorylation domain of EINtr (EINNtr), using a hybrid approach involving X-ray, homology, and sparse nuclear magnetic resonance. We found that the overall fold and active-site structure of the two complexes are conserved in order to maintain productive phosphorylation, however, the interface surface potential differs between the two complexes, which prevents cross-reaction. C1 [Strickland, Madeleine; Tjandra, Nico] NHLBI, Lab Mol Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA. [Stanley, Ann Marie; Botos, Istvan; Buchanan, Susan K.] Natl Inst Diabet & Digest & Kidney Dis, Lab Mol Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. [Wang, Guangshun] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA. [Schwieters, Charles D.] NIH, Off Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [Peterkofsky, Alan] NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Tjandra, N (reprint author), NHLBI, Lab Mol Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA.; Peterkofsky, A (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM peterkofsky@nih.gov; tjandran@nhlbi.nih.gov FU Intramural Research Programs of the NHLBI at the NIH; NIDDK at the NIH; CIT at the NIH; Eppley Institute at the University of Nebraska Medical Center; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX We acknowledge Kang Chen for EIN Ntr backbone NMR experiment data collection and analysis, Duck-Yeon Lee for assistance with LCMS, Marie-Paule Strub for assistance with protein purification, Grzegorz Pisczek for assistance with SPR, Alexander Grishaev for assistance with SAXS, and Rolf Swenson, Ana Opina, and Olga Vasalatiy for synthesis of the Lu-M8-SPy and Yb-M8-SPy tags for pseudocontact shifts. We also acknowledge the Intramural Research Programs of the NHLBI, NIDDK, and CIT, at the NIH, and the Eppley Institute at the University of Nebraska Medical Center for funding. We would like to thank the staff at the Southeast Regional Collaborative Access Team (SER-CAT) beamline at the Advanced Photon Source, Argonne National Laboratory, for their assistance during data collection. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. W-31-109-Eng-38. NR 43 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD DEC 6 PY 2016 VL 24 IS 12 BP 2127 EP 2137 DI 10.1016/j.str.2016.10.007 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA EJ4UB UT WOS:000393211300012 PM 27839951 ER PT J AU Cheng, Y Cawley, NX Yanik, T Murthy, SRK Liu, C Kasikci, F Abebe, D Loh, YP AF Cheng, Y. Cawley, N. X. Yanik, T. Murthy, S. R. K. Liu, C. Kasikci, F. Abebe, D. Loh, Y. P. TI A human carboxypeptidase E/NF-alpha 1 gene mutation in an Alzheimer's disease patient leads to dementia and depression in mice SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID HIPPOCAMPAL NEUROGENESIS; MEMORY DEFICITS; TAU; ANTIDEPRESSANTS; PHOSPHORYLATION; NEUROPROTECTION; DEGENERATION; EPIGENETICS; CONVERTASE; TANGLES AB Patients with Alzheimer's disease (AD), a common dementia among the aging population, often also suffer from depression. This comorbidity is poorly understood. Although most forms of AD are not genetically inherited, we have identified a new human mutation in the carboxypeptidase E (CPE)/neurotrophic factor-alpha 1 (NF-alpha 1) gene from an AD patient that caused memory deficit and depressive-like behavior in transgenic mice. This mutation consists of three adenosine inserts, introducing nine amino acids, including two glutamines into the mutant protein, herein called CPE-QQ. Expression of CPE-QQ in Neuro2a cells demonstrated that it was not secreted, but accumulated in the endoplasmic reticulum and was subsequently degraded by proteasomes. Expression of CPE-QQ in rat hippocampal neurons resulted in cell death, through increased ER stress and decreased expression of pro-survival protein, BCL-2. Transgenic mice expressing CPE-QQ did not show any difference in the processing enzyme activity of CPE compared with wild-type mice. However, the transgenic mice exhibited poor memory, depressive-like behavior, severely decreased dendrites in the hippocampal CA3 region and medial prefrontal cortex indicative of neurodegeneration, hyperphosphorylation of tau at Ser(396), and diminished neurogenesis in the dentate gyrus at 50 weeks old. All these pathologies are associated with AD and the latter with depression and were observed in 50-week-old mice. Interestingly, the younger CPE-QQ mice (11 weeks old) did not show deficits in dendrite outgrowth and neurogenesis. This study has uncovered a human CPE/NF-alpha 1 gene mutation that could lead to comorbidity of dementia and depression, emphasizing the importance of this gene in cognitive function. C1 [Cheng, Y.; Cawley, N. X.; Murthy, S. R. K.; Liu, C.; Abebe, D.; Loh, Y. P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Neurobiol, NIH, Bldg 49,Room 6A-10,49 Convent Dr, Bethesda, MD 20892 USA. [Yanik, T.; Kasikci, F.] Middle East Tech Univ, Dept Biol Sci, Ankara, Turkey. RP Loh, YP (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Neurobiol, NIH, Bldg 49,Room 6A-10,49 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; Scientific and Technological Research Council of Turkey (TUBITAK) [111T449] 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 and the Scientific and Technological Research Council of Turkey (TUBITAK), Project Number 111T449. We thank Dr Hao Yang Tan (Lieber Institute for Brain Development, Johns Hopkins University), Dr Harish Pant (NINDS) for their critical reading of this manuscript, Professor Stephen O'Rahilly, Cambridge University, UK for helpful suggestions and Lynn Holtzclaw and Dr Vincent Schram (NICHD Microscopy Core Facility) for their assistance, and Zhaojin Li for her assistance with some of the proteosomal inhibitor experiments. We also thank Drs William Wetsel and Ramona Rodriguiz for helpful discussions on the behavioral data. We thank Dr Leila Toulabi (NICHD) for her help in bioinfomatic search for CPE-QQ mutation in different Genomic database. NR 51 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 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD DEC 6 PY 2016 VL 6 AR e973 DI 10.1038/tp.2016.237 PG 12 WC Psychiatry SC Psychiatry GA EI0BN UT WOS:000392136800006 PM 27922637 ER PT J AU Sade, Y Toker, L Kara, NZ Einat, H Rapoport, S Moechars, D Berry, GT Bersudsky, Y Agam, G AF Sade, Y. Toker, L. Kara, N. Z. Einat, H. Rapoport, S. Moechars, D. Berry, G. T. Bersudsky, Y. Agam, G. TI IP3 accumulation and/or inositol depletion: two downstream lithium's effects that may mediate its behavioral and cellular changes SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID CEREBRAL-CORTEX SLICES; MANIC-DEPRESSIVE PATIENTS; BIPOLAR DISORDER; PHOSPHOINOSITIDE METABOLISM; RAT-BRAIN; IN-VIVO; 1,4,5-TRISPHOSPHATE RECEPTOR; REGULATES AUTOPHAGY; HUNTINGTONS-DISEASE; TRANSPORT-SYSTEM AB Lithium is the prototype mood stabilizer but its mechanism is still unresolved. Two hypotheses dominate-the consequences of lithium's inhibition of inositol monophosphatase at therapeutically relevant concentrations (the 'inositol depletion' hypothesis), and of glycogen-synthase kinase-3. To further elaborate the inositol depletion hypothesis that did not decisively determine whether inositol depletion per se, or phosphoinositols accumulation induces the beneficial effects, we utilized knockout mice of either of two inositol metabolism-related genes-IMPA1 or SMIT1, both mimic several lithium's behavioral and biochemical effects. We assessed in vivo, under non-agonist-stimulated conditions, H-3-inositol incorporation into brain phosphoinositols and phosphoinositides in wild-type, lithium-treated, IMPA1 and SMIT1 knockout mice. Lithium treatment increased frontal cortex and hippocampal phosphoinositols labeling by several fold, but decreased phosphoinositides labeling in the frontal cortex of the wild-type mice of the IMPA1 colony strain by similar to 50%. Inositol metabolites were differently affected by IMPA1 and SMIT1 knockout. Inositoltrisphosphate administered intracerebroventricularly affected bipolar-related behaviors and autophagy markers in a lithium-like manner. Namely, IP3 but not IP1 reduced the immobility time of wild-type mice in the forced swim test model of antidepressant action by 30%, an effect that was reversed by an antagonist of all three IP3 receptors; amphetamine-induced hyperlocomotion of wild-type mice (distance traveled) was 35% reduced by IP3 administration; IP3 administration increased hippocampal messenger RNA levels of Beclin-1 (required for autophagy execution) and hippocampal and frontal cortex protein levels ratio of Beclin-1/p62 by about threefold (p62 is degraded by autophagy). To conclude, lithium affects the phosphatidylinositol signaling system in two ways: depleting inositol, consequently decreasing phosphoinositides; elevating inositol monophosphate levels followed by phosphoinositols accumulation. Each or both may mediate lithium-induced behavior. C1 [Sade, Y.; Kara, N. Z.; Agam, G.] Ben Gurion Univ Negev, Dept Clin Biochem & Pharmacol, IL-84170 Beer Sheva, Israel. [Sade, Y.; Kara, N. Z.; Bersudsky, Y.; Agam, G.] Ben Gurion Univ Negev, Psychiat Res Unit, IL-84170 Beer Sheva, Israel. [Sade, Y.; Kara, N. Z.; Bersudsky, Y.; Agam, G.] Ben Gurion Univ Negev, Fac Hlth Sci, IL-84170 Beer Sheva, Israel. [Sade, Y.; Bersudsky, Y.; Agam, G.] Mental Hlth Ctr, IL-84170 Beer Sheva, Israel. [Toker, L.] Univ British Columbia, Dept Psychiat, Vancouver, BC, Canada. [Toker, L.] Univ British Columbia, Ctr High Throughput Biol, Vancouver, BC, Canada. [Kara, N. Z.; Einat, H.] Tel Aviv Yaffo Acad Coll, Sch Behav Sci, Tel Aviv, Israel. [Rapoport, S.] NIA, Brain Physiol & Metab Sect, Lab Neurosci, NIH, Bethesda, MD 20892 USA. [Moechars, D.] Johnson & Johnson Pharmaceut Res & Dev, Beerse, Belgium. [Berry, G. T.] Harvard Med Sch, Childrens Hosp Boston, Metab Program, Div Genet, Boston, MA USA. RP Agam, G (reprint author), Ben Gurion Univ Negev, Dept Clin Biochem & Pharmacol, IL-84170 Beer Sheva, Israel.; Agam, G (reprint author), Ben Gurion Univ Negev, Psychiat Res Unit, IL-84170 Beer Sheva, Israel.; Agam, G (reprint author), Ben Gurion Univ Negev, Fac Hlth Sci, IL-84170 Beer Sheva, Israel.; Agam, G (reprint author), Mental Hlth Ctr, IL-84170 Beer Sheva, Israel. EM galila@bgu.ac.il NR 79 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 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD DEC 6 PY 2016 VL 6 AR e968 DI 10.1038/tp.2016.217 PG 10 WC Psychiatry SC Psychiatry GA EI0BN UT WOS:000392136800001 PM 27922641 ER PT J AU Davidson, D Zhong, MC Pandolfi, PP Bolland, S Xavier, RJ Seed, B Li, X Gu, H Veillette, A AF Davidson, Dominique Zhong, Ming-Chao Pandolfi, Pier Paolo Bolland, Silvia Xavier, Ramnik J. Seed, Brian Li, Xin Gu, Hua Veillette, Andre TI The Csk-Associated Adaptor PAG Inhibits Effector T Cell Activation in Cooperation with Phosphatase PTPN22 and Dok Adaptors SO CELL REPORTS LA English DT Article ID PROTEIN-KINASE P50(CSK); TRANSMEMBRANE ADAPTER; NEGATIVE REGULATION; LYMPHOCYTE DEVELOPMENT; ANTIGEN RECEPTOR; LIPID RAFTS; CBL; FAMILY; AUTOIMMUNITY; REGULATOR AB The transmembrane adaptor PAG (Cbp) has been proposed to mediate membrane recruitment of Csk, a cytoplasmic protein tyrosine kinase playing a critical inhibitory role during T cell activation, by inactivating membrane-associated Src kinases. However, this model has not been validated by genetic evidence. Here, we demonstrate that PAG-deficient mice display enhanced T cell activation responses in effector, but not in naive, T cells. PAG-deficient mice also have augmented T cell-dependent autoimmunity and greater resistance to T cell anergy. Interestingly, in the absence of PAG, Csk becomes more associated with alternative partners; i.e., phosphatase PTPN22 and Dok adaptors. Combining PAG deficiency with PTPN22 or Dok adaptor deficiency further enhances effector T cell responses. Unlike PAG, Cbl ubiquitin ligases inhibit the activation of naive, but not of effector, T cells. Thus, Csk-associating PAG is a critical component of the inhibitory machinery controlling effector T cell activation in cooperation with PTPN22 and Dok adaptors. C1 [Davidson, Dominique; Zhong, Ming-Chao; Veillette, Andre] Inst Rech Clin Montreal, Lab Mol Oncol, Montreal, PQ H2W 1R7, Canada. [Pandolfi, Pier Paolo] Beth Israel Deaconess Med Ctr, Canc Res Inst, Boston, MA 02215 USA. [Bolland, Silvia] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Xavier, Ramnik J.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Seed, Brian] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Li, Xin; Gu, Hua] Inst Rech Clin Montreal, Lab Mol Immunol, Montreal, PQ H2W 1R7, Canada. [Gu, Hua; Veillette, Andre] Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada. [Gu, Hua; Veillette, Andre] McGill Univ, Dept Med, Montreal, PQ H3G 1Y6, Canada. RP Davidson, D; Veillette, A (reprint author), Inst Rech Clin Montreal, Lab Mol Oncol, Montreal, PQ H2W 1R7, Canada.; Veillette, A (reprint author), Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada.; Veillette, A (reprint author), McGill Univ, Dept Med, Montreal, PQ H3G 1Y6, Canada. EM dominique.davidson@ircm.qc.ca; veillea@ircm.qc.ca FU Canadian Institutes of Health Research (FRN) [143338] FX We thank the members of the A.V. lab for discussions. This work was supported by a grant from the Canadian Institutes of Health Research (FRN #143338) (to A.V.). A.V. holds the Canada Research Chair in Signaling in the Immune System. NR 32 TC 0 Z9 0 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD DEC 6 PY 2016 VL 17 IS 10 BP 2776 EP 2788 DI 10.1016/j.celrep.2016.11.035 PG 13 WC Cell Biology SC Cell Biology GA EG2SK UT WOS:000390894200024 PM 27926878 ER PT J AU Ambrozak, A Steinebach, C Gardner, ER Beedie, SL Schnakenburg, G Figg, WD Gutschow, M AF Ambrozak, Agnieszka Steinebach, Christian Gardner, Erin R. Beedie, Shaunna L. Schnakenburg, Gregor Figg, William D. Guetschow, Michael TI Synthesis and Antiangiogenic Properties of Tetrafluorophthalimido and Tetrafluorobenzamido Barbituric Acids SO CHEMMEDCHEM LA English DT Article DE angiogenesis; barbituric acids; phthalimides; tetrafluorobenzamides; tetrafluorophthalimides ID FACTOR-ALPHA PRODUCTION; TETRAFLUORINATED THALIDOMIDE ANALOGS; HYDANTOIN REARRANGEMENT; MOLECULAR-STRUCTURE; CRYSTAL-STRUCTURE; AMINO-ACIDS; INHIBITORS; ANGIOGENESIS; TERATOGENICITY; DERIVATIVES AB The development of novel thalidomide derivatives as immunomodulatory and anti-angiogenic agents has revived over the last two decades. Herein we report the design and synthesis of three chemotypes of barbituric acids derived from the thalidomide structure: phthalimido-, tetrafluorophthalimido-, and tetrafluorobenzamidobarbituric acids. The latter were obtained by a new tandem reaction, including a ring opening and a decarboxylation of the fluorine-activated phthalamic acid intermediates. Thirty compounds of the three chemotypes were evaluated for their anti-angiogenic properties in an ex vivo assay by measuring the decrease in microvessel outgrowth in rat aortic ring explants. Tetrafluorination of the phthalimide moiety in tetrafluorophthalimidobarbituric acids was essential, as all of the nonfluorinated counterparts lost anti-angiogenic activity. An opening of the five-membered ring and the accompanying increased conformational freedom, in case of the corresponding tetrafluorobenzamidobarbituric acids, was well tolerated. Their activity was retained, although their molecular structures differ in torsional flexibility and possible hydrogenbond networking, as revealed by comparative X-ray crystallographic analyses. C1 [Ambrozak, Agnieszka; Steinebach, Christian; Guetschow, Michael] Univ Bonn, Inst Pharmaceut, Pharmaceut Chem 1, Immenburg 4, D-53121 Bonn, Germany. [Gardner, Erin R.] NCI, Clin Pharmacol Program, NIH, Bethesda, MD 20892 USA. [Beedie, Shaunna L.; Figg, William D.] NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. [Schnakenburg, Gregor] Univ Bonn, Inst Inorgan Chem, Gerhard Domagk Str 1, D-53121 Bonn, Germany. RP Gutschow, M (reprint author), Univ Bonn, Inst Pharmaceut, Pharmaceut Chem 1, Immenburg 4, D-53121 Bonn, Germany. EM guetschow@uni-bonn.de NR 54 TC 0 Z9 0 U1 2 U2 2 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1860-7179 EI 1860-7187 J9 CHEMMEDCHEM JI ChemMedChem PD DEC 6 PY 2016 VL 11 IS 23 BP 2621 EP 2629 DI 10.1002/cmdc.201600496 PG 9 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EG8FY UT WOS:000391292600008 PM 27805767 ER PT J AU Gordon, LA Kumar, P Brooks, KM Kellogg, A McManus, M Alfaro, RM Nghiem, K George, JM Lozier, J Penzak, SR Hadigan, C AF Gordon, Lori A. Kumar, Parag Brooks, Kristina M. Kellogg, Anela McManus, Maryellen Alfaro, Raul M. Nghiem, Khanh George, Jomy M. Lozier, Jay Penzak, Scott R. Hadigan, Colleen TI Antiretroviral Boosting Agent Cobicistat Increases the Pharmacokinetic Exposure and Anticoagulant Effect of Dabigatran in HIV-Negative Healthy Volunteers SO CIRCULATION LA English DT Letter DE anticoagulants; antiretroviral; cobicistat; dabigatran; drug-drug interaction; pharmacodynamics; pharmacokinetics; thrombin time C1 [Gordon, Lori A.; Kumar, Parag; Brooks, Kristina M.; Alfaro, Raul M.; George, Jomy M.; Penzak, Scott R.] NIH, Clin Pharmacokinet Res Unit, Clin Ctr Pharm Dept, 10 Ctr Dr,Rm 1C-230G, Bethesda, MD 20892 USA. [Nghiem, Khanh; Lozier, Jay] NIH, Clin Res Ctr, Ctr Clin, Dept Lab Med, Bldg 10, Bethesda, MD 20892 USA. [Hadigan, Colleen] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Gordon, Lori A.] Xavier Univ Louisiana, Coll Pharm, New Orleans, LA USA. [Kellogg, Anela] Leidos Biomed Res Inc, Frederick, MD USA. [McManus, Maryellen] Parker Tide Corp, Washington, DC USA. [Penzak, Scott R.] Univ North Texas Syst, Coll Pharm, Dept Pharmacotherapy, Ft Worth, TX USA. RP Kumar, P (reprint author), NIH, Clin Pharmacokinet Res Unit, Clin Ctr Pharm Dept, 10 Ctr Dr,Rm 1C-230G, Bethesda, MD 20892 USA. EM Parag.kumar@nih.gov FU Intramural NIH HHS [Z99 AI999999, Z99 CL999999, ZIA CL006005-04, ZIA CL006005-02, ZIA CL006005-01, ZIA CL006005-03] NR 5 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 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD DEC 6 PY 2016 VL 134 IS 23 BP 1909 EP 1911 DI 10.1161/CIRCULATIONAHA.116.025257 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EF6CP UT WOS:000390418100019 PM 27920076 ER PT J AU Hamdi, Y Soucy, P Adoue, V Michailidou, K Canisius, S Lemacon, A Droit, A Andrulis, IL Anton-Culver, H Arndt, V Baynes, C Blomqvist, C Bogdanova, NV Bojesen, SE Bolla, MK Bonanni, B Borresen-Dale, AL Brand, JS Brauch, H Brenner, H Broeks, A Burwinkel, B Chang-Claude, J Couch, FJ Cox, A Cross, SS Czene, K Darabi, H Dennis, J Devilee, P Dork, T Dos-Santos-Silva, I Eriksson, M Fasching, PA Figueroa, J Flyger, H Garcia-Closas, M Giles, GG Goldberg, MS Gonzalez-Neira, A Grenaker-Alnaes, G Guenel, P Haeberle, L Haiman, CA Hamann, U Hallberg, E Hooning, MJ Hopper, JL Jakubowska, A Jones, M Kabisch, M Kataja, V Lambrechts, D Le Marchand, L Lindblom, A Lubinski, J Mannermaa, A Maranian, M Margolin, S Marme, F Milne, RL Neuhausen, SL Nevanlinna, H Neven, P Olswold, C Peto, J Plaseska-Karanfilska, D Pylkas, K Radice, P Rudolph, A Sawyer, EJ Schmidt, MK Shu, XO Southey, MC Swerdlow, A Tollenaar, RAEM Tomlinson, I Torres, D Truong, T Vachon, C Van Den Ouweland, AMW Wang, Q Winqvist, R Zheng, W Benitez, J Chenevix-Trench, G Dunning, AM Pharoah, PDP Kristensen, V Hall, P Easton, DF Pastinen, T Nord, S Simard, J AF Hamdi, Yosr Soucy, Penny Adoue, Veronique Michailidou, Kyriaki Canisius, Sander Lemacon, Audrey Droit, Arnaud Andrulis, Irene L. Anton-Culver, Hoda Arndt, Volker Baynes, Caroline Blomqvist, Carl Bogdanova, Natalia V. Bojesen, Stig E. Bolla, Manjeet K. Bonanni, Bernardo Borresen-Dale, Anne-Lise Brand, Judith S. Brauch, Hiltrud Brenner, Hermann Broeks, Annegien Burwinkel, Barbara Chang-Claude, Jenny Couch, Fergus J. Cox, Angela Cross, Simon S. Czene, Kamila Darabi, Hatef Dennis, Joe Devilee, Peter Doerk, Thilo Dos-Santos-Silva, Isabel Eriksson, Mikael Fasching, Peter A. Figueroa, Jonine Flyger, Henrik Garcia-Closas, Montserrat Giles, Graham G. Goldberg, Mark S. Gonzalez-Neira, Anna Grenaker-Alnaes, Grethe Guenel, Pascal Haeberle, Lothar Haiman, Christopher A. Hamann, Ute Hallberg, Emily Hooning, Maartje J. Hopper, John L. Jakubowska, Anna Jones, Michael Kabisch, Maria Kataja, Vesa Lambrechts, Diether Le Marchand, Loic Lindblom, Annika Lubinski, Jan Mannermaa, Arto Maranian, Mel Margolin, Sara Marme, Frederik Milne, Roger L. Neuhausen, Susan L. Nevanlinna, Heli Neven, Patrick Olswold, Curtis Peto, Julian Plaseska-Karanfilska, Dijana Pylkaes, Katri Radice, Paolo Rudolph, Anja Sawyer, Elinor J. Schmidt, Marjanka K. Shu, Xiao-Ou Southey, Melissa C. Swerdlow, Anthony Tollenaar, Rob A. E. M. Tomlinson, Ian Torres, Diana Truong, Therese Vachon, Celine Van Den Ouweland, Ans M. W. Wang, Qin Winqvist, Robert Zheng, Wei Benitez, Javier Chenevix-Trench, Georgia Dunning, Alison M. Pharoah, Paul D. P. Kristensen, Vessela Hall, Per Easton, Douglas F. Pastinen, Tomi Nord, Silje Simard, Jacques CA NBCS Collaborators KConFab AOCS Investigators TI Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21 SO ONCOTARGET LA English DT Article DE breast cancer; genetic susceptibility; association studies; differential allelic expression; cis-regulatory variants ID GENOME-WIDE ASSOCIATION; BRCA1 MUTATION CARRIERS; DNA-DAMAGE RESPONSE; OVARIAN-CANCER; COMMON VARIANTS; MISSENSE SUBSTITUTIONS; CONFER SUSCEPTIBILITY; FUNCTIONAL VARIANTS; ANALYSES REVEAL; HUMAN-CELLS AB There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/ or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10(-6)). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10(-14)), MRPS18C (P = 1.94x10(-27)) and FAM175A (P = 3.83x10(-3)), explaining about 20%, 14% and 1%, respectively of the variance in expression of these genes in breast carcinomas. C1 [Hamdi, Yosr; Soucy, Penny; Anton-Culver, Hoda; Simard, Jacques] Univ Laval, Ctr Hospitalier Univ Quebec, Res Ctr, Genom Ctr, Quebec City, PQ, Canada. [Adoue, Veronique] Inst Natl Sante & Rech Med, U1043, Toulouse, France. CNRS, Toulouse, France. Univ Toulouse 3, Univ Toulouse, Ctr Physiopathol Toulouse Purpan, Toulouse, France. [Michailidou, Kyriaki; Bolla, Manjeet K.; Dennis, Joe; Wang, Qin] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Michailidou, Kyriaki] Cyprus Inst Neurol & Genet, Dept Elect Microscopy Mol Pathol, Nicosia, Cyprus. [Canisius, Sander; Broeks, Annegien; Schmidt, Marjanka K.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Lemacon, Audrey; Droit, Arnaud] Univ Laval, Dept Mol Med, Fac Med, Ctr Rech CHU Quebec, Quebec City, PQ, Canada. [Andrulis, Irene L.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Arndt, Volker; Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Baynes, Caroline; Maranian, Mel; Pharoah, Paul D. P.; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Blomqvist, Carl] Univ Helsinki, Helsinki Univ Hosp, Dept Oncol, Helsinki, Finland. [Bogdanova, Natalia V.] Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany. [Bogdanova, Natalia V.; Doerk, Thilo] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. [Bojesen, Stig E.] Copenhagen Univ Hosp, Herlevand Gentofte Hosp, Copenhagen Gen Populat Study, Herlev, Denmark. Copenhagen Univ Hosp, Herlevand Gentofte Hosp, Copenhagen Gen Populat Study, Herlev, Denmark. [Bojesen, Stig E.] Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Herlev, Denmark. [Bojesen, Stig E.] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. [Bonanni, Bernardo] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy. [Borresen-Dale, Anne-Lise; Grenaker-Alnaes, Grethe; Kristensen, Vessela; Nord, Silje] Oslo Univ Hosp, Radiumhosp, Canc Res Inst, Dept Canc Genet, Oslo, Norway. [Brand, Judith S.; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostatist, Stockholm, Sweden. [Brauch, Hiltrud] Clin Pharmacol, Margarete Fischer Bosch Inst, Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, Tubingen, Germany. [Brauch, Hiltrud; Brenner, Hermann] German Canc Res Ctr, German Canc Consortium, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Brenner, Hermann] Natl Ctr Tumor Dis, Heidelberg, Germany. [Burwinkel, Barbara; Marme, Frederik] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany. [Chang-Claude, Jenny; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Chang-Claude, Jenny] Univ Med Ctr Hamburg Eppendorf, Univ Canc Ctr Hamburg, Hamburg, Germany. Haukeland Hosp, Dept Oncol, Bergen, Norway. Univ Bergen, Inst Med, Sect Oncol, Bergen, Norway. Akershus Univ Hosp, Dept Pathol, Lorenskog, Norway. Akershus Univ Hosp, Dept Breast Endocrine Surg, Lorenskog, Norway. Oslo Univ Hosp, Dept Breast & Endocrine Surg, Oslo, Norway. Vestre Viken, Dept Res, Drammen, Norway. Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway. Oslo Univ Hosp, Radiumhosp, Natl Advisory Unit Late Effects Canc Treatment, Oslo, Norway. Oslo Univ Hosp, Radiumhosp, Dept Oncol, Oslo, Norway. Oslo Univ Hosp, Radiumhosp, Dept Radiol & Nucl Med, Oslo, Norway. [NBCS Collaborators] Oslo Univ Hosp, Oslo, Norway. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Cox, Angela] Univ Sheffield, Dept Oncol & Metab, Sheffield Canc Res, Sheffield, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands. [Dos-Santos-Silva, Isabel; Peto, Julian] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Dos-Santos-Silva, Isabel; Peto, Julian] London Sch Hyg & Trop Med, Dept Non Commun Dis Epidemiol, London, England. [Fasching, Peter A.; Haeberle, Lothar] Friedrich Alexander Univ Erlangen Nuremberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Dept Obstet & Gynaecol, Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, Div Hematol & Oncol, Dept Med, David Geffen Sch Med, Los Angeles, CA USA. [Figueroa, Jonine] Univ Edinburgh, Sch Med, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland. [Figueroa, Jonine; Garcia-Closas, Montserrat] Natl Canc Inst, Div Canc Epidemiol & Genet, Rockville, MD USA. [Flyger, Henrik] Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Breast Surg, Herlev, Denmark. [Giles, Graham G.; Milne, Roger L.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.; Hopper, John L.; Milne, Roger L.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostatist, Melbourne, Vic, Australia. [Goldberg, Mark S.] McGill Univ, Dept Med, Montreal, PQ, Canada. [Goldberg, Mark S.] McGill Univ, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ, Canada. [Gonzalez-Neira, Anna; Benitez, Javier] Spanish Natl Canc Res Ctr, Human Canc Genet Program, Madrid, Spain. [Guenel, Pascal; Truong, Therese] Univ Paris Saclay, Univ Paris Sud, Canc & Environm Grp, Ctr Res Epidemiol & Populat Hlth CESP,INSERM, Villejuif, France. [Haiman, Christopher A.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Hamann, Ute; Kabisch, Maria; Torres, Diana] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany. [Hallberg, Emily; Olswold, Curtis; Vachon, Celine] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Hooning, Maartje J.] Erasmus MC Canc Inst, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. [Jakubowska, Anna; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Jones, Michael] Inst Canc Res, Div Genet & Epidemiol, London, England. [Kataja, Vesa; Mannermaa, Arto] Univ Eastern Finland, Canc Ctr Eastern Finland, Kuopio, Finland. [Kataja, Vesa] Jyvaskyla Cent Hosp, Cent Finland Hosp Dist, Jyvaskyla, Finland. [Lambrechts, Diether] Vesalius Res Ctr, Leuven, Belgium. [Lambrechts, Diether] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI USA. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Mannermaa, Arto] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland. [Mannermaa, Arto] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, Kuopio, Finland. [Margolin, Sara] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Marme, Frederik] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany. [Neuhausen, Susan L.] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA. [Nevanlinna, Heli] Univ Helsinki, Helsinki Univ Hosp, Dept Obstet & Gynecol, Helsinki, Finland. [Neven, Patrick] Univ Hosp Leuven, Dept Oncol, Multidisciplinary Breast Ctr, Leuven, Belgium. [Plaseska-Karanfilska, Dijana] Macedonian Acad Sci & Arts, Res Ctr Genet Engn & Biotechnol Georgi Efremov, Skopje, Macedonia. [Pylkaes, Katri; Winqvist, Robert] Univ Oulu, Bioctr Oulu, Canc & Translat Med Res Unit, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Pylkaes, Katri; Winqvist, Robert; Dunning, Alison M.] Ctr Oulu, Northern Finland Lab, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Sawyer, Elinor J.] Kings Coll London, Guys Hosp, Res Oncol, London, England. [Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Dept Med,Div Epidemiol, Nashville, TN USA. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Swerdlow, Anthony] Inst Canc Res, Div Genet & Epidemiol, London, England. [Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, London, England. [Tollenaar, Rob A. E. M.] Leiden Univ, Ctr Med, Dept Surg, Leiden, Netherlands. [Tomlinson, Ian] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Tomlinson, Ian] Univ Oxford, Oxford NIHR Biomed Res Ctr, Oxford, England. [Torres, Diana] Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia. [Van Den Ouweland, Ans M. W.] Erasmus Univ, Med Ctr, Dept Clin Genet, Rotterdam, Netherlands. [KConFab AOCS Investigators] Univ Melbourne, Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Benitez, Javier] Ctr Invest Red Enfermedades Raras, Valencia, Spain. [Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld, Australia. [Kristensen, Vessela] Univ Oslo, Oslo Univ Hosp, Dept Clin Mol Biol, Oslo, Norway. [Pastinen, Tomi] McGill Univ, Dept Human Genet, Montreal, PQ, Canada. [Pastinen, Tomi] McGill Univ, Dept Human Genet, Montreal, PQ, Canada. McGill Univ, Montreal, PQ, Canada. Genome Quebec Innovat Ctr, Montreal, PQ, Canada. RP Simard, J (reprint author), Univ Laval, Ctr Hospitalier Univ Quebec, Res Ctr, Genom Ctr, Quebec City, PQ, Canada. EM Jacques.Simard@crchudequebec.ulaval.ca RI Brenner, Hermann/B-4627-2017; Nord, Silje/R-5212-2016; Dork, Thilo/J-8620-2012; OI Brenner, Hermann/0000-0002-6129-1572; Nord, Silje/0000-0002-3271-5356; Dunning, Alison Margaret/0000-0001-6651-7166 FU Canadian Institutes of Health Research [CRN-87521]; Ministry of Economy Innovation and Exportations [PSR-SIIRI-701]; Government of Canada through Genome Canada; Canadian Institutes of Health Research; Ministere de l'Economie; de la Science et de l'Innovation du Quebec through Genome Quebec; Quebec Breast Cancer Foundation; Canada Research Chair in Oncogenetics; Norwegian Regional Health authorities [2014061]; Cancer Research UK [C1287/A10118, C1287/A12014, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565, C490/A10124]; European Community's Seventh Framework Programme [223175, HEALTH-F2-2009-223175]; National Institutes of Health [CA128978, R01 CA77398]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR); Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; National Cancer Institute (USA) [UM1 CA164920]; National Health and Medical Research Council of Australia; New South Wales Cancer Council; Victorian Health Promotion Foundation (Australia); Victorian Breast Cancer Research Consortium; Dutch Cancer Society [NKI 2007-3839, 2009 4363, RUL 1997-1505, DDHK 2004-3124, DDHK 2009-4318]; BBMRI-NL - Dutch government [NWO 184.021.007]; Dutch National Genomics Initiative; ELAN-Fond of the University Hospital of Erlangen; Cancer Research UK; Breast Cancer; NHS; National Cancer Research Network (NCRN); NIHR Comprehensive Biomedical Research Centre; Guy's & St. Thomas' NHS Foundation Trust; Oxford Biomedical Research Center; Dietmar-Hopp Foundation; Helmholtz Society; German Cancer Research Center (DKFZ); Fondation de France; Institut National du Cancer (INCa); Ligue Nationale contre le Cancer; Ligue contre le Cancer Grand Ouest; Agence Nationale de Securite Sanitaire (ANSES); Agence Nationale de la Recherche (ANR); Chief Physician Johan Boserup and Lise Boserup Fund; Danish Medical Research Council; Herlev Hospital; Instituto de Salud Carlos III; Red Tematica de Investigacion Cooperativa en Cancer; Asociacion Espanola Contra el Cancer; Fondo de Investigacion Sanitario [PI11/00923, PI12/00070]; California Breast Cancer; California Breast Cancer Research Fund [97-10500]; California Department of Public Health [103885]; Lon V Smith Foundation [LVS39420]; Baden Wurttemberg Ministry of Science, Research and Arts; German Cancer Aid (Deutsche Krebshilfe); Federal Ministry of Education and Research (BMBF) Germany [01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114, 01KH0402]; Robert Bosch Foundation, Stuttgart; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance; Institute of the Ruhr University Bochum (IPA), Bochum; Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany; Helsinki University Central Hospital Research Fund; Academy of Finland [266528, 250083, 122715, 251314]; Finnish Cancer Society; Nordic Cancer Union; Sigrid Juselius Foundation; Friends of Hannover Medical School; Rudolf Bartling Foundation; Stockholm County Council; Karolinska Institutet; Swedish Cancer Society; Gustav V Jubilee foundation; Bert von Kantzows foundation; special Government Funding (EVO) of Kuopio University Hospital grants; Cancer Fund of North Savo; Finnish Cancer Organizations; University of Eastern Finland; National Breast Cancer Foundation; Queensland Cancer Fund; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Council of Tasmania; Cancer Council of South Australia; Cancer Foundation of Western Australia; United States Army Medical Research and Materiel Command [DAMD17-01-1-0729]; Cancer Council Victoria; Cancer Council New South Wales; Cancer Council South Australia; Cancer Council Tasmania; National Health and Medical Research Council of Australia (NHMRC) [400413, 400281, 199600]; NHMRC; Stichting tegen Kanker [232-2008, 196-2010]; FWO; Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419]; Hamburg Cancer Society; Italian Association for Cancer Research (AIRC); Fondazione IRCCS Istituto Nazionale Tumori [5/1000]; NIH [CA192393, CA116167, CA176785, CA63464, CA54281, CA098758, CA132839]; NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; VicHealth; Australian NHMRC [209057, 251553, 504711]; Ministry of Economic Development, Innovation and Export Trade [PSR-SIIRI-701]; Research Council of Norway [193387/V50, 193387/H10]; South Eastern Norway Health Authority [39346, 27208]; Norwegian Cancer Society [419616 - 71248 - PR-2006-0282]; K.G. Jebsen Centre for Breast Cancer Research; Finnish Cancer Foundation; University of Oulu; University of Oulu Support Foundation; special Governmental EVO funds; Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL) [CP16]; Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA; Marit and Hans Rausings Initiative against Breast Cancer; Agency for Science, Technology and Research of Singapore (A*STAR); US National Institute of Health (NIH); Susan G. Komen Breast Cancer Foundation; Yorkshire Cancer Research [S295, S299, S305PA]; Sheffield Experimental Cancer Medicine Centre; UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; BRL (Basic Research Laboratory) program through the National Research Foundation of Korea - Ministry of Education, Science and Technology [2012-0000347]; NUS start-up Grant; National University Cancer Institute Singapore (NCIS) Centre Grant; NMRC Clinician Scientist Award; Biomedical Research Council [05/1/21/19/425]; DKFZ; Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; Institute of Cancer Research (ICR), London; [KULPFV/10/016-SymBioSysII]; [PBZ_KBN_122/P05/2004] FX This work was supported by the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program - grant # CRN-87521, the Ministry of Economy Innovation and Exportations-grant # PSR-SIIRI-701 and by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, and the Ministere de l'Economie, de la Science et de l'Innovation du Quebec through Genome Quebec and The Quebec Breast Cancer Foundation for the PERSPECTIVE project. Jacques Simard is Chairholder of the Canada Research Chair in Oncogenetics. Silje Nord is financed by a carrier grant from the Norwegian Regional Health authorities (Grant number 2014061).; BCAC is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Community's Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow. M.C.S. is a NHMRC Senior Research Fellow. The ABCS study was supported by the Dutch Cancer Society [grants NKI 2007-3839; 2009 4363]; BBMRI-NL, which is a Research Infrastructure financed by the Dutch government (NWO 184.021.007); and the Dutch National Genomics Initiative. The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breast Cancer Now and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). ES is supported by NIHR Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, United Kingdom. IT is supported by the Oxford Biomedical Research Center. