FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Guo, L Liu, F Chen, S Yang, X Huang, J He, J Jaquish, CE Zhao, Q Gu, CC Hixson, JE Gu, D AF Guo, L. Liu, F. Chen, S. Yang, X. Huang, J. He, J. Jaquish, C. E. Zhao, Q. Gu, C. C. Hixson, J. E. Gu, D. TI Common variants in the Na+-coupled bicarbonate transporter genes and salt sensitivity of blood pressure: the GenSalt study SO JOURNAL OF HUMAN HYPERTENSION LA English DT Article ID DIETARY-SODIUM; CARDIOVASCULAR-DISEASE; METABOLIC-ACIDOSIS; BASE-LINE; HYPERTENSION; COTRANSPORTER; SYSTEM; POLYMORPHISMS; ASSOCIATION; POTASSIUM AB The current study comprehensively examined the association between common variants in the Na+-coupled bicarbonate transporter (NCBT) genes and blood pressure (BP) responses to dietary sodium intervention. A 7-day low-sodium followed by a 7-day high-sodium dietary intervention was conducted among 1906 Han participants from rural areas of northern China. Nine BP measurements were obtained at baseline and each intervention using a random-zero sphygmomanometer. A mixed-effect model was used to assess the additive associations of 76 common variants in five NCBT genes, including SLC4A4, SLC4A5, SLC4A7, SLC4A8 and SLC4A10, with salt sensitivity phenotypes. The Bonferroni method was used to adjust for multiple testing. SLC4A4 marker rs4254735 was significantly associated with diastolic BP (DBP) response to low-sodium intervention (P = 5.05 x 10(-4)), with mean (95% confidence interval (CI)) response of -2.91 (-3.21, -2.61) and -0.40 (-1.84, 1.05) mmHg for genotype AA and AG, respectively. In addition, BP responses to high-sodium intervention significantly increased with the number of minor C alleles of SLC4A4 marker rs10022637. Mean systolic BP responses among those with genotypes TT, CT and CC were 4.62 (4.29, 4.99), 5.94 (5.31, 6.58) and 6.00 (3.57, 8.43) mmHg (P = 1.14 x 10(-4)); mean DBP responses were 1.72 (1.41, 2.03), 3.22 (2.52, 3.92) and 3.94 (1.88, 5.99) mmHg (P = 2.26 x 10(-5)) and mean arterial pressure responses were 2.69 (2.40, 2.97), 4.13 (3.57, 4.70) and 4.61 (2.51, 6.71) mmHg (P = 2.07 x 10(-6)), respectively. In brief, the present study indicated that common variants in the SLC4A4 gene might contribute to the variation of BP responses to dietary sodium intake in Han Chinese population. C1 [Guo, L.; Liu, F.; Chen, S.; Yang, X.; Huang, J.; Gu, D.] Chinese Acad Med Sci, State Key Lab Cardiovasc Dis, Dept Epidemiol, Fuwai Hosp,Natl Ctr Cardiovasc Dis, Beijing, Peoples R China. [Guo, L.; Liu, F.; Chen, S.; Yang, X.; Huang, J.; Gu, D.] Peking Union Med Coll, 167 Beilishi Rd, Beijing 100037, Peoples R China. [He, J.; Zhao, Q.] Tulane Univ, Dept Epidemiol, Sch Publ Hlth & Trop Med, New Orleans, LA 70118 USA. [Jaquish, C. E.] NHLBI, Div Prevent & Populat Sci, NIH, Bldg 10, Bethesda, MD 20892 USA. [Gu, C. C.] Washington Univ, St Louis Sch Med, Div Biostat, St Louis, MO USA. [Hixson, J. E.] Univ Texas Houston, Sch Publ Hlth, Dept Epidemiol, Houston, TX USA. RP Gu, D (reprint author), Peking Union Med Coll, 167 Beilishi Rd, Beijing 100037, Peoples R China.; Gu, D (reprint author), Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Fuwai Hosp, State Key Lab Cardiovasc Dis, 167 Beilishi Rd, Beijing 100037, Peoples R China. EM gudongfeng@vip.sina.com FU National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA [U01HL072507, R01HL087263, R01HL090682]; High-Tech Research and Development Program of China (863 Plan) from the Ministry of Science and Technology of China [2012AA02A516] FX The Genetic Epidemiology Network of Salt Sensitivity (GenSalt) is supported by research grants (U01HL072507, R01HL087263 and R01HL090682) from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. This study is also funded by a research grant (2012AA02A516) from the High-Tech Research and Development Program of China (863 Plan) from the Ministry of Science and Technology of China. NR 33 TC 2 Z9 2 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9240 EI 1476-5527 J9 J HUM HYPERTENS JI J. Hum. Hypertens. PD SEP PY 2016 VL 30 IS 9 BP 543 EP 548 DI 10.1038/jhh.2015.113 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DT2OA UT WOS:000381318500005 PM 26582410 ER PT J AU Perera, AP Mehta, GU Pratt, D Quezado, MM Gilbert, MR Heiss, JD AF Perera, Andrea P. Mehta, Gautam U. Pratt, Drew Quezado, Martha M. Gilbert, Mark R. Heiss, John D. TI Diagnosis of a growing radiation-induced skull lesion in a patient: an unusual scar SO JOURNAL OF NEUROSURGERY LA English DT Article DE fibroblast; lesion; skull; radiotherapy; oncology ID INDUCED FIBROSIS; CRANIAL FASCIITIS; DIFFERENTIATION; RADIOTHERAPY AB New lesions arising from within an area of previous irradiation often present a diagnostic dilemma, with new malignancy or metastasis of particular concern. The authors report a case of reactive fibroblast proliferation emerging from a previous radiation field and presenting as a growing lesion of the frontal and parietal skull. Following complete gross resection of the skull lesion and histopathological analysis, it was discovered that this lesion consisted of dense fibroblast proliferation with areas of osteonecrosis. This unusual reactive phenomenon offers a novel differential diagnosis for a new contrast-enhancing lesion in a region of previous radiation. C1 [Perera, Andrea P.] Queen Mary Univ London, Barts & London SMD, London, England. [Perera, Andrea P.; Mehta, Gautam U.; Heiss, John D.] NINDS, Surg Neurol Branch, 10 Ctr Dr,Rm 3D20,MSC 1414, Bethesda, MD 20892 USA. [Pratt, Drew; Quezado, Martha M.] NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Gilbert, Mark R.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Heiss, JD (reprint author), NINDS, NIH, Surg Neurol Branch, 10 Ctr Dr,Rm 3D20,MSC 1414, Bethesda, MD 20892 USA. EM heissj@ninds.nih.gov OI Heiss, John/0000-0002-3890-0165 FU Intramural Research Program at the National Institute of Neurological Disorders; Stroke (NINDS) at the National Institutes of Health (NIH) FX This work was supported by the Intramural Research Program at the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health (NIH). NR 14 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 EI 1933-0693 J9 J NEUROSURG JI J. Neurosurg. PD SEP PY 2016 VL 125 IS 3 BP 561 EP 564 DI 10.3171/2015.7.JNS15989 PG 4 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA DT8YS UT WOS:000381782300005 PM 26684773 ER PT J AU Mertan, FV Greer, MD Shih, JH George, AK Kongnyuy, M Muthigi, A Merino, MJ Wood, BJ Pinto, PA Choyke, PL Turkbey, B AF Mertan, Francesca V. Greer, Matthew D. Shih, Joanna H. George, Arvin K. Kongnyuy, Michael Muthigi, Akhil Merino, Maria J. Wood, Bradford J. Pinto, Peter A. Choyke, Peter L. Turkbey, Baris TI Prospective Evaluation of the Prostate Imaging Reporting and Data System Version 2 for Prostate Cancer Detection SO JOURNAL OF UROLOGY LA English DT Article DE prostate; magnetic resonance imaging; diffusion magnetic resonance imaging ID PI-RADS; BIOPSY; GUIDELINES; DIAGNOSIS; FUSION AB Purpose: Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) was developed to standardize the interpretation and reporting of multiparametric prostate magnetic resonance imaging and provide guidelines for biopsy of multiparametric magnetic resonance imaging findings. We prospectively evaluated the cancer detection rate at each overall PI-RADSv2 score. Materials and Methods: This prospective study included 62 consecutive patients with 116 lesions who underwent multiparametric prostate magnetic resonance imaging at 3T with PI-RADSv2 evaluation and subsequent targeted magnetic resonance imaging/transrectal ultrasound fusion guided biopsy and concurrent 12-core systematic prostate biopsy between May and September 2015. Median patient age and prostate specific antigen values were 65.5 years( range 50.3 to 76.6) and 7.10 ng/ml( range 0.47 to 863.0), respectively. Mean lesion size was 12.7 mm overall. Lesion based cancer detection rates for all tumors and for Gleason 3+4 or greater tumors at each PI-RADSv2 score were calculated. Univariate analysis was performed to assess differences in the cancer detection rate among PI-RADSv2 scores. Results: A total of 116 lesions in 62 patients were evaluated prospectively ( 0 PI-RADS 1, 18 PI-RADS 2, 19 PI-RADS 3, 47 PI-RADS 4, 32 PI-RADS 5), and the patients underwent magnetic resonance/transrectal ultrasound fusion guided biopsy and systematic biopsy. Histopathology revealed 55 of 116( 47.4%) cancers( 17 Gleason 3+3, 16 Gleason 3+4, 6 Gleason 4+3, 12 Gleason 4+4, 3 Gleason 4+5 and 1 Gleason 5+4). Based on targeted biopsy on a per lesion basis, the overall cancer detection rates of PI-RADS 2, 3, 4 and 5 scores for all tumors was 22.2%, 15.8%, 29.8% and 78.1%, respectively. The cancer detection rate of PI-RADS 2, 3, 4 and 5 scores for Gleason 3_4 or greater tumors was 5.6%, 0%, 21.3% and 75%, respectively. Differences in the cancer detection rate between overall PI-RADS 4 and 5 scores were significant( p < 0.001 for Gleason greater than 3+3 and Gleason 3+4 or greater cancers). Conclusions: A PI-RADS score of 5 had the highest prospective cancer detection rate (78%). A PI-RADS score of 4 had only a 30% cancer detection rate, which is lower than expected. Surprisingly, no or few significant cancers were detected at a PI-RADS score of 3 (16%). These early prospective data suggest that current criteria result in a high false-positive rate that lowers the cancer detection rate. Therefore, stricter criteria may be needed in the future to decrease false-positives and increase the cancer detection rate for PI-RADS scores of 3, 4 and 5. C1 [Mertan, Francesca V.; Greer, Matthew D.; Choyke, Peter L.; Turkbey, Baris] NCI, Mol Imaging Program, 10 Ctr Dr,MSC 1182,Bldg 10,Room B3B85, Bethesda, MD 20892 USA. [George, Arvin K.; Kongnyuy, Michael; Muthigi, Akhil; Pinto, Peter A.] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, Bldg 10, Bethesda, MD 20892 USA. [Wood, Bradford J.] NCI, Ctr Intervent Oncol, Bethesda, MD 20892 USA. [Wood, Bradford J.] NIH, Ctr Clin, Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Shih, Joanna H.] NCI, Div Canc Treatment & Diag, Biometr Res Program, NIH, Rockville, MD USA. RP Turkbey, B (reprint author), NCI, Mol Imaging Program, 10 Ctr Dr,MSC 1182,Bldg 10,Room B3B85, Bethesda, MD 20892 USA. EM turkbeyi@mail.nih.gov OI Greer, Matthew/0000-0003-4409-4398 NR 14 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD SEP PY 2016 VL 196 IS 3 BP 690 EP 696 DI 10.1016/j.juro.2016.04.057 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA DT1WF UT WOS:000381272100019 PM 27101772 ER PT J AU Turkbey, B Pinto, PA AF Turkbey, Baris Pinto, Peter A. TI Serial Anatomical Prostate Ultrasound during Prostate Cancer Active Surveillance SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 [Turkbey, Baris; Pinto, Peter A.] NCI, NIH, Bethesda, MD 20892 USA. RP Turkbey, B (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD SEP PY 2016 VL 196 IS 3 BP 733 EP 733 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA DT1WF UT WOS:000381272100029 PM 27264350 ER PT J AU Chai, TC Moalli, PA Richter, HE Lake, AG Kim, HY Nager, CW Sirls, LT Brubaker, L Kusek, JW AF Chai, Toby C. Moalli, Pamela A. Richter, Holly E. Lake, AeuMuro G. Kim, Hae-Young Nager, Charles W. Sirls, Larry T. Brubaker, Linda Kusek, John W. TI Preoperative Urodynamic Parameters (Valsalva Leak Point Pressure and Maximum Urethral Closure Pressure), Urinary Collagen and Plasma Vitamin D Levels as Predictors of Mid Urethral Sling Surgery Outcome SO JOURNAL OF UROLOGY LA English DT Article DE urethra; suburethral sling; urodynamics; biomarkers; outcome assessment (health care) ID NUTRITION-EXAMINATION-SURVEY; NATIONAL-HEALTH; N-TELOPEPTIDE; WOMEN; INCONTINENCE AB Purpose: To determine the best predictor of the mid urethral sling outcome we calculated the AUC of ROC curves of preoperative parameters, including Valsalva leak point pressure, maximum urethral closure pressure, urinary NTx (N-telopeptide of crosslinked type I collagen) and plasma vitamin D values (D2, D3 and D2 plus D3). Materials and Methods: This was an ancillary study of TOMUS (Trial of Mid-urethral Slings) and the ValUE (Value of Urodynamics Evaluation) trial in which subjects underwent mid urethral sling surgery for stress urinary incontinence. Valsalva leak point pressure and maximum urethral closure pressure were measured in 427 subjects, whereas NTx, vitamin D2, vitamin D3 and vitamin D2 plus D3 levels were obtained from 150, 116, 115 and 116 subjects respectively. Outcome success was defined using identical outcome (subjective and objective) variables for all subjects. ROC curves with corresponding AUC values were compared. Results: TOMUS and ValUE subjects were significantly different in age, body mass index, UDI (Urogenital Distress Inventory) scores. TOMUS subjects had a lower surgical success rate compared to ValUE subjects (66.3% vs 76.0%, p = 0.03). The AUC values of Valsalva leak point pressure, maximum urethral closure pressure, NTx, and vitamins D2, D3 and D2 plus D3 were 0.542, 0.561, 0.702, 0.627, 0.645 and 0.640, respectively. The AUC of NTx was significantly higher than the AUCs of Valsalva leak point pressure and maximum urethral closure pressure (p = 0.02 and 0.03, respectively). Conclusions: Urinary NTx was the best predictor of the mid urethral sling outcome. This test is not only noninvasive, it is also modifiable. Finding ideal modifiable risk factors prior to mid urethral sling surgery should be subject to future investigations. C1 [Chai, Toby C.; Lake, AeuMuro G.] Yale Univ, Sch Med, Dept Urol, 789 Howard Ave,FMP 309,POB 208058, New Haven, CT 06520 USA. [Chai, Toby C.; Lake, AeuMuro G.] Yale Univ, Sch Med, Dept Obstet Gynecol & Reprod Sci, New Haven, CT USA. [Moalli, Pamela A.] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Richter, Holly E.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Kim, Hae-Young] New England Res Inst, 9 Galen St, Watertown, MA 02172 USA. [Nager, Charles W.] Univ Calif San Diego, Dept Reprod Med, San Diego, CA 92103 USA. [Sirls, Larry T.] Beaumont Hosp, Dept Urol, Royal Oak, MI USA. [Brubaker, Linda] Loyola Univ, Chicago, IL 60611 USA. [Kusek, John W.] NIDDK, Bethesda, MD 20892 USA. RP Chai, TC (reprint author), Yale Univ, Sch Med, Dept Urol, 789 Howard Ave,FMP 309,POB 208058, New Haven, CT 06520 USA. EM toby.chai@yale.edu FU National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases [U01-DK058229] FX Supported by National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases U01-DK058229. NR 13 TC 1 Z9 1 U1 2 U2 2 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 SEP PY 2016 VL 196 IS 3 BP 819 EP 823 DI 10.1016/j.juro.2016.03.177 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA DT1WF UT WOS:000381272100065 PM 27113967 ER PT J AU Garcia-Beltran, WF Holzemer, A Martrus, G Chung, AW Pacheco, Y Simoneau, CR Rucevic, M Lamothe-Molina, PA Pertel, T Kim, TE Dugan, H Alter, G Dechanet-Merville, J Jost, S Carrington, M Altfeld, M AF Garcia-Beltran, Wilfredo F. Hoelzemer, Angelique Martrus, Gloria Chung, Amy W. Pacheco, Yovana Simoneau, Camille R. Rucevic, Marijana Lamothe-Molina, Pedro A. Pertel, Thomas Kim, Tae-Eun Dugan, Haley Alter, Galit Dechanet-Merville, Julie Jost, Stephanie Carrington, Mary Altfeld, Marcus TI Open conformers of HLA-F are high-affinity ligands of the activating NK-cell receptor KIR3DS1 SO NATURE IMMUNOLOGY LA English DT Article ID IMMUNOGLOBULIN-LIKE RECEPTOR; NATURAL-KILLER-CELL; MHC-I MOLECULES; CUTTING EDGE; DISEASE PROGRESSION; SURFACE EXPRESSION; PROTEIN; HIV-1; ANTIBODIES; COMPLEX AB The activating natural killer (NK)-cell receptor KIR3DS1 has been linked to the outcome of various human diseases, including delayed progression of disease caused by human immunodeficiency virus type 1 (HIV-1), yet a ligand that would account for its biological effects has remained unknown. We screened 100 HLA class I proteins and found that KIR3DS1 bound to HLA-F, a result we confirmed biochemically and functionally. Primary human KIR3DS1(+) NK cells degranulated and produced antiviral cytokines after encountering HLA-F and inhibited HIV-1 replication in vitro. Activation of CD4(+) T cells triggered the transcription and surface expression of HLA-F mRNA and HLA-F protein, respectively, and induced binding of KIR3DS1. HIV-1 infection further increased the transcription of HLA-F mRNA but decreased the binding of KIR3DS1, indicative of a mechanism for evading recognition by KIR3DS1(+) NK cells. Thus, we have established HLA-F as a ligand of KIR3DS1 and have demonstrated cell-context-dependent expression of HLA-F that might explain the widespread influence of KIR3DS1 in human disease. C1 [Garcia-Beltran, Wilfredo F.; Hoelzemer, Angelique; Chung, Amy W.; Pacheco, Yovana; Simoneau, Camille R.; Rucevic, Marijana; Lamothe-Molina, Pedro A.; Kim, Tae-Eun; Dugan, Haley; Alter, Galit; Jost, Stephanie; Carrington, Mary; Altfeld, Marcus] MGH MIT & Harvard, Ragon Inst, Cambridge, MA USA. [Hoelzemer, Angelique; Martrus, Gloria; Altfeld, Marcus] Leibniz Inst Expt Virol, Heinrich Pette Inst, Hamburg, Germany. [Hoelzemer, Angelique] Univ Med Ctr Eppendorf, Dept Internal Med 1, Hamburg, Germany. [Pacheco, Yovana] Univ Nuestra Senora Rosario, Fac Ciencias, Dept Maternat, Bogota, Colombia. [Pertel, Thomas] Harvard Med Sch, Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA USA. [Dechanet-Merville, Julie] Univ Bordeaux, CNRS, UMR 5164, Bordeaux, France. [Carrington, Mary] Frederick Natl Lab Canc Res, Canc & Inflammat Program, Expt Immunol Lab, Leidos Biomed Res, Frederick, MD USA. RP Altfeld, M (reprint author), MGH MIT & Harvard, Ragon Inst, Cambridge, MA USA.; Altfeld, M (reprint author), Leibniz Inst Expt Virol, Heinrich Pette Inst, Hamburg, Germany. EM marcus.altfeld@hpi.uni-hamburg.de FU Ragon Institute Flow Cytometry Core and Virology Core; US National Institutes of Health [R01-AI067031-08, P01-AI104715, F31AI116366]; US National Institutes of Health (Intramural Research Program, Frederick National Lab, Center for Cancer Research); National Institute of General Medical Sciences [T32GM007753]; Ragon Institute of MGH; Ragon Institute of MIT; Ragon Institute of Harvard; Frederick National Laboratory for Cancer Research [HHSN261200800001E]; Heinrich-Pette Institute-Leibniz Institute for Experimental Virology (Program Area Antiviral Targets and Strategies); German Center for Infection Research FX We thank C. Korner and A. Crespo for advice and discussions; D. Campana (St. Jude Children's Research Hospital) for K562 cells expressing mbIL-15 and CD137L; C. Brander (Ragon Institute of MGH, MIT, and Harvard) for 721.221 cells transduced to express HLA; J. Strominger (Harvard University) for 721.221-HLA-G cells; F. Zhang (Broad Institute of MIT and Harvard) for the lentiCas9-Blast plasmid; L. Ferreira (Harvard University) and T. Meissner (Harvard University) for beta2m-targeting single-guide RNA plasmid; and the Ragon Institute Flow Cytometry Core and Virology Core for support and assistance. Supported by the US National Institutes of Health (R01-AI067031-08 and P01-AI104715; F31AI116366 to W.F.G.-B.; the Intramural Research Program, Frederick National Lab, Center for Cancer Research), the National Institute of General Medical Sciences (T32GM007753), the Ragon Institute of MGH, MIT and Harvard, the Frederick National Laboratory for Cancer Research (HHSN261200800001E), the Heinrich-Pette Institute-Leibniz Institute for Experimental Virology (Program Area Antiviral Targets and Strategies) and the German Center for Infection Research. The content is solely the responsibility of the authors and does not necessarily represent the official views or policies of the National Institute of General Medical Sciences, the National Institutes of Health, or the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 50 TC 6 Z9 6 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD SEP PY 2016 VL 17 IS 9 BP 1067 EP 1074 DI 10.1038/ni.3513 PG 8 WC Immunology SC Immunology GA DT9OO UT WOS:000381832000010 PM 27455421 ER PT J AU Heilig, M Epstein, DH Nader, MA Shaham, Y AF Heilig, Markus Epstein, David H. Nader, Michael A. Shaham, Yavin TI Time to connect: bringing social context into addiction neuroscience SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID OPIOID-RECEPTOR GENE; CORTICOTROPIN-RELEASING-FACTOR; PLACEBO-CONTROLLED TRIAL; RANDOMIZED CONTROLLED-TRIAL; SUBSTANCE USE DISORDERS; ALCOHOL-DEPENDENCE; DRUG-ADDICTION; ANIMAL-MODELS; DOUBLE-BLIND; ATTACHMENT BEHAVIOR AB Research on the neural substrates of drug reward, withdrawal and relapse has yet to be translated into significant advances in the treatment of addiction. One potential reason is that this research has not captured a common feature of human addiction: progressive social exclusion and marginalization. We propose that research aimed at understanding the neural mechanisms that link these processes to drug seeking and drug taking would help to make addiction neuroscience research more clinically relevant. C1 [Heilig, Markus] Linkoping Univ, Ctr Social & Affect Neurosci, Dept Clin & Expt Med IKE, SE-58183 Linkoping, Sweden. [Epstein, David H.; Shaham, Yavin] NIDA, Intramural Res Program, NIH, Baltimore, MD 21044 USA. [Nader, Michael A.] Wake Forest Sch Med, Dept Physiol & Pharmacol, Winston Salem, NC 27157 USA. RP Heilig, M (reprint author), Linkoping Univ, Ctr Social & Affect Neurosci, Dept Clin & Expt Med IKE, SE-58183 Linkoping, Sweden. EM markus.heilig@liu.se FU Swedish Research Council; Intramural Research Program of the US National Institutes of Health; US National Institute on Drug Abuse [DA010584, DA017763] FX The writing of this article was supported in part by a grant from the Swedish Research Council (M.H.), the Intramural Research Program of the US National Institutes of Health and the US National Institute on Drug Abuse (D.H.E. and Y.S.) and grants DA010584 and DA017763 (M.A.N.). The authors are grateful to S. N. Haber at the University of Rochester, New York, USA, and her co-workers for producing and providing Figure 3. The authors apologize to their many friends and colleagues for not citing many reviews and empirical papers relevant to the topic of their paper, owing to format restrictions. NR 127 TC 4 Z9 4 U1 11 U2 21 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X EI 1471-0048 J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD SEP PY 2016 VL 17 IS 9 BP 592 EP 599 DI 10.1038/nrn.2016.67 PG 8 WC Neurosciences SC Neurosciences & Neurology GA DU5MK UT WOS:000382255600012 PM 27277868 ER PT J AU Bandres-Ciga, S Price, TR Barrero, FJ Escamilla-Sevilla, F Pelegrina, J Arepalli, S Hernandez, D Gutierrez, B Cervilla, J Rivera, M Rivera, A Ding, JH Vives, F Nalls, M Singleton, A Duran, R AF Bandres-Ciga, Sara Price, Timothy Ryan Barrero, Francisco Javier Escamilla-Sevilla, Francisco Pelegrina, Javier Arepalli, Sampath Hernandez, Dena Gutierrez, Blanca Cervilla, Jorge Rivera, Margarita Rivera, Alberto Ding, Jing-hui Vives, Francisco Nalls, Michael Singleton, Andrew Duran, Raquel TI Genome-wide assessment of Parkinson's disease in a Southern Spanish population SO NEUROBIOLOGY OF AGING LA English DT Article DE Parkinson's disease; Genetics; GWAS; Southern Spain ID RISK LOCI; GENETIC RISK; MUTATIONS; ASSOCIATION; ONSET; METAANALYSIS; AGE; IDENTIFICATION; VARIANTS; COMPLEX AB Here, we set out to study the genetic architecture of Parkinson's disease (PD) through a Genome-Wide Association Study in a Southern Spanish population. About 240 PD cases and 192 controls were geno-typed on the NeuroX array. We estimated genetic variation associated with PD risk and age at onset (AAO). Risk profile analyses for PD and AAO were performed using a weighted genetic risk score. Total heritability was estimated by genome-wide complex trait analysis. Rare variants were screened with single-variant and burden tests. We also screened for variation in known PD genes. Finally, we explored runs of homozygosity and structural genomic variations. We replicate PD association (uncorrected p-value < 0.05) at the following loci: ACMSD/TMEM163, MAPT, STK39, MIR4697, and SREBF/RAI1. Subjects in the highest genetic risk score quintile showed significantly increased risk of PD versus the lowest quintile (odds ratio - 3.6, p-value < 4e(-7)), but no significant difference in AAO. We found evidence of runs of homozygosity in 2 PD-associated regions: one intersecting the HLA-DQB1 gene in 6 patients and 1 control; and another intersecting the GBA-SYT11 gene in PD case. The GBA N370S and the LRRK2 G2019S variants were found in 8 and 7 cases, respectively, replicating previous work. A structural variant was found in 1 case in the PARK2 gene locus. This current work represents a comprehensive assessment at a genome-wide level characterizing a novel population in PD genetics. (C) 2016 Elsevier Inc. All rights reserved. C1 [Bandres-Ciga, Sara; Vives, Francisco; Duran, Raquel] Univ Granada, Ctr Invest Biomed CIBM, Dept Physiol, Granada 18016, Spain. [Bandres-Ciga, Sara; Gutierrez, Blanca; Cervilla, Jorge; Rivera, Margarita; Vives, Francisco; Duran, Raquel] Univ Granada, Ctr Invest Biomed CIBM, Inst Neurosci Federico Oloriz, Granada 18016, Spain. [Price, Timothy Ryan; Arepalli, Sampath; Hernandez, Dena; Rivera, Alberto; Ding, Jing-hui; Nalls, Michael; Singleton, Andrew] NIA, Neurogenet Lab, NIH, Bethesda, MD USA. [Barrero, Francisco Javier; Pelegrina, Javier] Univ Hosp San Cecilio, Movement Disorders Unit, Granada, Spain. [Escamilla-Sevilla, Francisco] Univ Hosp Virgen Nieves, Inst Invest Biosanitaria IBS, Dept Neurol, Movement Disorders Unit, Granada, Spain. [Gutierrez, Blanca; Cervilla, Jorge; Rivera, Margarita] Univ Granada, Ctr Invest Biomed CIBM, Dept Psychiat, Granada, Spain. [Gutierrez, Blanca; Cervilla, Jorge; Rivera, Margarita] Univ Granada, CIBER Salud Mental CIBERSAM, Granada, Spain. RP Duran, R (reprint author), Univ Granada, Ctr Invest Biomed CIBM, Dept Physiol, Granada 18016, Spain.; Duran, R (reprint author), Univ Granada, Ctr Invest Biomed CIBM, Inst Neurosci Federico Oloriz, Granada 18016, Spain. EM rduran@ugr.es RI Cervilla, Jorge/O-2106-2016; DURAN , RAQUEL/D-7784-2016; OI Cervilla, Jorge/0000-0001-6891-1992; DURAN , RAQUEL/0000-0002-5749-8968; Bandres Ciga, Sara/0000-0003-0056-1361 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services [ZO1 AG000949]; Junta de Andalucia [PI0322/2009]; Andalusian Society of Neurology; FPU fellowship [FPU12-01885]; Spanish Ministry of Education and Science [EST14/0061]; [CVI-6476]; [PSI2014-57643] FX The authors are grateful to the participants in this study without whom this work would not have been possible. Sara Bandres Ciga and Timothy Ryan Price contributed equally to this work. Andrew Singleton, Michael Nalls, Dena Hernandez, Raquel Duran, and Francisco Vives contributed to study concept, design, revision, and critique. Sampath Arepalli and Sara Bandres Ciga contributed for execution of the laboratory work. Timothy Ryan Price, Sara Bandres Ciga, Alberto Rivera, and Jing-Hui Ding contributed for data analysis. Francisco Barrero-Hernandez, Francisco Escamilla-Sevilla, Javier Pelegrina, Blanca Gutierrez, Jorge Cervilla, and Margarita Rivera contributed to neurological-clinical assessment, patient and control recruitment, and sample collection. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, part of the Department of Health and Human Services (project ZO1 AG000949), the following grants from the Junta de Andalucia; PI0322/2009 to the group CTS-6682; CVI-6476 and PSI2014-57643 to the CTS-438 group, and a research award from the Andalusian Society of Neurology. Sara Bandres Ciga held an FPU fellowship FPU12-01885 and a short-term stay grant EST14/0061 from the Spanish Ministry of Education and Science. NR 45 TC 0 Z9 0 U1 10 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD SEP PY 2016 VL 45 AR 213.e3 DI 10.1016/j.neurobiolaging.2016.06.001 PG 7 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA DS9HF UT WOS:000381092900026 PM 27393345 ER PT J AU Padayatty, SJ Levine, M AF Padayatty, S. J. Levine, M. TI Vitamin C: the known and the unknown and Goldilocks SO ORAL DISEASES LA English DT Review DE vitamin C; dehydroascorbic acid; vitamin C transport; scurvy; dose-concentration relationship; recommended dietary allowance ID L-ASCORBIC-ACID; HYPOXIA-INDUCIBLE FACTOR; RECOMMENDED DIETARY ALLOWANCE; CHRONIC GRANULOMATOUS-DISEASE; PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; ENDOTHELIUM-DEPENDENT VASODILATION; PERFORMANCE LIQUID-CHROMATOGRAPHY; HUMAN ERYTHROCYTE-MEMBRANES; ACUTE MYOCARDIAL-INFARCTION; RANDOMIZED CONTROLLED-TRIAL AB Vitamin C (Ascorbic Acid), the antiscorbutic vitamin, cannot be synthesized by humans and other primates, and has to be obtained from diet. Ascorbic acid is an electron donor and acts as a cofactor for fifteen mammalian enzymes. Two sodium-dependent transporters are specific for ascorbic acid, and its oxidation product dehydroascorbic acid is transported by glucose transporters. Ascorbic acid is differentially accumulated by most tissues and body fluids. Plasma and tissue vitamin C concentrations are dependent on amount consumed, bioavailability, renal excretion, and utilization. To be biologically meaningful or to be clinically relevant, in vitro and in vivo studies of vitamin C actions have to take into account physiologic concentrations of the vitamin. In this paper, we review vitamin C physiology; the many phenomena involving vitamin C where new knowledge has accrued or where understanding remains limited; raise questions about the vitamin that remain to be answered; and explore lines of investigations that are likely to be fruitful. C1 [Padayatty, S. J.; Levine, M.] NIDDK, Mol & Clin Nutr Sect, Digest Dis Branch, NIH, Bldg 10,Room 4D52,MSC 1372, Bethesda, MD 20892 USA. RP Padayatty, SJ (reprint author), NIDDK, Mol & Clin Nutr Sect, Digest Dis Branch, NIH, Bldg 10,Room 4D52,MSC 1372, Bethesda, MD 20892 USA. EM sebastianp@intra.niddk.nih.gov FU Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [1ZIADK053211-08] FX This work was supported by the Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (Project no: 1ZIADK053211-08). SJP thanks Drs. Michael Espey, Peter Eck, and Nermi Parrow for helpful suggestions; Dr. Eck for information on SVCT SNPs deposited in databases; and Ethan Tyler, NIH Medical Arts, for new and modified illustrations. NR 331 TC 1 Z9 1 U1 23 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1354-523X EI 1601-0825 J9 ORAL DIS JI Oral Dis. PD SEP PY 2016 VL 22 IS 6 BP 463 EP 493 DI 10.1111/odi.12446 PG 31 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DS8PB UT WOS:000381044200003 PM 26808119 ER PT J AU Arimbasseri, AG Iben, J Wei, FY Rijal, K Tomizawa, K Hafner, M Maraia, RJ AF Arimbasseri, Aneeshkumar G. Iben, James Wei, Fan-Yan Rijal, Keshab Tomizawa, Kazuhito Hafner, Markus Maraia, Richard J. TI Evolving specificity of tRNA 3-methyl-cytidine-32 (m(3)C32) modification: a subset of tRNAs(Ser) requires N-6-isopentenylation of A37 SO RNA LA English DT Article DE anticodon loop; isopentenylation; tRNA-HySeq ID MULTIPLE SEQUENCE ALIGNMENT; TRNA(PHE) ANTICODON LOOP; BINDING PROTEIN ABP140; SERINE TRANSFER-RNA; SACCHAROMYCES-CEREVISIAE; THERMUS-THERMOPHILUS; NUCLEOTIDE-SEQUENCES; HIGH-THROUGHPUT; BOVINE LIVER; LA PROTEIN AB Post-transcriptional modifications of anticodon loop (ACL) nucleotides impact tRNA structure, affinity for the ribosome, and decoding activity, and these activities can be fine-tuned by interactions between nucleobases on either side of the anticodon. A recently discovered ACL modification circuit involving positions 32, 34, and 37 is disrupted by a human disease-associated mutation to the gene encoding a tRNA modification enzyme. We used tRNA-HydroSeq (-HySeq) to examine (3)methyl-cytidine-32 (m(3)C32), which is found in yeast only in the ACLs of tRNAs(Ser) and tRNAs(Thr). In contrast to that reported for Saccharomyces cerevisiae in which all m(3)C32 depends on a single gene, TRM140, the m(3)C32 of tRNAs(Ser) and tRNAs(Thr) of the fission yeast S. pombe, are each dependent on one of two related genes, trm140(+) and trm141(+), homologs of which are found in higher eukaryotes. Interestingly, mammals and other vertebrates contain a third homolog and also contain m(3)C at new sites, positions 32 on tRNAs(Arg) and C47:3 in the variable arm of tRNAs(Ser). More significantly, by examining S. pombe mutants deficient for other modifications, we found that m(3)C32 on the three tRNAs(Ser) that contain anticodon base A36, requires N-6-isopentenyl modification of A37 (i(6)A37). This new C32 A37 ACL circuitry indicates that i(6)A37 is a pre- or corequisite for m(3)C32 on these tRNAs. Examination of the tRNA database suggests that such circuitry may be more expansive than observed here. The results emphasize two contemporary themes, that tRNA modifications are interconnected, and that some specific modifications on tRNAs of the same anticodon identity are species-specific. C1 [Arimbasseri, Aneeshkumar G.; Iben, James; Rijal, Keshab] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Wei, Fan-Yan; Tomizawa, Kazuhito] Kumamoto Univ, Dept Mol Physiol, Fac Life Sci, Kumamoto 8600862, Japan. [Hafner, Markus] NIAMSD, Natl Inst Hlth, Bethesda, MD 20892 USA. [Maraia, Richard J.] US PHS, Commissioned Corps, Washington, DC 20201 USA. [Arimbasseri, Aneeshkumar G.] North Carolina State Univ, Dept Biomol & Chem Engn, Raleigh, NC 27606 USA. RP Maraia, RJ (reprint author), US PHS, Commissioned Corps, Washington, DC 20201 USA. EM maraiar@mail.nih.gov OI Arimbasseri, Gopalakrishnan Aneeshkumar/0000-0001-5266-2688 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health FX A.G.A. thanks S. Mattijssen for cell lines and advice with tissue culture, and M. Blum for media preparation. This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. NR 57 TC 1 Z9 1 U1 0 U2 1 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 SEP PY 2016 VL 22 IS 9 BP 1400 EP 1410 DI 