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). The CECILE study was funded by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Ligue contre le Cancer Grand Ouest, Agence Nationale de Securite Sanitaire (ANSES), Agence Nationale de la Recherche (ANR). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The CNIO-BCS was supported by the Instituto de Salud Carlos III, the Red Tematica de Investigacion Cooperativa en Cancer and grants from the Asociacion Espanola Contra el Cancer and the Fondo de Investigacion Sanitario (PI11/00923 and PI12/00070). The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398).; Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. HAC receives support from the Lon V Smith Foundation (LVS39420). The ESTHER study was supportd by a grant from the Baden Wurttemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The HEBCS was financilly supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, The Nordic Cancer Union and the Sigrid Juselius Foundation. The HMBCS was supported by a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation. Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Swedish Cancer Society, The Gustav V Jubilee foundation and and Bert von Kantzows foundation. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, and by the strategic funding of the University of Eastern Finland. kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command [DAMD17-01-1-0729], Cancer Council Victoria, Queensland Cancer Fund, Cancer Council New South Wales, Cancer Council South Australia, The Cancer Foundation of Western Australia, Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; 400413, 400281, 199600). G.C.T. and P.W. are supported by the NHMRC. RB was a Cancer Institute NSW Clinical Research Fellow. LMBC is supported by the 'Stichting tegen Kanker' (232-2008 and 196-2010). Diether Lambrechts is supported by the FWO and the KULPFV/10/016-SymBioSysII. The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419], the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. MBCSG (Milan Breast Cancer Study Group) is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects "5x1000").; The MCBCS was supported by the NIH grants CA192393, CA116167, CA176785 an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201], and the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. The MEC was support by NIH grants CA63464, CA54281, CA098758 and CA132839. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program - grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade - grant # PSR-SIIRI-701. The NBCS has been supported by the Research Council of Norway grant 193387/V50 (to A-L Borresen-Dale and V.N. Kristensen) and grant 193387/H10 (to A-L Borresen-Dale and V.N. Kristensen), South Eastern Norway Health Authority (grant 39346 to A-L Borresen-Dale and 27208 to V.N. Kristensen) and the Norwegian Cancer Society (to A-L Borresen-Dale and 419616 - 71248 - PR-2006-0282 to V.N. Kristensen). It has received funding from the K.G. Jebsen Centre for Breast Cancer Research (2012-2015). The OBCS was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland (grant number 250083, 122715 and Center of Excellence grant number 251314), the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the University of Oulu, the University of Oulu Support Foundation and the special Governmental EVO funds for Oulu University Hospital-based research activities. The Ontario Familial Breast Cancer Registry (OFBCR) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The pKARMA study was supported by Marit and Hans Rausings Initiative against Breast Cancer. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. The SBCS was supported by Yorkshire Cancer Research S295, S299, S305PA and Sheffield Experimental Cancer Medicine Centre. SEARCH is funded by a programme grant from Cancer Research UK [C490/A10124] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge.; SEBCS was supported by the BRL (Basic Research Laboratory) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012-0000347). SGBCC is funded by the NUS start-up Grant, National University Cancer Institute Singapore (NCIS) Centre Grant and the NMRC Clinician Scientist Award. Additional controls were recruited by the Singapore Consortium of Cohort Studies-Multi-ethnic cohort (SCCS-MEC), which was funded by the Biomedical Research Council, grant number: 05/1/21/19/425. SKKDKFZS is supported by the DKFZ. The SZBCS was supported by Grant PBZ_KBN_122/P05/2004. The TNBCC was supported by: a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation. The UKBGS is funded by Breast Cancer Now and the Institute of Cancer Research (ICR), London. ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. NR 90 TC 1 Z9 1 U1 9 U2 9 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD DEC 6 PY 2016 VL 7 IS 49 BP 80140 EP 80163 DI 10.18632/oncotarget.12818 PG 24 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EE8LO UT WOS:000389877500009 PM 27792995 ER PT J AU Bessede, E Molina, S Amador, LA Dubus, P Staedel, C Chambonnier, L Buissonniere, A Sifre, E Giese, A Benejat, L Rousseau, B Costet, P Sacks, DB Megraud, F Varon, C AF Bessede, Emilie Molina, Silvia Amador, Luis Acuna Dubus, Pierre Staedel, Cathy Chambonnier, Lucie Buissonniere, Alice Sifre, Elodie Giese, Alban Benejat, Lucie Rousseau, Benoit Costet, Pierre Sacks, David B. Megraud, Francis Varon, Christine TI Deletion of IQGAP1 promotes Helicobacter pylori-induced gastric dysplasia in mice and acquisition of cancer stem cell properties in vitro SO ONCOTARGET LA English DT Article DE EMT; gastric cancer; CD44; E-cadherin; Zeb ID EPITHELIAL-CELLS; E-CADHERIN; CAGA; EXPRESSION; ADHESION; REGULATOR; CARCINOMA; MIGRATION; PROTEINS; POLARITY AB Helicobacter pylori infection is responsible for gastric carcinogenesis but host factors are also implicated. IQGAP1, a scaffolding protein of the adherens junctions interacting with E-cadherin, regulates cellular plasticity and proliferation. In mice, IQGAP1 deficiency leads to gastric hyperplasia. The aim of this study was to elucidate the consequences of IQGAP1 deletion on H. pylori-induced gastric carcinogenesis. Transgenic mice deleted for iqgap1 and WT littermates were infected with Helicobacter sp., and histopathological analyses of the gastric mucosa were performed. IQGAP1 and E-cadherin expression was evaluated in gastric tissues and in gastric epithelial cell lines in response to H. pylori infection. The consequences of IQGAP1 deletion on gastric epithelial cell behaviour and on the acquisition of cancer stem cell (CSC)-like properties were evaluated. After one year of infection, iqgap1+/- mice developed more preneoplastic lesions and up to 8 times more gastrointestinal neoplasia (GIN) than WT littermates. H. pylori infection induced IQGAP1 and E-cadherin delocalization from cell-cell junctions. In vitro, knock-down of IQGAP1 favoured the acquisition of a mesenchymal phenotype and CSC-like properties induced by H. pylori infection. Our results indicate that alterations in IQGAP1 signalling promote the emergence of CSCs and gastric adenocarcinoma development in the context of an H. pylori infection. C1 [Bessede, Emilie; Molina, Silvia; Amador, Luis Acuna; Chambonnier, Lucie; Buissonniere, Alice; Sifre, Elodie; Benejat, Lucie; Megraud, Francis; Varon, Christine] Univ Bordeaux, Bacteriol Lab, Bordeaux, France. [Bessede, Emilie; Molina, Silvia; Amador, Luis Acuna; Chambonnier, Lucie; Buissonniere, Alice; Sifre, Elodie; Benejat, Lucie; Megraud, Francis; Varon, Christine] INSERM, U853, Bordeaux, France. [Dubus, Pierre; Giese, Alban] Univ Bordeaux, Histol & Pathol Mol Tumeurs EA2406, Bordeaux, France. [Staedel, Cathy] Univ Bordeaux, RNA Nat & Artificial Regulat ARNA Lab, Bordeaux, France. [Rousseau, Benoit] INSERM, U869, Bordeaux, France. [Staedel, Cathy] Univ Bordeaux, Animalerie A2, Serv Commun Animaleries, Bordeaux, France. [Rousseau, Benoit] Univ Bordeaux, Serv Commun Animaleries, Animalerie A2, Bordeaux, France. [Costet, Pierre] Univ Bordeaux, Serv Commun Animaleries, Animalerie Transgen, Bordeaux, France. [Sacks, David B.] NIH, Dept Lab Med, Bldg 10, Bethesda, MD 20892 USA. [Giese, Alban] Univ Bordeaux, SIRIC BRIO, Expt Pathol Platform, Bordeaux, France. RP Bessede, E (reprint author), Univ Bordeaux, Bacteriol Lab, Bordeaux, France.; Bessede, E (reprint author), INSERM, U853, Bordeaux, France. EM ebessede@gmail.com FU French 'Association pour la Recherche contre le Cancer' [8412]; Institut National du Cancer [07/3D1616/IABC-23-12/NC-NG]; Conseil Regional d'Aquitaine [20071301017, 20081302203]; SIRIC BRIO (Site de Recherche Integree sur le Cancer -Bordeaux Recherche Integree Oncologie) [INCa-DGOS-Inserm 6046]; National Institutes of Health Intramural Research Program FX This project was supported by the French 'Association pour la Recherche contre le Cancer' (grant number 8412), 'Institut National du Cancer' (grant number 07/3D1616/IABC-23-12/NC-NG), 'Conseil Regional d'Aquitaine' (grant number 20071301017 and 20081302203) and the SIRIC BRIO (Site de Recherche Integree sur le Cancer -Bordeaux Recherche Integree Oncologie) [Grant: INCa-DGOS-Inserm 6046]. We thank Andre Bernards (Massachusetts General Hospital Center for Cancer Research, Charlestown, MA, USA) for giving access to the iqgap1 knockout mice and for helpful discussions; Patrick Auguste (INSERM U1029, University of Bordeaux, Bordeaux, France) for IQGAP1 siRNAs and antibodies; Denis Collet (Digestive Surgery of Haut-Leveque Hospital, University Hospital of Bordeaux, France) and Serge Evrard and Isabelle Soubeyran (Bergonie Institute, Bordeaux, France) and Genevieve Belleannee (Pathology Department, Haut Leveque Hospital, University Hospital Center, Pessac, france) for providing human gastric tissue samples from consenting patients; David Cappellen (EA2406 University of Bordeaux) and Violaine Moreau (INSERM U1053, University of Bordeaux, Bordeaux, France) for helpful discussions; DBS is supported by the National Institutes of Health Intramural Research Program and Laura Biguet for technical support. NR 29 TC 0 Z9 0 U1 2 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD DEC 6 PY 2016 VL 7 IS 49 BP 80688 EP 80699 DI 10.18632/oncotarget.12486 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EE8LO UT WOS:000389877500050 PM 27729612 ER PT J AU Neveu, MA De Preter, G Joudiou, N Bol, A Brender, JR Saito, K Kishimoto, S Gregoire, V Jordan, BF Krishna, MC Feron, O Gallez, B AF Neveu, Marie-Aline De Preter, Geraldine Joudiou, Nicolas Bol, Anne Brender, Jeffery R. Saito, Keita Kishimoto, Shun Gregoire, Vincent Jordan, Benedicte F. Krishna, Murali C. Feron, Olivier Gallez, Bernard TI Multi-modality imaging to assess metabolic response to dichloroacetate treatment in tumor models SO ONCOTARGET LA English DT Article DE tumor metabolism; DCA; O-17 MRS; hyperpolarized C-13-MRI; F-18-FDG PET ID IN-VIVO; MITOCHONDRIAL METABOLISM; SODIUM DICHLOROACETATE; AEROBIC GLYCOLYSIS; CANCER; CELLS; RAT; DCA; PROLIFERATION; SPECTROSCOPY AB Reverting glycolytic metabolism is an attractive strategy for cancer therapy as upregulated glycolysis is a hallmark in various cancers. Dichloroacetate (DCA), long used to treat lactic acidosis in various pathologies, has emerged as a promising anticancer drug. By inhibiting the pyruvate dehydrogenase kinase, DCA reactivates the mitochondrial function and decreases the glycolytic flux in tumor cells resulting in cell cycle arrest and apoptosis. We recently documented that DCA was able to induce a metabolic switch preferentially in glycolytic cancer cells, leading to a more oxidative phenotype and decreasing proliferation, while oxidative cells remained less sensitive to DCA treatment. To evaluate the relevance of this observation in vivo, the aim of the present study was to characterize the effect of DCA in glycolytic MDA-MB-231 tumors and in oxidative SiHa tumors using advanced pharmacodynamic metabolic biomarkers. Oxygen consumption, studied by O-17 magnetic resonance spectroscopy, glucose uptake, evaluated by F-18-FDG PET and pyruvate transformation into lactate, measured using hyperpolarized C-13-magnetic resonance spectroscopy, were monitored before and 24 hours after DCA treatment in tumor bearing mice. In both tumor models, no clear metabolic shift was observed. Surprisingly, all these imaging parameters concur to the conclusion that both glycolytic tumors and oxidative tumors presented a similar response to DCA. These results highlight a major discordance in metabolic cancer cell bioenergetics between in vitro and in vivo setups, indicating critical role of the local microenvironment in tumor metabolic behaviors. C1 [Neveu, Marie-Aline; De Preter, Geraldine; Joudiou, Nicolas; Jordan, Benedicte F.; Gallez, Bernard] Catholic Univ Louvain, Louvain Drug Res Inst, Biomed Magnet Resonance Res Grp, Brussels, Belgium. [Bol, Anne; Gregoire, Vincent] Catholic Univ Louvain, Radiat Oncol Dept, Brussels, Belgium. [Bol, Anne; Gregoire, Vincent] Catholic Univ Louvain, Inst Expt & Clin Res, Ctr Mol Imaging Radiotherapy & Oncol, Brussels, Belgium. [Brender, Jeffery R.; Saito, Keita; Kishimoto, Shun; Krishna, Murali C.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. [Feron, Olivier] Catholic Univ Louvain, Inst Expt & Clin Res, Pole Pharmacol & Therapeut, Brussels, Belgium. RP Gallez, B (reprint author), Catholic Univ Louvain, Louvain Drug Res Inst, Biomed Magnet Resonance Res Grp, Brussels, Belgium. EM bernard.gallez@uclouvain.be FU Belgian National Fund for Scientific Research (F.S.R.-FNRS) [PDR T.0107.13]; Action de Recherches Concertees ARC [14/19-058]; Belgian Science Policy Office Interuniversity Attraction Pole IUAP [P7/03]; National Institute of Health (NIH) FX This work was supported by grants from the Belgian National Fund for Scientific Research (F.S.R.-FNRS; PDR T.0107.13); the Action de Recherches Concertees ARC 14/19-058; Belgian Science Policy Office Interuniversity Attraction Pole IUAP #P7/03; and intramural National Institute of Health (NIH) funds. NR 31 TC 0 Z9 0 U1 4 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD DEC 6 PY 2016 VL 7 IS 49 BP 81741 EP 81749 DI 10.18632/oncotarget.13176 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EE8LO UT WOS:000389877500130 PM 28082726 ER PT J AU Maumet, C Auer, T Bowring, A Chen, G Das, S Flandin, G Ghosh, S Glatard, T Gorgolewski, KJ Helmer, KG Jenkinson, M Keator, DB Nichols, BN Poline, JB Reynolds, R Sochat, V Turner, J Nichols, TE AF Maumet, Camille Auer, Tibor Bowring, Alexander Chen, Gang Das, Samir Flandin, Guillaume Ghosh, Satrajit Glatard, Tristan Gorgolewski, Krzysztof J. Helmer, Karl G. Jenkinson, Mark Keator, David B. Nichols, B. Nolan Poline, Jean-Baptiste Reynolds, Richard Sochat, Vanessa Turner, Jessica Nichols, Thomas E. TI Sharing brain mapping statistical results with the neuroimaging data model SO SCIENTIFIC DATA LA English DT Article ID FMRI; REPRODUCIBILITY; METAANALYSIS; TRANSPARENCY; NEUROSCIENCE; EVOLUTION; ONTOLOGY AB Only a tiny fraction of the data and metadata produced by an fMRI study is finally conveyed to the community. This lack of transparency not only hinders the reproducibility of neuroimaging results but also impairs future meta-analyses. In this work we introduce NIDM-Results, a format specification providing a machine-readable description of neuroimaging statistical results along with key image data summarising the experiment. NIDM-Results provides a unified representation of mass univariate analyses including a level of detail consistent with available best practices. This standardized representation allows authors to relay methods and results in a platform-independent regularized format that is not tied to a particular neuroimaging software package. Tools are available to export NIDM-Result graphs and associated files from the widely used SPM and FSL software packages, and the NeuroVault repository can import NIDM-Results archives. The specification is publically available at: http://nidm.nidash.org/specs/nidm-results.html. C1 [Maumet, Camille; Bowring, Alexander; Nichols, Thomas E.] Univ Warwick, WMG, Coventry CV4 7AL, W Midlands, England. [Auer, Tibor] MRC Cognit & Brain Sci Unit, Cambridge CB2 7EF, England. [Chen, Gang; Reynolds, Richard] NIMH, Sci & Stat Comp Core, NIH, Bethesda, MD 20892 USA. [Das, Samir; Glatard, Tristan] Montreal Neurol Inst, Ludmer Ctr, McGill Ctr Integrat Neurosci, Montreal, PQ H3A 2B4, Canada. [Flandin, Guillaume] UCL, Inst Neurol, Wellcome Trust Ctr Neuroimaging, London WC1N 3BG, England. [Ghosh, Satrajit] MIT, McGovern Inst Brain, Cambridge, MA 02139 USA. [Glatard, Tristan] Univ Claude Bernard Lyon 1, INSA Lyon, Inserm U1044, Univ Lyon,CREATIS,CNRS UMR5220, F-69100 Villeurbanne, France. [Gorgolewski, Krzysztof J.; Sochat, Vanessa] Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. [Helmer, Karl G.] Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. [Jenkinson, Mark] Univ Oxford, Oxford OX3 9DU, England. [Keator, David B.] Univ Calif Irvine, Dept Neurol, Dept Comp Sci, Dept Psychiat & Human Behav, Irvine, CA 92697 USA. [Nichols, B. Nolan] SRI Int, Ctr Hlth Sci, Menlo Pk, CA 94025 USA. [Poline, Jean-Baptiste] Univ Calif Berkeley, H Wheeler Jr Brain Imaging Ctr, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. [Turner, Jessica] Georgia State Univ, Psychol & Neurosci, Atlanta, GA 30302 USA. [Nichols, Thomas E.] Univ Warwick, Dept Stat, Coventry CV4 7AL, W Midlands, England. RP Maumet, C (reprint author), Univ Warwick, WMG, Coventry CV4 7AL, W Midlands, England. EM c.m.j.maumet@warwick.ac.uk OI Gorgolewski, Krzysztof/0000-0003-3321-7583; Ghosh, Satrajit/0000-0002-5312-6729; Nichols, Nolan/0000-0003-1099-3328 FU Wellcome Trust [100309/Z/12/Z]; Medical Research Council (United Kingdom) [MC-A060-53114]; NIH [AA012388, AA021697, AA021697-04S1, 1R01EB020740-01A1, 1P41EB019936-01A1]; NIH-NIBIB grant [P41-EB019936]; Laura and John Arnold Foundation; NIH-NIDA grant [U24-038653]; Function Biomedical Informatics Re-search Network [NIH 1 [U24 U24 RR021992]]; BIRN Coordinating Center [NIH 1 [U24 RR025736-01], NIH U24 RR025736-01]; Conte Center on Brain Programming in Adolescent Vulnerabilities [1P50MH096889-01A1]; NIMH; NINDS Intramural Research Programs of the NIH/HHS, USA [ZICMH002888]; Morphometry Biomedical Informatics Research Network (MBIRN) [NIH U24 RR021382]; Irving Ludmer Family Foundation; Ludmer Centre for Neuroinformatics and Mental Health FX We gratefully acknowledge Matthew Webster, Paul McCarthy, Eugene Duff and Steve Smith, from the FMRIB and Robert Cox and Ziad Saad from the NIH, for their inputs on the integration of NIDM-Results within FSL and AFNI; as well as the NIDASH task force members for their inputs during the development of the model. We also gratefully acknowledge the Tracey group at FMRIB for sharing their pain datasets used in the meta-analysis. The INCF supported and organised the task force meetings in which the model was discussed. A.B., C.M. and T.E.N. were supported by the Wellcome Trust [100309/Z/12/Z]. T.A. was supported by the Medical Research Council (United Kingdom) [MC-A060-53114]. BNN was supported by NIH grants [AA012388, AA021697, AA021697-04S1]. S.G. was partially supported by NIH grants [1R01EB020740-01A1, 1P41EB019936-01A1]. J.B.P. was partially supported by a NIH-NIBIB grant [P41-EB019936], the Laura and John Arnold Foundation and by a NIH-NIDA grant [U24-038653]. D.B.K. was supported by the Function Biomedical Informatics Re-search Network (NIH 1 [U24 U24 RR021992]), the BIRN Coordinating Center (https://www.nitrc.org/projects/birn/; NIH 1 [U24 RR025736-01]) and the Conte Center on Brain Programming in Adolescent Vulnerabilities [1P50MH096889-01A1]. G.C. and R.R. were supported by the NIMH and NINDS Intramural Research Programs (ZICMH002888) of the NIH/HHS, USA. K.J.G. was sponsored by the Laura and John Arnold Foundation. K.G.H. was supported by the Morphometry Biomedical Informatics Research Network (MBIRN, NIH U24 RR021382), the BIRN Coordinating Center (NIH U24 RR025736-01). S.D. and T.G. were supported by the Irving Ludmer Family Foundation and the Ludmer Centre for Neuroinformatics and Mental Health. NR 54 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 2052-4463 J9 SCI DATA JI Sci. Data PD DEC 6 PY 2016 VL 3 AR UNSP 160102 DI 10.1038/sdata.2016.102 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EF3QC UT WOS:000390238300001 PM 27922621 ER PT J AU McCafferty, CL Sergeev, YV AF McCafferty, Caitlyn L. Sergeev, Yuri V. TI Dataset of eye disease-related proteins analyzed using the unfolding mutation screen SO SCIENTIFIC DATA LA English DT Article; Data Paper ID MISSENSE MUTATIONS; RESIDUE DEPTH; WEB SERVER; ATOM DEPTH; PREDICTION; STABILITY; RECOGNITION; SURFACE AB A number of genetic diseases are a result of missense mutations in protein structure. These mutations can lead to severe protein destabilization and misfolding. The unfolding mutation screen (UMS) is a computational method that calculates unfolding propensities for every possible missense mutation in a protein structure. The UMS validation demonstrated a good agreement with experimental and phenotypical data. 15 protein structures (a combination of homology models and crystal structures) were analyzed using UMS. The standard and clustered heat maps, and patterned protein structure from the analysis were stored in a UMS library. The library is currently composed of 15 protein structures from 14 inherited eye diseases including retina degenerations, glaucoma, and cataracts, and contains data for 181,110 mutations. The UMS protein library introduces 13 new human models of eye disease related proteins and is the first collection of the consistently calculated unfolding propensities, which could be used as a tool for the express analysis of novel mutations in clinical practice, next generation sequencing, and genotype-to-phenotype relationships in inherited eye disease. C1 [McCafferty, Caitlyn L.; Sergeev, Yuri V.] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. RP Sergeev, YV (reprint author), NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. EM sergeevy@nei.nih.gov NR 27 TC 1 Z9 1 U1 1 U2 1 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 DEC 6 PY 2016 VL 3 AR UNSP 160112 DI 10.1038/sdata.2016.112 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EF3QD UT WOS:000390238400007 PM 27922631 ER PT J AU Iwasa, KH AF Iwasa, Kuni H. TI Energy Output from a Single Outer Hair Cell SO BIOPHYSICAL JOURNAL LA English DT Article ID GUINEA-PIG; COCHLEAR AMPLIFICATION; FORCE GENERATION; HIGH-FREQUENCY; PIEZOELECTRIC MODEL; LATERAL MEMBRANE; VOLTAGE-SENSOR; MOTOR PROTEIN; CAPACITANCE; MOTILITY AB Electromotility of outer hair cells (OHCs) has been extensively studied with in vitro experiments because of its physiological significance to the cochlear amplifier, which provides the exquisite sensitivity and frequency selectivity of the mammalian ear. However, these studies have been performed largely under load-free conditions or with static load, while these cells function in vivo in a dynamic environment, receiving electrical energy to enhance mechanical oscillation in the inner ear. This gap leaves uncertainties in addressing a key issue, how much mechanical energy an OHC provides. This study is an attempt of bridging the gap by introducing a simple one-dimensional model for electromotility of OHC in a dynamic environment: This model incorporates a feedback loop involving the receptor potential and the mechanical load on OHC, and leads to an analytical expression for the membrane capacitance, which explicitly describes the dependence on the elastic load, viscous drag, and the mass. The derived equation of motion was examined in a mass-less model system with realistic parameter values for OHC. It was found that viscous drag is more effective than elastic load in enhancing the receptor potential that drives the cell. For this reason, it is expected that OHCs are more effective in counteracting viscous drag than providing elastic energy to the system. C1 [Iwasa, Kuni H.] Stanford Univ, Sch Med, Dept Otolaryngol, Stanford, CA 94305 USA. [Iwasa, Kuni H.] NIDCD, NIH, Bethesda, MD 20892 USA. RP Iwasa, KH (reprint author), Stanford Univ, Sch Med, Dept Otolaryngol, Stanford, CA 94305 USA.; Iwasa, KH (reprint author), NIDCD, NIH, Bethesda, MD 20892 USA. EM kuni.iwasa@gmail.com FU NIH [5R01DC00791008]; Intramural Research Program of the NIH National Institute on Deafness and Other Communication Disorders FX Discussion with Dr. Charles Steele and Yanli Wang motivated to start the present work at Stanford, partially supported by NIH 5R01DC00791008 to Stanford University. A part of the work was done during my stay at Niels Bohr Institute, Copenhagen, and Max Planck Institute for Physics of Complex Systems, Dresden. It was also supported in part by the Intramural Research Program of the NIH National Institute on Deafness and Other Communication Disorders. NR 39 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD DEC 6 PY 2016 VL 111 IS 11 BP 2500 EP 2511 DI 10.1016/j.bpj.2016.10.021 PG 12 WC Biophysics SC Biophysics GA EE4HW UT WOS:000389563900019 PM 27926851 ER PT J AU Brennan, PF AF Brennan, Patricia Flatley TI The National Library of Medicine: Accelerating Discovery, Delivering Information, Improving Health SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material C1 [Brennan, Patricia Flatley] Natl Lib Med, Bethesda, MD USA. RP Brennan, PF (reprint author), NIH, Natl Lib Med, Bldg 38,8600 Rockville Pike, Bethesda, MD 20894 USA. EM patti.brennan@nih.gov NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD DEC 6 PY 2016 VL 165 IS 11 BP 808 EP + DI 10.7326/M16-1737 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA EE0KO UT WOS:000389263900009 PM 27537845 ER PT J AU Nagai, YJ Kikuchi, E Lerchner, W Inoue, K Ji, B Eldridge, MAG Kaneko, H Kimura, Y Oh-Nishi, A Hori, YK Kato, YK Hirabayashi, T Fujimoto, A Kumata, K Zhang, MR Aoki, I Suhara, T Higuchi, M Takada, M Richmond, BJ Minamimoto, T AF Nagai, Yuji Kikuchi, Erika Lerchner, Walter Inoue, Ken-ichi Ji, Bin Eldridge, Mark A. G. Kaneko, Hiroyuki Kimura, Yasuyuki Oh-Nishi, Arata Hori, Yukiko Kato, Yoko Hirabayashi, Toshiyuki Fujimoto, Atsushi Kumata, Katsushi Zhang, Ming-Rong Aoki, Ichio Suhara, Tetsuya Higuchi, Makoto Takada, Masahiko Richmond, Barry J. Minamimoto, Takafumi TI PET imaging-guided chemogenetic silencing reveals a critical role of primate rostromedial caudate in reward evaluation SO Nature Communications LA English DT Article ID CLOZAPINE-N-OXIDE; NEURONAL-ACTIVITY; ORBITOFRONTAL CORTEX; PREFRONTAL CORTEX; RHINAL CORTEX; BRAIN; PERFORMANCE; MOTIVATION; PREFERENCE; CIRCUITS AB The rostromedial caudate (rmCD) of primates is thought to contribute to reward value processing, but a causal relationship has not been established. Here we use an inhibitory DREADD (Designer Receptor Exclusively Activated by Designer Drug) to repeatedly and non-invasively inactivate rmCD of macaque monkeys. We inject an adeno-associated viral vector expressing the inhibitory DREADD, hM4Di, into the rmCD bilaterally. To visualize DREADD expression in vivo, we develop a non-invasive imaging method using positron emission tomography (PET). PET imaging provides information critical for successful chemogenetic silencing during experiments, in this case the location and level of hM4Di expression, and the relationship between agonist dose and hM4Di receptor occupancy. Here we demonstrate that inactivating bilateral rmCD through activation of hM4Di produces a significant and reproducible loss of sensitivity to reward value in monkeys. Thus, the rmCD is involved in making normal judgments about the value of reward. C1 [Nagai, Yuji; Kikuchi, Erika; Ji, Bin; Kaneko, Hiroyuki; Kimura, Yasuyuki; Oh-Nishi, Arata; Hori, Yukiko; Kato, Yoko; Hirabayashi, Toshiyuki; Fujimoto, Atsushi; Suhara, Tetsuya; Higuchi, Makoto; Minamimoto, Takafumi] Natl Inst Quantum & Radiol Sci & Technol, Natl Inst Radiol Sci, Dept Funct Brain Imaging, Inage Ku, 4-9-1 Anagawa, Chiba 2638555, Japan. [Lerchner, Walter; Eldridge, Mark A. G.; Richmond, Barry J.] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Inoue, Ken-ichi; Takada, Masahiko] Kyoto Univ, Primate Res Inst, Syst Neurosci Sect, Inuyama, Aichi 4848506, Japan. [Kumata, Katsushi; Zhang, Ming-Rong] Natl Inst Quantum & Radiol Sci & Technol, Natl Inst Radiol Sci, Dept Radiopharmaceut Dev, Inage Ku, 4-9-1 Anagawa, Chiba 2638555, Japan. [Aoki, Ichio] Natl Inst Quantum & Radiol Sci & Technol, Natl Inst Radiol Sci, Dept Mol Imaging & Theranost, Inage Ku, 4-9-1 Anagawa, Chiba 2638555, Japan. RP Minamimoto, T (reprint author), Natl Inst Quantum & Radiol Sci & Technol, Natl Inst Radiol Sci, Dept Funct Brain Imaging, Inage Ku, 4-9-1 Anagawa, Chiba 2638555, Japan. EM minamimoto.takafumi@qst.go.jp RI Minamimoto, Takafumi/D-6610-2012; OI Minamimoto, Takafumi/0000-0003-4305-0174; Inoue, Ken-ichi/0000-0002-5683-5280; Kimura, Yasuyuki/0000-0002-7927-9483 FU PRESTO/JST; JSPS KAKENHI [JP25135736, JP26282221, JP15H05917, JP15H01419, JP25640011]; IRP-NIMH/NIH; Brain/MINDS; SRPBS from AMED; cooperative research program at PRI, Kyoto University; National Bio-Resource Project 'Japanese Monkeys' of MEXT, Japan FX We thank J. Kamei, R. Yamaguchi, Y. Matsuda, Y. Toyoda, M. Kurokawa, Y. Iwasawa, S. Shibata, N. Nitta, Y. Ozawa, M. Fujiwara, K. Nagaya and V. Der Minassian for their technical assistance, Dr K. Takemoto for his technical suggestions, and the staff of Department of Radiopharmaceuticals Development, NIRS, for support with radiosynthesis. This study was supported by PRESTO/JST and JSPS KAKENHI JP25135736, JP26282221 and JP15H05917 (to T.M.), JP15H01419 (to T.H.), JP25640011 (to M.T.), by the IRP-NIMH/NIH (B.J.R., W.L. and M.A.G.E.), by Brain/MINDS and the SRPBS from AMED, by the cooperative research program at PRI, Kyoto University and by National Bio-Resource Project 'Japanese Monkeys' of MEXT, Japan. NR 30 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 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD DEC 6 PY 2016 VL 7 AR 13605 DI 10.1038/ncomms13605 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE0LX UT WOS:000389267700002 PM 27922009 ER PT J AU Shamanna, RA Lu, HM de Freitas, JK Tian, J Croteau, DL Bohr, VA AF Shamanna, Raghavendra A. Lu, Huiming de Freitas, Jessica K. Tian, Jane Croteau, Deborah L. Bohr, Vilhelm A. TI WRN regulates pathway choice between classical and alternative non-homologous end joining SO Nature Communications LA English DT Article ID DOUBLE-STRAND BREAKS; WERNER-SYNDROME PROTEIN; DNA-REPAIR; HOMOLOGOUS RECOMBINATION; MAMMALIAN-CELLS; KU COMPLEX; RESECTION; EXONUCLEASE; MRE11; SENESCENCE AB Werner syndrome (WS) is an accelerated ageing disorder with genomic instability caused by WRN protein deficiency. Many features seen in WS can be explained by the diverse functions of WRN in DNA metabolism. However, the origin of the large genomic deletions and telomere fusions are not yet understood. Here, we report that WRN regulates the pathway choice between classical (c)- and alternative (alt)-nonhomologous end joining (NHEJ) during DNA double-strand break (DSB) repair. It promotes c-NHEJ via helicase and exonuclease activities and inhibits alt-NHEJ using non-enzymatic functions. When WRN is recruited to the DSBs it suppresses the recruitment of MRE11 and CtIP, and protects the DSBs from 5' end resection. Moreover, knockdown of Wrn, alone or in combination with Trf2 in mouse embryonic fibroblasts results in increased telomere fusions, which were ablated by Ctip knockdown. We show that WRN regulates alt-NHEJ and shields DSBs from MRE11/CtIP-mediated resection to prevent large deletions and telomere fusions. C1 [Shamanna, Raghavendra A.; Lu, Huiming; de Freitas, Jessica K.; Tian, Jane; Croteau, Deborah L.