10.1261/rna.056259.116 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DU1GV UT WOS:000381957100011 PM 27354703 ER PT J AU Koob, GF AF Koob, George F. TI Corticotropin-Releasing Factor From Rodents to Primates: Translational Hope Expresses Itself, Pun Intended SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID STRESS; BEHAVIORS; CRF C1 [Koob, George F.] NIAAA, NIH, Bethesda, MD USA. RP Koob, GF (reprint author), NIAAA, 5635 Fishers Lane,Room 2001,Suite 2000, Rockville, MD 20852 USA. EM george.koob@nih.gov RI koob, george/P-8791-2016 NR 10 TC 0 Z9 0 U1 1 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 SEP 1 PY 2016 VL 80 IS 5 BP 340 EP 342 DI 10.1016/j.biopsych.2016.06.015 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DS5RR UT WOS:000380840500004 PM 27499011 ER PT J AU Grillon, C Ernst, M AF Grillon, Christian Ernst, Monique TI Gain in Translation: Is It Time for Thigmotaxis Studies in Humans? SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID PROGRESS; ANXIETY; MODEL C1 [Grillon, Christian; Ernst, Monique] NIMH, Sect Neurobiol Fear & Anxiety, NIH, Bethesda, MD 20892 USA. RP Grillon, C (reprint author), NIMH, MAP, 15K North Dr,Bldg 15K,Room 203,MSC 2670, Bethesda, MD 20892 USA. EM christian.grillon@nih.gov FU Intramural NIH HHS [Z01 MH002798-07]; NIMH NIH HHS [Z01 MH002798] NR 10 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD SEP 1 PY 2016 VL 80 IS 5 BP 343 EP 344 DI 10.1016/j.biopsych.2016.07.003 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DS5RR UT WOS:000380840500005 PM 27499012 ER PT J AU Lansford, JE Bornstein, MH Deater-Deckard, K Dodge, KA Al-Hassan, SM Bacchini, D Bombi, AS Chang, L Chen, BB Di Giunta, L Malone, PS Oburu, P Pastorelli, C Skinner, AT Sorbring, E Steinberg, L Tapanya, S Alampay, LP Tirado, LMU Zelli, A AF Lansford, Jennifer E. Bornstein, Marc H. Deater-Deckard, Kirby Dodge, Kenneth A. Al-Hassan, Suha M. Bacchini, Dario Bombi, Anna Silvia Chang, Lei Chen, Bin-Bin Di Giunta, Laura Malone, Patrick S. Oburu, Paul Pastorelli, Concetta Skinner, Ann T. Sorbring, Emma Steinberg, Laurence Tapanya, Sombat Alampay, Liane P. Uribe Tirado, Liliana M. Zelli, Arnaldo TI How International Research on Parenting Advances Understanding of Child Development SO CHILD DEVELOPMENT PERSPECTIVES LA English DT Article DE child development; culture; international research; parenting ID 9 COUNTRIES; ACCEPTANCE-REJECTION; ADJUSTMENT; DISCIPLINE; NORMATIVENESS; ASSOCIATIONS; AMERICAN; CULTURE; CHINESE; WARMTH AB International research on parenting and child development can advance our understanding of similarities and differences in how parenting is related to children's development across countries. Challenges to conducting international research include operationalizing culture, disentangling effects within and between countries, and balancing emic and etic perspectives. Benefits of international research include testing whether findings regarding parenting and child development replicate across diverse samples, incorporating cultural and contextual diversity to foster more inclusive and representative research samples and investigators than has typically occurred, and understanding how children develop in proximal parenting and family and distal international contexts. C1 [Lansford, Jennifer E.; Dodge, Kenneth A.; Malone, Patrick S.; Skinner, Ann T.] Duke Univ, Durham, NC 27706 USA. [Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Deater-Deckard, Kirby] Univ Massachusetts, Amherst, MA 01003 USA. [Al-Hassan, Suha M.] Hashemite Univ, Zarqa, Jordan. [Al-Hassan, Suha M.] Emirates Coll Adv Educ, Abu Dhabi, U Arab Emirates. [Bacchini, Dario] Univ Naples 2, Naples, Italy. [Bombi, Anna Silvia; Di Giunta, Laura; Pastorelli, Concetta] Univ Roma La Sapienza, Rome, Italy. [Chang, Lei] Univ Macau, Zhuhai, Peoples R China. [Chen, Bin-Bin] Fudan Univ, Shanghai, Peoples R China. [Oburu, Paul] Maseno Univ, Kisumu, Kenya. [Sorbring, Emma] Univ West, Trollhattan, Sweden. [Steinberg, Laurence] Temple Univ, Philadelphia, PA 19122 USA. [Steinberg, Laurence] King Abdulaziz Univ, Jeddah, Saudi Arabia. [Tapanya, Sombat] Chiang Mai Univ, Chiang Mai, Thailand. [Alampay, Liane P.] Ateneo Manila Univ, Quezon City, Philippines. [Uribe Tirado, Liliana M.] Univ San Buenaventura, Cali, Colombia. [Zelli, Arnaldo] Univ Rome Foro Italico, Rome, Italy. RP Lansford, JE (reprint author), Duke Univ, Ctr Child & Family Policy, Box 90545, Durham, NC 27708 USA. EM lansford@duke.edu OI ZELLI, Arnaldo/0000-0003-4020-8159 FU Jacobs Foundation; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [RO1-HD054805]; Fogarty International Center [RO3-TW008141]; National Institute on Drug Abuse [K01DA024116, 2K05 DA015226]; Intramural Research Program of the National Institutes of Health/NICHD FX This article was prepared, in part, during a Marbach Residence Program funded by the Jacobs Foundation. The research featured in this article was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; Grant RO1-HD054805) and the Fogarty International Center (Grant RO3-TW008141). Patrick S. Malone is supported by Grant K01DA024116 from the National Institute on Drug Abuse. Kenneth A. Dodge is supported by Senior Scientist award 2K05 DA015226 from the National Institute on Drug Abuse. This research also was supported by the Intramural Research Program of the National Institutes of Health/NICHD. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or NICHD. NR 42 TC 0 Z9 0 U1 7 U2 10 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1750-8592 EI 1750-8606 J9 CHILD DEV PERSPECT JI Child Develop. Perspect. PD SEP PY 2016 VL 10 IS 3 BP 202 EP 207 DI 10.1111/cdep.12186 PG 6 WC Psychology, Developmental SC Psychology GA DS7GV UT WOS:000380952100011 PM 27725843 ER PT J AU Vergallo, R Xing, L Minami, Y Soeda, T Ong, DS Gao, L Lee, H Guagliumi, G Biasucci, LM Crea, F Yu, B Uemura, S O'Donnell, CJ Jang, IK AF Vergallo, Rocco Xing, Lei Minami, Yoshiyasu Soeda, Tsunenari Ong, Daniel S. Gao, Lei Lee, Hang Guagliumi, Giulio Biasucci, Luigi M. Crea, Filippo Yu, Bo Uemura, Shiro O'Donnell, Christopher J. Jang, Ik-Kyung TI Associations between the Framingham Risk Score and coronary plaque characteristics as assessed by three-vessel optical coherence tomography SO CORONARY ARTERY DISEASE LA English DT Article DE coronary artery disease; Framingham Risk Score; optical coherence tomography ID INTRAVASCULAR ULTRASOUND; ATHEROSCLEROTIC PLAQUE; HEART-DISEASE; ETHNIC-GROUPS; PROGRESSION; ARTERY; CALCIFICATION; BURDEN; VALIDATION; PREDICTION AB Objectives This study sought to explore the association between the Framingham Risk Score (FRS) and coronary plaque characteristics assessed by optical coherence tomography (OCT) imaging. Background Clinical prediction models are useful for identifying high-risk patients. However, coronary events often occur in individuals estimated to be at low risk. Methods A total of 254 patients with coronary artery disease who underwent three-vessel OCT were divided into tertiles according to FRS. Nonculprit plaque characteristics were compared among the three groups. Results A total of 663 plaques were analyzed. FRS was significantly associated with calcification [37% (low FRS) vs. 46% (intermediate FRS) vs. 70% (high FRS); P<0.001] and neovascularization [39% (low FRS) vs. 41% (intermediate FRS) vs. 56% (high FRS); P<0.001], but not with lipid-rich plaques or thin-cap fibroatheroma (TCFA). On multivariate analysis, FRS was an independent predictor of the presence of both calcification and neovascularization. There were no deaths, two acute myocardial infarctions, and 15 nontarget lesion revascularizations at the 1-year followup. The event rate increased progressively across FRS tertiles [2.4% (low FRS) vs. 7.1% (intermediate FRS) vs. 8.6% (high FRS); P=0.186]. The c-statistic for FRS to predict future clinical events was 0.628 (95% confidence interval, 0.500-0.757). The addition of both calcification and TCFA to FRS provided incremental prognostic value [c-statistics: 0.761 (95% confidence interval, 0.631-0.890)]. Conclusion The present study showed significant associations between FRS and the presence of coronary calcification and neovascularization in nonculprit plaques. The combination of FRS and OCT-detected calcifications and TCFA provides improved prognostic ability in identifying patients with known coronary artery disease who are at risk of recurrent events. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Vergallo, Rocco; Xing, Lei; Minami, Yoshiyasu; Soeda, Tsunenari; Ong, Daniel S.; Gao, Lei; O'Donnell, Christopher J.; Jang, Ik-Kyung] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, GRB 800,55 Fruit St, Boston, MA 02114 USA. [Lee, Hang] Harvard Med Sch, Massachusetts Gen Hosp, Biostat Ctr, Boston, MA USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Xing, Lei; Yu, Bo] Harbin Med Univ, Dept Cardiol, Affiliated Hosp 2, Harbin, Peoples R China. [Guagliumi, Giulio] Osped Papa Giovanni XXIII, Cardiovasc Dept, Bergamo, Italy. [Biasucci, Luigi M.; Crea, Filippo] Univ Cattolica Sacro Cuore, Dept Cardiovasc Med, Rome, Italy. [Uemura, Shiro] Nara Med Univ, Dept Cardiol, Nara, Japan. [Jang, Ik-Kyung] Kyung Hee Univ, Div Cardiol, Seoul, South Korea. RP Jang, IK (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, GRB 800,55 Fruit St, Boston, MA 02114 USA. EM ijang@mgh.harvard.edu FU Michael and Kathryn Park; Gill and Allan Gray; St Jude Medical; Italian Society of Cardiology Award for Research Abroad and the 'Enrico ed Enrica Sovena' Foundation, Rome, Italy FX Dr Jang's research was supported by Michael and Kathryn Park, and by Gill and Allan Gray. Dr Jang has received grants and consulting fees from St Jude Medical. Dr Vergallo was supported by the 2013 Italian Society of Cardiology Award for Research Abroad and the 'Enrico ed Enrica Sovena' Foundation, Rome, Italy. For the remaining authors there are no conflicts of interest. NR 28 TC 0 Z9 0 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0954-6928 EI 1473-5830 J9 CORONARY ARTERY DIS JI Coronary Artery Dis. PD SEP PY 2016 VL 27 IS 6 BP 460 EP 466 DI 10.1097/MCA.0000000000000383 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DS5FI UT WOS:000380806300005 PM 27218146 ER PT J AU Lewandowski, LB Kaplan, MJ AF Lewandowski, Laura B. Kaplan, Mariana J. TI Update on cardiovascular disease in lupus SO CURRENT OPINION IN RHEUMATOLOGY LA English DT Review DE atherosclerosis; cardiovascular disease; interferons; neutrophil extracellular traps; systemic lupus erythematosus ID NEUTROPHIL EXTRACELLULAR TRAPS; INTERNATIONAL INCEPTION COHORT; LOW-DENSITY-LIPOPROTEIN; 25-HYDROXYVITAMIN D DEFICIENCY; POPULATION-BASED COHORT; CORONARY-HEART-DISEASE; RISK-FACTORS; SUBCLINICAL ATHEROSCLEROSIS; ENDOTHELIAL DYSFUNCTION; METABOLIC SYNDROME AB Purpose of review Atherosclerotic cardiovascular disease confers significant morbidity and mortality in patients with systemic lupus erythematosus (SLE) and cannot be fully explained by traditional cardiovascular risk factors. Recent immunologic discoveries have outlined putative pathways in SLE that may also accelerate the development of atherosclerosis. Recent findings Aberrant innate and adaptive immune responses implicated in lupus pathogenesis may also contribute to the development of accelerated atherosclerosis in these patients. Defective apoptosis, abnormal lipoprotein function, autoantibodies, aberrant neutrophil responses, and a dysregulated type I interferon pathway likely contribute to endothelial dysfunction. SLE macrophages have an inflammatory phenotype that may drive progression of plaque. Summary Recent discoveries have placed increased emphasis on the immunology of atherosclerotic cardiovascular disease. Understanding the factors that drive the increased risk for cardiovascular disease in SLE patients may provide selective therapeutic targets for reducing inflammation and improving outcomes in atherosclerosis. C1 [Lewandowski, Laura B.; Kaplan, Mariana J.] NIAMSD, Syst Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Kaplan, MJ (reprint author), NIAMS, Syst Autoimmun Branch, NIH, 10 Ctr Dr,6D47C, Bethesda, MD 20892 USA. EM Mariana.kaplan@nih.gov FU NIAMS/NIH; Lupus Research Institute FX This work was supported by the Intramural Research Program, NIAMS/NIH and the Lupus Research Institute. NR 114 TC 0 Z9 0 U1 10 U2 12 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 SEP PY 2016 VL 28 IS 5 BP 460 EP 468 DI 10.1097/BOR.0000000000000307 PG 9 WC Rheumatology SC Rheumatology GA DS5AS UT WOS:000380793500002 ER PT J AU Janssen, I Chen, CC Millo, CM Ling, A Taieb, D Lin, FI Adams, KT Wolf, KI Herscovitch, P Fojo, AT Buchmann, I Kebebew, E Pacak, K AF Janssen, Ingo Chen, Clara C. Millo, Corina M. Ling, Alexander Taieb, David Lin, Frank I. Adams, Karen T. Wolf, Katherine I. Herscovitch, Peter Fojo, Antonio T. Buchmann, Inga Kebebew, Electron Pacak, Karel TI PET/CT comparing Ga-68-DOTATATE and other radiopharmaceuticals and in comparison with CT/MRI for the localization of sporadic metastatic pheochromocytoma and paraganglioma SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article DE Ga-68-DOTATATE; F-18-FDG; Pheochromocytoma; Paraganglioma; Metastatic ID POSITRON-EMISSION-TOMOGRAPHY; I-123-MIBG SPECT; TUMORS; SDHB; DIAGNOSIS; CANCER; HEAD; NEUROENDOCRINE; METAANALYSIS; SUPERIORITY AB Pheochromocytomas/paragangliomas (PPGLs) and their metastases are tumors that predominantly express somatostatin receptor 2 (SSR2). Ga-68-DOTA(0)-Tyr(3)-octreotate (Ga-68-DOTATATE) is a PET radiopharmaceutical with both high and selective affinity for SSRs. The purpose of this study was to evaluate the utility of Ga-68-DOTATATE in comparison with other specific and nonspecific radiopharmaceuticals recommended in the current guidelines for the localization of metastatic sporadic PPGL by PET/CT. This prospective study included 22 patients (15 men, 7 women; aged 50.0 +/- 13.9 years) with confirmed metastatic PPGL, a negative family history for PPGL, and negative genetic testing, who underwent Ga-68-DOTATATE, F-18-fluoro-2-deoxy-D-glucose (F-18-FDG) PET/CT, and CT/MRI. Only 12 patients underwent an additional F-18-fluorodihydroxyphenylalanine (F-18-FDOPA) PET/CT scan and only 11 patients underwent an additional F-18-fluorodopamine (F-18-FDA) PET/CT scan. The rates of detection of metastatic lesions were compared among all the imaging studies. A composite of all functional and anatomical imaging studies served as the imaging comparator. Ga-68-DOTATATE PET/CT showed a lesion-based detection rate of 97.6 % (95 % confidence interval, CI, 95.8 - 98.7 %). F-18-FDG PET/CT, F-18-FDOPA PET/CT, F-18-FDA PET/CT, and CT/MRI showed detection rates of 49.2 % (CI 44.5 - 53.6 %; p < 0.01), 74.8 % (CI 69.0 - 79.9 %); p < 0.01), 77.7 % (CI 71.5 - 82.8 %; p < 0.01), and 81.6 % (CI 77.8 - 84.8 %; p < 0.01), respectively. The results of this study demonstrate the superiority of Ga-68-DOTATATE PET/CT in the localization of sporadic metastatic PPGLs compared to all other functional and anatomical imaging modalities, and suggest modification of future guidelines towards this new imaging modality. C1 [Janssen, Ingo; Adams, Karen T.; Wolf, Katherine I.; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Adult & Reprod Endocrinol, NIH, Bldg 10,CRC,Room 1E-3140,10 Ctr Dr MSC 1109, Bethesda, MD 20892 USA. [Janssen, Ingo; Buchmann, Inga] Univ Hosp Schleswig Holstein, Nucl Med Sect, Dept Radiol & Nucl Med, Campus Lubeck,Ratzeburger Allee 160, D-23538 Lubeck, Germany. [Chen, Clara C.] NIH, Nucl Med Div Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Millo, Corina M.; Herscovitch, Peter] NIH, Positron Emiss Tomog Dept, Ctr Clin, Bethesda, MD 20892 USA. [Ling, Alexander] NIH, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Taieb, David] Aix Marseille Univ, La Timone Univ Hosp, Dept Nucl Med, CERIMED, Marseille, France. [Lin, Frank I.] NCI, Canc Imaging Program, NIH, Bethesda, MD 20892 USA. [Fojo, Antonio T.] NCI, Endocrine Oncol Branch, Bethesda, MD 20892 USA. [Kebebew, Electron] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Adult & Reprod Endocrinol, NIH, Bldg 10,CRC,Room 1E-3140,10 Ctr Dr MSC 1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported, in part, by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 37 TC 2 Z9 2 U1 8 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 EI 1619-7089 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD SEP PY 2016 VL 43 IS 10 BP 1784 EP 1791 DI 10.1007/s00259-016-3357-x PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DS3RJ UT WOS:000380700100005 PM 26996779 ER PT J AU Melo, DR Miller, DL Chang, L Moroz, B Linet, MS Simon, SL AF Melo, Dunstana R. Miller, Donald L. Chang, Lienard Moroz, Brian Linet, Martha S. Simon, Steven L. TI ORGAN DOSES FROM DIAGNOSTIC MEDICAL RADIOGRAPHY-TRENDS OVER EIGHT DECADES (1930 TO 2010) SO HEALTH PHYSICS LA English DT Article DE diagnostic radiology; dose; absorbed; epidemiology; radiation; medical ID X-RAY EXAMINATIONS; ACTIVE BONE-MARROW; COMPUTED RADIOGRAPHY; CHEST RADIOGRAPHY; NATIONWIDE EVALUATION; PATIENT DOSIMETRY; RADIATION RISKS; UNITED-STATES; RADIOLOGY; POPULATION AB This study provides a retrospective assessment of doses to 13 organs for the most common radiographic examinations conducted between the 1930s and 2010, taking into account typical technical parameters used for radiography during those years. This study is intended to be a resource on changes in medical diagnostic radiation exposure over time with a specific purpose of supporting retrospective epidemiological studies of radiation health risks. The authors derived organ doses to the brain, esophagus, thyroid, red bone marrow, lungs, breast, heart, stomach, liver, colon, urinary bladder, ovaries, and testes based on 14 common radiographic procedures and compared, when possible, with doses reported in the literature. These dose estimates were based on radiographic exposure parameters described in textbooks widely used by radiologic technologists in training from 1939 to 2010. The derived estimated doses presented here are believed to be representative of typical organs for an average-size adult who might be considered to be similar to the reference person. There were large variations in organ doses noted among the different types of radiographic examinations. Doses were highest in organs within the area imaged and next highest in organs in close proximity to the area imaged. Estimated organ doses have declined substantially [overall 22-fold (+/- 38)] over time as a consequence of changes in technology, imaging protocols and protective measures. For some examinations, only slight differences were observed in doses for the decades of the 1960s, 1970s, and 1980s due to minor changes in technical parameters. Substantial dose reductions were observed in the 1990s and 2000s. C1 [Melo, Dunstana R.] NCI, DCEG, NIH, Bethesda, MD 20892 USA. [Melo, Dunstana R.] Melohill Technol, Rockville, MD USA. [Miller, Donald L.] US FDA, Silver Spring, MD USA. [Chang, Lienard; Moroz, Brian; Linet, Martha S.; Simon, Steven L.] NCI, DCEG, Bethesda, MD 20892 USA. RP Melo, DR (reprint author), 1 Res Court,Suite 450, Rockville, MD 20850 USA. EM dunstana.melo@melohilltech.com FU Intramural Research Program of the National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. We express our appreciation to Alice Sigurdson (NCI, retired) for encouragement, insight and support and to Charles Myers of the Division of Radiological Health, Center for Devices and Radiological Health, Food and Drug Administration for his assistance in defining radiography fields for examinations conducted in past decades. NR 75 TC 0 Z9 0 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD SEP PY 2016 VL 111 IS 3 BP 235 EP 255 DI 10.1097/HP.0000000000000524 PG 21 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 DS4PX UT WOS:000380764100001 PM 27472750 ER PT J AU Wiener, L Viola, A Kearney, J Mullins, LL Sherman-Bien, S Zadeh, S Farkas-Patenaude, A Pao, M AF Wiener, Lori Viola, Adrienne Kearney, Julia Mullins, Larry L. Sherman-Bien, Sandra Zadeh, Sima Farkas-Patenaude, Andrea Pao, Maryland CA Lone Parent Study Grp TI Impact of Caregiving for a Child With Cancer on Parental Health Behaviors, Relationship Quality, and Spiritual Faith: Do Lone Parents Fare Worse? SO JOURNAL OF PEDIATRIC ONCOLOGY NURSING LA English DT Article DE health behavior; pediatric cancer; caregivers; psychosocial; spiritual faith; relationships ID PEDIATRIC CANCER; MOTHERS; STRESS; SINGLE; LIFE; FATHERS; CARE AB Caregiving stress has been associated with changes in the psychological and physical health of parents of children with cancer, including both partnered and single parents. While parents who indicate single on a demographic checklist are typically designated as single parents, a parent can be legally single and still have considerable support caring for an ill child. Correspondingly, an individual can be married/partnered and feel alone when caring for a child with serious illness. In the current study, we report the results from our exploratory analyses of parent self-reports of behavior changes during their child's treatment. Parents (N = 263) of children diagnosed with cancer were enrolled at 10 cancer centers. Parents reported significant worsening of all their own health behaviors surveyed, including poorer diet and nutrition, decreased physical activity, and less time spent engaged in enjoyable activities 6 to 18 months following their child's diagnosis. More partnered parents found support from friends increased or stayed the same since their child's diagnosis, whereas a higher proportion of lone parents reported relationships with friends getting worse. More lone parents reported that the quality of their relationship with the ill child's siblings had gotten worse since their child's diagnosis. Spiritual faith increased for all parents. C1 [Wiener, Lori; Viola, Adrienne; Zadeh, Sima] NCI, Pediat Oncol Branch, Bldg 10,Room 1-6466, Bethesda, MD 20892 USA. [Viola, Adrienne] Rutgers Robert Wood Johnson Med Sch, Newark, NJ USA. [Kearney, Julia] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Mullins, Larry L.] Oklahoma State Univ, Coll Arts & Sci, Dept Psychol, Psychol, Stillwater, OK 74078 USA. [Mullins, Larry L.] Oklahoma State Univ, Coll Arts & Sci, Res, Stillwater, OK 74078 USA. [Sherman-Bien, Sandra] Miller Childrens Hosp, Jonathan Jaques Childrens Canc Ctr, Long Beach, CA USA. [Farkas-Patenaude, Andrea] Dana Farber Canc Inst, Psychol Res Serv, Boston, MA 02115 USA. [Farkas-Patenaude, Andrea] Dana Farber Canc Inst, Clin Serv, Boston, MA 02115 USA. [Pao, Maryland] NIMH, Bethesda, MD 20892 USA. RP Wiener, L (reprint author), NCI, Pediat Oncol Branch, Bldg 10,Room 1-6466, Bethesda, MD 20892 USA. EM wienerl@nih.gov FU National Cancer Institute; National Institute of Mental Health intramural programs of the National Institutes of Health FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work is supported [in part] by the National Cancer Institute and the National Institute of Mental Health intramural programs of the National Institutes of Health. This funding supported the design and conduct of the study; the collection, management, analysis, and interpretation of the data; preparation, review, and approval of the article; and the decision to submit the article for publication. The Andre Sobel River of Life Foundation contributed the gift cards for the study participants.hD; and Sean Phipps, PhD. NR 24 TC 0 Z9 0 U1 5 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1043-4542 EI 1532-8457 J9 J PEDIATR ONCOL NURS JI J. Pediatr. Oncol. Nurs. PD SEP-OCT PY 2016 VL 33 IS 5 BP 378 EP 386 DI 10.1177/1043454215616610 PG 9 WC Oncology; Nursing SC Oncology; Nursing GA DS7JV UT WOS:000380960700007 PM 26668211 ER PT J AU Saposnik, G Cohen, LG Mamdani, M Pooyania, S Ploughman, M Cheung, D Shaw, J Hall, J Nord, P Dukelow, S Nilanont, Y De los Rios, F Olmos, L Levin, M Teasell, R Cohen, A Thorpe, K Laupacis, A Bayley, M AF Saposnik, Gustavo Cohen, Leonardo G. Mamdani, Muhammad Pooyania, Sepideth Ploughman, Michelle Cheung, Donna Shaw, Jennifer Hall, Judith Nord, Peter Dukelow, Sean Nilanont, Yongchai De los Rios, Felipe Olmos, Lisandro Levin, Mindy Teasell, Robert Cohen, Ashley Thorpe, Kevin Laupacis, Andreas Bayley, Mark CA Stroke Outcomes Res Canada TI Efficacy and safety of non-immersive virtual reality exercising in stroke rehabilitation (EVREST): a randomised, multicentre, single-blind, controlled trial SO LANCET NEUROLOGY LA English DT Article ID MOTOR FUNCTION-TEST; UPPER-LIMB; REGIONAL BURDEN; CLINICAL-TRIAL; GLOBAL BURDEN; SURVIVORS; RECOVERY; IMPAIRMENT; MOVEMENT; DISEASE AB Background Non-immersive virtual reality is an emerging strategy to enhance motor performance for stroke rehabilitation. There has been rapid adoption of non-immersive virtual reality as a rehabilitation strategy despite the limited evidence about its safety and effectiveness. Our aim was to compare the safety and efficacy of virtual reality with recreational therapy on motor recovery in patients after an acute ischaemic stroke. Methods In this randomised, controlled, single-blind, parallel-group trial we enrolled adults (aged 18-85 years) who had a first-ever ischaemic stroke and a motor deficit of the upper extremity score of 3 or more (measured with the Chedoke-McMaster scale) within 3 months of randomisation from 14 in-patient stroke rehabilitation units from four countries (Canada [11], Argentina [1], Peru [1], and Thailand [1]). Participants were randomly allocated (1: 1) by a computer-generated assignment at enrolment to receive a programme of structured, task-oriented, upper extremity sessions (ten sessions, 60 min each) of either non-immersive virtual reality using the Nintendo Wii gaming system (VRWii) or simple recreational activities (playing cards, bingo, Jenga, or ball game) as add-on therapies to conventional rehabilitation over a 2 week period. All investigators assessing outcomes were masked to treatment assignment. The primary outcome was upper extremity motor performance measured by total time to complete the Wolf Motor Function Test (WMFT) at the end of the 2 week intervention period, analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NTC01406912. Findings The study was done between May 12, 2012, and Oct 1, 2015. We randomly assigned 141 patients: 71 received VRWii therapy and 70 received recreational activity. 121 (86%) patients (59 in the VRWii group and 62 in the recreational activity group) completed the final assessment and were included in the primary analysis. Each group improved WMFT performance time relative to baseline (decrease in median time from 43.7 s [IQR 26.1-68.0] to 29.7 s [21.4-45.2], 32.0% reduction for VRWii vs 38.0 s [IQR 28.0-64.1] to 27.1 s [21.2-45.5], 28.7% reduction for recreational activity). Mean time of conventional rehabilitation during the trial was similar between groups (VRWii, 373 min [SD 322] vs recreational activity, 397 min [345]; p=0.70) as was the total duration of study intervention (VRWii, 528 min [SD 155] vs recreational activity, 541 min [142]; p=0.60). Multivariable analysis adjusted for baseline WMFT score, age, sex, baseline Chedoke-McMaster, and stroke severity revealed no signifi cant diff erence between groups in the primary outcome (adjusted mean estimate of diff erence in WMFT: 4.1 s, 95% CI -14.4 to 22.6). There were three serious adverse events during the trial, all deemed to be unrelated to the interventions (seizure after discharge and intracerebral haemorrhage in the recreational activity group and heart attack in the VRWii group). Overall incidences of adverse events and serious adverse events were similar between treatment groups. Interpretation In patients who had a stroke within the 3 months before enrolment and had mild-to-moderate upper extremity motor impairment, non-immersive virtual reality as an add-on therapy to conventional rehabilitation was not superior to a recreational activity intervention in improving motor function, as measured by WMFT. Our study suggests that the type of task used in motor rehabilitation post-stroke might be less relevant, as long as it is intensive enough and task-specifi c. Simple, low-cost, and widely available recreational activities might be as eff ective as innovative non-immersive virtual reality technologies. C1 [Saposnik, Gustavo] Univ Toronto, St Michaels Hosp, Div Neurol, Toronto, ON M5C 1R6, Canada. [Saposnik, Gustavo; Cheung, Donna] Univ Toronto, St Michaels Hosp, Stroke Program, Toronto, ON M5C 1R6, Canada. [Cohen, Leonardo G.] NINDS, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Saposnik, Gustavo; Mamdani, Muhammad; Hall, Judith; Cohen, Ashley; Thorpe, Kevin; Laupacis, Andreas] St Michaels Hosp, Li Ka Shing Knowledge Inst, Toronto, ON, Canada. [Pooyania, Sepideth] Riverview Hlth Ctr, Winnipeg, MB, Canada. [Ploughman, Michelle] Mem Univ, Miller Ctr, St John, NF, Canada. [Shaw, Jennifer; Bayley, Mark] Univ Toronto, UHN Toronto Rehabil Inst, Toronto, ON M5C 1R6, Canada. [Nord, Peter] Providence Healthcare, Toronto, ON, Canada. [Dukelow, Sean] Foothills Med Ctr, Calgary, AB, Canada. [Nilanont, Yongchai] Mahidol Univ, Siriraj Hosp, Bangkok, Thailand. [De los Rios, Felipe] Hosp Nacl Cayetano Heredia, Lima, Peru. [Olmos, Lisandro] Escobar, FLENI Rehabil Inst, Buenos Aires, DF, Argentina. [Levin, Mindy] McGill Univ, CRIR Res Ctr, Jewish Rehabil Hosp, Montreal, PQ, Canada. [Teasell, Robert] Univ Western Ontario, Parkwood Inst, London, ON, Canada. RP Saposnik, G (reprint author), Univ Toronto, Stroke Outcomes Res & Virtual Real Ctr, Stroke Outcome Res Canada Working Grp, St Michaels Hosp,Dept Med, 55 Queen St E, Toronto, ON M5C 1R6, Canada. EM saposnikg@smh.ca OI Dukelow, Sean/0000-0002-0609-981X FU South East Toronto Stroke Network FX The authors are indebted to all participants of the EVREST trial. We are very grateful to allied health members at each site who were instrumental for the successful implementation of EVREST. The authors would like to thank co-operative students at Li Ka Shing Knowledge Institute for their assistance with database development and data entry. The authors thank Sarah Blanton and Steven Wolf for the facilitation of the training video and suggestions regarding the analysis of the WMFT. The authors are most grateful for the initial funding provided by South East Toronto Stroke Network and to Jacqueline Willems for the unconditional support with the early organisation of the study design and coordination. NR 34 TC 2 Z9 2 U1 20 U2 33 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD SEP PY 2016 VL 15 IS 10 BP 1019 EP 1027 DI 10.1016/S1474-4422(16)30121-1 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DT1ZJ UT WOS:000381280300018 PM 27365261 ER PT J AU Goldstein, DS Jinsmaa, Y Sullivan, P Holmes, C Kopin, IJ Sharabi, Y AF Goldstein, David S. Jinsmaa, Yunden Sullivan, Patti Holmes, Courtney Kopin, Irwin J. Sharabi, Yehonatan TI 3,4-Dihydroxyphenylethanol (Hydroxytyrosol) Mitigates the Increase in Spontaneous Oxidation of Dopamine During Monoamine Oxidase Inhibition in PC12 Cells SO NEUROCHEMICAL RESEARCH LA English DT Article DE Hydroxytyrosol; DOPET; DOPAL; Cysteinyl-dopamine; Monoamine oxidase; Parkinson's disease ID OLIVE OIL; RED WINE; DISEASES; ADDUCTS; DAMAGE AB The catecholaldehyde hypothesis predicts that monoamine oxidase (MAO) inhibition should slow the progression of Parkinson's disease, by decreasing production of the autotoxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL). Inhibiting MAO, however, diverts the fate of cytoplasmic dopamine toward potentially harmful spontaneous oxidation products, indicated by increased 5-S-cysteinyl-dopamine (Cys-DA) levels. 3,4-Dihydroxyphenylethanol (hydroxytyrosol) is an abundant anti-oxidant phenol in constituents of the Mediterranean diet. Whether hydroxytyrosol alters enzymatic or spontaneous oxidation of dopamine has been unknown. Rat pheochromocytoma PC12 cells were incubated with hydroxytyrosol (10 A mu M, 180 min) alone or with the MAO-A inhibitor clorgyline (1 nM) or the MAO-B inhibitors rasagiline or selegiline (0.5 A mu M). Hydroxytyrosol decreased levels of DOPAL by 30 % and Cys-DA by 49 % (p < 0.0001 each). Co-incubation with hydroxytyrosol prevented the increases in Cys-DA seen with all 3 MAO inhibitors. Hydroxytyrosol therefore inhibits both enzymatic and spontaneous oxidation of endogenous dopamine and mitigates the increase in spontaneous oxidation during MAO inhibition. C1 [Goldstein, David S.; Jinsmaa, Yunden; Sullivan, Patti; Holmes, Courtney; Kopin, Irwin J.; Sharabi, Yehonatan] NINDS, Clin Neurocardiol Sect, CNP, DIR,NIH, 9000 Rockville Pike,Bldg 10 Rm 5N220, Bethesda, MD 20892 USA. [Sharabi, Yehonatan] Chaim Sheba Med Ctr, Sackler Fac Med, Tel Aviv, Israel. [Sharabi, Yehonatan] Tel Aviv Univ, Tel Aviv, Israel. RP Goldstein, DS (reprint author), NINDS, Clin Neurocardiol Sect, CNP, DIR,NIH, 9000 Rockville Pike,Bldg 10 Rm 5N220, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov FU Intramural NIH HHS [ZIA NS003125-06, ZIA NS003034-10, Z99 NS999999] NR 20 TC 1 Z9 1 U1 7 U2 7 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 EI 1573-6903 J9 NEUROCHEM RES JI Neurochem. Res. PD SEP PY 2016 VL 41 IS 9 BP 2173 EP 2178 DI 10.1007/s11064-016-1959-0 PG 6 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DS3XV UT WOS:000380716900001 PM 27220335 ER PT J AU Bolanos-Guzman, CA Zarate, CA AF Bolanos-Guzman, Carlos A. Zarate, Carlos A., Jr. TI Underrepresented Minorities in Science: ACNP Strives to Increase Minority Representation and Inclusion SO NEUROPSYCHOPHARMACOLOGY LA English DT Editorial Material ID ACADEMIC MEDICINE; DISPARITIES; FACULTY C1 [Bolanos-Guzman, Carlos A.] Texas A&M Univ, Dept Psychol, 3245 TAMU, College Stn, TX 77843 USA. [Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Bethesda, MD USA. [Zarate, Carlos A., Jr.] NIMH, Div Intramural Res Program, Sect Neurobiol & Treatment Mood Disorders, Bethesda, MD USA. RP