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM vbohr@nih.gov FU intramural Research Program of the National Institute on Aging, National Institutes of Health, USA FX intramural Research Program of the National Institute on Aging, National Institutes of Health, USA. NR 61 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 DEC 6 PY 2016 VL 7 AR 13785 DI 10.1038/ncomms13785 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED9HW UT WOS:000389181800001 PM 27922005 ER PT J AU Miranda, P Giraldez, T Holmgren, M AF Miranda, Pablo Giraldez, Teresa Holmgren, Miguel TI Interactions of divalent cations with calcium binding sites of BK channels reveal independent motions within the gating ring SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE SLO1 channel; FRET; allosteric regulation; divalent ions ID ACTIVATED POTASSIUM CHANNELS; CA2+-ACTIVATED K+ CHANNEL; VOLTAGE SENSOR; TRANSMITTER RELEASE; BETA-SUBUNIT; CA2+ BINDING; RAT MUSCLE; N-TERMINUS; MG2+; SENSITIVITY AB Large-conductance voltage-and calcium-activated K+ (BK) channels are key physiological players in muscle, nerve, and endocrine function by integrating intracellular Ca2+ and membrane voltage signals. The open probability of BK channels is regulated by the intracellular concentration of divalent cations sensed by a large structure in the BK channel called the "gating ring," which is formed by four tandems of regulator of conductance for K+ (RCK1 and RCK2) domains. In contrast to Ca2+ that binds to both RCK domains, Mg2+, Cd2+, or Ba2+ interact preferentially with either one or the other. Interaction of cations with their binding sites causes molecular rearrangements of the gating ring, but how these motions occur remains elusive. We have assessed the separate contributions of each RCK domain to the cation-induced gating-ring structural rearrangements, using patchclamp fluorometry. Here we show that Mg2+ and Ba2+ selectively induce structural movement of the RCK2 domain, whereas Cd2+ causes motions of RCK1, in all cases substantially smaller than those elicited by Ca2+. By combining divalent species interacting with unique sites, we demonstrate that RCK1 and RCK2 domains move independently when their specific binding sites are occupied. Moreover, binding of chemically distinct cations to both RCK domains is additive, emulating the effect of fully occupied Ca2+ binding sites. C1 [Miranda, Pablo; Holmgren, Miguel] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Giraldez, Teresa] Univ La Laguna, Dept Ciencias Med Basicas, Inst Tecnol Biomed, San Cristobal la Laguna 38071, Spain. [Giraldez, Teresa] Univ La Laguna, Ctr Invest Biomed Canarias, San Cristobal la Laguna 38071, Spain. RP Miranda, P (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM pablo.mirandafernandez2@nih.gov FU NIH (National Institute of Neurological Disorders and Stroke); Spanish Ministry of Economy and Competitiveness [SAF2013-50085-EXP]; European Research Council under the European Union's Horizon Research and Innovation Programme [648936] FX We thank Deepa Srikumar for technical assistance. M. H. and P. M. were supported by the intramural section of the NIH (National Institute of Neurological Disorders and Stroke). T. G. was funded by the Spanish Ministry of Economy and Competitiveness (Grant SAF2013-50085-EXP) and the European Research Council under the European Union's Horizon 2020 Research and Innovation Programme (Grant 648936). NR 54 TC 0 Z9 0 U1 2 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 6 PY 2016 VL 113 IS 49 BP 14055 EP 14060 DI 10.1073/pnas.1611415113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE3XX UT WOS:000389536700041 PM 27872281 ER PT J AU Cruse, G Yin, Y Fukuyama, T Desai, A Arthur, GK Baumer, W Beaven, MA Metcalfe, DD AF Cruse, Glenn Yin, Yuzhi Fukuyama, Tomoki Desai, Avanti Arthur, Greer K. Baumer, Wolfgang Beaven, Michael A. Metcalfe, Dean D. TI Exon skipping of Fc epsilon RI beta eliminates expression of the high-affinity IgE receptor in mast cells with therapeutic potential for allergy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mast cell; allergy; IgE receptor; oligonucleotides; dermatitis ID K(CA)3.1 K+ CHANNELS; SIGNALING PATHWAYS; ANTI-IGE; DISEASES; SURVIVAL; SUBUNIT; ACTIVATION; CHAIN; AGGREGATION; MIGRATION AB Allergic diseases are driven by activation of mast cells and release of mediators in response to IgE-directed antigens. However, there are no drugs currently available that can specifically down-regulate mast cell function in vivo when chronically administered. Here, we describe an innovative approach for targeting mast cells in vitro and in vivo using antisense oligonucleotide-mediated exon skipping of the beta-subunit of the high-affinity IgE receptor (Fc epsilon RI beta) to eliminate surface high-affinity IgE receptor (Fc epsilon RI) expression and function, rendering mast cells unresponsive to IgE-mediated activation. As Fc epsilon RI beta expression is restricted to mast cells and basophils, this approach would selectively target these cell types. Given the success of exon skipping in clinical trials to treat genetic diseases such as Duchenne muscular dystrophy, we propose that exon skipping of Fc epsilon RI beta is a potential approach for mast cell-specific treatment of allergic diseases. C1 [Cruse, Glenn; Fukuyama, Tomoki; Arthur, Greer K.; Baumer, Wolfgang] North Carolina State Univ, Coll Vet Med, Dept Mol Biomed Sci, Raleigh, NC 27607 USA. [Cruse, Glenn; Yin, Yuzhi; Desai, Avanti; Metcalfe, Dean D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Beaven, Michael A.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Cruse, G (reprint author), North Carolina State Univ, Coll Vet Med, Dept Mol Biomed Sci, Raleigh, NC 27607 USA.; Cruse, G (reprint author), NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. EM gpcruse@ncsu.edu FU Division of Intramural Research of National Institute of Allergy and Infectious Diseases and National Heart, Lung, and Blood Institute within the NIH FX We thank Dr. Ana Olivera (NIAID, NIH) for discussions and Sarah Ehling (Department of Molecular Biomedical Sciences, North Carolina State University) for technical assistance. Financial support was provided by the Division of Intramural Research of National Institute of Allergy and Infectious Diseases and National Heart, Lung, and Blood Institute within the NIH, and from departmental start-up funds (to G.C.) (Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University). NR 48 TC 0 Z9 0 U1 4 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 6 PY 2016 VL 113 IS 49 BP 14115 EP 14120 DI 10.1073/pnas.1608520113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE3XX UT WOS:000389536700051 PM 27872312 ER PT J AU Proietti, C Zakrzewski, M Watkins, TS Berger, B Hasan, S Ratnatunga, CN Brion, MJ Crompton, PD Miles, JJ Doolan, DL Krause, L AF Proietti, Carla Zakrzewski, Martha Watkins, Thomas S. Berger, Bernard Hasan, Shihab Ratnatunga, Champa N. Brion, Marie-Jo Crompton, Peter D. Miles, John J. Doolan, Denise L. Krause, Lutz TI Mining, visualizing and comparing multidimensional biomolecular data using the Genomics Data Miner (GMine) Web-Server7 SO Scientific Reports LA English DT Article ID HUMORAL IMMUNE-RESPONSES; CD4(+) T-CELLS; PLASMODIUM-FALCIPARUM; PROTEIN MICROARRAYS; BIOMARKER DISCOVERY; MALARIA VACCINE; GENE-EXPRESSION; ACTIVATION; PROTECTION; IDENTIFICATION AB Genomics Data Miner (GMine) is a user-friendly online software that allows non-experts to mine, cluster and compare multidimensional biomolecular datasets. Various powerful visualization techniques are provided, generating high quality figures that can be directly incorporated into scientific publications. Robust and comprehensive analyses are provided via a broad range of data-mining techniques, including univariate and multivariate statistical analysis, supervised learning, correlation networks, clustering and multivariable regression. The software has a focus on multivariate techniques, which can attribute variance in the measurements to multiple explanatory variables and confounders. Various normalization methods are provided. Extensive help pages and a tutorial are available via a wiki server. Using GMine we reanalyzed proteome microarray data of host antibody response against Plasmodium falciparum. Our results support the hypothesis that immunity to malaria is a higher-order phenomenon related to a pattern of responses and not attributable to any single antigen. We also analyzed gene expression across resting and activated T cells, identifying many immune-related genes with differential expression. This highlights both the plasticity of T cells and the operation of a hardwired activation program. These application examples demonstrate that GMine facilitates an accurate and in-depth analysis of complex molecular datasets, including genomics, transcriptomics and proteomics data. C1 [Proietti, Carla; Zakrzewski, Martha; Watkins, Thomas S.; Hasan, Shihab; Ratnatunga, Champa N.; Miles, John J.; Doolan, Denise L.; Krause, Lutz] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. [Berger, Bernard] Nestle Res Ctr, Lausanne, Switzerland. [Hasan, Shihab; Brion, Marie-Jo; Krause, Lutz] Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld, Australia. [Crompton, Peter D.] NIAID, Malaria Infect Biol & Immun Unit, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Miles, John J.; Doolan, Denise L.] James Cook Univ, Ctr Biosecur & Trop Infect Dis, Australian Inst Trop Hlth & Med, Cairns, Qld, Australia. RP Krause, L (reprint author), QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia.; Krause, L (reprint author), Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld, Australia. EM l.krause@uq.edu.au FU Australian Government; NHMRC [APP1078987, APP1069281]; NHMRC Career Development Fellowship; NHMRC Principal Research Fellowship; Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases; Perpetual [FR2013/0946] FX We would like to thank all GMine users who have provided valuable feedback, gave suggestions on how to improve the software or helped to identify problems and bugs. We also acknowledge the National eResearch Collaboration Tools and Resources (Nectar) project for providing cloud computing resources for GMine. The Translational Research Institute is supported by a grant from the Australian Government. This work was supported by project grant funding the NHMRC (APP1069281 & APP1078987) and Perpetual (FR2013/0946). JJM is supported by the NHMRC Career Development Fellowship. DLD is supported by an NHMRC Principal Research Fellowship. PDC is supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. 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 2045-2322 J9 SCI REP-UK JI Sci Rep PD DEC 6 PY 2016 VL 6 AR 38178 DI 10.1038/srep38178 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE2MV UT WOS:000389419500001 PM 27922118 ER PT J AU Khatami, M AF Khatami, Mahin TI Safety concerns and hidden agenda behind HPV vaccines: another generation of drug-dependent society? SO CLINICAL AND TRANSLATIONAL MEDICINE LA English DT Article DE American health status; Autophagy; Baby Boomer generation; Big pharma; Bioenergetics; Cancer/medical establishment; Cancer molecular tsunami; Common sense; Fraud in cancer research; GMOs; Gut-microbiota hazard/benefit ratio; Government Welfare Program; HPV vaccines; Humanity; 'Medical/scientific ponzi schemes'; Molecular false flags; National Cancer Institute (NCI); Mitophagy; Obamacare insurance; VP Biden Moonshot Initiative; Yin-Yang of inflammation; Immunity; Targeted therapy; Precision or Personalized medicine; The National Institutes of Health (NIH) ID UNRESOLVED INFLAMMATION; CANCER; VACCINATION; DISEASES; THERAPY AB Analyses of data and hidden agenda behind repeated failed outcomes of cancer research and therapy, status of American health, safety concerns for HPV vaccines and future research considerations are summarized in this commentary. A closer look at cancer science reveals that highly power structure (system) in medical establishment vs. anti-system and chaos in cancer research ('medical/scientific ponzi schemes') is potent recipe for failed therapeutics that kills patients but generates huge corporate profit. American health status ranks last among other developed nations despite the highest amount that USA invests in healthcare. This is a wake-up call to make sure that the evil part of human being does not prevent the health services that the public deserves. Otherwise, 'it does not matter how many resources you have, if you don't know, or don't want to know, how to use them, they will never be enough'. Answer to cancer and improved public health is possible only by switching the current corruptive and abusive culture of 'who you know' to a culture of 'what you know'. Policy makers and professionals in decision making roles are urged to return to common sense and logics that our Forefathers used to serve the public. C1 [Khatami, Mahin] NCI, NIH, Bethesda, MD 20892 USA. RP Khatami, M (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mkgoodness@aol.com NR 20 TC 0 Z9 0 U1 6 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2001-1326 J9 CLIN TRANSL MED JI Clin. Transl. Med. PD DEC 5 PY 2016 VL 5 AR 46 DI 10.1186/s40169-016-0126-1 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EH7KS UT WOS:000391952400002 PM 27921284 ER PT J AU Khire, A Jo, KH Kong, D Akhshi, T Blachon, S Cekic, AR Hynek, S Ha, A Loncarek, J Mennella, V Avidor-Reiss, T AF Khire, Atul Jo, Kyoung H. Kong, Dong Akhshi, Tara Blachon, Stephanie Cekic, Anthony R. Hynek, Sarah Ha, Andrew Loncarek, Jadranka Mennella, Vito Avidor-Reiss, Tomer TI Centriole Remodeling during Spermiogenesis in Drosophila SO CURRENT BIOLOGY LA English DT Article ID CENTROSOME; GAMETOGENESIS; FERTILIZATION; MELANOGASTER; DUPLICATION; REDUCTION; CILIOGENESIS; ENCODES; ZYGOTE; ROLES AB The first cell of an animal (zygote) requires centrosomes that are assembled from paternally inherited centrioles and maternally inherited pericentriolar material (PCM) [1]. In some animals, sperm centrioles with typical ultrastructure are the origin of the first centrosomes in the zygote [2-4]. In other animals, however, sperm centrioles lose their proteins and are thought to be degenerated and non-functional during spermiogenesis [5, 6]. Here, we show that the two sperm centrioles (the giant centriole [GC] and the proximal centriole-like structure [PCL]) in Drosophila melanogaster are remodeled during spermiogenesis through protein enrichment and ultrastructure modification in parallel to previously described centrosomal reduction [7]. We found that the ultrastructure of the matured sperm (spermatozoa) centrioles is modified dramatically and that the PCL does not resemble a typical centriole. We also describe a new phenomenon of Poc1 enrichment of the atypical centrioles in the spermatozoa. Using various mutants, protein expression during spermiogenesis, and RNAi knockdown of paternal Poc1, we found that paternal Poc1 enrichment is essential for the formation of centrioles during spermiogenesis and for the formation of centrosomes after fertilization in the zygote. Altogether, these findings demonstrate that the sperm centrioles are remodeled both in their protein composition and in ultrastructure, yet they are functional and are essential for normal embryogenesis in Drosophila. C1 [Khire, Atul; Jo, Kyoung H.; Cekic, Anthony R.; Hynek, Sarah; Ha, Andrew; Avidor-Reiss, Tomer] Univ Toledo, Dept Biol Sci, 3050 W Towerview Blvd, Toledo, OH 43606 USA. [Kong, Dong; Loncarek, Jadranka] NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, Frederick, MD 21702 USA. [Akhshi, Tara; Mennella, Vito] Univ Toronto, Hosp Sick Children, Dept Biochem, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Blachon, Stephanie] Hybrigen Serv, 3-5 Impasse Reille, F-75014 Paris, France. RP Avidor-Reiss, T (reprint author), Univ Toledo, Dept Biol Sci, 3050 W Towerview Blvd, Toledo, OH 43606 USA. EM tomer.avidorreiss@utoledo.edu FU NSF [DMR-1121262]; MRI program [NSF DMR-1229693]; National Science Foundation [1121176]; National Institute of General Medical Sciences [R01GM098394] FX We would like to thank Dr. Alan D. Hammer for editing; Dotty Sorenson, Sasha Meshinchi, Jeff Harrison, and Chris Edwards for assistance at the Microscopy & Image Analysis Laboratory (MIL) in the University of Michigan Medical School; EPIC facility (NUANCE Center-Northwestern University, supported by NSF DMR-1121262); the CryoCluster equipment (received support from the MRI program, NSF DMR-1229693); the International Institute for Nano technology (IIN); the State of Illinois, through the IIN and Charlene Wilke at the Biological Imaging Facility in the Northwestern University; and Emily Simone and Michaela Roberts for technical assistance. We would like to thank Dr. Jordan Raff for the D-PLP antibody, Dr. Timothy Megraw for the Cnn antibody, Dr. Barbara Wakimoto for Drosophila male sterile mutant, Dr. Yukiko Yamashita for Bam/Gal4 fly line, Dr. Clemens Carbard for the cPoc1AGFP and BGFP lines, Bloomington Stock Center for the poc1c06059 mutant flies, and Dr. David Glover for the GFPAna1 line. This work was supported by grant 1121176 (MCB) from the National Science Foundation and R01GM098394 from the National Institute of General Medical Sciences. NR 24 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD DEC 5 PY 2016 VL 26 IS 23 BP 3183 EP 3189 DI 10.1016/j.cub.2016.07.006 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EE4QS UT WOS:000389590500024 PM 28094036 ER PT J AU Kaltcheva, MM Lewandoski, M AF Kaltcheva, Maria M. Lewandoski, Mark TI Evolution: Enhanced Footing for Snake Limb Development SO CURRENT BIOLOGY LA English DT Editorial Material ID SONIC-HEDGEHOG; LEGS; EXPRESSION; ORIGIN C1 [Kaltcheva, Maria M.; Lewandoski, Mark] NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. RP Lewandoski, M (reprint author), NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. EM Lewandom@mail.nih.gov NR 20 TC 0 Z9 0 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD DEC 5 PY 2016 VL 26 IS 23 BP R1237 EP R1240 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EE4QS UT WOS:000389590500014 PM 27923134 ER PT J AU Fernandez-Alvarez, A Bez, C O'Toole, ET Morphew, M Cooper, JP AF Fernandez-Alvarez, Alfonso Bez, Cecile O'Toole, Eileen T. Morphew, Mary Cooper, Julia Promisel TI Mitotic Nuclear Envelope Breakdown and Spindle Nucleation Are Controlled by lnterphase Contacts between Centromeres and the Nuclear Envelope SO DEVELOPMENTAL CELL LA English DT Article ID YEAST SCHIZOSACCHAROMYCES-POMBE; FISSION YEAST; POLE BODY; MEIOTIC SPINDLE; CELL-CYCLE; PORE COMPLEXES; IN-VIVO; CAENORHABDITIS-ELEGANS; ELECTRON-MICROSCOPY; DROSOPHILA EMBRYOS AB Faithful genome propagation requires coordination between nuclear envelope (NE) breakdown, spindle formation, and chromosomal events. The conserved linker of nucleoskeleton and cytoskeleton (LING) complex connects fission yeast centromeres and the centrosome, across the NE, during interphase. During meiosis, LINC connects the centrosome with telomeres rather than centromeres. We previously showed that loss of telomere-LINC contacts compromises meiotic spindle formation. Here, we define the precise events regulated by telomere-LINC contacts and address the analogous possibility that centromeres regulate mitotic spindle formation. We develop conditionally inactivated LINC complexes in which the conserved SUN-domain protein Sad1 remains stable but severs interphase centromere-LINC contacts. Strikingly, the loss of such contacts abolishes spindle formation. We pinpoint the defect to a failure in the partial NE breakdown required for centrosome insertion into the NE, a step analogous to mammalian NE breakdown. Thus, interphase chromosome-LINC contacts constitute a cell-cycle control device linking nucleoplasmic and cytoplasmic events. C1 [Fernandez-Alvarez, Alfonso; Cooper, Julia Promisel] NCI, Telomere Biol Sect, LBMB, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Fernandez-Alvarez, Alfonso; Bez, Cecile; Cooper, Julia Promisel] Canc Res UK, London Res Inst, Telomere Biol Lab, 44 Lincolns Inn Fields, London WC2A 3LY, England. [O'Toole, Eileen T.; Morphew, Mary] Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA. [Bez, Cecile] PRA Hlth Sci Paris, F-92300 Levallois Perret, France. RP Fernandez-Alvarez, A; Cooper, JP (reprint author), NCI, Telomere Biol Sect, LBMB, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Fernandez-Alvarez, A; Cooper, JP (reprint author), Canc Res UK, London Res Inst, Telomere Biol Lab, 44 Lincolns Inn Fields, London WC2A 3LY, England. EM alfonso.fernandezalvarez@nih.gov; julie.cooper@nih.gov RI Fernandez-Alvarez, Alfonso/N-1249-2016 FU NCI; Cancer Research UK; European Research Council; EMBO long-term fellowship FX We thank Victor A. Tallada for fruitful discussions and for suggesting the cut11.1 background to assess the effects of sad1.2 on nuclear efflux. We thank Mark Winey for discussion and connecting us with the Boulder EM team. We thank Alex Fennell, lain Hagan, Kazunori Tomita, and our lab members for discussions, lain Hagan and Yasushi Hiraoka for strains, Michael Lichten for critical comments on the manuscript, and Takashi Toda and Aldona Chmielewska for reagents and advice on isolating temperature-sensitive mutants. This work was supported by the NCI, the Cancer Research UK, the European Research Council, and an EMBO long-term fellowship to A.F.A. NR 75 TC 1 Z9 1 U1 7 U2 7 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 DEC 5 PY 2016 VL 39 IS 5 BP 544 EP 559 DI 10.1016/j.devcel.2016.10.021 PG 16 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA EE6PM UT WOS:000389734700005 PM 27889481 ER PT J AU Preger-Ben Noon, E Davis, FP Stern, DL AF Preger-Ben Noon, Ella Davis, Fred P. Stern, David L. TI Evolved Repression Overcomes Enhancer Robustness SO DEVELOPMENTAL CELL LA English DT Article ID CIS-REGULATORY EVOLUTION; BINDING-SITE CLUSTERS; GENE-EXPRESSION; TRANSCRIPTIONAL REGULATION; MORPHOLOGICAL EVOLUTION; DROSOPHILA EMBRYO; TRANSGENIC RNAI; NEURAL CREST; UNDERLIES; GENOME AB Biological systems display extraordinary robustness. Robustness of transcriptional enhancers results mainly from clusters of binding sites for the same transcription factor, and it is not clear how robust enhancers can evolve loss of expression through point mutations. Here, we report the high resolution functional dissection of a robust enhancer of the shavenbaby gene that has contributed to morphological evolution. We found that robustness is encoded by many binding sites for the transcriptional activator Arrowhead and that, during evolution, some of these activator sites were lost, weakening enhancer activity. Complete silencing of enhancer function, however, required evolution of a binding site for the spatially restricted potent repressor Abrupt. These findings illustrate that recruitment of repressor binding sites can overcome enhancer robustness and may minimize pleiotropic consequences of enhancer evolution. Recruitment of repression may be a general mode of evolution to break robust regulatory linkages. C1 [Preger-Ben Noon, Ella; Davis, Fred P.; Stern, David L.] Howard Hughes Med Inst, Janelia Res Campus, 19700 Helix Dr, Ashburn, VA 20147 USA. [Davis, Fred P.] NIAMS, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP Preger-Ben Noon, E; Stern, DL (reprint author), Howard Hughes Med Inst, Janelia Res Campus, 19700 Helix Dr, Ashburn, VA 20147 USA. EM pregere@janelia.hhmi.org; sternd@janelia.hhmi.org FU Human Frontier Science Program [LT000528/2011]; EMBO [ALTF 1364-2010] FX We thank Jessica Treisman, Steve Crews, VDRC, and the Bloomington Drosophila Stock Center for fly stocks and reagents. We thank Aishwarya Korgaonkar for help with protein purification. We thank the Janelia Fly Core Facility for help with fly work and the Flow Cytometry Resource Facility at Princeton University for sorting experiments. E.P.B.N is grateful for the generous hospitality of Paul Schedl and his laboratory members, especially Tsutomu Aoki and Girish Deshpande, and of Adi Salzberg and her laboratory members. We thank Nicolas Frankel, Anastasios Pavlopoulos, and Stern and Schedl laboratory members for helpful discussions. The manuscript was improved by the critical comments of Richard Mann, Francois Payre, and Nicolas Frankel. E.P.B.N was supported by post-doctoral fellowships from the Human Frontier Science Program (LT000528/2011) and EMBO (ALTF 1364-2010). NR 66 TC 0 Z9 0 U1 2 U2 2 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 DEC 5 PY 2016 VL 39 IS 5 BP 572 EP 584 DI 10.1016/j.devcel.2016.10.010 PG 13 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA EE6PM UT WOS:000389734700007 PM 27840106 ER PT J AU Liu, YJ Yang, XY Huang, ZQ Huang, P Zhang, Y Deng, L Wang, ZT Zhou, ZJ Liu, Y Kalish, H Khachab, NM Chen, XY Nie, ZH AF Liu, Yijing Yang, Xiangyu Huang, Zhiqi Huang, Peng Zhang, Yang Deng, Lin Wang, Zhantong Zhou, Zijian Liu, Yi Kalish, Heather Khachab, Niveen M. Chen, Xiaoyuan Nie, Zhihong TI Magneto-Plasmonic Janus Vesicles for Magnetic Field-Enhanced Photoacoustic and Magnetic Resonance Imaging of Tumors SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE Janus vesicles; magnetic resonance imaging; nanoparticles; photoacoustic imaging; self-assembly ID IRON-OXIDE NANOPARTICLES; BIOMEDICAL APPLICATIONS; CONTRAST AGENTS; CANCER; THERAPY; ASSEMBLIES; RELAXIVITY; DELIVERY; MRI; NANOMATERIALS AB Magneto-plasmonic Janus vesicles (JVs) integrated with gold nanoparticles (AuNPs) and magnetic NPs (MNPs) were prepared asymmetrically in the membrane for invivo cancer imaging. The hybrid JVs were produced by coassembling a mixture of hydrophobic MNPs, free amphiphilic block copolymers (BCPs), and AuNPs tethered with amphiphilic BCPs. Depending on the size and content of NPs, the JVs acquired spherical or hemispherical shapes. Among them, hemispherical JVs containing 50nm AuNPs and 15nm MNPs showed a strong absorption in the near-infrared (NIR) window and enhanced the transverse relaxation (T-2) contrast effect, as a result of the ordering and dense packing of AuNPs and MNPs in the membrane. The magneto-plasmonic JVs were used as drug delivery vehicles, from which the release of a payload can be triggered by NIR light and the release rate can be modulated by a magnetic field. Moreover, the JVs were applied as imaging agents for invivo bimodal photoacoustic (PA) and magnetic resonance (MR) imaging of tumors by intravenous injection. With an external magnetic field, the accumulation of the JVs in tumors was significantly increased, leading to a signal enhancement of approximately 2-3 times in the PA and MR imaging, compared with control groups without a magnetic field. C1 [Liu, Yijing; Huang, Zhiqi; Liu, Yi; Nie, Zhihong] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. [Liu, Yijing; Yang, Xiangyu; Wang, Zhantong; Zhou, Zijian; Kalish, Heather; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Liu, Yijing; Yang, Xiangyu; Wang, Zhantong; Zhou, Zijian; Kalish, Heather; Chen, Xiaoyuan] NIBIB, Trans NIH Shared Resource Biomed Engn & Phys Sci, NIH, Bethesda, MD 20892 USA. [Huang, Peng] Shenzhen Univ, Guangdong Key Lab Biomed Measurements & Ultrasoun, Sch Biomed Engn, Shenzhen 518060, Peoples R China. [Zhang, Yang; Deng, Lin; Khachab, Niveen M.] KAUST, Dept Chem Sci & Engn, Adv Membranes & Porous Mat Ctr, Smart Hybrid Mat SHMs Lab, Thuwal 239556900, Saudi Arabia. RP Nie, ZH (reprint author), Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA.; Chen, XY (reprint author), NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA.; Chen, XY (reprint author), NIBIB, Trans NIH Shared Resource Biomed Engn & Phys Sci, NIH, Bethesda, MD 20892 USA.; Khachab, NM (reprint author), KAUST, Dept Chem Sci & Engn, Adv Membranes & Porous Mat Ctr, Smart Hybrid Mat SHMs Lab, Thuwal 239556900, Saudi Arabia. EM niveen.khashab@kaust.edu.sa; shawn.chen@nih.gov; znie@umd.edu FU National Science Foundation [DMR-1255377, CHE-1505839]; 3M Non-tenured Faculty Award; King Abdullah University of Science and Technology [CRG-2015]; Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health; National Science Foundation of China [81401465, 51573096]; NSF; MRSEC Shared Experimental Facilities FX Z.N. gratefully acknowledges the financial support of the National Science Foundation (grants: DMR-1255377, CHE-1505839) and 3M Non-tenured Faculty Award. N.M.K. and Z.N. further acknowledge support provided by a King Abdullah University of Science and Technology CRG-2015 grant. The work was also supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. P.H. acknowledges financial support from National Science Foundation of China (81401465, 51573096). We acknowledge Maryland NanoCenter and its NispLab. NispLab is supported, in part, by the NSF in partnership with MRSEC Shared Experimental Facilities. NR 45 TC 1 Z9 1 U1 64 U2 64 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 DEC 5 PY 2016 VL 55 IS 49 BP 15297 EP 15300 DI 10.1002/anie.201608338 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA ED9WL UT WOS:000389224000018 PM 27862808 ER PT J AU Pope, GR Tilve, S McArdle, CA Lolait, SJ O'Carroll, AM AF Pope, George R. Tilve, Sharada McArdle, Craig A. Lolait, Stephen J. O'Carroll, Anne-Marie TI Agonist-induced internalization and desensitization of the apelin receptor SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE G protein-coupled receptor; Apelin; Apelin receptor; Intracellular trafficking; Signalling; Extracellular-signal-regulated kinase (ERK) ID DYNAMIN-DEPENDENT INTERNALIZATION; SPONTANEOUSLY HYPERTENSIVE-RATS; BETA-ADRENERGIC-RECEPTOR; G-PROTEIN; HORMONE RECEPTORS; MEDIATED ENDOCYTOSIS; ENDOGENOUS LIGAND; BLOOD-PRESSURE; APJ RECEPTOR; ARRESTIN AB Apelin acts via the G protein-coupled apelin receptor (APJ) to mediate effects on cardiovascular and fluid homeostasis. G protein-coupled receptor (GPCR) trafficking has an important role in the regulation of receptor signalling pathways and cellular functions, however in the case of APJ the mechanisms and proteins involved in apelin-induced trafficking are not well understood. We generated a stable HEK-293 cell line expressing N-terminus HA-tagged mouse (m) APJ, and used a semi-automated imaging protocol to quantitate APJ trafficking and ERK1/2 activation following stimulation with [Pyr(1)] apelin-13. The mechanisms of [Pyr(1)]apelin-13-induced internalization and desensitization were explored using dominant-negative mutant (DNM) cDNA constructs of G protein-coupled receptor kinase 2 (GRK2), beta-arrestin1, EPS15 and dynamin. The di-phosphorylated ERK1/2 (ppERK1/2) response to [Pyr1]apelin-13 desensitized during sustained stimulation, due to upstream APJ-specific adaptive changes. Furthermore, [Pyr1]apelin-13 stimulation caused internalization of mAPJ via clathrin coated vesicles (CCVs) and also caused a rapid reduction in cell surface and whole cell HA-mAPJ. Our data suggest that upon continuous agonist exposure GRK2-mediated phosphorylation targets APJ to CCVs that are internalized from the cell surface in a beta-arrestin1-independent, EPS15- and dynamin-dependent manner. Internalization does not appear to contribute to the desensitization of APJ-mediated ppERK1/2 activation in these cells. (C) 2016 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY license. C1 [Pope, George R.; Tilve, Sharada; McArdle, Craig A.; Lolait, Stephen J.; O'Carroll, Anne-Marie] Univ Bristol, Sch Clin Sci, Labs Integrat Neurosci & Endocrinol, Whitson St, Bristol BS1 3NY, Avon, England. [Tilve, Sharada] NHLBI, Dev Neurobiol Sect, NIH, 10 Ctr Dr MSC 1754, Bethesda, MD 20892 USA. RP O'Carroll, AM (reprint author), Univ Bristol, Sch Clin Sci, Labs Integrat Neurosci & Endocrinol, Whitson St, Bristol BS1 3NY, Avon, England. EM a.m.ocarroll@bristol.ac.uk OI McArdle, Craig/0000-0003-4836-5351 FU Biotechnology and Biological Sciences Research Council [BB/D00196X/1] FX This work was supported by the Biotechnology and Biological Sciences Research Council (grant No. BB/D00196X/1). NR 50 TC 0 Z9 0 U1 18 U2 18 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD DEC 5 PY 2016 VL 437 IS C BP 108 EP 119 DI 10.1016/j.mce.2016.07.040 PG 12 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA EA2FM UT WOS:000386408200010 PM 27492965 ER PT J AU Bjelobaba, I Janjic, MM Tavcar, JS Kucka, M Tomic, M Stojilkovic, SS AF Bjelobaba, Ivana Janjic, Marija M. Tavcar, Jovana S. Kucka, Marek Tomic, Melanija Stojilkovic, Stanko S. TI The relationship between basal and regulated Gnrhr expression in rodent pituitary gonadotrophs SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE Gonadotrophs; L beta T2 cells; GnRH; Gnrhr; Protein kinase C; ERK1/2 ID HORMONE RECEPTOR GENE; PROTEIN-KINASE-C; HOMOLOGOUS UP-REGULATION; MESSENGER-RNA LEVELS; TRANSCRIPTIONAL ACTIVATION; LUTEINIZING-HORMONE; RESPONSE ELEMENT; CELLS; ORGANIZATION; INHIBITORS AB Hypothalamic GnRH together with gonadal steroids and activins/inhibin regulate its receptor gene (Gnrhr) expression in vivo, which leads to crucial changes in GnRHR numbers on the plasma membrane. This is accompanied by alterations in the gonadotroph sensitivity and responsiveness during physiologically relevant situations. Here we investigated basal and GnRH-regulated Gnrhr expression in rodent pituitary gonadotrophs in vitro. In pituitary cells from adult animals cultured in the absence of GnRH and steroid hormones, the Gnrhr expression was progressively reduced but not completely abolished. The basal Gnrhr expression was also operative in L beta T2 immortalized gonadotrophs never exposed to GnRH. In both cell types, basal transcription was sufficient for the expression of functional GnRHRs. Continuous application of GnRH transiently elevated the Gnrhr expression in cultured pituitary cells followed by a sustained fall without affecting basal transcription. Both basal and regulated Gnrhr transcriptions were dependent on the protein kinase C signaling pathway. The GnRH-regulated Gnrhr expression was not operative in embryonal pituitary and L beta T2 cells and was established neonatally, the sex-specific response patterns were formed at the juvenile-peripubertal stage and there was a strong correlation between basal and regulated gene expression during development. Thus, the age-dependent basal and regulated Gnrhr transcription could account for the initial blockade and subsequent activation of the reproductive system during development. (C) 2016 Published by Elsevier Ireland Ltd. C1 [Bjelobaba, Ivana; Janjic, Marija M.; Tavcar, Jovana S.; Kucka, Marek; Tomic, Melanija; Stojilkovic, Stanko S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Signaling, NIH, Bethesda, MD 20892 USA. [Bjelobaba, Ivana] Univ Belgrade, Inst Biol Res Sinisa Stankov, Belgrade 11001, Serbia. [Kucka, Marek] Friedrich Miescher Lab Max Planck Soc, Tubingen, Germany. RP Stojilkovic, SS (reprint author), NICHD, Bldg 49,Room 6A-36,49 Convent Dr, Bethesda, MD USA. EM stojilks@mail.nih.gov FU Intramural Research Program of the National Institute of Child Health and Human Development [ZIA DH000195-23] FX This work was supported by the Intramural Research Program of the National Institute of Child Health and Human Development (ZIA DH000195-23). NR 69 TC 0 Z9 0 U1 9 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD DEC 5 PY 2016 VL 437 IS C BP 302 EP 311 DI 10.1016/j.mce.2016.08.040 PG 10 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA EA2FM UT WOS:000386408200028 PM 27569529 ER PT J AU Coulibaly, YI Coulibaly, SY Dolo, H Konate, S Diallo, AA Doumbia, SS Soumaoro, L Coulibaly, ME Dicko, I Sangare, MB Dembele, B Sangare, M Dembele, M Toure, YT Kelly-Hope, L Polman, K Kyelem, D Traore, SF Bockarie, M Klion, AD Nutman, TB AF Coulibaly, Yaya I. Coulibaly, Siaka Y. Dolo, Housseini Konate, Siaka Diallo, Abdallah A. Doumbia, Salif S. Soumaoro, Lamine Coulibaly, Michel E. Dicko, Ilo Sangare, Moussa B. Dembele, Benoit Sangare, Modibo Dembele, Massitan Toure, Yeya T. Kelly-Hope, Louise Polman, Katja Kyelem, Dominique Traore, Sekou F. Bockarie, Moses Klion, Amy D. Nutman, Thomas B. TI Dynamics of antigenemia and transmission intensity of Wuchereria bancrofti following cessation of mass drug administration in a formerly highly endemic region of Mali SO PARASITES & VECTORS LA English DT Article DE Wuchereria bancrofti; Transmission assessment survey; Anopheles gambiae complex; Mass drug administration; Post-MDA surveillance ID LYMPHATIC FILARIASIS TRANSMISSION; INFECTION; MOSQUITOS; PROGRAMS; SURVEILLANCE; ELIMINATION; IMPACT; TOOLS; RATES; FOCUS AB Background: After seven annual rounds of mass drug administration (MDA) in six Malian villages highly endemic for Wuchereria bancrofti (overall prevalence rate of 42.7%), treatment was discontinued in 2008. Surveillance was performed over the ensuing 5 years to detect recrudescence. Methods: Circulating filarial antigen (CFA) was measured using immunochromatographic card tests (ICT) and Og4C3 ELISA in 6-7 year-olds. Antibody to the W. bancrofti infective larval stage (L3) antigen, Wb123, was tested in the same population in 2012. Microfilaraemia was assessed in ICT-positive subjects. Anopheles gambiae complex specimens were collected monthly using human landing catch (HLC) and pyrethrum spray catch (PSC). Anopheles gambiae complex infection with W. bancrofti was determined by dissection and reverse transcriptase polymerase chain reaction (RT-PCR) of mosquito pools. Results: Annual CFA prevalence rates using ICT in children increased over time from 0% (0/289) in 2009 to 2. 7% (8/301) in 2011, 3.9% (11/285) in 2012 and 4.5% (14/309) in 2013 (trend chi(2) = 11.85, df = 3, P = 0.0006). Wb123 antibody positivity rates in 2013 were similar to the CFA prevalence by ELISA (5/285). Although two W. bancrofti-infected Anopheles were observed by dissection among 12,951 mosquitoes collected by HLC, none had L3 larvae when tested by L3-specific RT-PCR. No positive pools were detected among the mosquitoes collected by pyrethrum spray catch. Whereas ICT in 6-7 year-olds was the major surveillance tool, ICT positivity was also assessed in older children and adults (8-65 years old). CFA prevalence decreased in this group from 4.9% (39/800) to 3.5% (28/795) and 2.8% (50/1,812) in 2009, 2011 and 2012, respectively (trend.2 = 7.361, df = 2, P = 0.0067). Some ICT-positive individuals were microfilaraemic in 2009 [2.6% (1/39)] and 2011 [8.3% (3/36)], but none were positive in 2012 or 2013. Conclusion: Although ICT rates in children increased over the 5-year surveillance period, the decrease in ICT prevalence in the older group suggests a reduction in transmission intensity. This was consistent with the failure to detect infective mosquitoes or microfilaraemia. The threshold of ICT positivity in children may need to be re-assessed and other adjunct surveillance tools considered. C1 [Coulibaly, Yaya I.; Coulibaly, Siaka Y.; Dolo, Housseini; Konate, Siaka; Diallo, Abdallah A.; Doumbia, Salif S.; Soumaoro, Lamine; Coulibaly, Michel E.; Dicko, Ilo; Sangare, Moussa B.; Dembele, Benoit; Sangare, Modibo; Traore, Sekou F.] Fac Med & Odontostomatol, Int Ctr Excellence Res, Filariasis Unit, Bamako, Mali. [Dembele, Massitan] Natl Lymphat Filariasis Eliminat Program, Bamako, Mali. [Toure, Yeya T.] Fac Med & Odontostomatol Bamako, Bamako, Mali. [Coulibaly, Yaya I.; Kelly-Hope, Louise] Univ Liverpool Liverpool Sch Trop Med, Filarial Program, Support Unit, Liverpool, Merseyside, England. [Polman, Katja] Inst Trop Med, Dept Biomed Sci, Antwerp, Belgium. [Kyelem, Dominique] Task Force Global Hlth, Neglected Trop Dis Support Ctr, Decatur, GA USA. [Bockarie, Moses] Univ Liverpool Liverpool Sch Trop Med, Dept Vector Biol, Liverpool L3 5QA, Merseyside, England. [Klion, Amy D.; Nutman, Thomas B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD USA. RP Coulibaly, YI (reprint author), Fac Med & Odontostomatol, Int Ctr Excellence Res, Filariasis Unit, Bamako, Mali.; Coulibaly, YI (reprint author), Univ Liverpool Liverpool Sch Trop Med, Filarial Program, Support Unit, Liverpool, Merseyside, England. EM yicoulibaly@icermali.org FU WHO/UNDP/World Bank Special Program for Tropical Diseases grant [A00583]; Task Force for Global Health; Division of Intramural Research, NIAID, NIH FX This study was funded by the WHO/UNDP/World Bank Special Program for Tropical Diseases grant (ID A00583) to SFT and the Task Force for Global Health. This study was funded in part by the Division of Intramural Research, NIAID, NIH. The funding bodies did not play any role in the study design, data collection, analysis and interpretation, nor the decision to write the manuscript. NR 32 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 1756-3305 J9 PARASITE VECTOR JI Parasites Vectors PD DEC 3 PY 2016 VL 9 AR 628 DI 10.1186/s13071-016-1911-9 PG 9 WC Parasitology SC Parasitology GA EI3DS UT WOS:000392370500004 PM 27912789 ER PT J AU Khalid, W Rozi, S Ali, TS Azam, I Mullen, MT Illyas, S Un-Nisa, Q Soomro, N Kamal, AK AF Khalid, Wardah Rozi, Shafquat Ali, Tazeen Saeed Azam, Iqbal Mullen, Michael T. Illyas, Saleem Un-Nisa, Qamar Soomro, Nabila Kamal, Ayeesha Kamran TI Quality of life after stroke in Pakistan SO BMC Neurology LA English DT Article DE Stroke Specific Quality of life scale (SSQOLS); Post-stroke depression; LMIC (Lower middle income country); FGD'S (Focus group discussion) Sequential Mix Methods; Triangulation; Epidemiology; Complications; Chronic Disease ID SPOUSAL CAREGIVERS; SURVIVORS; HEALTH; REHABILITATION; PREVALENCE; DEPRESSION; BURDEN; PROSPECTS; SCALE AB Background: There is very little information about the quality of life (QOL) of stroke survivors in LMIC countries with underdeveloped non communicable health infrastructures, who bear two thirds of the global stroke burden. Methodology: We used a sequential mix methods approach. First, a quantitative analytical cross-sectional study was conducted on 700 participants, who constituted 350 stroke survivor and their caregiver dyads. QOL of stroke survivor was assessed via Stroke Specific Quality of Life Scale (SSQOLS) whereas QOL of caregivers was assessed through RAND-36. In addition; we assessed complications, psychosocial and functional disability of stroke survivors. Following this quantitative survey, caregivers were qualitatively interviewed to uncover contextually relevant themes that would evade quantitative surveys. Multiple linear regression technique was applied to report adjusted beta-coefficients with 95% C. I. Results: The QOL study was conducted from January 2014 till June 2014, in two large private and public centers. At each center, 175 dyads were interviewed to ensure representativeness. Median age of stroke survivors was 59(17) years, 68% were male, 60% reported depression and 70% suffered post-stroke complications. The mean SSQOLS score was 164.18 +/- 32.30. In the final model severe functional disability [adj beta -33.77(-52.44, -15.22)], depression [adj beta 23.74(- 30.61,-16.82)], hospital admissions [adj beta-5.51(-9.23,-1.92)] and severe neurologic pain [adj beta -12.41(-20.10,-4.77)] negatively impacted QOL of stroke survivors (P < 0.01). For caregivers, mean age was 39.18 +/- 13.44 years, 51% were female and 34% reported high stress levels. Complementary qualitative study revealed that primary caregivers were depressed, frustrated, isolated and also disappointed by health services. Conclusion: The QOL of Stroke survivors as reported by SSQOLS score was better than compared to those reported from other LMIC settings. However, Qualitative triangulation revealed that younger caregivers felt isolated, depressed, overwhelmed and were providing care at great personal cost. There is a need to develop cost effective holistic home support interventions to improve lives of the survivor dyad as a unit. C1 [Khalid, Wardah] Natl Inst Hlth, Fogarty Int Ctr, Int Cerebrovasc Translat Clin Res Training Progra, Karachi, Pakistan. [Khalid, Wardah] Aga Khan Univ, Karachi, Pakistan. [Rozi, Shafquat] Aga Khan Univ, Clin Res Track, Dept Community Hlth Sci Epidemiol & Biostat, Karachi, Pakistan. [Ali, Tazeen Saeed] Sch Nursing & Midwifery SONAM, Karachi, Pakistan. [Ali, Tazeen Saeed; Azam, Iqbal] Aga Khan Univ Hosp, Dept Community Hlth Sci, Karachi, Pakistan. [Mullen, Michael T.] Univ Penn, Dept Neurol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Illyas, Saleem] DOW Univ Hlth Sci, Dev Ctr, Karachi, Pakistan. [Un-Nisa, Qamar] DOW Univ Hlth Sci, Dept Neurol, Karachi, Pakistan. [Un-Nisa, Qamar] Aga Khan Univ, Neurol Sect, Dept Med, Karachi, Pakistan. [Soomro, Nabila] DOW Univ Hlth Sci, Inst Phys Med & Rehabil, Karachi, Pakistan. [Kamal, Ayeesha Kamran] Aga Khan Univ, Fogarty Int Ctr, Int Cerebrovasc Translat Clin Res Training Progra, Stadium Rd, Karachi 74800, Pakistan. [Kamal, Ayeesha Kamran] Aga Khan Univ, Natl Inst Neurol Disorders & Stroke, Stadium Rd, Karachi 74800, Pakistan. [Kamal, Ayeesha Kamran] Aga Khan Univ, Dept Med, Karachi, Pakistan. RP Kamal, AK (reprint author), Aga Khan Univ, Natl Inst Neurol Disorders & Stroke, Stadium Rd, Karachi 74800, Pakistan.; Kamal, AK (reprint author), Aga Khan Univ, Dept Med, Karachi, Pakistan. EM ayeesha.kamal@aku.edu FU Fogarty International Center [5D43TW008660-04]; National Institute of Neurologic Disorders and Stroke of the National Institutes of Health, USA FX The study is funded by Award Number 5D43TW008660-04 from the Fogarty International Center and the National Institute of Neurologic Disorders and Stroke of the National Institutes of Health, USA. NR 45 TC 0 Z9 0 U1 9 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2377 J9 BMC NEUROL JI BMC Neurol. PD DEC 3 PY 2016 VL 16 AR 250 DI 10.1186/s12883-016-0774-1 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA EE0MH UT WOS:000389268800001 PM 27912744 ER PT J AU Romanyukha, A Folio, L Lamart, S Simon, SL Lee, C AF Romanyukha, Anna Folio, Les Lamart, Stephanie Simon, Steven L. Lee, Choonsik TI BODY SIZE-SPECIFIC EFFECTIVE DOSE CONVERSION COEFFICIENTS FOR CT SCANS SO RADIATION PROTECTION DOSIMETRY LA English DT Article ID COMPUTED-TOMOGRAPHY; MEDICAL EXPOSURES; ORGAN; PHANTOMS; PHOTONS AB Effective dose from computed tomography (CT) examinations is usually estimated using the scanner-provided dose-length product and using conversion factors, also known as k-factors, which correspond to scan regions and differ by age according to five categories: 0, 1, 5, 10 y and adult. However, patients often deviate from the standard body size on which the conversion factor is based. In this study, a method for deriving body size-specific k-factors is presented, which can be determined from a simple regression curve based on patient diameter at the centre of the scan range. Using the International Commission on Radiological Protection reference paediatric and adult computational phantoms paired with Monte Carlo simulation of CT X-ray beams, the authors derived a regression-based k-factor model for the following CT scan types: head-neck, head, neck, chest, abdomen, pelvis, abdomen-pelvis (AP) and chest-abdomen-pelvis (CAP). The resulting regression functions were applied to a total of 105 paediatric and 279 adult CT scans randomly sampled from patients who underwent chest, AP and CAP scans at the National Institutes of Health Clinical Center. The authors have calculated and compared the effective doses derived from the conventional age-specific k-factors with the values computed using their body size-specific k-factor. They found that by using the age-specific k-factor, paediatric patients tend to have underestimates (up to 3-fold) of effective dose, while underweight and overweight adult patients tend to have underestimates (up to 2.6-fold) and overestimates (up to 4.6-fold) of effective dose, respectively, compared with the effective dose determined from their body size-dependent factors. The authors present these size-specific k-factors as an alternative to the existing age-specific factors. The body size-specific k-factor will assess effective dose more precisely and on a more individual level than the conventional age-specific k-factors and, hence, improve awareness of the true exposure, which is important for the clinical community to understand. C1 [Romanyukha, Anna; Lamart, Stephanie; Simon, Steven L.; Lee, Choonsik] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Folio, Les] NIH, Radiol & Imaging Sci Clin Ctr, Bldg 10, Bethesda, MD 20892 USA. [Lamart, Stephanie] CEA, SREIT, IRCM, DSV,Lab Radio Toxicol, Bruyeres Le Chatel, France. RP Lee, C (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM leechoonsik@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This work was supported by the intramural research program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 24 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0144-8420 EI 1742-3406 J9 RADIAT PROT DOSIM JI Radiat. Prot. Dosim. PD DEC 2 PY 2016 VL 172 IS 4 BP 428 EP 437 DI 10.1093/rpd/ncv511 PG 10 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 EJ4IH UT WOS:000393179700014 PM 26755767 ER PT J AU Oakley, MS Verma, N Zheng, H Anantharaman, V Takeda, K Gao, YM Myers, TG Pham, PT Mahajan, B Kumar, N Sangweme, D Tripathi, AK Mlambo, G Aravind, L Kumar, S AF Oakley, Miranda S. Verma, Nitin Zheng, Hong Anantharaman, Vivek Takeda, Kazuyo Gao, Yamei Myers, Timothy G. Phuong Thao Pham Mahajan, Babita Kumar, Nirbhay Sangweme, Davison Tripathi, Abhai K. Mlambo, Godfree Aravind, L. Kumar, Sanjai TI Molecular Markers of Radiation Induced Attenuation in Intrahepatic Plasmodium falciparum Parasites SO PLOS ONE LA English DT Article ID MULTIPLE SEQUENCE ALIGNMENT; PROTEIN PALMITOYLATION; IRRADIATED SPOROZOITES; MALARIA; IDENTIFICATION; IMMUNIZATION; EXPRESSION; PROTECTION; UBIQUITIN; GENE AB Experimental immunization with radiation attenuated sporozoites (RAS) and genetically attenuated sporozoites has proved to be a promising approach for malaria vaccine development. However, parasite biomarkers of growth attenuation and enhanced immune protection in response to radiation remain poorly understood. Here, we report on the effect of an attenuating dose of.-irradiation (15 krad) on the Plasmodium falciparum sporozoite (PfSPZ) ultrastructure by electron microscopy, growth rate of liver stage P. falciparum in liver cell cultures, and genome-wide transcriptional profile of liver stage parasites by microarray. We find that.-irradiation treated PfSPZ retained a normal cellular structure except that they were vacuous with a partially disrupted plasma membrane and inner membrane complex. A similar infection rate was observed by.-irradiation-treated and untreated PfSPZ in human HCO-4 liver cells (0.47% versus 0.49%, respectively) on day 3 post-infection. In the microarray studies, cumulatively, 180 liver stage parasite genes were significantly transcriptionally altered on day 3 and/or 6 post-infection. Among the transcriptionally altered biomarkers, we identified a signature of seven candidate parasite genes that associated with functionally diverse pathways that may regulate radiation induced cell cycle arrest of the parasite within the hepatocyte. A repertoire of 14 genes associated with protein translation is transcriptionally overexpressed within the parasite by radiation. Additionally, 37 genes encode proteins expressed on the cell surface or exported into the host cell, 4 encode membrane associated transporters, and 10 encode proteins related to misfolding and stress-related protein processing. These results have significantly increased the repertoire of novel targets for 1) biomarkers of safety to define proper attenuation, 2) generating genetically attenuated parasite vaccine candidates, and 3) subunit candidate vaccines against liver stage malaria. C1 [Oakley, Miranda S.; Verma, Nitin] US FDA, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Zheng, Hong; Phuong Thao Pham; Mahajan, Babita; Kumar, Sanjai] US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. [Anantharaman, Vivek; Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. [Takeda, Kazuyo; Gao, Yamei] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Silver Spring, MD USA. [Myers, Timothy G.] NIAID, Genom Technol Sect, Res Technol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kumar, Nirbhay; Sangweme, Davison; Tripathi, Abhai K.; Mlambo, Godfree] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Kumar, S (reprint author), US FDA, Div Emerging & Transfus Transmitted Dis, Ctr Biol Evaluat & Res, Silver Spring, MD 20993 USA. EM Sanjai.kumar@fda.hhs.gov FU FDA intramural research program; PATH-Malaria Vaccine Initiative FX This research was supported by the FDA intramural research program and a research grant from the PATH-Malaria Vaccine Initiative. NR 58 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 DEC 2 PY 2016 VL 11 IS 12 AR e0166814 DI 10.1371/journal.pone.0166814 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE3TF UT WOS:000389520600014 PM 27911910 ER PT J AU Orfano, AS Duarte, APM Molina-Cruz, A Pimenta, PF Barillas-Mury, C AF Orfano, Alessandra S. Duarte, Ana Paula M. Molina-Cruz, Alvaro Pimenta, Paulo F. Barillas-Mury, Carolina TI Plasmodium yoelii nigeriensis (N67) Is a Robust Animal Model to Study Malaria Transmission by South American Anopheline Mosquitoes SO PLOS ONE LA English DT Article ID COMPLEMENT; AQUASALIS; GAMBIAE; VIVAX; SUSCEPTIBILITY; DETERMINANT; INFECTION; PARASITES; DARLINGI; IMMUNITY AB Malaria is endemic in the American continent and the Amazonian rainforest is the region with the highest risk of transmission. However, the lack of suitable experimental models to infect malaria vectors from the Americas has limited the progress to understand the biology of transmission in this region. Anopheles aquasalis, a major vector in coastal areas of South America, was found to be highly refractory to infection with two strains of Plasmodium falciparum (NF54 and 7G8) and with Plasmodium berghei (mouse malaria), even when the micro biota was eliminated with antibiotics and oxidative stress was reduced with uric acid. In contrast, An. aquasalis females treated with antibiotics and uric acid are susceptible to infection with a second murine parasite, Plasmodium yoelii nigeriensis N67 (PyN67). Anopheles albimanus, one of the main malaria vectors in Central America, Southern Mexico and the Caribbean, was more susceptible to infection with PyN67 than An. aquasalis, even in the absence of any pre-treatment, but was still less susceptible than Anopheles stephensi. Disruption of the complement-like system in An. albimanus significantly enhanced PyN67 infection, indicating that the mosquito immune system is mounting effective antiplasmodial responses. PyN67 has the ability to infect a broad range of anophelines and is an excellent model to study malaria transmission by South American vectors. C1 [Orfano, Alessandra S.; Duarte, Ana Paula M.; Molina-Cruz, Alvaro; Barillas-Mury, Carolina] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Orfano, Alessandra S.; Duarte, Ana Paula M.; Pimenta, Paulo F.] Fundacao Oswaldo Cruz FIOCRUZ, Ctr Pesquisas Rene Rachou, Lab Med Entomol, Belo Horizonte, MG, Brazil. [Duarte, Ana Paula M.; Pimenta, Paulo F.] Fundacao Med Trop Dr Heitor Vieira Dourado, Manaus, Amazonas, Brazil. RP Molina-Cruz, A; Barillas-Mury, C (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA.; Pimenta, PF (reprint author), Fundacao Oswaldo Cruz FIOCRUZ, Ctr Pesquisas Rene Rachou, Lab Med Entomol, Belo Horizonte, MG, Brazil.; Pimenta, PF (reprint author), Fundacao Med Trop Dr Heitor Vieira Dourado, Manaus, Amazonas, Brazil. EM amolina-cruz@niaid.nih.gov; pimenta@cpqrr.fiocruz.br; cbarillas@niaid.nih.gov FU Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Conselho Nacional de Desenvolvimento Tecnologico (CNPq-PAPES); Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES); Fundacoes de Amparo a Pesquisas do Amazonas e de Minas Gerais (FAPEAM e FAPEMIG); FIOCRUZ; CNPq; CAPES post-doctoral fellowship FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health and the following Brazilian agencies: Conselho Nacional de Desenvolvimento Tecnologico (CNPq-PAPES), Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) and the Fundacoes de Amparo a Pesquisas do Amazonas e de Minas Gerais (FAPEAM e FAPEMIG). ASO was supported by PhD fellowships from FIOCRUZ and CNPq; and APMD by a CAPES post-doctoral fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 1 Z9 1 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 DEC 2 PY 2016 VL 11 IS 12 AR e0167178 DI 10.1371/journal.pone.0167178 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE3TF UT WOS:000389520600025 PM 27911924 ER PT J AU Chen, HY Ma, SL Huang, W Ji, LD Leung, VHK Jiang, HL Yao, XQ Tang, NLS AF Chen, Holly Y. Ma, Suk Ling Huang, Wei Ji, Lindan Leung, Vincent H. K. Jiang, Honglin Yao, Xiaoqiang Tang, Nelson L. S. TI The mechanism of transactivation regulation due to polymorphic short tandem repeats (STRs) using IGF1 promoter as a model SO Scientific Reports LA English DT Article ID BREAST-CANCER RISK; GROWTH-FACTOR 1; GENE-EXPRESSION; HUMAN GENOME; TRANSCRIPTIONAL REGULATION; MAMMOGRAPHIC DENSITY; MULTIETHNIC COHORT; PROSTATE-CANCER; CORE PROMOTER; MICROSATELLITES AB Functional short tandem repeats (STR) are polymorphic in the population, and the number of repeats regulates the expression of nearby genes (known as expression STR, eSTR). STR in IGF1 promoter has been extensively studied for its association with IGF1 concentration in blood and various clinical traits and represents an important eSTR. We previously used an in-vitro luciferase reporter model to examine the interaction between STRs and SNPs in IGF1 promoter. Here, we further explored the mechanism how the number of repeats of the STR regulates gene transcription. An inverse correlation between the number of repeats and the extent of transactivation was found in a haplotype consisting of three promoter SNPs (C-STR-T-T). We showed that these adjacent SNPs located outside the STR were required for the STR to function as eSTR. The C allele of rs35767 provides a binding site for CCAAT/enhancer-binding-protein delta (C/EBPD), which is essential for the gradational transactivation property of eSTR and FOXA3 may also be involved. Therefore, we propose a mechanism in which the gradational transactivation by the eSTR is caused by the interaction of one or more transcriptional complexes located outside the STR, rather than by direct binding to a repeat motif of the STR. C1 [Chen, Holly Y.; Leung, Vincent H. K.; Tang, Nelson L. S.] Chinese Univ Hong Kong, Fac Med, Dept Chem Pathol, Shatin, Hong Kong, Peoples R China. [Ma, Suk Ling] Chinese Univ Hong Kong, Fac Med, Dept Psychiat, Shatin, Hong Kong, Peoples R China. [Huang, Wei] Chinese Acad Med Sci, State Key Lab Bioact Subst & Funct Nat Med, Dept Pharmaceut, Inst Mat Med, Beijing, Peoples R China. [Huang, Wei] Peking Union Med Coll, Beijing, Peoples R China. [Ji, Lindan] Ningbo Univ, Sch Med, Zhejiang Prov Key Lab Pathophysiol, Dept Biochem & Mol Biol, Ningbo, Zhejiang, Peoples R China. [Jiang, Honglin] Virginia Polytech Inst & State Univ, Dept Anim & Poultry Sci, Blacksburg, VA 24061 USA. [Yao, Xiaoqiang; Tang, Nelson L. S.] Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. [Tang, Nelson L. S.] Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Lab Genet Dis Susceptibil, Shatin, Hong Kong, Peoples R China. [Tang, Nelson L. S.] Chinese Univ Hong Kong, Shenzhen Res Inst, Funct Genom & Biostat Comp Lab, Hong Kong, Hong Kong, Peoples R China. [Tang, Nelson L. S.] KIZ CUHK Joint Lab Bioresources & Mol Res Common, Kunming, Peoples R China. [Chen, Holly Y.] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. RP Tang, NLS (reprint author), Chinese Univ Hong Kong, Fac Med, Dept Chem Pathol, Shatin, Hong Kong, Peoples R China.; Tang, NLS (reprint author), Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China.; Tang, NLS (reprint author), Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Lab Genet Dis Susceptibil, Shatin, Hong Kong, Peoples R China.; Tang, NLS (reprint author), Chinese Univ Hong Kong, Shenzhen Res Inst, Funct Genom & Biostat Comp Lab, Hong Kong, Hong Kong, Peoples R China.; Tang, NLS (reprint author), KIZ CUHK Joint Lab Bioresources & Mol Res Common, Kunming, Peoples R China. EM nelsontang@cuhk.edu.hk FU NSFC [31171213, 81402747]; Shenzhen Science and Technology Innovation Committee [GJHS20120702105523299]; CUHK's Shenzhen Development Office FX We hereby thank all the members in our lab for their discussions on this project and Miss LO Pui Shan for preparing the typeset of the manuscript. The work was supported by NSFC (31171213 & 81402747), Shenzhen Science and Technology Innovation Committee (GJHS20120702105523299) and grant from CUHK's Shenzhen Development Office. NR 46 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 2045-2322 J9 SCI REP-UK JI Sci Rep PD DEC 2 PY 2016 VL 6 AR 38225 DI 10.1038/srep38225 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED9JN UT WOS:000389186100001 PM 27910883 ER PT J AU Bukalo, O Lee, PR Fields, RD AF Bukalo, Olena Lee, Philip R. Fields, R. Douglas TI BDNF mRNA abundance regulated by antidromic action potentials and AP-LTD in hippocampus SO NEUROSCIENCE LETTERS LA English DT Article DE LTD; BDNF; Slow wave sleep; Antidromic action potentials; Sharp wave ripple complexes ID LONG-TERM DEPRESSION; HIGH-FREQUENCY STIMULATION; RAT VISUAL-CORTEX; NEUROTROPHIC FACTOR; SYNAPTIC PLASTICITY; GENE-EXPRESSION; BRAIN; SLEEP; SUPPRESSION; RECEPTORS AB Action-potential-induced LTD (AP-LTD) is a form of synaptic plasticity that reduces synaptic strength in CA1 hippocampal neurons firing antidromically during sharp-wave ripples. This firing occurs during slow wave sleep and quiet moments of wakefulness, which are periods of offline replay of neural sequences learned during encoding sensory information. Here we report that rapid and persistent down-regulation of different mRNA transcripts of the BDNFgene accompanies AP-LTD, and that AP-LTD is abolished in mice with the BDNF gene knocked out in CA1 hippocampal neurons. These findings increase understanding of the mechanism of AP-LTD and the cellular mechanisms of memory consolidation. Published by Elsevier Ireland Ltd. C1 [Bukalo, Olena; Lee, Philip R.; Fields, R. Douglas] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Nervous Syst Dev & Plast Sect, Bethesda, MD USA. [Bukalo, Olena] NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD USA. RP Fields, RD (reprint author), NICHD, NIH, Bldg 35,Room 2A211,MSC 3713, Bethesda, MD 20892 USA. EM fieldsd@mail.nih.gov FU NICHD [HD000713] FX We thank Jonathan Cohen for BDNF primer design and Alexei Morozov for providing BDNF foxed mice. This research was supported by funds for intramural research at NICHD, HD000713. NR 41 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD DEC 2 PY 2016 VL 635 BP 97 EP 102 DI 10.1016/j.neulet.2016.10.023 PG 6 WC Neurosciences SC Neurosciences & Neurology GA ED8CX UT WOS:000389100700016 PM 27760383 ER PT J AU Ngalame, NNO Makia, NL Waalkes, MP Tokar, EJ AF Ngalame, Ntube N. O. Makia, Ngome L. Waalkes, Michael P. Tokar, Erik J. TI Mitigation of arsenic-induced acquired cancer phenotype in prostate cancer stem cells by miR-143 restoration SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Arsenic; Prostate; Stem cells; miRNA; Cancer ID MALIGNANT-TRANSFORMATION; MATRIX METALLOPROTEINASES; TUMOR-SUPPRESSOR; EPITHELIAL-CELLS; BREAST-CANCER; LIM KINASE; EXPRESSION; MICRORNA-143; GROWTH; MICE AB Inorganic arsenic, an environmental contaminant and a human carcinogen is associated with prostate cancer. Emerging evidence suggests that cancer stem cells (CSCs) are the driving force of carcinogenesis. Chronic arsenic exposure malignantly transforms the human normal prostate stem/progenitor cell (SC) line, WPE-stem to arsenic-cancer SCs (As-CSCs), through unknown mechanisms. MicroRNAs (miRNAs) are small, non-coding RNAs that negatively regulate gene expression at the posttranscriptional level. In prior work, miR-143 was markedly downregulated in As-CSCs, suggesting a role in arsenic-induced malignant transformation. In the present study, we investigated whether loss of miR-143 expression is important in arsenic-induced transformation of prostate SCs. Restoration of miR-143 in As-CSCs was achieved by lentivirus-mediated miR-143 overexpression. Cells were assessed bi-weekly for up to 30 weeks to examine mitigation of cancer phenotype. Secreted matrix metalloproteinase (MMP) activity was increased by arsenic-induced malignant transformation, but miR-143 restoration decreased secreted MMP-2 and MMP-9 enzyme activities compared with scramble controls. Increased cell proliferation and apoptotic resistance, two hallmarks of cancer, were decreased upon miR-143 restoration. Increased apoptosis was associated with decreased BCL2 and BCL-XL expression. miR-143 restoration dysregulated the expression of SC/CSC self-renewal genes including NOTCH-1, BMI-1, OCT4 and ABCG2. The anticancer effects of miR-143 overexpression appeared to be mediated by targeting and inhibiting LIMK1 protein, and the phosphorylation of cofilin, a LIMK1 substrate. These findings clearly show that miR-143 restoration mitigated multiple cancer characteristics in the As-CSCs, suggesting a potential role in arsenic-induced transformation of prostate SCs. Thus, miR-143 is a potential biomarker and therapeutic target for arsenic-induced prostate cancer. Published by Elsevier Inc. C1 [Ngalame, Ntube N. O.; Makia, Ngome L.; Waalkes, Michael P.; Tokar, Erik J.] NIEHS, Stem Cell Toxicol Grp, Natl Toxicol Program Lab, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. RP Tokar, EJ (reprint author), Div Natl Toxicol Program, Natl Toxicol Program Lab, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM ngalamenn@niehs.nih.gov; makianl@niehs.nih.gov; waalkes@niehs.nih.gov; tokare@mail.nih.gov FU Intramural Program funds from National Institute of Environmental Health Sciences, Division of the National Toxicology Program [ES102925] FX The authors wish to thank the NIEHS Viral Vector Core for the packaging of the lentiviral particles, and Matt Bell for his assistance in preparation of the graphics. This work was totally supported by Intramural Program funds from National Institute of Environmental Health Sciences, Division of the National Toxicology Program (ES102925). NR 59 TC 2 Z9 2 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 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD DEC 1 PY 2016 VL 312 SI SI BP 11 EP 18 DI 10.1016/j.taap.2015.12.013 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EE8JA UT WOS:000389870300003 PM 26721309 ER PT J AU Romieu, I Margetts, B Barquera, S Gomes, FD Gunter, M Hwalla, N Kampman, E Leitzmann, M Potischman, N Slimani, N Vorster, E Willett, WC Winichagoon, P Wiseman, M AF Romieu, Isabelle Margetts, Barrie Barquera, Simon Gomes, Fabio da Silva Gunter, Marc Hwalla, Nahla Kampman, Ellen Leitzmann, Michael Potischman, Nancy Slimani, Nadia Vorster, Este Willett, Walter C. Winichagoon, Pattanee Wiseman, Martin CA Int Canc Res Funders Nutrition Wor TI Strengthening the evidence base for nutrition and cancer in low and middle income countries SO JOURNAL OF GLOBAL HEALTH LA English DT Editorial Material C1 [Romieu, Isabelle; Slimani, Nadia] Int Agcy Res Canc, Nutr & Metab Sect, Lyon, France. [Margetts, Barrie] Univ Southampton, Southampton Gen Hosp, Fac Med, Southampton, Hants, England. [Barquera, Simon] Inst Nacl Salud Publ, Ctr Invest Nutr & Salud, Cuernavaca, Morelos, Mexico. [Gomes, Fabio da Silva] Natl Canc Inst Brazil INCA, Food Nutr & Canc Div, Rio De Janeiro, Brazil. [Gunter, Marc] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Hwalla, Nahla] Amer Univ Beirut, Fac Agr & Food Sci, Beirut, Lebanon. [Kampman, Ellen] Wageningen Univ, Div Human Nutr, Wageningen, Netherlands. [Leitzmann, Michael] Univ Regensburg, Dept Epidemiol & Prevent Med, Regensburg, Germany. [Potischman, Nancy] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Vorster, Este] North West Univ, Fac Hlth Sci, CEN, Potchefstroom, South Africa. [Willett, Walter C.] Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Winichagoon, Pattanee] Mahidol Univ Salaya, Inst Nutr, Nakhon Pathom, Thailand. [Wiseman, Martin] World Canc Res Fund Int, London, England. RP Romieu, I (reprint author), Int Agcy Res Canc, 153 Cours Albert Thomas, F-69372 Lyon 08, France. EM RomieuI@iarc.fr FU International Agency for Research on Cancer FX International Agency for Research on Cancer. NR 5 TC 0 Z9 0 U1 0 U2 0 PU UNIV EDINBURGH, GLOBAL HEALTH SOC PI EDINBURGH PA CENTRE POPULATION HEALTH SCIENCES, TEVIOT PL, EDINBURGH, EH8 9AG, ENGLAND SN 2047-2978 EI 2047-2986 J9 J GLOB HEALTH JI J. Glob. Health PD DEC PY 2016 VL 6 IS 2 AR 020306 DI 10.7189/jogh.06.020306 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EO8YN UT WOS:000396976500007 ER PT J AU Lock, M Malayeri, AA Mian, OY Mayr, NA Herman, JM Lo, SS AF Lock, Michael Malayeri, Ashkan A. Mian, Omar Y. Mayr, Nina A. Herman, Joseph M. Lo, Simon S. TI Computed tomography imaging assessment of postexternal beam radiation changes of the liver SO FUTURE ONCOLOGY LA English DT Review DE hepatocellular carcinoma; radiation therapy/radiotherapy; stereotactic radiotherapy ID RESPONSE EVALUATION CRITERIA; STEREOTACTIC BODY RADIOTHERAPY; SOLID TUMORS RECIST; HEPATOCELLULAR-CARCINOMA; EUROPEAN ASSOCIATION; FOLLOW-UP; METASTASES; THERAPY; CANCER; CT AB Radiation is being used for patients with primary and secondary liver cancers, as a rapidly evolving treatment. However, postradiation imaging changes of the liver are not well understood and therefore challenging to interpret. Distinguishing normal radiation changes from residual or recurrent disease is difficult. Size and contrast enhancement have been used to guide interpretation and clinical recommendations, but normal radiation changes can make interpretation difficult and are not accounted for in available guidelines. Knowledge of dose-and time-dependent changes in addition to imaging findings, such as morphological and enhancement patterns, provides useful differentiating parameters. This paper reviews recent studies using computed tomography that can guide interpretation and help differentiate tumor from benign changes after external beam radiation. C1 [Lock, Michael] Univ Western Ontario, Dept Radiat Oncol, London Reg Canc Program, London, ON, Canada. [Malayeri, Ashkan A.] NIH, Dept Radiol, Bldg 10, Bethesda, MD 20892 USA. [Mian, Omar Y.; Herman, Joseph M.] Johns Hopkins Univ, Dept Radiat Oncol, Baltimore, MD USA. [Mayr, Nina A.; Lo, Simon S.] Univ Washington, Dept Radiat Oncol, Sch Med, Seattle, WA USA. RP Lock, M (reprint author), Univ Western Ontario, Dept Radiat Oncol, London Reg Canc Program, London, ON, Canada. EM michael.lock@lhsc.on.ca FU Elekta AB through the International Oligometastasis Consortium; AstraZeneca Limited; Accuray Incorporated; 3M Canada; Abbvie Corporation FX SS Lo has received research funding from Elekta AB through the International Oligometastasis Consortium. He has also received travel support and honorarium from Varian Medical Systems and Accuray Incorporated. MI Lock has received fees as a consultant or research funding from AstraZeneca Limited, Accuray Incorporated, 3M Canada and Abbvie Corporation. 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 36 TC 0 Z9 0 U1 1 U2 1 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1479-6694 EI 1744-8301 J9 FUTURE ONCOL JI Future Oncol. PD DEC PY 2016 VL 12 IS 23 BP 2729 EP 2739 DI 10.2217/fon-2016-0165 PG 11 WC Oncology SC Oncology GA EL1PC UT WOS:000394391300009 PM 27576360 ER PT J AU Lauterbach, MD Schildkrout, B Benjamin, S Gregory, MD AF Lauterbach, Margo D. Schildkrout, Barbara Benjamin, Sheldon Gregory, Michael D. TI The importance of rare diseases for psychiatry SO LANCET PSYCHIATRY LA English DT Editorial Material ID FRONTOTEMPORAL DEMENTIA; DISORDER C1 [Lauterbach, Margo D.] Sheppard Pratt Hlth Syst, Neuropsychiat Program Sheppard Pratt, Baltimore, MD 21285 USA. [Lauterbach, Margo D.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Schildkrout, Barbara] Harvard Med Sch, Dept Psychiat, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Benjamin, Sheldon] Univ Massachusetts, Sch Med, Dept Psychiat, Worcester, MA 01655 USA. [Benjamin, Sheldon] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA USA. [Gregory, Michael D.] NIMH, Sect Integrat Neuroimaging, Clin & Translat Neurosci Branch, NIH, Bethesda, MD 20892 USA. RP Lauterbach, MD (reprint author), Sheppard Pratt Hlth Syst, Neuropsychiat Program Sheppard Pratt, Baltimore, MD 21285 USA.; Lauterbach, MD (reprint author), Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. EM mlauterbach@sheppardpratt.org FU Leonard and Helen R Stulman Charitable Foundation; Women's Hospital Foundation, Inc. FX SB and MDL are partners in and authors for Brain Educators LLC, publishers of neuropsychiatric educational resources and The Brain Card (R). BS declare no competing interests. MDG's authorship was in his private capacity. The views expressed in this article do not necessarily represent the views of or endorsement by the US Government or the National Institutes of Health. MDL is supported by funds from the Leonard and Helen R Stulman Charitable Foundation and the Women's Hospital Foundation, Inc. This paper was a project of the Neuropsychiatry Committee of the Group for Advancement of Psychiatry (GAP). The authors acknowledge Lindsey MacGillivray of the University of Toronto for help in formulating multiple stages of this manuscript. NR 15 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 2215-0374 J9 LANCET PSYCHIAT JI Lancet Psychiatry PD DEC PY 2016 VL 3 IS 12 BP 1098 EP 1100 PG 4 WC Psychiatry SC Psychiatry GA EN9UP UT WOS:000396345400008 PM 27889002 ER PT J AU Prasad, R Poltoratsky, V Hou, EW Wilson, SH AF Prasad, Rajendra Poltoratsky, Vladimir Hou, Esther W. Wilson, Samuel H. TI Rev1 is a base excision repair enzyme with 5 '-deoxyribose phosphate lyase activity SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DNA-POLYMERASE-BETA; CLASS SWITCH RECOMBINATION; XRCC1-DNA LIGASE-III; SOMATIC HYPERMUTATION; BRCT DOMAIN; IN-VITRO; PROTEIN INTERACTS; SUBSTRATE-BINDING; DAMAGE TOLERANCE; BOVINE TESTIS AB Rev1 is amember of the Y-family of DNA polymerases and is known for its deoxycytidyl transferase activity that incorporates dCMP into DNA and its ability to function as a scaffold factor for other Y-family polymerases in translesion bypass events. Rev1 also is involved in mutagenic processes during somatic hypermutation of immunoglobulin genes. In light of the mutation pattern consistent with dCMP insertion observed earlier in mouse fibroblast cells treated with a base excision repair-inducing agent, we questioned whether Rev1 could also be involved in base excision repair (BER). Here, we uncovered a weak 5' -deoxyribose phosphate (5' -dRP) lyase activity in mouse Rev1 and demonstrated the enzyme can mediate BER in vitro. The full-length Rev1 protein and its catalytic core domain are similar in their ability to support BER in vitro. The dRP lyase activity in both of these proteins was confirmed by NaBH4 reduction of the Schiff base intermediate and kinetics studies. Limited proteolysis, mass spectrometry and deletion analysis localized the dRP lyase active site to the C-terminal segment of Rev1' s catalytic core domain. These results suggest that Rev1 could serve as a backup polymerase in BER and could potentially contribute to AID-initiated antibody diversification through this activity. C1 [Prasad, Rajendra; Poltoratsky, Vladimir; Hou, Esther W.; Wilson, Samuel H.] NIEHS, Genome Integr & Struct Biol Lab, NIH, 111 TW Alexander Dr,POB 12233,MD F3-01, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Genome Integr & Struct Biol Lab, NIH, 111 TW Alexander Dr,POB 12233,MD F3-01, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01ES050158, Z01ES050159] FX Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01ES050158 and Z01ES050159]. Funding for open access charge: Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01ES050158 and Z01ES050159]. NR 70 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 DEC PY 2016 VL 44 IS 22 BP 10824 EP 10833 DI 10.1093/nar/gkw869 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EN1AP UT WOS:000395742900025 PM 27683219 ER PT J AU Kuznedelov, K Mekler, V Lemak, S Tokmina-Lukaszewska, M Datsenko, KA Jain, I Savitskaya, E Mallon, J Shmakov, S Bothner, B Bailey, S Yakunin, AF Severinov, K Semenova, E AF Kuznedelov, Konstantin Mekler, Vladimir Lemak, Sofia Tokmina-Lukaszewska, Monika Datsenko, Kirill A. Jain, Ishita Savitskaya, Ekaterina Mallon, John Shmakov, Sergey Bothner, Brian Bailey, Scott Yakunin, Alexander F. Severinov, Konstantin Semenova, Ekaterina TI Altered stoichiometry Escherichia coli Cascade complexes with shortened CRISPR RNA spacers are capable of interference and primed adaptation SO NUCLEIC ACIDS RESEARCH LA English DT Article ID GUIDED SURVEILLANCE COMPLEX; CAS ADAPTIVE IMMUNITY; ANTIVIRAL DEFENSE; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; DNA TARGET; E. COLI; SYSTEM; RECOGNITION; SEQUENCE AB The Escherichia coli type I-E CRISPR-Cas system Cascade effector is a multisubunit complex that binds CRISPR RNA (crRNA). Through its 32-nucleotide spacer sequence, Cascade-bound crRNA recognizes protospacers in foreign DNA, causing its destruction during CRISPR interference or acquisition of additional spacers in CRISPR array during primed CRISPR adaptation. Within Cascade, the crRNA spacer interacts with a hexamer of Cas7 sub-units. We show that crRNAs with a spacer length reduced to 14 nucleotides cause primed adaptation, while crRNAs with spacer lengths of more than 20 nucleotides cause both primed adaptation and target interference in vivo. Shortened crRNAs assemble into altered-stoichiometry Cascade effector complexes containing less than the normal amount of Cas7 subunits. The results show that Cascade assembly is driven by crRNA and suggest that multisubunit type I CRISPR effectors may have evolved from much simpler ancestral complexes. C1 [Kuznedelov, Konstantin; Mekler, Vladimir; Jain, Ishita; Severinov, Konstantin; Semenova, Ekaterina] Rutgers State Univ, Waksman Inst Microbiol, Piscataway, NJ 08854 USA. [Lemak, Sofia; Yakunin, Alexander F.] Univ Toronto, Dept Chem Engn & Appl Chem, Toronto, ON M5S 3E5, Canada. [Tokmina-Lukaszewska, Monika; Bothner, Brian] Montana State Univ, Dept Chem & Biochem, Bozeman, MT 59717 USA. [Datsenko, Kirill A.] Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. [Savitskaya, Ekaterina; Shmakov, Sergey; Severinov, Konstantin] Skolkovo Inst Sci & Technol, Skolkovo 143025, Russia. [Savitskaya, Ekaterina; Severinov, Konstantin] Russian Acad Sci, Inst Mol Genet, Moscow 123182, Russia. [Mallon, John; Bailey, Scott] Johns Hopkins Univ, Dept Biochem & Mol Biol, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Shmakov, Sergey] NIH, NCBI, NLM, Bethesda, MD 20894 USA. [Severinov, Konstantin] Peter Great St Petersburg State Polytech Univ, St Petersburg 195251, Russia. RP Severinov, K; Semenova, E (reprint author), Rutgers State Univ, Waksman Inst Microbiol, Piscataway, NJ 08854 USA.; Severinov, K (reprint author), Skolkovo Inst Sci & Technol, Skolkovo 143025, Russia.; Severinov, K (reprint author), Russian Acad Sci, Inst Mol Genet, Moscow 123182, Russia.; Severinov, K (reprint author), Peter Great St Petersburg State Polytech Univ, St Petersburg 195251, Russia. EM severik@waksman.rutgers.edu; semenova@waksman.rutgers.edu FU National Institutes of Health (NIH) [GM10407, 5P20RR02437, GM097330]; Russian Science Foundation [14-14-00988]; Ministry of Education and Science of the Russian Federation [14.B25.31.0004]; Russian Foundation for Basic Research [16-04-00767]; Department of Energy [DE-SC0012518]; M.J. Murdock Charitable Trust; Charles and Johanna Busch Memorial Fund; Natural Sciences and Engineering research Council of Canada (NSERC) [RGPIN-2015-04745]; Skolkovo Institute of Science and Technology; Charles and Johanna Busch predoctoral fellowship; Russan Science Foundation [14-14-00988] FX National Institutes of Health (NIH) [GM10407 to K.S; 5P20RR02437 to B.B.; GM097330 to S.B.]; Russian Science Foundation [14-14-00988 to K.S.] and Ministry of Education and Science of the Russian Federation [14.B25.31.0004 to K.S.]; Russian Foundation for Basic Research [16-04-00767 to E. Savitskaya]; Department of Energy [DE-SC0012518 to B.B.]; M.J. Murdock Charitable Trust [to B.B.]; The Charles and Johanna Busch Memorial Fund [predoctoral fellowship to I.J.]; Natural Sciences and Engineering research Council of Canada (NSERC) [Strategic Network Grant IBN and Discovery grant RGPIN-2015-04745 to S.L. and A.F.Y.]. Funding for open access charge: Skolkovo Institute of Science and Technology; The Russan Science Foundation [14-14-00988], I.J. was supported by Charles and Johanna Busch predoctoral fellowship. NR 41 TC 2 Z9 2 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 DEC PY 2016 VL 44 IS 22 BP 10849 EP 10861 DI 10.1093/nar/gkw914 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EN1AP UT WOS:000395742900027 PM 27738137 ER PT J AU Rajappa-Titu, L Suematsu, T Munoz-Tello, P Long, M Demir, O Cheng, KJ Stagno, JR Luecke, H Amaro, RE Aphasizheva, I Aphasizhev, R Thore, S AF Rajappa-Titu, Lional Suematsu, Takuma Munoz-Tello, Paola Long, Marius Demir, Ozlem Cheng, Kevin J. Stagno, Jason R. Luecke, Hartmut Amaro, Rommie E. Aphasizheva, Inna Aphasizhev, Ruslan Thore, Stephane TI RNA Editing TUTase 1: structural foundation of substrate recognition, complex interactions and drug targeting SO NUCLEIC ACIDS RESEARCH LA English DT Article ID TERMINAL URIDYLYL TRANSFERASE; CID1 POLY(U) POLYMERASE; EDITOSOME-LIKE COMPLEX; PARTICLE MESH EWALD; TRYPANOSOMA-BRUCEI; MESSENGER-RNA; CRYSTAL-STRUCTURE; GENE-EXPRESSION; GUIDE RNA; MITOCHONDRIA AB Terminal uridyltransferases (TUTases) execute 3' RNA uridylation across protists, fungi, metazoan and plant species. Uridylation plays a particularly prominent role in RNA processing pathways of kinetoplastid protists typified by the causative agent of African sleeping sickness, Trypanosoma brucei. In mitochondria of this pathogen, most mRNAs are internally modified by U-insertion/deletion editing while guide RNAs and rRNAs are U-tailed. The founding member of TUTase family, RNA editing TUTase 1 (RET1), functions as a subunit of the 3' processome in uridylation of gRNA precursors and mature guide RNAs. Along with KPAP1 poly(A) polymerase, RET1 also participates in mRNA translational activation. RET1 is divergent from human TUTases and is essential for parasite viability in the mammalian host and the insect vector. Given its robust in vitro activity, RET1 represents an attractive target for trypanocide development. Here, we report high-resolution crystal structures of the RET1 catalytic core alone and in complex with UTP analogs. These structures reveal a tight docking of the conserved nucleotidyl transferase bi-domain module with a RET1-specific C2H2 zinc finger and RNA recognition (RRM) domains. Fur-thermore, we define RET1 region required for incorporation into the 3' processome, determinants for RNA binding, subunit oligomerization and processive UTP incorporation, and predict druggable pockets. C1 [Rajappa-Titu, Lional; Munoz-Tello, Paola; Long, Marius; Thore, Stephane] Univ Geneva, Dept Mol Biol, CH-1211 Geneva, Switzerland. [Suematsu, Takuma; Aphasizheva, Inna; Aphasizhev, Ruslan] Boston Univ, Dept Mol & Cell Biol, Sch Dent Med, Boston, MA 02118 USA. [Demir, Ozlem; Cheng, Kevin J.; Amaro, Rommie E.] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA. [Demir, Ozlem; Cheng, Kevin J.; Amaro, Rommie E.] Univ Calif San Diego, Natl Biomed Computat Resource, La Jolla, CA 92093 USA. [Stagno, Jason R.; Luecke, Hartmut] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. [Aphasizhev, Ruslan] Boston Univ, Dept Biochem, Sch Med, Boston, MA 02118 USA. [Thore, Stephane] INSERM, U1212, ARNA Lab, F-33000 Bordeaux, France. [Thore, Stephane] CNRS UMR5320, ARNA Lab, F-33000 Bordeaux, France. [Thore, Stephane] Univ Bordeaux, ARNA Lab, F-33000 Bordeaux, France. [Munoz-Tello, Paola] Scripps Res Inst Scripps Florida, Dept Mol Therapeut, Jupiter, FL 33458 USA. [Stagno, Jason R.] NCI, Struct Biophys Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Thore, S (reprint author), Univ Geneva, Dept Mol Biol, CH-1211 Geneva, Switzerland.; Aphasizhev, R (reprint author), Boston Univ, Dept Mol & Cell Biol, Sch Dent Med, Boston, MA 02118 USA.; Aphasizhev, R (reprint author), Boston Univ, Dept Biochem, Sch Med, Boston, MA 02118 USA.; Thore, S (reprint author), INSERM, U1212, ARNA Lab, F-33000 Bordeaux, France.; Thore, S (reprint author), CNRS UMR5320, ARNA Lab, F-33000 Bordeaux, France.; Thore, S (reprint author), Univ Bordeaux, ARNA Lab, F-33000 Bordeaux, France. EM ruslana@bu.edu; stephane.thore@inserm.fr FU Swiss National Science Foundation [31003A-140924, 31003A-124909]; National Institutes of Health [AI091914, AI101057]; Director's New Innovator Award Program NIH DP2 [OD007237]; National Biomedical Computation Resource through NIH [P41 GM103426]; University of Geneva FX Swiss National Science Foundation [31003A-140924, 31003A-124909 to S.T.]; National Institutes of Health [AI091914, AI101057 to R.A.]; Director's New Innovator Award Program NIH DP2 [OD007237 to REA]; National Biomedical Computation Resource through NIH [P41 GM103426 to R.E.A.]. Funding for open access charge: University of Geneva. NR 65 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 DEC PY 2016 VL 44 IS 22 BP 10862 EP 10878 DI 10.1093/nar/gkw917 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EN1AP UT WOS:000395742900028 PM 27744351 ER PT J AU Faure, G Ogurtsov, AY Shabalina, SA Koonin, EV AF Faure, Guilhem Ogurtsov, Aleksey Y. Shabalina, Svetlana A. Koonin, Eugene V. TI Role of mRNA structure in the control of protein folding SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SYNONYMOUS CODON USAGE; SECONDARY STRUCTURE; IN-VIVO; GENE-EXPRESSION; TRANSLATION EFFICIENCY; ELONGATION RATES; ESCHERICHIA-COLI; RIBOSOME; GENOME; SEQUENCE AB Specific structures in mRNA modulate translation rate and thus can affect protein folding. Using the protein structures from two eukaryotes and three prokaryotes, we explore the connections between the protein compactness, inferred from solvent accessibility, and mRNA structure, inferred from mRNA folding energy (Delta G). In both prokaryotes and eukaryotes, the Delta G value of the most stable 30 nucleotide segment of the mRNA (Delta Gmin) strongly, positively correlates with protein solvent accessibility. Thus, mRNAs containing exceptionally stable secondary structure elements typically encode compact proteins. The correlations between Delta G and protein compactness are much more pronounced in predicted ordered parts of proteins compared to the predicted disordered parts, indicative of an important role of mRNA secondary structure elements in the control of protein folding. Additionally, Delta G correlates with the mRNA length and the evolutionary rate of synonymous positions. The correlations are partially independent and were used to construct multiple regression models which explain about half of the variance of protein solvent accessibility. These findings suggest amodel in which them RNA structure, particularly exceptionally stable RNA structural elements, act as gauges of protein co-translational folding by reducing ribosome speed when the nascent peptide needs time to form and optimize the core structure. C1 [Faure, Guilhem; Ogurtsov, Aleksey Y.; Shabalina, Svetlana A.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU Intramural funds of the US Department of Health and Human Services FX Intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). The open access publication charge for this paper has been waived by Oxford University Press - NAR Editorial Board members are entitled to one free paper per year in recognition of their work on behalf of the journal. NR 105 TC 0 Z9 0 U1 3 U2 3 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 DEC PY 2016 VL 44 IS 22 BP 10898 EP 10911 DI 10.1093/nar/gkw671 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EN1AP UT WOS:000395742900030 PM 27466388 ER PT J AU Larriba, Y Rueda, C Fernandez, MA Peddada, SD AF Larriba, Yolanda Rueda, Cristina Fernandez, Miguel A. Peddada, Shyamal D. TI Order restricted inference for oscillatory systems for detecting rhythmic signals SO NUCLEIC ACIDS RESEARCH LA English DT Article ID CYCLE-REGULATED GENES; CELL-CYCLE; CIRCADIAN CLOCK; TIME-SERIES; MICROARRAY DATA; FISSION YEAST; SPACED DATA; EXPRESSION; IDENTIFICATION; ALGORITHM AB Motivation: Many biological processes, such as cell cycle, circadian clock, menstrual cycles, are governed by oscillatory systems consisting of numerous components that exhibit rhythmic patterns over time. It is not always easy to identify such rhythmic components. For example, it is a challenging problem to identify circadian genes in a given tissue using time-course gene expression data. There is a great potential for misclassifying non-rhythmic as rhythmic genes and vice versa. This has been a problem of considerable interest in recent years. In this article we develop a constrained inference based methodology called Order Restricted Inference for Oscillatory Systems (ORIOS) to detect rhythmic signals. Instead of using mathematical functions (e.g. sinusoidal) to describe shape of rhythmic signals, ORIOS uses mathematical inequalities. Consequently, it is robust and not limited by the biologist's choice of the mathematical model. We studied the performance of ORIOS using simulated as well as real data obtained from mouse liver, pituitary gland and data from NIH3T3, U2OS cell lines. Our results suggest that, for a broad collection of patterns of gene expression, ORIOS has substantially higher power to detect true rhythmic genes in comparison to some popular methods, while also declaring substantially fewer non-rhythmic genes as rhythmic. Availability and Implementation: A user friendly code implemented in R language can be downloaded from http://www.niehs.nih.gov/ research/atniehs/labs/bb/staff/peddada/index. cfm. Contact: peddada@ niehs.nih.gov C1 [Larriba, Yolanda; Rueda, Cristina; Fernandez, Miguel A.] Univ Valladolid, Dept Estadist & Invest Operat, Paseo Belen 7, E-47011 Valladolid, Spain. [Peddada, Shyamal D.] NIEHS, Biostat & Computat Biol Branch, Alexander Dr, Res Triangle Pk, NC 27709 USA. RP Peddada, SD (reprint author), NIEHS, Biostat & Computat Biol Branch, Alexander Dr, Res Triangle Pk, NC 27709 USA. EM peddada@niehs.nih.gov FU Spanish Ministerio de Ciencia e Innovacion [MTM2015-71217-R]; Spanish Ministerio de Educacion, Cultura y Deporte [FPU14/04534]; Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS) [Z01 ES101744-04]; NIEHS FX Spanish Ministerio de Ciencia e Innovacion [MTM2015-71217-R to C.R. and M.A.F.]; Spanish Ministerio de Educacion, Cultura y Deporte [FPU14/04534 to Y.L.]; Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS) [Z01 ES101744-04 to S.D.P.]. Funding for open access charge: NIEHS. NR 45 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 DEC PY 2016 VL 44 IS 22 AR e163 DI 10.1093/nar/gkw771 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EN1AP UT WOS:000395742900003 PM 27596593 ER PT J AU Dunkhase, E Ludwig, KU Knapp, M Skibola, CF Figueiredo, JC Hosking, FJ Ellinghaus, E Landi, MT Ma, HX Nakagawa, H Kim, JW Han, JL Yang, P Bohmer, AC Mattheisen, M Nothena, MM Mangold, E AF Dunkhase, Eva Ludwig, Kerstin U. Knapp, Michael Skibola, Christine F. Figueiredo, Jane C. Hosking, Fay Julie Ellinghaus, Eva Landi, Maria Teresa Ma, Hongxia Nakagawa, Hidewaki Kim, Jong-Won Han, Jiali Yang, Ping Boehmer, Anne C. Mattheisen, Manuel Noethena, Markus M. Mangold, Elisabeth TI Nonsyndromic cleft lip with or without cleft palate and cancer: Evaluation of a possible common genetic background through the analysis of GWAS data SO GENOMICS DATA LA English DT Article DE Cleft lip; Cleft palate; Genome-wide association study; Single nucleotide polymorphism; Cancer ID GENOME-WIDE ASSOCIATION; DIFFUSE GASTRIC-CANCER; SUSCEPTIBILITY LOCI; PROSTATE-CANCER; CONGENITAL-MALFORMATIONS; HEPATOCELLULAR-CARCINOMA; COLORECTAL-CANCER; CHILDHOOD-CANCER; RISK LOCI; MULTIPLE LOCI AB Previous research suggests a genetic overlap between nonsyndromic cleft lip with or without cleft palate (NSCL/P) and cancer. The aim of the present study was to identify common genetic risk loci for NSCL/P and cancer entities that have been reported to co-occur with orofacial clefting. This was achieved through the investigation of large genome-wide association study datasets. Investigations of 12 NSCL/P single nucleotide polymorphisms (SNPs) in 32 cancer datasets, and 204 cancer SNPs in two NSCL/P datasets, were performed. The SNPs rs13041247 (20q12) and rs6457327 (6p21.33) showed suggestive evidence for an association with both NSCL/P and a specific cancer entity. These loci harbor genes of biological relevance to oncogenesis (MAFB and OCT4, respectively). This study is the first to characterize possible pleiotropic risk loci for NSCL/P and cancer in a systematic manner. The data represent a starting point for future research by identifying a genetic link between NSCL/P and cancer. (C) 2016 Published by Elsevier Inc. C1 [Dunkhase, Eva; Ludwig, Kerstin U.; Mattheisen, Manuel; Noethena, Markus M.; Mangold, Elisabeth] Univ Bonn, Inst Human Genet, Sigmund Freud Str 25, D-53127 Bonn, Germany. [Boehmer, Anne C.; Mattheisen, Manuel; Noethena, Markus M.] Univ Bonn, Life & Brain Ctr, Dept Genom, Sigmund Freud Str 25, D-53127 Bonn, Germany. [Knapp, Michael; Mattheisen, Manuel] Univ Bonn, Inst Med Biometry Informat & Epidemiol, Sigmund Freud Str 25, D-53127 Bonn, Germany. [Skibola, Christine F.] Univ Alabama Birmingham, Dept Epidemiol, 1665 Univ Blvd, Birmingham, AL 35294 USA. [Figueiredo, Jane C.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, 1975 Zonal Ave, Los Angeles, CA 90033 USA. [Hosking, Fay Julie] Inst Canc Res, Div Genet & Epidemiol, 15 Cotswold Rd, Sutton SM2 5NG, Surrey, England. [Ellinghaus, Eva] Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Schittenhelmstr 12, D-24105 Kiel, Germany. [Landi, Maria Teresa] NCI, NIH, DHHS, 9609 Med Ctr Dr, Rockville, MD 20850 USA. [Ma, Hongxia] Nanjing Med Univ, Sch Publ Hlth, Dept Epidemiol, 140 Hanzhong Rd, Nanjing 210029, Jiangsu, Peoples R China. [Nakagawa, Hidewaki] RIKEN, Ctr Integrat Med Sci, Lab Genome Sequencing Anal, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan. [Kim, Jong-Won] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Lab Med & Genet, 81 Irwon Ro, Seoul 06351, South Korea. [Han, Jiali] Indiana Univ, Melvin & Bren Simon Canc Ctr, Richard M Fairbanks Sch Publ Hlth, Dept Epidemiol, 535 Barnhill Dr, Indianapolis, IN 46202 USA. [Yang, Ping] Mayo Clin, 200 First St SW, Rochester, MN 55905 USA. RP Mangold, E (reprint author), Univ Bonn, Inst Human Genet, Sigmund Freud Str 25, D-53127 Bonn, Germany. EM e.mangold@uni-bonn.de RI Ellinghaus, Eva/E-6490-2012 OI Ellinghaus, Eva/0000-0003-2914-3382 FU Deutsche Forschungsgemeinschaft [FOR 423, MA 2546/3-1, KR 1912/7-1, NO 246/6-1, WI 1555/5-1]; National Institutes of Health [RO1CA1046282, RO1CA154643]; Mayo Foundation; BioBank Japan; Korean Health Technology RD Project [A120030]; Intramural Research Program of the National Institutes of Health, 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 [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]; American Cancer Society; NIH Genes, Environment and Health Initiative (GEI) [HG-06-033-NCI-01, RO1HL091172-01, U01HG004438, NIH HHSN268200782096C, U01 HG004446]; Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics; NIH [CA55769, CA127219, R01CA133996, CA121197, R01CA78812, U01CA63673]; Institut National du Cancer (INCa) in France; U.S. NCI [RO1 CA092039]; Deutsche Forschungsgemeinschaft (DFG) [BI 576/2-1, BI 576/2-2]; Helmholtz Association in Germany; Deutsche Krebshilfe; Targeted Financing from Estonian Government European Union through the European Regional Development Fund in the frame of Centre of Excellence in Genomics [SF0180142, ESF 6465]; 7 FP Project ECOGENE; [NCI-CA77118]; [CA80127] FX We thank all affected individuals and their families for their participation in this study, as well as the German support group for persons with cleft lip and/or palate (Deutsche Selbsthilfevereinigung fur Lippen-Gaumen-Fehlbildungen e.V.). The study was supported by the Deutsche Forschungsgemeinschaft (FOR 423 and individual grants MA 2546/3-1, KR 1912/7-1, NO 246/6-1 and WI 1555/5-1). In particular, we thank the following researchers for the provision of data: deCODE Genetics (Reykjavik, Iceland); Victor Enciso (The Institute of Cancer Research, Sutton, Surrey, UK); Susan L. Slager (Mayo Clinic, Rochester, MN, USA); and Peter Kraft (Harvard School of Public Health, Boston, MA, USA). The study was also supported by Richard S. Houlston (The Institute of Cancer Research, Sutton, Surrey, UK); Noralane M. Lindor (Mayo Clinic, Department of Health Sciences Research, Mayo Clinic Arizona, USA); and Zhibin Hu and Hongbing Shen of Nanjing Medical University.; Christine F Skibola was supported by the National Institutes of Health RO1CA1046282 and RO1CA154643.; Ping Yang received support from grants NCI-CA77118 and CA80127, and from the Mayo Foundation.; Hidewaki Nakagawa was supported by BioBank Japan.; Jong-Won Kim was supported by the Korean Health Technology R&D Project (A120030).; The Environment and Genetics in Lung Cancer Etiology (EAGLE), Prostate, Lung, Colon, Ovary Screening Trial (PLCO), and Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) studies were supported by the Intramural Research Program of the National Institutes of Health, 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 (NO1-CN-25514), Georgetown University (NO1-CN-25522), the Pacific Health Research Institute (NO1-CN-25515), the Henry Ford Health System (NO1-CN-25512), the University of Minnesota, (NO1-CN-25513), Washington University (NO1-CN-25516), the University of Pittsburgh (NO1-CN-25511), the University of Utah (NO1-CN-25524), the Marshfield Clinic Research Foundation (NO1-CN-25518), the University of Alabama at Birmingham (NO1-CN-75022), Westat, Inc. (NO1-CN-25476), and the University of California, Los Angeles (NO1-CN-25404). The Cancer Prevention Study-II (CPS-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 the EAGLE study and part of the PLCO. Genotyping for the remaining part of PLCO and all ATBC and CPS-II samples were supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. The "Texas" study was supported by NIH grants CA55769, CA127219, R01CA133996, and CA121197. The Central European study was supported by the Institut National du Cancer (INCa) in France and the U.S. NCI (RO1 CA092039). The CARET study was supported by NIH grants R01CA78812 and U01CA63673. LUCY was partly funded by the Deutsche Forschungsgemeinschaft (DFG, BI 576/2-1; BI 576/2-2), and genotyping was funded by the Helmholtz Association in Germany. The Heidelberg sample collection was partly supported by the Deutsche Krebshilfe. The Estonian study was supported by Targeted Financing from Estonian Government (SF0180142 and ESF 6465) European Union through the European Regional Development Fund in the frame of Centre of Excellence in Genomics and 7 FP Project ECOGENE. NR 72 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-5960 J9 GENOM DATA JI Genom. Data PD DEC PY 2016 VL 10 BP 22 EP 29 DI 10.1016/j.gdata.2016.08.017 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA EM4ZA UT WOS:000395320500006 PM 27630819 ER PT J AU Peng, L Zhang, H Hao, YY Xu, FH Yang, JJ Zhang, RH Lu, GM Zheng, ZH Cui, M Qi, CF Chen, C Wang, J Hu, Y Wang, D Pierce, S Li, LW Xiong, HB AF Peng, Liang Zhang, Hui Hao, Yuanyuan Xu, Feihong Yang, Jianjun Zhang, Ruihua Lu, Geming Zheng, Zihan Cui, Miao Qi, Chen-Feng Chen, Chun Wang, Juan Hu, Yuan Wang, Di Pierce, Susan Li, Liwu Xiong, Huabao TI Reprogramming macrophage orientation by microRNA 146b targeting transcription factor IRF5 SO EBIOMEDICINE LA English DT Article DE