Bolanos-Guzman, CA (reprint author), Texas A&M Univ, Dept Psychol, 3245 TAMU, College Stn, TX 77843 USA. EM bolanos-guzman@tamu.edu NR 17 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 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD SEP PY 2016 VL 41 IS 10 BP 2421 EP 2423 DI 10.1038/npp.2016.71 PG 3 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DT7FV UT WOS:000381653400001 PM 27510298 ER PT J AU Fedota, JR Matous, AL Salmeron, BJ Gu, H Ross, TJ Stein, EA AF Fedota, John R. Matous, Allison L. Salmeron, Betty Jo Gu, Hong Ross, Thomas J. Stein, Elliot A. TI Insula Demonstrates a Non-Linear Response to Varying Demand for Cognitive Control and Weaker Resting Connectivity With the Executive Control Network in Smokers SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID FMRI GROUP-ANALYSIS; SMOKING CUES; FUNCTIONAL CONNECTIVITY; CIGARETTE-SMOKING; PREFRONTAL CORTEX; DEFAULT-MODE; BRAIN; ADDICTION; NICOTINE; CONFLICT AB Deficits in cognitive control processes are a primary characteristic of nicotine addiction. However, while network-based connectivity measures of dysfunction have frequently been observed, empirical evidence of task-based dysfunction in these processes has been inconsistent. Here, in a sample of smokers (n = 35) and non-smokers (n = 21), a previously validated parametric flanker task is employed to characterize addiction-related alterations in responses to varying (ie, high, intermediate, and low) demands for cognitive control. This approach yields a demand-response curve that aims to characterize potential non-linear responses to increased demand for control, including insensitivities or lags in fully activating the cognitive control network. We further used task-based differences in activation between groups as seeds for resting-state analysis of network dysfunction in an effort to more closely link prior inconsistencies in task-related activation with evidence of impaired network connectivity in smokers. For both smokers and non-smokers, neuroimaging results showed similar increases in activation in brain areas associated with cognitive control. However, reduced activation in right insula was seen only in smokers and only when processing intermediate demand for cognitive control. Further, in smokers, this task-modulated right insula showed weaker functional connectivity with the superior frontal gyros, a component of the task-positive executive control network These results demonstrate that the neural instantiation of salience attribution in smokers is both more effortful to fully activate and has more difficulty communicating with the exogenous, task-positive, executive control network. Together, these findings further articulate the cognitive control dysfunction associated with smoking and illustrate a specific brain circuit potentially responsible. C1 [Fedota, John R.; Matous, Allison L.; Salmeron, Betty Jo; Gu, Hong; Ross, Thomas J.; Stein, Elliot A.] NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. RP Fedota, JR (reprint author), NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM john.fedota@nih.gov RI Salmeron, Betty Jo/M-1793-2016; OI Salmeron, Betty Jo/0000-0003-1699-9333; Ross, Thomas/0000-0002-7745-3572 FU National Institute on Drug Abuse (NIDA), Intramural Research Program; FDA grant [NDA13001-001-00000] FX This study was supported by the National Institute on Drug Abuse (NIDA), Intramural Research Program and FDA grant NDA13001-001-00000 to EAS. The authors declare no conflict of interest. NR 53 TC 1 Z9 1 U1 2 U2 5 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 SEP PY 2016 VL 41 IS 10 BP 2557 EP 2565 DI 10.1038/npp.2016.62 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DT7FV UT WOS:000381653400014 PM 27112116 ER PT J AU Wiers, CE Shokri-Kojori, E Wong, CT Abi-Dargham, A Demiral, SB Tomasi, D Wang, GJ Volkow, ND AF Wiers, Corinde E. Shokri-Kojori, Ehsan Wong, Christopher T. Abi-Dargham, Anissa Demiral, Sukru B. Tomasi, Dardo Wang, Gene-Jack Volkow, Nora D. TI Cannabis Abusers Show Hypofrontality and Blunted Brain Responses to a Stimulant Challenge in Females but not in Males SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; NATIONAL EPIDEMIOLOGIC SURVEY; GLUCOSE-METABOLISM; GENDER-DIFFERENCES; COCAINE ABUSERS; DOPAMINE TRANSPORTER; RECEPTOR AVAILABILITY; ORBITOFRONTAL CORTEX; ORAL METHYLPHENIDATE; PREFRONTAL CORTEX AB The extent to which cannabis is deleterious to the human brain is not well understood. Here, we test whether cannabis abusers (CA) have impaired frontal function and reactivity to dopaminergic signaling, which are fundamental to relapse in addiction. We measured brain glucose metabolism using PET and [F-18]FDG both at baseline (placebo) and after challenge with methylphenidate (MP), a dopamine enhancing drug, in 24 active CA (50% female) and 24 controls (HC; 50% female). Results show that (i) CA had lower baseline glucose metabolism than HC in frontal cortex including anterior cingulate, which was associated with negative emotionality. (ii) MP increased whole-brain glucose metabolism in HC but not in CA; and group by challenge effects were most profound in putamen, caudate, midbrain, thalamus, and cerebellum. In CA, MP-induced metabolic increases in putamen correlated negatively with addiction severity. (id) There were significant gender effects, such that both the group differences at baseline in frontal metabolism and the attenuated regional brain metabolic responses to MP were observed in female CA but not in male CA. As for other drug addictions, reduced baseline frontal metabolism is likely to contribute to relapse in CA. The attenuated responses to MP in midbrain and striatum are consistent with decreased brain reactivity to dopamine stimulation and might contribute to addictive behaviors in CA. The gender differences suggest that females are more sensitive than males to the adverse effects of cannabis in brain. C1 [Wiers, Corinde E.; Shokri-Kojori, Ehsan; Wong, Christopher T.; Demiral, Sukru B.; Tomasi, Dardo; Wang, Gene-Jack; Volkow, Nora D.] NIAAA, NIH, Bethesda, MD USA. [Abi-Dargham, Anissa] Columbia Univ, Dept Psychiat, Div Translat Imaging, New York, NY USA. [Abi-Dargham, Anissa] New York State Psychiat Inst & Hosp, New York, NY USA. [Volkow, Nora D.] NIDA, NIH, Bethesda, MD USA. RP Wiers, CE; Volkow, ND (reprint author), NIAAA, Lab Neuroimaging, NIH, 10 Ctr Dr,Room B2L 124, Bethesda, MD 20892 USA. EM corinde.wiers@nih.gov; nvolkow@nida.nih.gov FU NIH/NIAAA intramural grant [Y1AA-3009]; German Research Foundation FX We thank Karen Torres, Barbara Hubbard, Millard Jayne, Yana Studentsova, Payton King, Pauline Carter, Donald Warner, Joanna Fowler, and Ruben Baler for their contributions. The work was supported by NIH/NIAAA intramural grant Y1AA-3009 to NDV. CEW received a scholarship from the German Research Foundation. NR 62 TC 3 Z9 3 U1 6 U2 9 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 SEP PY 2016 VL 41 IS 10 BP 2596 EP 2605 DI 10.1038/npp.2016.67 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DT7FV UT WOS:000381653400018 PM 27156854 ER PT J AU Alonso, N Nebreda, AD Monczor, F Gutkind, JS Davio, C Fernandez, N Shayo, C AF Alonso, Natalia Diaz Nebreda, Antonela Monczor, Federico Silvio Gutkind, J. Davio, Carlos Fernandez, Natalia Shayo, Carina TI PI3K pathway is involved in ERK signaling cascade activation by histamine H2R agonist in HEK293T cells SO BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS LA English DT Article DE Histamine H2 receptor; ERK; PI3K; Cell proliferation; Cell signaling ID BETA-GAMMA-SUBUNITS; LEYDIG TUMOR-CELLS; STRUCTURAL INSTABILITY; CONSTITUTIVE ACTIVITY; INTERNATIONAL UNION; KINASE ACTIVATION; COLORECTAL-CANCER; REGULATED KINASES; BREAST-CANCER; RAP GTPASES AB Background: Histamine, through histamine H2 receptor (H2R), modulates different biological processes, involving the modulation of PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways. Many evidences have demonstrated the existence and importance of the crossregulation between these two signaling pathways. The aim of the present work was to determine the molecular mechanisms leading to PI3K and ERK pathways modulation induced by the H2R agonist amthamine and to evaluate the possible interplay between them. Methods: Phosphorylation levels of ERK and Akt were examined by Western blot in HEK293T cells expressing the human H2R, in the presence of H2R agonist and dominant negative mutants or pharmacological inhibitors of different proteins/pathways. Transcriptional activity assays were assessed to determine SRE activity. Amthamine-mediated cellular proliferation was investigated in MA-10A cells in the presence of PI3K inhibitor. Results: H2R agonist inhibits PI3K/Akt/mTOR and stimulates Ras/MEK/ERK pathways. Moreover, PI3K/Akt/mTOR signaling inhibition is necessary to achieve H2R mediated ERK activation. In the presence of a constitutive active mutant of Akt, amthamine is not able to mediate ERK activation. This crosstalk affects classical ERK downstream targets such as Elk1 phosphorylation and the transcriptional activity of the SRE, classically associated to proliferation. We further demonstrate that amthamine-induced proliferation in Leydig MA-10 tumor cells, is enhanced by LY294002, a PI3K inhibitor. Conclusions: These results describe a crosstalk between PI3K/AKT/mTOR and Ras/MEK/ERK pathways induced by H2R stimulation with implications in cell proliferation. General significance: This work indicates that the modulation of PI3K/AKT/mTOR pathway by H2R in turn regulates Ras/MEK/ERK activation conditioning the proliferative capacity of the cells. (C) 2016 Elsevier B.V. All rights reserved. C1 [Alonso, Natalia; Diaz Nebreda, Antonela; Shayo, Carina] Consejo Nacl Invest Cient & Tecn, Lab Patol & Farmacol Mol, IBYME, Buenos Aires, DF, Argentina. [Monczor, Federico; Davio, Carlos; Fernandez, Natalia] Univ Buenos Aires, Fac Farm & Bioquim, Catedra Quim Med, Buenos Aires, DF, Argentina. [Monczor, Federico; Davio, Carlos; Fernandez, Natalia] UBA CONICET, Fac Farm & Bioquim, Inst Invest Farmacol, ININFA, Junin 956, Buenos Aires, DF, Argentina. [Silvio Gutkind, J.] NIDR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Alonso, Natalia] Ctr Invest Ciencias Vet & Agron, Inst Biotecnol, Inst Nacl Tecnol Agr, Buenos Aires, DF, Argentina. [Silvio Gutkind, J.