Interleukin 10; miR-146b; Macrophage; CRISPR/Cas9; Colitis ID TOLL-LIKE RECEPTORS; INTERLEUKIN-10 RECEPTOR; CHRONIC ENTEROCOLITIS; T-CELLS; COLITIS; POLARIZATION; IL-10; INFLAMMATION; MICE; EXPRESSION AB The regulation of macrophage orientation pathological conditions is important but still incompletely understood. Here, we show that IL-10 and Rag1 double knockout mice spontaneously develop colitis with dominant M1 macrophage phenotype, suggesting that IL-10 regulates macrophage orientation in inflammation. We demonstrate that IL-10 stimulation induced miR-146b expression, and that the expression of miR-146b was impaired in IL-10 deficient macrophages. Our data show that miR-146b targets IRF5, resulting in the regulation of macrophage activation. Furthermore, miR-146b deficient mice developed intestinal inflammation with enhanced M1 macrophage polarization. Finally, miR-146b mimic treatment significantly suppresses M1 macrophage activation and ameliorates colitis development in vivo. Collectively, the results suggest that IL-10 dependent miR-146b plays an important role in the modulation of M1 macrophage orientation. (C) 2016 The Authors. Published by Elsevier B.V. C1 [Peng, Liang; Zhang, Hui; Hao, Yuanyuan; Xu, Feihong; Yang, Jianjun; Zhang, Ruihua; Lu, Geming; Zheng, Zihan; Cui, Miao; Wang, Juan; Hu, Yuan; Wang, Di; Xiong, Huabao] Icahn Sch Med Mt Sinai, Inst Immunol, Dept Med, New York, NY 10029 USA. [Qi, Chen-Feng; Pierce, Susan] NIAID, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. [Chen, Chun; Li, Liwu] Virginia Tech, Ctr Inflammat, Dept Biol Sci, Blacksburg, VA 24061 USA. [Xiong, Huabao] Jining Med Coll, Inst Immunol & Mol Med, Jining 272067, Shangdong, Peoples R China. RP Xiong, HB (reprint author), Icahn Sch Med Mt Sinai, Inst Immunol, Box 1630,1 Gustave L Levy Pl, New York, NY 10029 USA. EM Huabao.Xiong@mssm.edu FU NIH [RO1AI104688] FX H.X. was supported by the NIH funding (RO1AI104688). NR 48 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2352-3964 J9 EBIOMEDICINE JI EBioMedicine PD DEC PY 2016 VL 14 BP 83 EP 96 DI 10.1016/j.ebiom.2016.10.041 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA EM4AP UT WOS:000395256000015 PM 27825654 ER PT J AU Sokol, RJ Spino, C Moore, J Bezerra, JA Whitington, PF Karpen, SJ Loomes, KM Ng, VL Venkat, VL Wang, KS Goodhue, CJ Sherker, AH Magee, JC Mack, CL AF Sokol, Ronald J. Spino, Cathie Moore, Jeffrey Bezerra, Jorge A. Whitington, Peter F. Karpen, Saul J. Loomes, Kathleen M. Ng, Vicky L. Venkat, Veena L. Wang, Kasper S. Goodhue, Catherine J. Sherker, Averell H. Magee, John C. Mack, Cara L. TI Intravenous Immunoglobulin (IVIG) Following Portoenterostomy in Infants with Biliary Atresia: a Phase 1/2A Trial SO HEPATOLOGY LA English DT Meeting Abstract CT 67th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 11-15, 2016 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Spino, Cathie; Moore, Jeffrey] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Sokol, Ronald J.; Mack, Cara L.] Univ Colorado, Sch Med, Dept Pediat, Sect Pediat Gastroenterol Hepatol & Nutr, Aurora, CO USA. [Bezerra, Jorge A.] Cincinnati Childrens Hosp Med, Div Pediat Gastroenterol Hepatol & Nutr, Cincinnati, OH USA. [Whitington, Peter F.] Ann & Robert H Lurie Childrens Hosp Chicago, Pediat Div Gastroenterol Hepatol & Nutr, Chicago, IL 60611 USA. [Karpen, Saul J.] Emory Univ, Sch Med, Childrens Healthcare Atlanta, Pediat Gastroenterol Hepatol & Nutr, Atlanta, GA USA. [Loomes, Kathleen M.] Childrens Hosp Philadelphia, Pediat Gastroenterol Hepatol & Nutr, Philadelphia, PA 19104 USA. [Ng, Vicky L.] Univ Toronto, Hosp Sick Children, Div Pediat Gastroenterol Hepatol & Nutr, Toronto, ON, Canada. [Venkat, Veena L.] Childrens Hosp Pittsburgh, Div Pediat Gastroenterol, Pittsburgh, PA 15213 USA. [Wang, Kasper S.; Goodhue, Catherine J.] Childrens Hosp Los Angeles, Div Pediat Surg, Los Angeles, CA 90027 USA. [Sherker, Averell H.] NIDDK, Liver Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Magee, John C.] Univ Michigan, Sch Med, Ann Arbor, MI USA. FU Mead Johnson Nutritionals; Shire/Lumena; FFF Enterprises; Molecular Genetics Laboratory; CHMC; Gilead FX Ronald J. Sokol - Advisory Committees or Review Panels: Yasoo Health, Inc.; Consulting: Roche, Ikaria, Otsuka American Pharmaceuticals, Alnylam, Retrophin, Alexion; Grant/Research Support: Mead Johnson Nutritionals, Shire/Lumena, FFF Enterprises; Jorge A. Bezerra - Grant/Research Support: Molecular Genetics Laboratory, CHMC, Gilead NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD DEC PY 2016 VL 64 IS 6 MA LB-8 BP 1123A EP 1123A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK4MF UT WOS:000393900200009 ER PT J AU Stravitz, RT Durkalski, VL Fontana, RJ Hanje, AJ Koch, D Hameed, B Ganger, DR Subramanian, R Doo, E Sherker, AH Lee, WM AF Stravitz, R. Todd Durkalski, Valerie L. Fontana, Robert J. Hanje, A. James Koch, David Hameed, Bilal Ganger, Daniel R. Subramanian, Ram Doo, Edward Sherker, Averell H. Lee, William M. TI Safety, Tolerability and Pharmacokinetics of L-Ornithine Phenylacetate in Patients with Acute Liver Injury/Failure SO HEPATOLOGY LA English DT Meeting Abstract CT 67th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY NOV 11-15, 2016 CL Boston, MA SP Amer Assoc Study Liver Dis C1 [Stravitz, R. Todd] Virginia Commonwealth Univ, Richmond, VA USA. [Durkalski, Valerie L.; Koch, David] Med Univ South Carolina, Charleston, SC USA. [Fontana, Robert J.] Univ Michigan, Ann Arbor, MI 48109 USA. [Hanje, A. James] Ohiio State Univ, Columbus, OH USA. [Hameed, Bilal] UC San Francisco, San Francisco, CA USA. [Ganger, Daniel R.] Northwestern Univ, Chicago, IL 60611 USA. [Subramanian, Ram] Emory Univ, Atlanta, GA 30322 USA. [Doo, Edward; Sherker, Averell H.] NIDDK, Bethesda, MD USA. [Lee, William M.] Univ Texas Southwestern, Dallas, TX USA. FU BMS; Jansen; Gilead; Tobira; Bristol Myers Squibb; Merck; Ocera FX Robert J. Fontana - Consulting: CLDF; Grant/Research Support: BMS, Jansen, Gilead; Bilal Hameed - Grant/Research Support: Gilead, Tobira; William M. Lee - Consulting: Novartis, Sanofi, Syntimune; Grant/Research Support: Bristol Myers Squibb, Merck, Gilead, Ocera NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD DEC PY 2016 VL 64 IS 6 MA LB-13 BP 1126A EP 1127A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK4MF UT WOS:000393900200014 ER PT J AU Fontana, RJ Engle, RE Scaglione, S Araya, V Shaikh, O Tillman, H Attar, N Purcell, RH Lee, WM AF Fontana, Robert John Engle, Ronald E. Scaglione, Steven Araya, Victor Shaikh, Obaid Tillman, Holly Attar, Nahid Purcell, Robert H. Lee, William M. CA US Acute Liver Failure Study Grp TI The Role of Hepatitis E Virus Infection in Adult Americans With Acute Liver Failure SO HEPATOLOGY LA English DT Article ID UNITED-STATES; ENZYME-IMMUNOASSAY; BLOOD-DONORS; ANTI-HEV; ANTIBODIES; SWINE; PREVALENCE; COUNTRIES; DISEASE; INJURY AB Acute hepatitis E virus (HEV) infection is a leading cause of acute liver failure (ALF) in many developing countries, yet rarely identified in Western countries. Given that antibody testing for HEV infection is not routinely obtained, we hypothesized that HEV-related ALF might be present and unrecognized in North American ALF patients. Serum samples of 681 adults enrolled in the U.S. Acute Liver Failure Study Group were tested for anti-HEV immunoglobulin (Ig) M and anti-HEV IgG levels. Subjects with a detectable anti-HEV IgM also underwent testing for HEV RNA. Mean patient age was 41.8 years, 32.9% were male, and ALF etiologies included acetaminophen (APAP) hepatotoxicity (29%), indeterminate ALF (23%), idiosyncratic drug-induced liver injury DILI (22%), acute hepatitis B virus infection (12%), autoimmune hepatitis (12%), and pregnancy-related ALF (2%). Three men ages 36, 39, and 70 demonstrated repeatedly detectable anti-HEV IgM, but all were HEV-RNA negative and had other putative diagnoses. The latter 2 subjects died within 3 and 11 days of enrollment whereas the 36-year-old underwent emergency liver transplantation on study day 2. At admission, 294 (43.4%) of the ALF patients were anti-HEV IgG positive with the seroprevalence being highest in those from the Midwest (50%) and lowest in those fromthe Southeast (28%). Anti-HEV IgG(+) subjects were significantly older, less likely to have APAP overdose, and had a lower overall 3-week survival compared to anti-HEV IgG-subjects (63% vs. 70%; P = 0.018). Conclusion: Acute HEV infection is very rare in adult Americans with ALF (i.e., 0.4%) and could not be implicated in any indeterminate, autoimmune, or pregnancy-related ALF cases. Past exposure to HEV with detectable anti-HEV IgG was significantly more common in the ALF patients compared to the general U.S. population. C1 [Fontana, Robert John] Univ Michigan, Dept Internal Med, 3912 Taubman Ctr, Ann Arbor, MI 48109 USA. [Engle, Ronald E.; Purcell, Robert H.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Scaglione, Steven] Loyola Med Ctr, Dept Internal Med, Maywood, IL USA. [Araya, Victor] Einstein Med Ctr, Philadelphia, PA USA. [Shaikh, Obaid] Univ Pittsburgh, Dept Internal Med, Pittsburgh, PA USA. [Tillman, Holly] Med Univ South Carolina, Dept Publ Hlth Sci, Charleston, SC 29425 USA. [Attar, Nahid; Lee, William M.] Univ Texas Southwestern, Dallas, TX USA. RP Fontana, RJ (reprint author), Univ Michigan, Dept Internal Med, 3912 Taubman Ctr, Ann Arbor, MI 48109 USA. EM rfontana@med.umich.edu FU National Institute of Diabetes, Digestive and Kidney Diseases [DK U-01-58369]; Tips Fund of Northwestern Medical Foundation; Jeanne Roberts and Rollin Fund of the Southwestern Medical Foundation; Intramural Research Program of the National Institute of Allergy and Infectious Diseases; Mary Ella King Fund of the Southwestern Medical Foundation FX We gratefully acknowledge the support provided by the members of The Acute Liver Failure Study Group. This study was funded by the National Institute of Diabetes, Digestive and Kidney Diseases (DK U-01-58369). Additional funding provided by the Tips Fund of Northwestern Medical Foundation and the Jeanne Roberts and Rollin and Mary Ella King Funds of the Southwestern Medical Foundation. This work was supported, in part, by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. NR 36 TC 3 Z9 3 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD DEC PY 2016 VL 64 IS 6 BP 1870 EP 1880 DI 10.1002/hep.28649 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK4MF UT WOS:000393900200046 PM 27215797 ER PT J AU Wang, RY Bare, P De Giorgi, V Matsuura, K Salam, KA Grandinetti, T Schechterly, C Alter, HJ AF Wang, Richard Y. Bare, Patricia De Giorgi, Valeria Matsuura, Kentaro Salam, Kazi Abdus Grandinetti, Teresa Schechterly, Cathy Alter, Harvey J. TI Preferential Association of Hepatitis C Virus With CD19(+) B Cells Is Mediated by Complement System SO HEPATOLOGY LA English DT Article ID BLOOD MONONUCLEAR-CELLS; PERIPHERAL-BLOOD; T-CELLS; INFECTION; ACTIVATION; LYMPHOCYTES; ENTRY; CRYOGLOBULINEMIA; LYMPHOMAGENESIS; MANIFESTATIONS AB Extrahepatic disease manifestations are common in chronic hepatitis C virus (HCV) infection. The mechanism of HCVrelated lymphoproliferative disorders is not fully understood. Recent studies have found that HCV in peripheral blood mononuclear cells from chronically infected patients is mainly associated with cluster of differentiation 19-positive (CD19(+)) B cells. To further elucidate this preferential association of HCV with B cells, we used in vitro cultured virus and uninfected peripheral blood mononuclear cells from healthy blood donors to investigate the necessary serum components that activate the binding of HCV to B cells. First, we found that the active serum components were present not only in HCV carriers but also in HCV recovered patients and HCV-negative, healthy blood donors and that the serum components were heat-labile. Second, the preferential binding activity of HCV to B cells could be blocked by anticomplement C3 antibodies. In experiments with complement-depleted serum and purified complement proteins, we demonstrated that complement proteins C1, C2, and C3 were required to activate such binding activity. Complement protein C4 was partially involved in this process. Third, using antibodies against cell surface markers, we showed that the binding complex mainly involved CD21 (complement receptor 2), CD19, CD20, and CD81; CD35 (complement receptor 1) was involved but had lower binding activity. Fourth, both anti-CD21 and anti-CD35 antibodies could block the binding of patient-derived HCV to B cells. Fifth, complement also mediated HCV binding to Raji cells, a cultured B-cell line derived from Burkitt's lymphoma. Conclusion: In chronic HCV infection, the preferential association of HCV with B cells is mediated by the complement system, mainly through complement receptor 2 (CD21), in conjunction with the CD19 and CD81 complex. C1 [Wang, Richard Y.; Bare, Patricia; De Giorgi, Valeria; Matsuura, Kentaro; Salam, Kazi Abdus; Grandinetti, Teresa; Schechterly, Cathy; Alter, Harvey J.] NIH, Ctr Clin, Dept Transfus Med, Bldg 10,Room 1C-711,NIH,10 Ctr Dr, Bethesda, MD 20892 USA. [Bare, Patricia] Consejo Nacl Invest Cient & Tecn, Acad Nacl Med, Inst Med Expt, Inst Invest Hematol, Buenos Aires, DF, Argentina. [Matsuura, Kentaro] Nagoya City Univ, Grad Sch Med Sci, Dept Gastroenterol & Metab, Nagoya, Aichi, Japan. [Salam, Kazi Abdus] Rajshahi Univ, Dept Biochem & Mol Biol, Rajshahi, Bangladesh. RP Alter, HJ (reprint author), NIH, Ctr Clin, Dept Transfus Med, Bldg 10,Room 1C-711,NIH,10 Ctr Dr, Bethesda, MD 20892 USA. EM HAlter@cc.nih.gov RI De Giorgi, Valeria/D-4582-2017 FU Intramural Research Program of Warren G. Magnuson Clinical Center, National Institutes of Health FX Supported by the Intramural Research Program of Warren G. Magnuson Clinical Center, National Institutes of Health. NR 47 TC 2 Z9 2 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD DEC PY 2016 VL 64 IS 6 BP 1900 EP 1910 DI 10.1002/hep.28842 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK4MF UT WOS:000393900200049 PM 27641977 ER PT J AU Huang, CR Ravin, SSD Paul, AR Heller, T Ho, N Datta, LW Zerbe, CS Marciano, BE Kuhns, DB Kader, HA Holland, SM Malech, HL Brant, SR AF Huang, Chengrui Ravin, Suk See De Paul, Adam R. Heller, Theo Ho, Nancy Datta, Lisa Wu Zerbe, Christa S. Marciano, Beatriz E. Kuhns, Douglas B. Kader, Howard A. Holland, Steven M. Malech, Harry L. Brant, Steven R. CA NIDDK IBD Genetics Consortium TI Genetic Risk for Inflammatory Bowel Disease Is a Determinant of Crohn's Disease Development in Chronic Granulomatous Disease SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE chronic granulomatous disease; inflammatory bowel disease; genetic risk score; immunodeficiency disorder; genetic interaction ID STEM-CELL TRANSPLANTATION; COMPLICATIONS; POLYMORPHISMS; ASSOCIATION; CONSORTIUM; FEATURES; REGISTRY; GAMMA AB Background: Approximately, one-third to one-half of children with chronic granulomatous disease (CGD) develop gastrointestinal inflammation characteristic of idiopathic inflammatory bowel disease (IBD), usually Crohn's disease. We hypothesized that the overall IBD genetic risk, determined by IBD genetic risk score (GRS), might in part determine IBD development in CGD. Methods: We reviewed medical records to establish IBD diagnoses in CGD subjects seen at NIAID. IBD risk single nucleotide polymorphism genotypes were determined using the Immunochip, and GRS were estimated by Mangrove. Results: Among 157 white patients with CGD, 55 were confirmed, 78 excluded, and 24 were uncertain for IBD. Two hundred one established, independent European IBD risk single nucleotide polymorphisms passed quality control. After sample quality control and removing non-IBD CGD patients with perianal disease, mean GRS for 40 unrelated patients with CGD-IBD was higher than 53 CGD non-IBD patients (in log(2)-scale 0.08 +/- 1.62 versus -0.67 +/- 1.64, P = 0.026) but lower than 239 IBD Genetics Consortium (IBDGC) young-onset Crohn's disease cases (0.76 +/- 1.60, P = 0.025). GRS for non-IBD CGD was similar to 609 IBDGC controls (-0.69 +/- 1.60, P = 0.95). Seven established IBD single nucleotide polymorphisms were nominally significant among CGD-IBD versus CGD non-IBD, including those near LACC1 (P = 0.005), CXCL14 (P = 0.007), and TNFSF15 (P = 0.016). Conclusions: The weight of the common IBD risk alleles are significant determinants of IBD in CGD. However, IBD risk gene burden among CGD children with IBD is significantly lower than that in nonsyndromic pediatric Crohn's disease, congruent with the concept that defective superoxide production in CGD is also a major IBD risk factor. Individual IBD genes might interact with the CGD defect to cause IBD in CGD. C1 [Huang, Chengrui; Brant, Steven R.] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Ravin, Suk See De; Malech, Harry L.] NIAID, Lab Host Defenses, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Paul, Adam R.; Kader, Howard A.] Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. [Paul, Adam R.; Datta, Lisa Wu; Brant, Steven R.] Johns Hopkins Univ, Sch Med, Dept Med, Meyerhoff Inflammatory Bowel Dis Ctr, Baltimore, MD 21205 USA. [Heller, Theo; Ho, Nancy] NIDDK, NIH, Bethesda, MD 20892 USA. [Zerbe, Christa S.; Marciano, Beatriz E.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kuhns, Douglas B.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Brant, SR (reprint author), Johns Hopkins Univ, Sch Med, Meyerhoff Inflammatory Bowel Dis Ctr, 1501 E Jefferson St,B136, Baltimore, MD 21231 USA. EM sbrant@jhmi.edu FU Intramural Research Program of NIAID [Z01-A1-00644, Z01-A1-00988]; NIH [DK062431] FX Supported by the Intramural Research Program of NIAID, NIH, Intramural project numbers Z01-A1-00644 and Z01-A1-00988 (S.S.D.R. and H.L.M.), NIH Grant DK062431 (S.R.B.) and the Robert E. Sadler, Jr Family (S.R.B.). NR 27 TC 0 Z9 0 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD DEC PY 2016 VL 22 IS 12 BP 2794 EP 2801 DI 10.1097/MIB.0000000000000966 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EK4JR UT WOS:000393893400005 PM 27861181 ER PT J AU Devlin, MJ King, WC Kalarchian, MA White, GE Marcus, MD Garcia, L Yanovski, SZ Mitchell, JE AF Devlin, Michael J. King, Wendy C. Kalarchian, Melissa A. White, Gretchen E. Marcus, Marsha D. Garcia, Luis Yanovski, Susan Z. Mitchell, James E. TI Eating pathology and experience and weight loss in a prospective study of bariatric surgery patients: 3-year follow-up SO INTERNATIONAL JOURNAL OF EATING DISORDERS LA English DT Article DE bariatric surgery; disordered eating; binge eating; loss of control eating; hunger ID LONGITUDINAL ASSESSMENT; SEVERE OBESITY; AXIS-I; DISORDERS; PSYCHOPATHOLOGY; OUTCOMES; COMORBIDITY; CANDIDATES; BEHAVIOR; HEALTH AB ObjectiveBariatric surgery results in significant long-term weight loss, albeit with considerable variability. This study examines the prognostic significance of eating pathology as determined by a structured interview, the Eating Disorder Examination-Bariatric Surgery Version (EDE-BSV). MethodParticipants (N=183) in this substudy of the Longitudinal Assessment of Bariatric Surgery (LABS) Research Consortium were assessed using the EDE-BSV, independent of clinical care, presurgery and annually postsurgery. We examined eating pathology and experiences at several frequency thresholds (present,monthly,weekly) over 3years, and utilized mixed models to test their associations with percentage weight loss from baseline at years 1, 2, and 3. ResultsThe prevalence of several forms of eating pathology declined pre- to 1-year postsurgery, including weekly objective bulimic episodes (11.6-1.3%), loss of control (LOC) eating (18.3-6.2%) and picking/nibbling (36.0-20.2%) (P for all <0.01), and regular evening hyperphagia (16.5-5.0%, P=0.01), but not cravings (P=0.93). Mean EDE global score, and hunger and enjoyment scores, also declined (P for all <0.01). These metrics remained lower than baseline through year-3 (P for all <0.01). Presurgery eating variables were not related to weight loss (P for all 0.05). However, postsurgery higher EDE global score and greater hunger were independently associated with less weight loss postsurgery (P for both 0.01), while cravings were associated with greater weight loss (P=0.03). DiscussionPathological eating behaviors and experiences are common presurgery and improve markedly following surgery. Postsurgery pathological eating-related experiences and attitudes and hunger may contribute to suboptimal weight loss. (c) 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:1058-1067) C1 [Devlin, Michael J.] Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, New York, NY 10032 USA. [King, Wendy C.; White, Gretchen E.] Univ Pittsburgh, Grad Sch Publ Hlth, Epidemiol, Pittsburgh, PA USA. [Kalarchian, Melissa A.] Duquesne Univ, Sch Nursing, Pittsburgh, PA USA. [Marcus, Marsha D.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Garcia, Luis] Sanford Hlth Syst, Fargo, ND USA. [Yanovski, Susan Z.] NIDDK, Div Digest Dis & Nutr, Bethesda, MD 20892 USA. [Mitchell, James E.] Neuropsychiat Res Inst, Fargo, ND USA. RP Devlin, MJ (reprint author), Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, New York, NY 10032 USA. EM mjd5@cumc.columbia.edu FU National Institute of Diabetes and Digestive and Kidney Diseases, Columbia [U01-DK66667]; Cornell University Medical Center CTSC; Neuropsychiatric Research Institute [U01-DK66471]; University of Pittsburgh Medical Center [U01-DK66585]; CTRC; National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK084979]; [DSS-U01DK066557]; [UL1-RR024996]; [UL1-RR0241531] FX Supported by Grant DSS-U01DK066557; Columbia, U01-DK66667 from The National Institute of Diabetes and Digestive and Kidney Diseases; Supported by Grant UL1-RR024996 from in collaboration; Cornell University Medical Center CTSC; Supported by Grant U01-DK66471 from Neuropsychiatric Research Institute; Supported by Grant U01-DK66585 from University of Pittsburgh Medical Center; Supported by Grant UL1-RR0241531 from in collaboration; CTRC; Supported by Grant R01 DK084979 from National Institute of Diabetes and Digestive and Kidney Diseases. NR 38 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0276-3478 EI 1098-108X J9 INT J EAT DISORDER JI Int. J. Eating Disord. PD DEC PY 2016 VL 49 IS 12 BP 1058 EP 1067 DI 10.1002/eat.22578 PG 10 WC Psychology, Clinical; Nutrition & Dietetics; Psychiatry; Psychology SC Psychology; Nutrition & Dietetics; Psychiatry GA EK1FP UT WOS:000393671500002 PM 27425771 ER PT J AU Galperin, MY Brover, V Tolstoy, I Yutin, N AF Galperin, Michael Y. Brover, Vyacheslav Tolstoy, Igor Yutin, Natalya TI Phylogenomic analysis of the family Peptostreptococcaceae (Clostridium cluster XI) and proposal for reclassification of Clostridium litorale (Fendrich et al. 1991) and Eubacterium acidaminophilum (Zindel et al. 1989) as Peptoclostridium litorale gen. nov comb. nov and Peptoclostridium acidaminophilum comb. nov. SO INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY LA English DT Article ID NCBI TAXONOMY DATABASE; LIVING TREE PROJECT; GENOME SEQUENCE; MICROBIAL CONSORTIUM; GENERA; DECHLORINATION; STICKLANDII; SORDELLII; DIFFICILE; BACTERIA AB In 1994, analyses of clostridial 16S rRNA gene sequences led to the assignment of 18 species to Clostridium cluster XI, separating them from Clostridium sensu stricto (Clostridium cluster I) Subsequently, most cluster XI species have been assigned to the family Peptostreptococcaceae with some species being reassigned to new genera. However, several misclassified Clostridium species remained, creating a taxonomic conundrum and confusion regarding their status. Here, we have re-examined the phylogeny of cluster XI species by comparing the 16S rRNA gene based trees with protein-and genome-based trees, where available. The resulting phylogeny of the Peptostreptococcaceae was consistent with the recent proposals on creating seven new genera within this family. This analysis also revealed a tight clustering of Clostridium litorale and Eubacterium acidaminophilum. Based on these data, we propose reassigning these two organisms to the new genus Peptoclostridium as Peptoclostridium litorale gen. nov. comb. nov. (the type species of the genus) and Peptoclostridium acidaminophilum comb. nov., respectively. As correctly noted in the original publications, the genera Acetoanaerobium and Proteocatella also fall within cluster XI, and can be assigned to the Peptostreptococcaceae. Clostridium sticklandii, which falls within radiation of genus Acetoanaerobium, is proposed to be reclassified as Acetoanaerobium sticklandii comb. nov. The remaining misnamed members of the Peptostreptococcaceae, [Clostridium] hiranonis, [Clostridium] paradoxum and [Clostridium] thermoalcaliphilum, still remain to be properly classified. C1 [Galperin, Michael Y.; Brover, Vyacheslav; Tolstoy, Igor; Yutin, Natalya] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Galperin, MY (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM galperin@ncbi.nlm.nih.gov FU NIH Intramural Research Program at the U.S. National Library of Medicine FX We thank Drs Aharon Oren (The Hebrew University of Jerusalem), Boris Belitsky (Tufts University) and Sean Turner (NCBI) for helpful comments and Drs Yuri Wolf and Eugene Koonin (NCBI) for advice on phylogenetic trees. This work was supported by the NIH Intramural Research Program at the U.S. National Library of Medicine. NR 52 TC 0 Z9 0 U1 2 U2 2 PU MICROBIOLOGY SOC PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER ST, LONDON WC1N 2JU, ERKS, ENGLAND SN 1466-5026 EI 1466-5034 J9 INT J SYST EVOL MICR JI Int. J. Syst. Evol. Microbiol. PD DEC PY 2016 VL 66 BP 5506 EP 5513 DI 10.1099/ijsem.0.001548 PN 12 PG 8 WC Microbiology SC Microbiology GA EJ6VM UT WOS:000393357900092 PM 27902180 ER PT J AU Nowakowski, GS Blum, KA Kahl, BS Friedberg, JW Baizer, L Little, RF Maloney, DG Sehn, LH Williams, ME Wilson, WH Leonard, JP Smith, SM AF Nowakowski, Grzegorz S. Blum, Kristie A. Kahl, Brad S. Friedberg, Jonathan W. Baizer, Lawrence Little, Richard F. Maloney, David G. Sehn, Laurie H. Williams, Michael E. Wilson, Wyndham H. Leonard, John P. Smith, Sonali M. TI Beyond RCHOP: A Blueprint for Diffuse Large B Cell Lymphoma Research SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID RITUXIMAB PLUS CYCLOPHOSPHAMIDE; RANDOMIZED CONTROLLED-TRIAL; HIGH-DOSE THERAPY; ELDERLY-PATIENTS; R-CHOP; AUTOLOGOUS TRANSPLANTATION; AGGRESSIVE LYMPHOMAS; FRONTLINE RITUXIMAB; PROGNOSTIC IMPACT; MYC AB Diffuse large B cell lymphoma (DLBCL) comprises multiple molecular and biological subtypes, resulting in a broad range of clinical outcomes. With standard chemoimmunotherapy, there remains an unacceptably high treatment failure rate in certain DLBCL subsets: activated B cell (ABC) DLBCL, double-hit lymphoma defined by the dual translocation of MYC and BCL2, dual protein-expressing lymphomas defined by the overexpression of MYC and BCL2, and older patients and those with central nervous system involvement. The main research challenges for DLBCL are to accurately identify molecular subsets and to determine if specific chemotherapy platforms and targeted agents offer differential benefit. The ultimate goal should be to maximize initial cure rates to improve long-term survival while minimizing toxicity. In particular, a frontline trial should focus on biologically defined risk groups not likely to be cured with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (R-CHOP). An additional challenge is to develop effective and personalized strategies in the relapsed setting, for which there is no current standard other than autologous stem cell transplantation, which benefits a progressively smaller proportion of patients. Relapsed/refractory DLBCL is the ideal setting for testing novel agents and new biomarker tools and will require a national call for biopsies to optimize discovery in this setting. Accordingly, the development of tools with both prognostic and predictive utility and the individualized application of new therapies should be the main priorities. This report identifies clinical research priorities for critical areas of unmet need in this disease. C1 [Nowakowski, Grzegorz S.] Mayo Clin, Dept Med, Rochester, MN USA. [Blum, Kristie A.] Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA. [Kahl, Brad S.] Washington Univ, Dept Med, Div Oncol, St Louis, MO USA. [Friedberg, Jonathan W.] Univ Rochester, Wilmot Canc Ctr, Rochester, NY USA. [Friedberg, Jonathan W.] Univ Rochester, Div Hematol Oncol, Rochester, NY USA. [Baizer, Lawrence] NCI, Coordinating Ctr Clin Trials, NIH, Bethesda, MD 20892 USA. [Little, Richard F.] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Wilson, Wyndham H.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Maloney, David G.] Univ Washington, Div Oncol, Seattle, WA 98195 USA. [Sehn, Laurie H.] British Colombia Canc Agcy, Vancouver, BC, Canada. [Williams, Michael E.] Univ Virginia, Dept Med, Charlottesville, VA USA. [Leonard, John P.] Weil Cornell Univ, Dept Med, New York, NY USA. [Smith, Sonali M.] Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. RP Nowakowski, GS (reprint author), Mayo Clin, 200 First St SW, Rochester, MN 55901 USA. EM nowakowski.grzegorz@mayo.edu FU Office of the Director, 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 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 DEC PY 2016 VL 108 IS 12 AR djw257 DI 10.1093/jnci/djw257 PG 8 WC Oncology SC Oncology GA EK4LP UT WOS:000393898500016 ER PT J AU Rimsza, L Fedoriw, Y Staudt, LM Melnick, A Gascoyne, R Crump, M Baizer, L Fu, K Hsi, E Chan, JWC McShane, L Leonard, JP Kahl, BS Little, RF Friedberg, JW Kostakoglu, L AF Rimsza, Lisa Fedoriw, Yuri Staudt, Louis M. Melnick, Ari Gascoyne, Randy Crump, Michael Baizer, Lawrence Fu, Kai Hsi, Eric Chan, John W. C. McShane, Lisa Leonard, John P. Kahl, Brad S. Little, Richard F. Friedberg, Jonathan W. Kostakoglu, Lale TI General Biomarker Recommendations for Lymphoma SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID RESPONSE ASSESSMENT; NETWORK; PET/CT AB Lymphoid malignancies are a heterogeneous group of tumors that have distinctive clinical and biological behaviors. The increasing prevalence of disease reflects both treatment advances and the fact that some of these tumors are indolent. The ability to determine treatment needs at diagnosis remains problematic for some of the tumors, such as in follicular lymphomas. Major clinical advances will likely depend on precision oncology that will enable identification of specific disease entities, prognostic determination at diagnosis, and identification of precise therapeutic targets and essential pathways. However, refinement in diagnostic evaluation is an evolving science. The ability to determine prognosis at diagnosis is variable, and for many of the lymphoid malignancies prognosis can only be made after initial treatment. Clinical trials that aim to evaluate specific features of these diseases are required in order to advance clinical practice that meaningfully addresses this important public health challenge. Herein, we describe the process and general recommendation from the National Cancer Institute (NCI) clinical trials planning meeting in November 2014 to address clinical trial design and biomarker proposals in the context of NCI-supported lymphoma clinical trials in the National Clinical Trials Network. C1 [Rimsza, Lisa] Mayo Clin, Dept Lab Med & Pathol, Scottsdale, AZ USA. [Fedoriw, Yuri] Univ N Carolina, Sch Med, Dept Pathol & Lab Med, Chapel Hill, NC USA. [Staudt, Louis M.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Melnick, Ari] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Gascoyne, Randy] British Columbia Canc Agcy, Dept Pathol & Lab Med, Vancouver, BC, Canada. [Crump, Michael] Univ Toronto, Princess Margaret Canc Ctr, Clin Canc Res Unit, Toronto, ON, Canada. [Baizer, Lawrence] NCI, Coordinating Ctr Clin Trials, Bethesda, MD 20892 USA. [Fu, Kai] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. Cleveland Clin Fdn, Dept Pathol & Lab Med, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Chan, John W. C.] City Hope Natl Med Ctr, Med Ctr, Dept Pathol, Duarte, CA USA. [McShane, Lisa] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. [Leonard, John P.] Weill Cornell Med, Dept Med, New York, NY USA. [Kahl, Brad S.] Washington Univ, Div Oncol, Dept Med, St Louis, MO USA. [Little, Richard F.] NCI, Clin Invest Branch, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Friedberg, Jonathan W.] Univ Rochester, Wilmot Canc Ctr, Rochester, NY USA. [Friedberg, Jonathan W.] Univ Rochester, Div Hematol Oncol, Rochester, NY USA. [Kostakoglu, Lale] Mt Sinai Med Ctr, Dept Radiol, New York, NY 10029 USA. RP Rimsza, L (reprint author), Mayo Clin Arizona, Dept Lab Med & Pathol, 13400 E Shea Blvd,CRB1-263, Scottsdale, AZ 85266 USA. EM rimsza.lisa@mayo.edu FU Office of the Director, 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 15 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 DEC PY 2016 VL 108 IS 12 AR djw250 DI 10.1093/jnci/djw250 PG 4 WC Oncology SC Oncology GA EK4LP UT WOS:000393898500014 ER PT J AU Unger, JM Till, C Thompson, IM Tangen, CM Goodman, PJ Wright, JD Barlow, WE Ramsey, SD Minasian, LM Hershman, DL AF Unger, Joseph M. Till, Cathee Thompson, Ian M., Jr. Tangen, Catherine M. Goodman, Phyllis J. Wright, Jason D. Barlow, William E. Ramsey, Scott D. Minasian, Lori M. Hershman, Dawn L. TI Long-term Consequences of Finasteride vs Placebo in the Prostate Cancer Prevention Trial SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID RISK; MEN; ASSOCIATION; HYPERPLASIA; INHIBITION; DEPRESSION; THERAPY AB Background: Finasteride has been found to reduce the risk of low-grade prostate cancer but to have no impact on overall survival. The long-term adverse and beneficial consequences of finasteride have not been examined. Methods: We used a linkage between data from the Prostate Cancer Prevention Trial (PCPT) and Medicare claims. Patients were examined by randomized study arm (finasteride vs placebo for 7 years) for long-term consequences of the intervention, including cardiac, endocrine, and sexual dysfunction, depression, diabetes, and benign prostatic hyperplasia (BPH)-related events. To examine time to events, we used cumulative incidence and Cox regression, adjusting for covariates. All statistical tests were two-sided. Results: A total of 13 935 of 18 880 participants (73.8%) in the PCPT were linked to Medicare claims, with median Medicare follow-up assessment time of 16 years from trial registration. There were no differences between finasteride and placebo participants with respect to important baseline factors or amount of Medicare follow-up assessment time. Finasteride patients had a 10% higher risk of new claims for depression (hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.01 to 1.19, P =.04) and a 6% lower risk of procedures for BPH-related events (primarily lower urinary tract symptoms; HR = 0.94, 95% CI = 0.89 to 1.00, P =.03). No other differences were found in rates of long-term consequences of intervention in the two study arms. Conclusions: Finasteride use is associated with reduced need for procedures for relief of BPH-related events and a modest increase in depression. Overall, there is little need to worry about long-term noncancer consequences of finasteride use in those who use it for treatment of symptomatic BPH, hair growth, or prevention of cancer. C1 [Unger, Joseph M.; Till, Cathee; Tangen, Catherine M.; Goodman, Phyllis J.; Barlow, William E.] Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, 1100 Fairview Ave N,M3-C102,POB19024, Seattle, WA 98109 USA. [Thompson, Ian M., Jr.] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. [Wright, Jason D.; Hershman, Dawn L.] Columbia Univ, New York, NY USA. [Ramsey, Scott D.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Minasian, Lori M.] US Natl Canc Inst, Canc Prevent Div, Rockville, MD USA. RP Unger, JM (reprint author), Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, 1100 Fairview Ave N,M3-C102,POB19024, Seattle, WA 98109 USA. EM junger@fredhutch.org FU National Institutes of Health, National Cancer Institute (NCI); NCI Community Oncology Research Program (NCORP) Research Base grant [5UG1CA189974-02]; NCI Community Clinical Oncology Program (CCOP) Research Base grant [U10CA037429]; National Cancer Institute [5UM1CA182883-03, NCI R01CA134964] FX This work was supported in part by the National Institutes of Health, National Cancer Institute (NCI), NCI Community Oncology Research Program (NCORP) Research Base grant 5UG1CA189974-02, NCI Community Clinical Oncology Program (CCOP) Research Base grant U10CA037429, and National Cancer Institute Grant 5UM1CA182883-03. Dr. Hershman (NCI R01CA134964) is recipient of grants from the National Cancer Institute. 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 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD DEC PY 2016 VL 108 IS 12 AR djw168 DI 10.1093/jnci/djw168 PG 7 WC Oncology SC Oncology GA EK4LP UT WOS:000393898500008 ER PT J AU Zuber, V Marconett, CN Shi, JX Hua, X Wheeler, W Yang, CC Song, L Dale, AM Laplana, M Risch, A Witoelar, A Thompson, WK Schork, AJ Bettella, F Wang, YP Djurovic, S Zhou, BY Borok, Z van der Heijden, HFM de Graaf, J Swinkels, D Aben, KK McKay, J Hung, RJ Bikeboller, H Stevens, VL Albanes, D Caporaso, NE Han, YH Wei, YY Panadero, MA Mayordomo, JI Christiani, DC Kiemeney, L Andreassen, OA Houlston, R Amos, CI Chatterjee, N Laird-Offringa, IA Mills, IG Landi, MT AF Zuber, Verena Marconett, Crystal N. Shi, Jianxin Hua, Xing Wheeler, William Yang, Chenchen Song, Lei Dale, Anders M. Laplana, Marina Risch, Angela Witoelar, Aree Thompson, Wesley K. Schork, Andrew J. Bettella, Francesco Wang, Yunpeng Djurovic, Srdjan Zhou, Beiyun Borok, Zea van der Heijden, Henricus F. M. de Graaf, Jacqueline Swinkels, Dorine Aben, Katja K. McKay, James Hung, Rayjean J. Bikeboller, Heike Stevens, Victoria L. Albanes, Demetrius Caporaso, Neil E. Han, Younghun Wei, Yongyue Panadero, Maria Angeles Mayordomo, Jose I. Christiani, David C. Kiemeney, Lambertus Andreassen, Ole A. Houlston, Richard Amos, Christopher I. Chatterjee, Nilanjan Laird-Offringa, Ite A. Mills, Ian G. Landi, Maria Teresa TI Pleiotropic Analysis of Lung Cancer and Blood Triglycerides SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID RISK; INFLAMMATION; VARIANTS; IMMUNITY; DISEASE AB Epidemiologically related traits may share genetic risk factors, and pleiotropic analysis could identify individual loci associated with these traits. Because of their shared epidemiological associations, we conducted pleiotropic analysis of genome-wide association studies of lung cancer (12 160 lung cancer case patients and 16 838 control subjects) and cardiovascular disease risk factors (blood lipids from 188 577 subjects, type 2 diabetes from 148 821 subjects, body mass index from 123 865 subjects, and smoking phenotypes from 74 053 subjects). We found that 6p22.1 (rs6904596, ZNF184) was associated with both lung cancer (P = 5.50x10(-6)) and blood triglycerides (P = 1.39x10(-5)). We replicated the association in 6097 lung cancer case patients and 204 657 control subjects (P = 2.40x10(-4)) and in 71 113 subjects with triglycerides data (P =.01). rs6904596 reached genome-wide significance in lung cancer meta-analysis (odds ratio = 1.15, 95% confidence interval = 1.10 to 1.21, P-combined = 5.20x10(-9)). The large sample size provided by the lipid GWAS data and the shared genetic risk factors between the two traits contributed to the uncovering of a hitherto unidentified genetic locus for lung cancer. C1 [Zuber, Verena; Witoelar, Aree; Bettella, Francesco; Wang, Yunpeng; Andreassen, Ole A.] Univ Oslo, Inst Clin Med, KG Jebsen Ctr Psychosis Res, NORMENT, Oslo, Norway. [Zuber, Verena; Mills, Ian G.] Univ Oslo, Nord EMBL Partnership, Ctr Mol Med Norway, Prostate Canc Res Grp, Oslo, Norway. [Zuber, Verena; Witoelar, Aree; Bettella, Francesco; Wang, Yunpeng; Andreassen, Ole A.] Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway. [Zuber, Verena] European Bioinformat Inst, European Mol Biol Lab, Wellcome Trust Genome Campus, Cambridge, England. [Marconett, Crystal N.; Yang, Chenchen; Laird-Offringa, Ite A.] Univ So Calif, Keck Sch Med, Dept Surg, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Marconett, Crystal N.; Yang, Chenchen; Laird-Offringa, Ite A.] Univ So Calif, Keck Sch Med, Dept Biochem & Mol Biol, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Zhou, Beiyun; Borok, Zea] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Will Rogers Inst,Pulm Res Ctr, Los Angeles, CA 90033 USA. [Zhou, Beiyun; Borok, Zea] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Div Pulm Crit Care & Sleep Med,Dept Med, Los Angeles, CA 90033 USA. [Shi, Jianxin; Hua, Xing; Song, Lei; Caporaso, Neil E.; Chatterjee, Nilanjan; Landi, Maria Teresa] NCI, Div Canc Epidemiol & Genet, NIH, US Publ Hlth Serv, Bethesda, MD 20892 USA. [Wheeler, William] Information Management Serv Inc, Rockville, MD USA. [Dale, Anders M.; Schork, Andrew J.] Univ Calif San Diego, Multimodal Imaging Lab, La Jolla, CA 92093 USA. [Dale, Anders M.; Schork, Andrew J.] Univ Calif San Diego, Ctr Human Dev, La Jolla, CA 92093 USA. [Dale, Anders M.] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Dale, Anders M.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Thompson, Wesley K.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Schork, Andrew J.] Univ Calif San Diego, Cognit Sci Grad Program, La Jolla, CA 92093 USA. [Laplana, Marina; Risch, Angela] German Canc Res Ctr, Div Epigen & Canc Risk Factors, Heidelberg, Germany. [Risch, Angela] Salzburg Univ, Dept Mol Biol, Salzburg, Austria. [Risch, Angela] TLRC H, Heidelberg, Germany. [Risch, Angela] German Ctr Lung Res DZL, Heidelberg, Germany. [Djurovic, Srdjan] Oslo Univ Hosp, Dept Med Genet, Oslo, Norway. [Mills, Ian G.] Oslo Univ Hosp, Dept Mol Oncol, Inst Canc Res, Oslo, Norway. [Mills, Ian G.] Oslo Univ Hosp, Dept Urol, Oslo, Norway. [Djurovic, Srdjan] Univ Bergen, NORMENT, KG Jebsen Ctr Psychosis Res, Dept Clin Sci, Bergen, Norway. [van der Heijden, Henricus F. M.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Nijmegen, Netherlands. [Swinkels, Dorine] Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Med Ctr, Nijmegen, Netherlands. [Aben, Katja K.] Netherlands Comprehens Canc Org, Utrecht, Netherlands. [McKay, James] WHO, IARC, Lyon, France. [Hung, Rayjean J.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [Bikeboller, Heike] Univ Med Gottingen, Zentrum Informat Stat & Epidemiol, Gottingen, Germany. [Stevens, Victoria L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Han, Younghun; Amos, Christopher I.] Dartmouth Coll, Ctr Genom Med, Dept Community & Family Med, Geisel Sch Med, 1 Med Ctr Dr, Lebanon, NH 03756 USA. [Wei, Yongyue; Panadero, Maria Angeles; Christiani, David C.] Harvard Sch Publ Hlth, Dept Epidemiol & Environm Hlth, Boston, MA USA. [Mayordomo, Jose I.] Ciudad Coria Hosp, Div Med Oncol, Coria, Spain. [Kiemeney, Lambertus] Univ Hosp, Div Med Oncol, Zaragoza, Spain. [Christiani, David C.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Div Pulm Crit Care, Boston, MA USA. [Houlston, Richard] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Mills, Ian G.] Queens Univ, Ctr Canc Res & Cell Biol, Prostate Canc UK Movember Ctr Excellence Prostate, Belfast, Antrim, North Ireland. RP Mills, IG (reprint author), Queens Univ, Ctr Canc Res & Cell Biol, Prostate Canc UK Movember Ctr Excellence Prostate, Belfast, Antrim, North Ireland.; Landi, MT (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Room 6E446,MSC 9769, Bethesda, MD 20892 USA.; Mills, IG (reprint author), Queens Univ Belfast, CCRCB, 97 Lisburn Rd, Belfast BT9 7BL, Antrim, North Ireland. EM I.Mills@qub.ac.uk; landim@mail.nih.gov OI Zuber, Verena/0000-0001-9827-1877; Laplana, Marina/0000-0002-2548-0704; van der Heijden, Erik/0000-0003-3596-518X; Houlston, Richard/0000-0002-5268-0242 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, MD.; Intramural Research Program of the National Institutes of Health, National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics; US Public Health Service from the NCI [N01-CN-45165, N01-RC45035, N01-RC-37004]; 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]; Westat, Inc. [NO1-CN-25476]; University of California, Los Angeles [NO1-CN25404]; American Cancer Society; National Institutes of Health (NIH); Genes, Environment and Health Initiative (GEI) [Z01 CP 010200]; NIH [U01 HG004446, 1 R01 HL114094, 1 P30 H101258, R37HL062569-13]; NIH GEI [U01HG 004438]; National Institutes of Health [R01 CA092824, P50 CA090578, R01 CA074386]; Chaire de pneumologie de la Fondation JD Begin de l'Universite Laval; Fondation de l'Institut universitaire de cardiologie et de pneumologie de Quebec; Respiratory Health Network of the FRQS; Canadian Institutes of Health Research [MOP - 123369]; Cancer Research Society and Read for the Cure; Fonds de recherche Quebec-Sante (FRQS); Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services; Ralph Edgington Chair in Medicine; department of Surgery, University of Southern California; Norris Comprehensive Cancer Center core grant from the National Cancer Institute [P30CA014089] FX This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, MD.; Transdisciplinary Research for Cancer of Lung (TRICL): National Institute of Health U19 CA148127-01 (PI: Amos), Canadian Cancer Society Research Institute (No. 020214, PI: Hung). The Environment and Genetics in Lung Cancer Etiology (EAGLE), Prostate, Lung, Colon, Ovary Screening Trial (PLCO), and Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) studies were supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics. ATBC was also supported by US Public Health Service contracts (N01-CN-45165, N01-RC45035, 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), the Pacific Health Research Institute (NO1-CN-25515), the Henry Ford Health System (NO1-CN-25512), the University of Minnesota (NO1-CN-25513), Washington University (NO1-CN-25516), the University of Pittsburgh (NO1-CN-25511), the University of Utah (NO1-CN-25524), the Marshfield Clinic Research Foundation (NO1-CN-25518), the University of Alabama at Birmingham (NO1-CN-75022), Westat, Inc. (NO1-CN-25476), and the University of California, Los Angeles (NO1-CN25404). The Cancer Prevention Study-II (CPS-II) Nutrition Cohort was supported by the American Cancer Society. Funding for the Lung Cancer and Smoking study was provided by the National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. Harvard Lung Study: The Harvard Lung Cancer Study is supported by the National Institutes of Health (R01 CA092824, P50 CA090578, and R01 CA074386).; Lung eQTL study: The lung eQTL study at Laval University was supported by the Chaire de pneumologie de la Fondation JD Begin de l'Universite Laval, the Fondation de l'Institut universitaire de cardiologie et de pneumologie de Quebec, the Respiratory Health Network of the FRQS, the Canadian Institutes of Health Research (MOP - 123369), and the Cancer Research Society and Read for the Cure. Y. Bosse is the recipient of a Junior 2 Research Scholar award from the Fonds de recherche Quebec-Sante (FRQS).; Lung meQTL study: The meQTL study based on the environment and Genetics in Lung Cancer Etiology (EAGLE) study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services.; Epigenetics: This study was supported by NIH grant 1 R01 HL114094 to IAL-O and ZB, NIH grants 1 P30 H101258 and R37HL062569-13 to ZB. ZB is supported by the Ralph Edgington Chair in Medicine. CNM was supported in part by the department of Surgery, University of Southern California. Generation of epigenetic data was supported in part by a Norris Comprehensive Cancer Center core grant, award number P30CA014089, from the National Cancer Institute. NR 15 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 DEC PY 2016 VL 108 IS 12 AR djw167 DI 10.1093/jnci/djw167 PG 4 WC Oncology SC Oncology GA EK4LP UT WOS:000393898500007 ER PT J AU Laudisio, A Gemma, A Fontana, DO Rivera, C Bandinelli, S Ferrucci, L Incalzi, RA AF Laudisio, Alice Gemma, Antonella Fontana, Davide O. Rivera, Chiara Bandinelli, Stefania Ferrucci, Luigi Incalzi, Raffaele Antonelli TI Self-Reported Masticatory Dysfunction and Mortality in Community Dwelling Elderly Adults: A 9-Year Follow-Up SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE masticatory dysfunction; mortality; community-dwelling elderly adults; epidemiology ID OLDER-ADULTS; VASCULAR-DISEASE; CHEWING PROBLEMS; DENTAL STATUS; TOOTH LOSS; ABILITY; DISABILITY; MALNUTRITION; POPULATION; DECLINE AB OBJECTIVES: To evaluate the association, if any, between masticatory dysfunction (MD) and mortality in older adults. DESIGN: The Invecchiare in Chianti (InCHIANTI) Study, a cohort study with 9-year follow-up. SETTING: Tuscany, Italy. PARTICIPANTS: Individuals aged 65 and older (N = 1,155). MEASUREMENTS: MD was self-reported; Cox regression was used to assess the association between self-reported MD and 9-year all-cause mortality. This association was also evaluated after stratifying according to use of dentures. Analyses were adjusted for potential con-founders, including demographic characteristics, lifestyle habits, comorbidities, nutrient intake, medications, and objective parameters. RESULTS: Four hundred five (35%) participants reported MD. Over the 9-year follow-up, 475 (41%) subjects died. According to Cox regression analysis, self-reported MD was associated with higher mortality (relative risk (RR) = 1.23, 95% confidence interval (CI) = 1.02-1.48), after adjusting for potential confounders. In participants with self-reported MD, uncorrected edentulism was the condition associated with the greatest risk of mortality (RR = 2.10, 95% CI = 1.07-4.14); use of dentures seemed to blunt this association (RR = 1.12, 95% CI = 0.87-1.44). CONCLUSION: Self-reported MD, chiefly when due to uncorrected edentulism, is associated with 9-year all-cause mortality in community-dwelling elderly adults. Further studies are needed to evaluate whether the timely correction of MD using adequate dentures can increase the survival of older adults. C1 [Laudisio, Alice; Fontana, Davide O.; Rivera, Chiara; Incalzi, Raffaele Antonelli] Univ Campus Biomed Roma, Dept Med, Unit Geriatr, Via Alvaro del Portillo 21, I-00128 Rome, Italy. [Gemma, Antonella] Azienda Sanit Locale Roma E, UOS Accesso & Presa Car Assistenziale, Rome, Italy. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Rehabil Unit, Florence, Italy. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. RP Laudisio, A (reprint author), Univ Campus Biomed Roma, Dept Med, Unit Geriatr, Via Alvaro del Portillo 21, I-00128 Rome, Italy. EM lavoralice@gmail.com FU Italian Ministry of Health [ICS110.1/RF97.71]; National Institute on Aging (NIA) [263 MD 9164, 263 MD 821336]; NIA [N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002]; Intramural Research Program of the NIA, National Institutes of Health, Baltimore, Maryland FX The InCHIANTI study baseline (1998e2000) was supported as a targeted project (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the National Institute on Aging (NIA) (Contracts 263 MD 9164 and 263 MD 821336). Follow-up 1 (2001-2003) was funded by the NIA (Contracts N.1-AG-1-1 and N.1-AG-1-2111); Follow-ups 2 and 3 (2004-2010) were financed by the NIA (Contract N01-AG-5-0002). Supported in part by the Intramural Research Program of the NIA, National Institutes of Health, Baltimore, Maryland. NR 31 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD DEC PY 2016 VL 64 IS 12 BP 2503 EP 2510 DI 10.1111/jgs.14331 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EK0AR UT WOS:000393589200029 PM 27889908 ER PT J AU Chalhoub, D Marques, E Meirelles, O Semba, RD Ferrucci, L Satterfield, S Nevitt, M Cauley, JA Harris, T AF Chalhoub, Didier Marques, Elisa Meirelles, Osorio Semba, Richard D. Ferrucci, Luigi Satterfield, Suzanne Nevitt, Michael Cauley, Jane A. Harris, Tamara CA Hlth ABC Study TI Association of Serum Klotho with Loss of Bone Mineral Density and Fracture Risk in Older Adults SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE aging; osteoporosis; sarcopenia; bone-muscle interactions; fracture risk assessment ID COMMUNITY-DWELLING ADULTS; OSTEOPOROSIS; WOMEN; STRENGTH; GENE; MASS; MEN AB OBJECTIVES: Klotho deficiency has been previously linked to aging-like phenotypes such as osteoporosis, cognitive impairment, and sarcopenia. Low serum klotho was shown to be related to grip strength and disability. Nonetheless, no previous study has explored the association between serum klotho and fractures. The purpose of this report is to examine the relationship of serum klotho with bone mineral density (BMD) loss and fractures in older adults. DESIGN: The Health, Aging, and Body Composition (Health ABC) Study is a longitudinal cohort study of 3,075 community-dwelling older adults. SETTING: US clinical centers. PARTICIPANTS: Two thousand seven hundred and seventy six well-functioning black and white adults aged 70 to 79 years with serum klotho measurements were followed up for a median of 5 years. MEASUREMENTS: Percent annualized BMD change and fracture risk were compared across klotho quartiles. A Poisson distribution was used to calculate age-adjusted fracture incidence rates, and Cox proportional hazards models for multivariable-adjusted hazard ratios. RESULTS: The annualized percent changes in hip, femoral neck, and vertebral BMD were similar across klotho quartiles. Participants experienced 507 nonspine fractures, 203 hip fractures, and 135 vertebral fractures. The Incidence rate (IR) of nonspine fractures was 17 per 1,000 personyears. The most frequent site was hip (IR = 6 per 1,000 person- years) and the IR of vertebral fractures was 3 per 1,000 person-years. There was no association between the lowest quartile of plasma klotho and nonspine (hazard ratio (HR) = 1.19, 95% confidence interval (CI) = 0.86-1.65), hip (HR = 1.34, 95% CI = 0.79-2.27), or vertebral fractures (HR = 1.17, 95% CI = 0.65-2.11). CONCLUSION: Although klotho gene is a susceptible gene for reduced BMD, klotho blood concentration does not appear to be a predictor of bone loss or fracture risk in well-functioning older adults. C1 [Chalhoub, Didier; Marques, Elisa; Meirelles, Osorio; Harris, Tamara] NIA, Intramural Res Program, Lab Epidemiol & Populat Sci, NIH, 7201 Wisconsin Ave, Baltimore, MD 20814 USA. [Semba, Richard D.] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Baltimore, MD 21224 USA. [Satterfield, Suzanne] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. [Nevitt, Michael] UCSF, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA USA. [Cauley, Jane A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. RP Chalhoub, D (reprint author), NIA, Intramural Res Program, Lab Epidemiol & Populat Sci, NIH, 7201 Wisconsin Ave, Baltimore, MD 20814 USA. EM didier.chalhoub@nih.gov FU National Institutes of Health [R01 AG27012, R01 AG028050, R01 HL094507]; National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA [R01-AG028050]; NINR [R01-NR012459]; Intramural Research Program of the NIH, National Institute on Aging; Hologic, Inc. FX This research was supported by National Institutes of Health grants R01 AG27012, R01 AG028050, R01 HL094507, National Institute on Aging (NIA) contracts #N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050; NINR grant R01-NR012459. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. We also acknowledge support from Hologic, Inc. NR 19 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD DEC PY 2016 VL 64 IS 12 BP E304 EP E308 DI 10.1111/jgs.14661 PG 5 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EK0AR UT WOS:000393589200011 PM 27910102 ER PT J AU Guo, H Cao, M Zou, SG Ye, BP Dong, YQ AF Guo, Hong Cao, Min Zou, Sige Ye, Boping Dong, Yuqing TI Cranberry Extract Standardized for Proanthocyanidins Alleviates beta-Amyloid Peptide Toxicity by Improving Proteostasis Through HSF-1 in Caenorhabditis elegans Model of Alzheimer's Disease SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Alzheimer's disease; Cranberry; beta-Amyloid; hsf-1; Proteostasis; Caenorhabditis elegans ID HEAT-SHOCK FACTOR; LIFE-SPAN; TEMPORAL REQUIREMENTS; LONGEVITY; PROTEOTOXICITY; STERILIZATION; MECHANISMS; PROTECTION; STRESS; DAF-16 AB A growing body of evidence suggests that nutraceuticals with prolongevity properties may delay the onset of Alzheimer's disease (AD). We recently demonstrated that a proanthocyanidins-standardized cranberry extract has properties that prolong life span and promote innate immunity in Caenorhabditis elegans. In this article, we report that supplementation of this cranberry extract delayed A beta toxicity-triggered body paralysis in the C elegans AD model. Genetic analyses indicated that the cranberry-mediated A beta toxicity alleviation required heat shock transcription factor (HSF)-1 rather than DAF-16 and SKN-1. Moreover, cranberry supplementation increased the transactivity of HSF-1 in an IIS-dependent manner. Further studies found that the cranberry extract relies on HSF-1 to significantly enhance the solubility of proteins in aged worms, implying an improved proteostasis in AD worms. Considering that HSF-1 plays a pivotal role in maintaining proteostasis, our results suggest that cranberry maintains the function of proteostasis through HSF-1, thereby protecting C elegans against A beta toxicity. Together, our findings elucidated the mechanism whereby cranberry attenuated A beta toxicity in C elegans and stressed the significance of proteostasis in the prevention of age-related diseases from a practical point of view. C1 [Guo, Hong; Cao, Min; Dong, Yuqing] Clemson Univ, Dept Biol Sci, Clemson, SC 29634 USA. [Guo, Hong; Ye, Boping] China Pharmaceut Univ, Sch Life Sci & Technol, Nanjing, Jiangsu, Peoples R China. [Cao, Min; Dong, Yuqing] Clemson Univ, Inst Engaged Aging, Clemson, SC USA. [Zou, Sige] NIA, Funct Genom Unit, Translat Gerontol Branch, Baltimore, MD 21224 USA. RP Dong, YQ (reprint author), Clemson Univ, Life Sci Facil 055A, Clemson, SC 29634 USA. EM ydong@clemson.edu FU Intramural Research Program at the National Institute on Aging, NIH; China National Science and Technology Major Projects for Key New Drugs Innovation [2012ZX09103301-018] FX This study was funded by Intramural Research Program at the National Institute on Aging, NIH (to S.Z.) and China National Science and Technology Major Projects for Key New Drugs Innovation (to B.Y., 2012ZX09103301-018). NR 55 TC 0 Z9 0 U1 4 U2 4 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 DEC PY 2016 VL 71 IS 12 BP 1564 EP 1573 DI 10.1093/gerona/glv165 PG 10 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EL2JW UT WOS:000394446900006 PM 26405062 ER PT J AU Best, JR Liu-Ambrose, T Boudreau, RM Ayonayon, HN Satterfield, S Simonsick, EM Studenski, S Yaffe, K Newman, AB Rosano, C AF Best, John R. Liu-Ambrose, Teresa Boudreau, Robert M. Ayonayon, Hilsa N. Satterfield, Suzanne Simonsick, Eleanor M. Studenski, Stephanie Yaffe, Kristine Newman, Anne B. Rosano, Caterina CA Hlth Aging Body Composition Study TI An Evaluation of the Longitudinal, Bidirectional Associations Between Gait Speed and Cognition in Older Women and Men SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Cognition; Gait; Physical activity; Physical function ID LOWER-EXTREMITY FUNCTION; PHYSICAL PERFORMANCE; EXECUTIVE FUNCTION; BODY-COMPOSITION; SUBSEQUENT DISABILITY; DECLINE; ADULTS; HEALTH; DEMENTIA; MEMORY AB Background: Few cohort studies have examined longitudinal associations between age-related changes in cognition and physical performance. Further, whether these associations differ for men versus women or can be attributed to differences in physical activity (PA) is unknown. Methods: Participants were 2,876 initially well-functioning community-dwelling older adults (aged 70-79 years at baseline; 52% female; 39% black) studied over a 9-year period. Usual gait speed, self-reported PA, and two cognitive measures-Digit Symbol Substitution Test (DSST) and Mini-Modified Mental State examination (3MS)-were assessed years 0 (ie, baseline), 4, and 9. Results: Early decline between years 0 and 4 in gait speed predicted later decline between years 4 and 9 in performance on the 3MS (beta = 0.10, p=.004) and on the DSST (beta = 0.16, p<.001). In contrast, the associations between early decline in cognition and later decline in gait speed were weaker and were non-significant after correcting for multiple comparisons (beta = 0.08, p=.019 for 3MS and beta=.06, p=.051 for DSST). All associations were similar for women and men and were unaltered when accounting for PA levels. Conclusions: The results indicate declining gait speed as a precursor to declining cognitive functioning, and suggest a weaker reciprocal process among older women and men. C1 [Best, John R.; Liu-Ambrose, Teresa] Univ British Columbia, Djavad Mowafaghian Ctr Brain Hlth, Vancouver, BC, Canada. [Best, John R.; Liu-Ambrose, Teresa] Univ British Columbia, Dept Phys Therapy, Vancouver, BC, Canada. [Best, John R.; Liu-Ambrose, Teresa] Vancouver Coastal Hlth Res Inst, Ctr Hip Hlth & Mobil, Vancouver, BC, Canada. [Boudreau, Robert M.; Newman, Anne B.; Rosano, Caterina] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Ayonayon, Hilsa N.; Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Simonsick, Eleanor M.; Studenski, Stephanie] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. RP Best, JR (reprint author), Univ British Columbia, Djavad Mowafaghian Ctr Brain Hlth, Liu Ambrose Lab, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada. EM john.best@ubc.ca FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA [R01-AG028050]; NINR [R01-NR012459]; Intramural Research Program of the NIH, National Institute on Aging; Canadian Institutes of Health Research; Michael Smith Foundation of Health Research FX This research was supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050, and NINR grant R01-NR012459. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Additional sources of funding: J.R.B. is a Canadian Institutes of Health Research and Michael Smith Foundation of Health Research Post-Doctoral Fellow. T.L-A. is a Canada Research Chair (Tier II) in Physical Activity, Mobility, and Cognitive Neuroscience. NR 41 TC 2 Z9 2 U1 3 U2 3 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 DEC PY 2016 VL 71 IS 12 BP 1616 EP 1623 DI 10.1093/gerona/glw066 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EL2JW UT WOS:000394446900013 PM 27069098 ER PT J AU Choi, S Reiter, DA Shardell, M Simonsick, EM Studenski, S Spencer, RG Fishbein, KW Ferrucci, L AF Choi, Seongjin Reiter, David A. Shardell, Michelle Simonsick, Eleanor M. Studenski, Stephanie Spencer, Richard G. Fishbein, Kenneth W. Ferrucci, Luigi TI P-31 Magnetic Resonance Spectroscopy Assessment of Muscle Bioenergetics as a Predictor of Gait Speed in the Baltimore Longitudinal Study of Aging SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Lower extremity performance; Walking speed; Bioenergetics; Muscle; Magnetic resonance spectroscopy ID GRAPHICAL USER-INTERFACE; HEALTHY OLDER-ADULTS; SKELETAL-MUSCLE; IN-VIVO; MITOCHONDRIAL RESPIRATION; AEROBIC CAPACITY; ENERGETIC COST; WALKING SPEED; DECLINE; FITNESS AB Background: Aerobic fitness and muscle bioenergetic capacity decline with age; whether such declines explain age-related slowing of walking speed is unclear. We hypothesized that muscle energetics and aerobic capacity are independent correlates of walking speed in simple and challenging performance tests and that they account for the observed age-related decline in walking speed in these same tests. Methods: Muscle bioenergetics was assessed as postexercise recovery rate of phosphocreatine (PCr), k(PCr), using phosphorus magnetic resonance spectroscopy (P-31-MRS) in 126 participants (53 men) of the Baltimore Longitudinal Study of Aging aged 26-91 years (mean = 72 years). Four walking tasks were administered-usual pace over 6 m and 150 seconds and fast pace over 6 m and 400 m. Separately, aerobic fitness was assessed as peak oxygen consumption (peak VO2) using a graded treadmill test. Results: All gait speeds, k(PCr), and peak VO2 were lower with older age. Independent of age, sex, height, and weight, both k(PCr) and peak VO2 were positively and significantly associated with fast pace and long distance walking but only peak VO2 and not k(PCr) was significantly associated with usual gait speed over 6 m. Both k(PCr) and peak VO2 substantially attenuated the association between age and gait speed for all but the least stressful walking task of 6 m at usual pace. Conclusion: Muscle bioenergetics assessed using P-31-MRS is highly correlated with walking speed and partially explains age-related poorer performance in fast and long walking tasks. C1 [Choi, Seongjin; Shardell, Michelle; Simonsick, Eleanor M.; Studenski, Stephanie; Ferrucci, Luigi] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Reiter, David A.; Spencer, Richard G.; Fishbein, Kenneth W.] NIA, Clin Invest Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Ferrucci, L (reprint author), NIA, Translat Gerontol Branch, NIH, Baltimore, MA 21225 USA. EM ferruccilu@mail.nih.gov FU Intramural Research Program of the National Institute on Aging, National Institute of Health, Baltimore, MD FX This work was funded by the Intramural Research Program of the National Institute on Aging, National Institute of Health, Baltimore, MD. NR 32 TC 2 Z9 2 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD DEC PY 2016 VL 71 IS 12 BP 1638 EP 1645 DI 10.1093/gerona/glw059 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EL2JW UT WOS:000394446900016 PM 27075894 ER PT J AU Jerome, GJ Ko, SU Shaffer, NSC Studenski, SA Ferrucci, L Simonsick, EM AF Jerome, Gerald J. Ko, Seung-uk Shaffer, Nancy S. Chiles Studenski, Stephanie A. Ferrucci, Luigi Simonsick, Eleanor M. TI Cross-Sectional and Longitudinal Associations Between Adiposity and Walking Endurance in Adults Age 60-79 SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Obesity; Fitness; Older adults; Walking endurance ID DISTANCE CORRIDOR WALK; INCIDENT MOBILITY LIMITATION; FUNCTIONING OLDER-ADULTS; BODY-MASS INDEX; CARDIORESPIRATORY FITNESS; PHYSICAL-ACTIVITY; MEANINGFUL CHANGE; LIFE-P; DISABILITY; OBESITY AB Background: The impact of excess weight on current and future walking endurance in nondisabled persons is unclear. This study examines the association between obesity and walking endurance among nondisabled persons both in late mid-life and early old age. Methods: Participants in the Baltimore Longitudinal Study of Aging aged 60-79 years (n = 406) who reported no walking limitations, and completed a 400-meter walk "as quickly as possible" without lower-extremity pain, and had a follow-up assessment within 1.7-4.2 years. Adiposity was assessed by weight, body mass index (BMI), BMI category, and percent fat mass by DXA. Results: Adjusting for age, sex, race, height, and physical activity, all adiposity measures were cross-sectionally associated with slower 400 meter time in both 60-69 and 70 to 79-year-olds (weight: beta = 1.0 and 1.2; BMI: beta = 2.8 and 3.6; and percent fat mass: beta = 2.0 and 2.0, respectively, all p<.001). With additional adjustment for initial 400-meter performance and follow-up time, in 60- to 69-year-olds, change in 400-meter time (positive beta indicates decline) was associated with all adiposity measures (weight: beta = 0.4; BMI: beta = 1.0; and percent fat mass: beta = 0.5; all p=.05) but not in the older group (weight: beta = -0.4; BMI: beta = -1.2; and percent fat mass: beta = -0.2; all p=.17). Conclusion: Excess weight and adiposity were associated with worse walking endurance in nondisabled persons aged 60-79 years and predicted accelerated decline in endurance in late mid-life adults. Weight management for mobility independence may be best targeted in obese persons approaching traditional retirement age. C1 [Jerome, Gerald J.] Towson Univ, Dept Kinesiol, 8000 York Rd, Towson, MD 21252 USA. [Ko, Seung-uk] Chonnam Natl Univ, Dept Mech Engn, Gwangju, South Korea. [Shaffer, Nancy S. Chiles; Studenski, Stephanie A.; Ferrucci, Luigi; Simonsick, Eleanor M.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. RP Jerome, GJ (reprint author), Towson Univ, Dept Kinesiol, 8000 York Rd, Towson, MD 21252 USA. EM gjerome@towson.edu FU Intramural Research Program of the National Institute on Aging FX This research was supported by the Intramural Research Program of the National Institute on Aging. NR 26 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 DEC PY 2016 VL 71 IS 12 BP 1661 EP 1666 DI 10.1093/gerona/glw054 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EL2JW UT WOS:000394446900019 PM 26984392 ER PT J AU Odden, MC Wu, CK Shlipak, MG Psaty, BM Katz, R Applegate, WB Harris, T Newman, AB Peralta, CA AF Odden, Michelle C. Wu, Chenkai Shlipak, Michael G. Psaty, Bruce M. Katz, Ronit Applegate, William B. Harris, Tamara Newman, Anne B. Peralta, Carmen A. CA Hlth ABC Study TI Blood Pressure Trajectory, Gait Speed, and Outcomes: The Health, Aging, and Body Composition Study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Blood pressure; Epidemiology; Function; Gait speed; Hypertension ID OLDER-ADULTS; LEIDEN 85-PLUS; ASSOCIATION; MORTALITY; FRAILTY AB Background: The present study aimed to (i) evaluate previous observations that the association of blood pressure (BP) with outcomes varies by gait speed and (ii) evaluate the association of subsequent changes in BP and cardiovascular risk. Methods: Participants included 2,669 adults aged 70-79 years in the Health, Aging, and Body Composition (Health ABC) study. Gait speed was dichotomized at >= 1.0 m/s over a 20-m test at baseline. BP was measured at baseline, and changes in BP over 5 years were evaluated using (i) population-based trajectory models and (ii) intraindividual mean and slope. Results: Over a mean of 10 years, there were 1,366 deaths, 336 first myocardial infarctions, and 295 first strokes. There was a differential pattern of association between baseline systolic BP and diastolic BP and outcomes among brisk and moderate speed walkers. For example, the association between higher diastolic BP and mortality was in the protective direction for moderate speed walkers (hazard ratio = 0.75; 95% confidence interval: 0.63, 0.91) per 10 mmHg higher, whereas it was null in brisk walkers (hazard ratio = 1.05; 95% confidence interval: 0.98, 1.11), p value for interaction.01. The 5-year population-based trajectories did not add important information beyond baseline BP. Individual slopes in both systolic BP and diastolic BP did not appear to have important associations with the outcomes. Conclusions: In this study, we found that the overall level of BP was associated with myocardial infarction, stroke, and death, and this association differed by baseline gait speed, whereas changes in BP were not associated with these outcomes. C1 [Odden, Michelle C.; Wu, Chenkai] Oregon State Univ, Sch Biol & Populat Hlth Sci, 141B Milam Hall, Corvallis, OR 97331 USA. [Shlipak, Michael G.; Peralta, Carmen A.] Univ Calif San Francisco, Dept Med, Kidney Hlth Res Collaborat, San Francisco, CA USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Shlipak, Michael G.; Peralta, Carmen A.] San Francisco VA Med Ctr, Dept Med, San Francisco, CA USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Sci, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Katz, Ronit] Univ Washington, Dept Med, Kidney Res Inst, Seattle, WA USA. [Applegate, William B.] Wake Forest Univ, Baptist Med Ctr, Internal Med & Geriatr Med, Winston Salem, NC 27109 USA. [Harris, Tamara] NIA, Geriatr Epidemiol Sect, Bethesda, MD 20892 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. RP Odden, MC (reprint author), Oregon State Univ, Sch Biol & Populat Hlth Sci, 141B Milam Hall, Corvallis, OR 97331 USA. EM Michelle.Odden@oregonstate.edu FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050, K01AG039387, R01AG46206]; NINR [R01-NR012459]; Intramural Research Program of the NIH, NIA FX The Health ABC study was supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050; and NINR grant R01-NR012459, and in part by the Intramural Research Program of the NIH, NIA. Additional support for this research was provided by NIA (K01AG039387, R01AG46206). NR 15 TC 2 Z9 2 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD DEC PY 2016 VL 71 IS 12 BP 1688 EP 1694 DI 10.1093/gerona/glw076 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EL2JW UT WOS:000394446900023 PM 27142696 ER PT J AU Odden, MC Wu, CK Shlipak, MG Psaty, BM Katz, R Applegate, WB Harris, T Newman, AB Peralta, CA AF Odden, Michelle C. Wu, Chenkai Shlipak, Michael G. Psaty, Bruce M. Katz, Ronit Applegate, William B. Harris, Tamara Newman, Anne B. Peralta, Carmen A. CA Hlth ABC Study TI Blood Pressure Trajectory, Gait Speed, and Outcomes: The Health, Aging, and Body Composition Study (vol 71, pg 1688, 2016) SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Correction C1 [Odden, Michelle C.; Wu, Chenkai] Oregon State Univ, Sch Biol & Populat Hlth Sci, 141B Milam Hall, Corvallis, OR 97331 USA. [Shlipak, Michael G.; Peralta, Carmen A.] Univ Calif San Francisco, Dept Med, Kidney Hlth Res Collaborat, San Francisco, CA USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Shlipak, Michael G.; Peralta, Carmen A.] San Francisco VA Med Ctr, Dept Med, San Francisco, CA USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, 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. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Katz, Ronit] Univ Washington, Dept Med, Kidney Res Inst, Seattle, WA USA. [Applegate, William B.] Wake Forest Univ, Baptist Med Ctr, Internal Med & Geriatr Med, Winston Salem, NC 27109 USA. [Harris, Tamara] NIA, Geriatr Epidemiol Sect, Bethesda, MD 20892 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. RP Odden, MC (reprint author), Oregon State Univ, Sch Biol & Populat Hlth Sci, 141B Milam Hall, Corvallis, OR 97331 USA. EM Michelle.Odden@oregonstate.edu NR 1 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 DEC PY 2016 VL 71 IS 12 BP E1 EP E1 DI 10.1093/gerona/glw230 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA EL2JW UT WOS:000394446900001 PM 27838648 ER PT J AU Rao, T Gao, R Takada, S Al Abo, M Chen, X Walters, KJ Pommier, Y Aihara, H AF Rao, Timsi Gao, Rui Takada, Saeko Al Abo, Muthana Chen, Xiang Walters, Kylie J. Pommier, Yves Aihara, Hideki TI Novel TDP2-ubiquitin interactions and their importance for the repair of topoisomerase II-mediated DNA damage SO NUCLEIC ACIDS RESEARCH LA English DT Article ID LYS48-LINKED POLYUBIQUITIN CHAIN; UBIQUITIN-BINDING DOMAINS; UBA DOMAIN; PHOSPHODIESTERASE 2; COVALENT COMPLEXES; PROTEIN-STRUCTURE; NMR-SPECTROSCOPY; STRUCTURAL BASIS; CHEMICAL-SHIFTS; TDP2 AB Tyrosyl DNA phosphodiesterase 2 (TDP2) is a multifunctional protein implicated in DNA repair, signal transduction and transcriptional regulation. In its DNA repair role, TDP2 safeguards genome integrity by hydrolyzing 5'-tyrosyl DNA adducts formed by abortive topoisomerase II (Top2) cleavage complexes to allow error-free repair of DNA double-strand breaks, thereby conferring cellular resistance against Top2 poisons. TDP2 consists of a C-terminal catalytic domain responsible for its phosphodiesterase activity, and a functionally uncharacterized N-terminal region. Here, we demonstrate that this N-terminal region contains a ubiquitin (Ub)-associated (UBA) domain capable of binding multiple forms of Ub with distinct modes of interactions and preference for either K48-or K63-linked polyUbs over monoUb. The structure of TDP2 UBA bound to monoUb shows a canonical mode of UBA-Ub interaction. However, the absence of the highly conserved MGF motif and the presence of a fourth alpha-helix make TDP2 UBA distinct from other known UBAs. Mutations in the TDP2 UBA-Ub binding interface do not affect nuclear import of TDP2, but severely compromise its ability to repair Top2-mediated DNA damage, thus establishing the importance of the TDP2 UBA-Ub interaction in DNA repair. The differential binding to multiple Ub forms could be important for responding to DNA damage signals under different contexts or to support the multi-functionality of TDP2. C1 [Rao, Timsi; Takada, Saeko; Aihara, Hideki] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. [Gao, Rui; Al Abo, Muthana; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Chen, Xiang; Walters, Kylie J.] NCI, Prot Proc Sect, Struct Biophys Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA. RP Aihara, H (reprint author), Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. EM aihar001@umn.edu FU National Institutes of Health [GM095558, GM118047]; Intramural Program of the National Cancer Institute, Center for Cancer Research [Z01 BC 006150, ZIA BC011627] FX National Institutes of Health [GM095558 and GM118047 to H.A., Intramural Program of the National Cancer Institute, Center for Cancer Research Z01 BC 006150 to Y.P. and ZIA BC011627 to K.J.W.]. Funding for open access charge: National Institutes of Health [GM095558 and GM118047 to H.A.]. NR 67 TC 0 Z9 0 U1 3 U2 3 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 DEC PY 2016 VL 44 IS 21 BP 10201 EP 10215 DI 10.1093/nar/gkw719 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EK5PX UT WOS:000393979400020 PM 27543075 ER PT J AU Willi, M Yoo, KH Wang, CC Trajanoski, Z Hennighausen, L AF Willi, Michaela Yoo, Kyung Hyun Wang, Chaochen Trajanoski, Zlatko Hennighausen, Lothar TI Differential cytokine sensitivities of STAT5-dependent enhancers rely on Stat5 autoregulation SO NUCLEIC ACIDS RESEARCH LA English DT Article ID MAMMARY-GLAND INVOLUTION; GENE-EXPRESSION; CHIP-SEQ; SIGNAL TRANSDUCER; SUPER-ENHANCER; EPITHELIUM; PREGNANCY; RECEPTOR; ROLES; NFIB AB Cytokines utilize the transcription factor STAT5 to control cell-specific genes at a larger scale than universal genes, with a mechanistic explanation yet to be supplied. Genome-wide studies have identified putative STAT5-based mammary-specific and universal enhancers, an opportunity to investigate mechanisms underlying their differential response to cytokines. We have now interrogated the integrity and function of both categories of regulatory elements using biological and genetic approaches. During lactation, STAT5 occupies mammary-specific and universal cytokine-responsive elements. Following lactation, prolactin levels decline and mammary-specific STAT5-dependent enhancers are decommissioned within 24 h, while universal regulatory complexes remain intact. These differential sensitivities are linked to STAT5 concentrations and the mammary-specific Stat5 autoregulatory enhancer. In its absence, mammary-specific enhancers, but not universal elements, fail to be fully established. Upon termination of lactation STAT5 binding to a subset of mammary enhancers is substituted by STAT3. No STAT3 binding was observed at the most sensitive STAT5 enhancers suggesting that upon hormone withdrawal their chromatin becomes inaccessible. Lastly, we demonstrate that the mammary-enriched transcription factors GR, ELF5 and NFIB associate with STAT5 at sites lacking bona fide binding motifs. This study provides, for the first time, molecular insight into the differential sensitivities of mammary-specific and universal cytokine-sensing enhancers. C1 [Willi, Michaela; Yoo, Kyung Hyun; Wang, Chaochen; Hennighausen, Lothar] NIDDK, Lab Genet & Physiol, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Willi, Michaela; Trajanoski, Zlatko] Med Univ Innsbruck, Div Bioinformat, Bioctr, A-6020 Innsbruck, Austria. [Yoo, Kyung Hyun] Sookmyung Womens Univ, Dept Life Syst, Seoul 140742, South Korea. RP Hennighausen, L (reprint author), NIDDK, Lab Genet & Physiol, US Natl Inst Hlth, Bethesda, MD 20892 USA. EM lotharh@mail.nih.gov FU IPR of the NIDDK/NIH; Intramural research program of the NIH FX IPR of the NIDDK/NIH. Funding for open access charge: Intramural research program of the NIH. NR 47 TC 2 Z9 2 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 DEC PY 2016 VL 44 IS 21 BP 10277 EP 10291 DI 10.1093/nar/gkw844 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EK5PX UT WOS:000393979400025 PM 27694626 ER PT J AU Beguin, P Charpin, N Koonin, EV Forterre, P Krupovic, M AF Beguin, Pierre Charpin, Nicole Koonin, Eugene V. Forterre, Patrick Krupovic, Mart TI Casposon integration shows strong target site preference and recapitulates protospacer integration by CRISPR-Cas systems SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SELF-SYNTHESIZING TRANSPOSONS; ADAPTIVE IMMUNITY; SPACER ACQUISITION; MECHANISTIC BASIS; ESCHERICHIA-COLI; ADAPTATION; EVOLUTION; SEQUENCES; DEFENSE; PROKARYOTES AB Casposons are a recently discovered group of large DNA transposons present in diverse bacterial and archaeal genomes. For integration into the host chromosome, casposons employ an endonuclease that is homologous to the Cas1 protein involved in protospacer integration by the CRISPR-Cas adaptive immune system. Here we describe the site-preference of integration by the Cas1 integrase (casposase) encoded by the casposon of the archaeon Acidulipro-fundum boonei. Oligonucleotide duplexes derived from the terminal inverted repeats (TIR) of the A. boonei casposon as well as mini-casposons flanked by the TIR inserted preferentially at a site reconstituting the original A. boonei target site. As in the A. boonei genome, the insertion was accompanied by a 15-bp direct target site duplication (TSD). The minimal functional target consisted of the 15-bp TSD segment and the adjacent 18-bp sequence which comprises the 3' end of the tRNA-Pro gene corresponding to the T psi C loop. The functional casposase target site bears clear resemblance to the leader sequence-repeat junction which is the target for protospacer integration catalyzed by the Cas1-Cas2 adaptation module of CRISPR-Cas. These findings reinforce the mechanistic similarities and evolutionary connection between the casposons and the adaptation module of the prokaryotic adaptive immunity systems. C1 [Beguin, Pierre; Charpin, Nicole; Forterre, Patrick; Krupovic, Mart] Inst Pasteur, Unite Biol Mol Gene Chez Extremophiles, 25 Rue Docteur Roux, F-75015 Paris, France. [Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Beguin, P; Krupovic, M (reprint author), Inst Pasteur, Unite Biol Mol Gene Chez Extremophiles, 25 Rue Docteur Roux, F-75015 Paris, France. EM pierre.beguin@pasteur.fr; krupovic@pasteur.fr FU European Research Council (ERC) [UE 340440]; US Department of Health and Human Services Intramural Funds; ERC [UE 340440] FX European Research Council (ERC) [UE 340440 to P.F.]; US Department of Health and Human Services Intramural Funds (to the National Library of Medicine) (to E.V.K.). Funding for open access charge: ERC [UE 340440 to P.F.]. NR 45 TC 2 Z9 2 U1 4 U2 4 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 DEC PY 2016 VL 44 IS 21 BP 10367 EP 10376 DI 10.1093/nar/gkw821 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EK5PX UT WOS:000393979400032 PM 27655632 ER PT J AU Dai, LS Chen, K Youngren, B Kulina, J Yang, A Guo, ZY Li, J Yu, P Gu, S AF Dai, Lisheng Chen, Kevin Youngren, Brenda Kulina, Julia Yang, Acong Guo, Zhengyu Li, Jin Yu, Peng Gu, Shuo TI Cytoplasmic Drosha activity generated by alternative splicing SO NUCLEIC ACIDS RESEARCH LA English DT Article ID III ENZYME DROSHA; MICRORNA BIOGENESIS; MICROPROCESSOR COMPLEX; MIRNA PROMOTERS; NONCODING RNA; RECOGNITION; PHOSPHORYLATION; IDENTIFICATION; TRANSCRIPTOME; LOCALIZATION AB RNase III enzyme Drosha interacts with DGCR8 to form the Microprocessor, initiating canonical microRNA (miRNA) maturation in the nucleus. Here, we re-evaluated where Drosha functions in cells using Drosha and/or DGCR8 knock out (KO) cells and cleavage reporters. Interestingly, a truncated Drosha mutant located exclusively in the cytoplasm cleaved pri-miRNA effectively in a DGCR8-dependent manner. In addition, we demonstrated that in vitro generated pri-miRNAs when transfected into cells could be processed to mature miRNAs in the cytoplasm. These results indicate the existence of cytoplasmic Drosha (c-Drosha) activity. Although a subset of endogenous pri-miRNAs become enriched in the cytoplasm of Drosha KO cells, it remains unclear whether pri-miRNA processing is the main function of c-Drosha. We identified two novel in-frame Drosha isoforms generated by alternative splicing in both HEK293T and HeLa cells. One isoform loses the putative nuclear localization signal, generating c-Drosha. Further analysis indicated that the c-Drosha isoform is abundant in multiple cell lines, dramatically variable among different human tissues and upregulated in multiple tumors, suggesting that c-Drosha plays a unique role in gene regulation. Our results reveal a new layer of regulation on the miRNA pathway and provide novel insights into the ever-evolving functions of Drosha. C1 [Dai, Lisheng; Chen, Kevin; Youngren, Brenda; Kulina, Julia; Yang, Acong; Gu, Shuo] NCI, Gene Regulat & Chromosome Biol Lab, NIH, Frederick, MD 21702 USA. [Guo, Zhengyu; Li, Jin; Yu, Peng] Texas A&M Univ, Dept Elect & Comp Engn, College Stn, TX 77843 USA. [Guo, Zhengyu; Li, Jin; Yu, Peng] Texas A&M Univ, TEES AgriLife Ctr Bioinformat & Genom Syst Engn, College Stn, TX 77843 USA. RP Gu, S (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, NIH, Frederick, MD 21702 USA. EM shuo.gu@nih.gov FU Intramural Research Program of National Cancer Institute, National Institutes of Health; TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering (CBGSE) at Texas AM University; ECE department; Texas A&M Engineering Experiment Station/Dwight Look College of Engineering at Texas AM University; NIH/NCI Intramural Research Program FX This work was supported by Intramural Research Program of National Cancer Institute, National Institutes of Health; ZG was supported by funding from TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering (CBGSE) at Texas A&M University. PY was supported by startup funding from the ECE department and Texas A&M Engineering Experiment Station/Dwight Look College of Engineering at Texas A&M University. Funding for open access charge: NIH/NCI Intramural Research Program. NR 59 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 DEC PY 2016 VL 44 IS 21 BP 10454 EP 10466 DI 10.1093/nar/gkw668 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EK5PX UT WOS:000393979400038 PM 27471035 ER PT J AU Ball, DA Mehta, GD Salomon-Kent, R Mazza, D Morisaki, T Mueller, F McNally, JG Karpova, TS AF Ball, David A. Mehta, Gunjan D. Salomon-Kent, Ronit Mazza, Davide Morisaki, Tatsuya Mueller, Florian McNally, James G. Karpova, Tatiana S. TI Single molecule tracking of Ace1p in Saccharomyces cerevisiae defines a characteristic residence time for non-specific interactions of transcription factors with chromatin SO NUCLEIC ACIDS RESEARCH LA English DT Article ID IN-VIVO; DRUG-RESISTANCE; MAMMALIAN-CELLS; RAPID EXCHANGE; FACTOR-BINDING; LIVING CELLS; LIVE CELLS; DNA; IDENTIFICATION; TECHNOLOGY AB In vivo single molecule tracking has recently developed into a powerful technique for measuring and understanding the transient interactions of transcription factors (TF) with their chromatin response elements. However, this method still lacks a solid foundation for distinguishing between specific and nonspecific interactions. To address this issue, we took advantage of the power of molecular genetics of yeast. Yeast TF Ace1p has only five specific sites in the genome and thus serves as a benchmark to distinguish specific from non-specific binding. Here, we show that the estimated residence time of the short-residencemolecules is essentially the same for Hht1p, Ace1p and Hsf1p, equaling 0.12-0.32 s. These three DNA-binding proteins are very different in their structure, function and intracellular concentration. This suggests that (i) short-residence molecules are bound to DNA non-specifically, and (ii) that nonspecific binding shares common characteristics between vastly different DNA-bound proteins and thus may have a common underlying mechanism. We develop new and robust procedure for evaluation of adverse effects of labeling, and new quantitative analysis procedures that significantly improve residence time measurements by accounting for fluorophore blinking. Our results provide a framework for the reliable performance and analysis of single molecule TF experiments in yeast. C1 [Ball, David A.; Mehta, Gunjan D.; Salomon-Kent, Ronit; Karpova, Tatiana S.] NCI, CCR LRBGE Opt Microscopy Core, NIH, Bethesda, MD 20892 USA. [Mazza, Davide] Ist Sci Osped San Raffaele, Ctr Imaging Sperimentale, I-20132 Milan, Italy. [Mazza, Davide] Univ Vita Salute San Raffaele, I-20132 Milan, Italy. [Morisaki, Tatsuya] Colorado State Univ, Dept Biochem & Mol Biol, Ft Collins, CO 80523 USA. [Mueller, Florian] Inst Pasteur, CNRS, Computat Imaging & Modeling Unit, URA 2582, F-75015 Paris, France. [McNally, James G.] Helmholtz Ctr Berlin, Inst Soft Matter & Funct Mat, D-12489 Berlin, Germany. RP Karpova, TS (reprint author), NCI, CCR LRBGE Opt Microscopy Core, NIH, Bethesda, MD 20892 USA. EM karpovat@mail.nih.gov FU Intramural Research Program of National Institutes of Health (NIH); National Cancer Institute (NCI); Center for Cancer Research (CCR) FX Intramural Research Program of National Institutes of Health (NIH), National Cancer Institute (NCI) and Center for Cancer Research (CCR). Funding for open access charge: Intramural Research Program of National Institutes of Health (NIH). NR 32 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 DEC PY 2016 VL 44 IS 21 AR e160 DI 10.1093/nar/gkw744 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EK5PX UT WOS:000393979400005 PM 27566148 ER PT J AU Bayefsky, MJ White, A Wakim, P Hull, SC Wasserman, D Chen, S Berkman, BE AF Bayefsky, Michelle J. White, Amina Wakim, Paul Hull, Sara Chandros Wasserman, David Chen, Stephanie Berkman, Benjamin E. TI Views of American OB/GYNs on the ethics of prenatal wholegenome sequencing SO PRENATAL DIAGNOSIS LA English DT Article ID CLINICAL IMPLEMENTATION; INFORMATION; MEDICINE; CHALLENGES; DIAGNOSIS; ATTITUDES AB Objective Given public demand for genetic information, the potential to perform prenatal whole-genome sequencing (PWGS) non-invasively in the future, and decreasing costs of whole-genome sequencing, it is likely that OB/GYN practice will include PWGS. The goal of this project was to explore OB/GYNs' views on the ethical issues surrounding PWGS and their preparedness for counseling patients on its use. Methods A national survey was administered to 2500 members of American Congress of Obstetricians and Gynecologists. Results A total of 1114 respondents completed the survey (response rate = 45%). OB/GYNs are most concerned with ordering non-medical fetal genetic information, are worried about increasing parental anxiety, and feel it is appropriate to be directive when counseling parents about PWGS. Furthermore, most OB/GYNs have limited knowledge of genetics, rely heavily on genetic counselors and would like more guidance regarding the clinical adoption of PWGS. Conclusion OB/GYNs do not completely accept or reject PWGS, but a substantial number have significant ethical and practical concerns. They are most concerned with issues that will directly affect their practices and interactions with patients, such as increasing parental anxiety and costs of care. Professional guidance would be instrumental in directing the adoption of PWGS and alleviating the ethical burden posed by PWGS on individual OB/GYNs. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. C1 [Bayefsky, Michelle J.; Hull, Sara Chandros; Wasserman, David; Chen, Stephanie; Berkman, Benjamin E.] NIH, Dept Bioeth, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [White, Amina] Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC USA. [Wakim, Paul] NIH, Biostat & Clin Epidemiol Serv, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Berkman, Benjamin E.] NHGRI, Bioeth Core, NIH, Bethesda, MD 20892 USA. RP Berkman, BE (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA.; Berkman, BE (reprint author), NHGRI, Bioeth Core, NIH, Bethesda, MD 20892 USA. EM berkmanbe@mail.nih.gov NR 37 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0197-3851 EI 1097-0223 J9 PRENATAL DIAG JI Prenat. Diagn. PD DEC PY 2016 VL 36 IS 13 BP 1250 EP 1256 DI 10.1002/pd.4968 PG 7 WC Genetics & Heredity; Obstetrics & Gynecology SC Genetics & Heredity; Obstetrics & Gynecology GA EJ4QJ UT WOS:000393201600014 PM 27862072 ER PT J AU Kaufman, AR Grenen, E Grady, M Leyva, B Ferrer, RA AF Kaufman, Annette R. Grenen, Emily Grady, Meredith Leyva, Bryan Ferrer, Rebecca A. TI Perceptions of Harm and Addiction of Snus: An Exploratory Study SO PSYCHOLOGY OF ADDICTIVE BEHAVIORS LA English DT Article DE snus; harm; addiction; eye-tracking; qualitative ID GRAPHIC WARNING LABELS; SMOKELESS TOBACCO; YOUNG-ADULTS; SMOKERS PERCEPTIONS; PRODUCTS; AWARENESS; SMOKING AB Tobacco companies in the United States are prohibited from making reduced harm claims without filing a modified risk tobacco product application with the Food and Drug Administration and obtaining an order to market as such. However, it is possible that product marketing may suggest reduced risk to individuals. This study examines perceptions, in particular those related to harm and addiction, of snus print advertisements using a combination of eye-tracking, survey, and semistructured interviews. Participants were 22 male smokers ages 19-29 (M = 26.64, SD = 2.92). Five snus advertisements were each displayed for 20 s and eye movements were tracked. Participants responded to questions about harm and addiction after each advertisement and interviews were conducted after seeing all advertisements. For each advertisement, descriptive statistics were calculated and regression analyses predicted harm and addiction perceptions from eye tracking areas of interest (e.g., warning label). Qualitative data were analyzed using inductive/deductive thematic analysis. For certain advertisements, areas of interest were significantly associated with harm and/or addiction perceptions. For example, higher total fixation duration on the graphic in the Smokeless for Smokers advertisement was associated with decreased perceptions of addiction (B = -.360, p = .048). Qualitative themes emerged and in many instances corroborated quantitative results. This study indicates that for some advertisements, attention on certain areas (measured through eye tracking) is associated with perceptions among young male smokers. Understanding how smokers perceive and understand products after viewing advertisements may inform regulations regarding claims about product harm and addiction and may guide public health efforts to educate smokers on the risks of emerging products. C1 [Kaufman, Annette R.; Grady, Meredith] NCI, Tobacco Control Res Branch, Behav Res Program, Div Canc Control & Populat Sci,NIH, 9609 Med Ctr Dr,3-E-546, Rockville, MD 20850 USA. [Grenen, Emily] ICF Int, Technol & Management Solut, Rockville, MD USA. [Leyva, Bryan] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Ferrer, Rebecca A.] NCI, Basic Biobehav & Psychol Sci Branch, Div Canc Control & Populat Sci, NIH, Rockville, MD USA. RP Kaufman, AR (reprint author), NCI, Tobacco Control Res Branch, Behav Res Program, Div Canc Control & Populat Sci,NIH, 9609 Med Ctr Dr,3-E-546, Rockville, MD 20850 USA. EM kaufmana@mail.nih.gov NR 32 TC 0 Z9 0 U1 1 U2 1 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 0893-164X EI 1939-1501 J9 PSYCHOL ADDICT BEHAV JI Psychol. Addict. Behav. PD DEC PY 2016 VL 30 IS 8 BP 895 EP 903 DI 10.1037/adb0000230 PG 9 WC Substance Abuse; Psychology, Multidisciplinary SC Substance Abuse; Psychology GA EK1GK UT WOS:000393673600012 PM 28068113 ER PT J AU Nordstrom, RJ AF Nordstrom, Robert J. TI The Quantitative Imaging Network in Precision Medicine SO TOMOGRAPHY LA English DT Article DE Quantitative Imaging Network; precision medicine; therapy response ID CANCER AB Precision medicine is a healthcare model that seeks to incorporate a wealth of patient information to identify and classify disease progression and to provide tailored therapeutic solutions for individual patients. Interventions are based on knowledge of molecular and mechanistic causes, pathogenesis and pathology of disease. Individual characteristics of the patients are then used to select appropriate healthcare options. Imaging is playing an increasingly important role in identifying relevant characteristics that help to stratify patients for different interventions. However, lack of standards, limitations in image-processing interoperability, and errors in data collection can limit the applicability of imaging in clinical decision support. Quantitative imaging is the attempt to extract reliable, numerical information from images to eliminate qualitative judgments and errors for providing accurate measures of tumor response to therapy or for predicting future response. This issue of Tomography reports quantitative imaging developments made by several members of the National Cancer Institute Quantitative Imaging Network, a program dedicated to the promotion of quantitative imaging methods for clinical decision support. C1 [Nordstrom, Robert J.] NCI, Canc Imaging Program, Div Canc Treatment & Diag, 9609 Med Ctr Dr, Bethesda, MD 20852 USA. RP Nordstrom, RJ (reprint author), NCI, Canc Imaging Program, Div Canc Treatment & Diag, 9609 Med Ctr Dr, Bethesda, MD 20852 USA. EM nordstrr@mail.nih.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU GRAPHO PUBLICATIONS PI ANN ARBOR PA PO BOX 131281, ANN ARBOR, MI 48112-1281 USA SN 2379-1381 J9 TOMOGRAPHY JI Tomography PD DEC PY 2016 VL 2 IS 4 BP 239 EP 241 DI 10.18383/j.tom.2016.00190 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EK4BG UT WOS:000393871500001 PM 28083563 ER PT J AU Farahani, K Kalpathy-Cramer, J Chenevert, TL Rubin, DL Sunderland, JJ Nordstrom, RJ Buatti, J Hylton, N AF Farahani, Keyvan Kalpathy-Cramer, Jayashree Chenevert, Thomas L. Rubin, Daniel L. Sunderland, John J. Nordstrom, Robert J. Buatti, John Hylton, Nola TI Computational Challenges and Collaborative Projects in the NCI Quantitative Imaging Network SO TOMOGRAPHY LA English DT Article DE quantitative imaging; cancer therapy; crowdsourcing; challenge; collaborative project AB The Quantitative Imaging Network (QIN) of the National Cancer Institute (NCI) conducts research in development and validation of imaging tools and methods for predicting and evaluating clinical response to cancer therapy. Members of the network are involved in examining various imaging and image assessment parameters through network-wide cooperative projects. To more effectively use the cooperative power of the network in conducting computational challenges in benchmarking of tools and methods and collaborative projects in analytical assessment of imaging technologies, the QIN Challenge Task Force has developed policies and procedures to enhance the value of these activities by developing guidelines and leveraging NCI resources to help their administration and manage dissemination of results. Challenges and Collaborative Projects (CCPs) are further divided into technical and clinical CCPs. As the first NCI network to engage in CCPs, we anticipate a variety of CCPs to be conducted by QIN teams in the coming years. These will be aimed to benchmark advanced software tools for clinical decision support, explore new imaging biomarkers for therapeutic assessment, and establish consensus on a range of methods and protocols in support of the use of quantitative imaging to predict and assess response to cancer therapy. C1 [Farahani, Keyvan; Nordstrom, Robert J.] NCI, Canc Imaging Program, 9609 Med Ctr Dr,4W-312, Bethesda, MD 20892 USA. [Kalpathy-Cramer, Jayashree] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Chenevert, Thomas L.] Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. [Rubin, Daniel L.] Stanford Univ, Dept Radiol Biomed Data Sci & Med Biomed Informat, Palo Alto, CA 94304 USA. [Sunderland, John J.] Univ Iowa, Dept Radiol, Iowa City, IA 52242 USA. [Buatti, John] Univ Iowa, Dept Radiat Oncol, Iowa City, IA USA. [Hylton, Nola] Univ Calif San Francisco, Dept Radiol, San Francisco, CA USA. RP Farahani, K (reprint author), NCI, Canc Imaging Program, 9609 Med Ctr Dr,4W-312, Bethesda, MD 20892 USA. EM farahani@nih.gov FU National Cancer Institute, National Institutes of Health [U01CA142555, U01CA190214, U01CA187947, U01CA166104, U01CA140206, U01CA151235, U01CA154601] FX This work was supported, in part, by grants from the National Cancer Institute, National Institutes of Health, U01CA142555, U01CA190214, U01CA187947, U01CA166104, U01CA140206, U01CA151235, and U01CA154601. NR 17 TC 0 Z9 0 U1 0 U2 0 PU GRAPHO PUBLICATIONS PI ANN ARBOR PA PO BOX 131281, ANN ARBOR, MI 48112-1281 USA SN 2379-1381 J9 TOMOGRAPHY JI Tomography PD DEC PY 2016 VL 2 IS 4 BP 242 EP 249 DI 10.18383/j.tom.2016.00265 PG 8 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EK4BG UT WOS:000393871500002 ER EF