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. RP Shayo, C (reprint author), Inst Biol & Med Expt, Vuelta Obligado 2490, RA-1428 Buenos Aires, DF, Argentina. EM carinashayo@hotmail.com FU Agencia Nacional de Promotion Cientifica y Tecnologica [PICT2013-0495, PICT2013-2050]; CONICET [PIP 2013-562]; Fundacion Rene Baron [002/2016] FX This work was supported by grants from the Agencia Nacional de Promotion Cientifica y Tecnologica (PICT2013-0495, -2050), and from CONICET (PIP 2013-562), as well as from Fundacion Rene Baron (002/2016). NR 53 TC 2 Z9 3 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4165 EI 1872-8006 J9 BBA-GEN SUBJECTS JI Biochim. Biophys. Acta-Gen. Subj. PD SEP PY 2016 VL 1860 IS 9 BP 1998 EP 2007 DI 10.1016/j.bbagen.2016.06.016 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DS2LQ UT WOS:000380601400018 PM 27316323 ER PT J AU Schade, A Walliser, C Wist, M Haas, J Vatter, P Kraus, JM Filingeri, D Havenith, G Kestler, HA Milner, JD Gierschik, P AF Schade, Anja Walliser, Claudia Wist, Martin Haas, Jennifer Vatter, Petra Kraus, Johann M. Filingeri, Davide Havenith, George Kestler, Hans A. Milner, Joshua D. Gierschik, Peter TI Cool-temperature-mediated activation of phospholipase C-gamma(2) in the human hereditary disease PLAID SO CELLULAR SIGNALLING LA English DT Article DE Phospholipase C-gamma(2); lnositol phospholipid; Rac2 GTPase; Split PH domain; Autoinhibition; Cold temperature sensitivity ID GAIN-OF-FUNCTION; B-CELL RECEPTOR; PHOSPHORYLATION-INDUCED ACTIVATION; COMMON VARIABLE IMMUNODEFICIENCY; PLECKSTRIN HOMOLOGY DOMAIN; C-GAMMA ISOZYMES; CA2+ ENTRY; SIGNALING COMPLEX; FUNCTION MUTATION; MAST-CELLS AB Deletions in the gene encoding signal-transducing inositol phospholipid-specific phospholipase C-gamma(2) (PLC gamma(2)) are associated with the novel human hereditary disease PLAID (PLC gamma(2)-associated antibody deficiency and immune dysregulation). PLAID is characterized by a rather puzzling concurrence of augmented and diminished functions of the immune system, such as cold urticaria triggered by only minimal decreases in temperature, autoimmunity, and immunodeficiency. Understanding of the functional effects of the genomic alterations at the level of the affected enzyme, PLC gamma(2), is currently lacking. PLC gamma(2) is critically involved in coupling various cell surface receptors to regulation of important functions of immune cells such as mast cells, B cells, monocytes/macrophages, and neutrophils. PLC gamma(2) is unique by carrying three Src (SH) and one split pleckstrin homology domain (spPH) between the two catalytic subdomains (spPHn-SH2n-SH2c-SH3-spPHc). Prevailing evidence suggests that activation of PLC gamma(2) is primarily due to loss of SH-region-mediated autoinhibition and/or enhanced plasma membrane trans location. Here, we show that the two PLAID PLC gamma(2) mutants lacking portions of the SH region are strongly (>100-fold), rapidly, and reversibly activated by cooling by only a few degrees. We found that the mechanism(s) underlying PLCy gamma(2) PLAID mutant activation by cool temperatures is distinct from a mere loss of SH-region-mediated autoinhibition and dependent on both the integrity and the pliability of the spPH domain. The results suggest a new mechanism of PLC gamma activation with unique thermodynamic features and assign a novel regulatory role to its spPH domain. Involvement of this mechanism in other human disease states associated with cooling such as exertional asthma and certain acute coronary events appears an intriguing possibility. (C) 2016 Elsevier Inc. All rights reserved. C1 [Schade, Anja; Walliser, Claudia; Wist, Martin; Haas, Jennifer; Vatter, Petra; Gierschik, Peter] Univ Ulm, Med Ctr, Inst Pharmacol & Toxicol, D-89070 Ulm, Germany. [Kraus, Johann M.; Kestler, Hans A.] Univ Ulm, Inst Med Syst Biol, D-89081 Ulm, Germany. [Filingeri, Davide; Havenith, George] Univ Loughborough, Environm Ergon Res Ctr, Loughborough LE11 3TU, Leics, England. [Milner, Joshua D.] NIAID, Allerg Inflammat Unit, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Filingeri, Davide] Univ Calif Berkeley, Ctr Environm Design Res, Berkeley, CA 94720 USA. RP Gierschik, P (reprint author), Univ Ulm, Med Ctr, Inst Pharmacol & Toxicol, Albert Einstein Allee 11, D-89081 Ulm, Germany. EM peter.gierschik@uni-ulm.de FU Deutsche Forschungsgemeinschaft (DFG) [SFB 1074, TP A8]; SFB [1074]; DFG Research Training Group [GRK1041]; International Graduate School in Molecular Medicine Ulm (IGradU) within the Excellence Initiative of the German Federal and State Governments [GSC 279] FX Work in P.G.'s laboratory is funded by grants from the Deutsche Forschungsgemeinschaft (DFG) (SFB 1074, TP A8). The contribution of J.K. and H.K. was supported by project Z1 of SFB 1074. A.S. was a fellow of the DFG Research Training Group GRK1041 and the International Graduate School in Molecular Medicine Ulm (IGradU) funded within the Excellence Initiative of the German Federal and State Governments (GSC 279). NR 66 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 EI 1873-3913 J9 CELL SIGNAL JI Cell. Signal. PD SEP PY 2016 VL 28 IS 9 BP 1237 EP 1251 DI 10.1016/j.cellsig.2016.05.010 PG 15 WC Cell Biology SC Cell Biology GA DS2JJ UT WOS:000380595500011 PM 27196803 ER PT J AU Singh, N Kumar, R Engwerda, C Sacks, D Nylen, S Sundar, S AF Singh, Neetu Kumar, Rajiv Engwerda, Christian Sacks, David Nylen, Susanne Sundar, Shyam TI Tumor necrosis factor alpha neutralization has no direct effect on parasite burden, but causes impaired IFN-gamma production by spleen cells from human visceral leishmaniasis patients SO CYTOKINE LA English DT Article DE Visceral leishmaniasis; TNF-alpha; Enbrel; IL-10; Splenic aspirate; Whole blood assay ID OF-THE-LITERATURE; MICE LACKING TNF; CUTANEOUS LEISHMANIASIS; T-CELLS; RHEUMATOID-ARTHRITIS; INFECTIOUS-DISEASES; FACTOR THERAPY; RECEPTOR P55; NITRIC-OXIDE; IN-VIVO AB The pro-inflammatory cytokine tumor necrosis factor (TNF)-alpha has an important role in control of experimental Leishmania donovani infection. Less is known about the role of TNF-alpha in human visceral leishmaniasis (VL). Evidence for a protective role is primarily based on case reports of VL development in individuals treated with TNF-alpha neutralizing antibody. In this study, we have evaluated how TNF-alpha neutralization affects parasite replication and cytokine production in ex vivo splenic aspirates (SA) from active VL patients. The effect of TNF-alpha neutralization on cell mediated antigen specific responses were also evaluated using whole blood cultures. Neutralization of TNF-alpha did not affect parasite numbers in SA cultures. Interferon (IFN)-gamma levels were significantly reduced, but interleukin (IL)-10 levels were unchanged in these cultures. Leishmania antigen stimulated SA produced significant TNF-alpha which suggests that TNF-alpha is actively produced in VL spleen. Further it stimulates IFN-gamma production, but no direct effect on parasite replication. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Singh, Neetu; Sundar, Shyam] Banaras Hindu Univ, Dept Med, Inst Med Sci, Varanasi 221005, Uttar Pradesh, India. [Kumar, Rajiv] Netaji Subhas Inst Technol, Div Biotechnol, New Delhi 110078, India. [Engwerda, Christian] QIMR Berghofer Med Res Inst, Immunol & Infect Lab, Herston, Qld 4006, Australia. [Sacks, David] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Nylen, Susanne] Karolinska Inst, Dept Microbiol, Stockholm, Sweden. [Kumar, Rajiv] Banaras Hindu Univ, Dept Biochem, Varanasi 221005, Uttar Pradesh, India. RP Sundar, S (reprint author), Banaras Hindu Univ, Dept Med, Inst Med Sci, Varanasi 221005, Uttar Pradesh, India.; Kumar, R (reprint author), Banaras Hindu Univ, Dept Biochem, Varanasi 221005, Uttar Pradesh, India. EM rajiv082@yahoo.com; drshyamsundar@hotmail.com FU Extramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) Tropical Medicine Research Centers [TMRC Grant] [IP50 AI074321]; UGC-CSIR, New Delhi, India FX This work was supported by the Extramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) Tropical Medicine Research Centers [TMRC Grant No. IP50 AI074321]. Neetu Singh is funded by UGC-CSIR, New Delhi, India. NR 46 TC 0 Z9 0 U1 3 U2 5 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 EI 1096-0023 J9 CYTOKINE JI Cytokine PD SEP PY 2016 VL 85 BP 184 EP 190 DI 10.1016/j.cyto.2016.06.013 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA DS2JO UT WOS:000380596000029 PM 27372917 ER PT J AU Jackson, JP Li, LH Chamberlain, ED Wang, HB Ferguson, SS AF Jackson, Jonathan P. Li, Linhou Chamberlain, Erica D. Wang, Hongbing Ferguson, Stephen S. TI Contextualizing Hepatocyte Functionality of Cryopreserved HepaRG Cell Cultures SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID CONSTITUTIVE ANDROSTANE RECEPTOR; FARNESOID-X-RECEPTOR; SALT EXPORT PUMP; IN-VITRO; CYTOCHROME-P450 ISOFORMS; HEPG2 CELLS; NUCLEAR TRANSLOCATION; INTRINSIC CLEARANCE; DRUG-METABOLISM; RAT HEPATOCYTES AB Over the last decade HepaRG cells have emerged as a promising alternative to primary human hepatocytes (PHH) and have been featured in over 300 research publications. Most of these reports employed freshly differentiated HepaRG cells that require time-consuming culture (similar to 28 days) for full differentiation. Recently, a cryopreserved, predifferentiated format of HepaRG cells (termed here "cryo-HepaRG") has emerged as a new model that improves global availability and experimental flexibility; however, it is largely unknown whether HepaRG cells in this format fully retain their hepatic characteristics. Therefore, we systematically investigated the hepatocyte functionality of cryo-HepaRG cultures in context with the range of interindividual variation observed with PHH in both sandwich-culture and suspension formats. These evaluations uncovered a novel adaptation period for the cryo-HepaRG format and demonstrated the impact of extracellular matrix on cryo-HepaRG functionality. Pharmacologically important drug-metabolizing alleles were genotyped in HepaRG cells and poor metabolizer alleles for CYP2D6, CYP2C9, and CYP3A5 were identified and consistent with higher frequency alleles found in individuals of Caucasian decent. We observed liver enzyme inducibility with aryl hydrocarbon receptor, constitutive androstane receptor (CAR), and pregnane X receptor activators comparable to that of sandwich-cultured PHH. Finally, we show for the first time that cryo-HepaRG supports proper CAR cytosolic sequestration and translocation to hepatocyte nuclei in response to phenobarbital treatment. Taken together, these data reveal important considerations for the use of this cell model and demonstrate that cryo-HepaRG are suitable for metabolism and toxicology screening. C1 [Jackson, Jonathan P.; Chamberlain, Erica D.; Ferguson, Stephen S.] ADME Tox, Cell Syst Div, Life Technol, Durham, NC USA. [Li, Linhou; Wang, Hongbing] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Jackson, Jonathan P.] QTS, Durham, NC USA. [Chamberlain, Erica D.] QPS, Newark, DE USA. [Ferguson, Stephen S.] NIEHS, Natl Toxicol Program Div, Bethesda, MD USA. RP Ferguson, SS (reprint author), 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM stephen.ferguson@nih.gov FU Life Technologies (Thermo Fisher) research and development FX The laboratory research was funded by Life Technologies (Thermo Fisher) research and development. Resources for data analysis and manuscript preparation were supported by the National Institutes of Health, National Institute of Environmental Health Sciences, the National Toxicology Program Division, and by Qualyst Transporter Solutions, Inc. NR 43 TC 1 Z9 1 U1 7 U2 9 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 EI 1521-009X J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD SEP PY 2016 VL 44 IS 9 BP 1463 EP 1479 DI 10.1124/dmd.116.069831 PG 17 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DS4IA UT WOS:000380743500005 PM 27338863 ER PT J AU Purdue, MP Silverman, DT AF Purdue, Mark P. Silverman, Debra T. TI Clearing the Air: Summarizing the Smoking-related Relative Risks of Bladder and Kidney Cancer SO EUROPEAN UROLOGY LA English DT Editorial Material C1 [Purdue, Mark P.; Silverman, Debra T.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Purdue, MP (reprint author), NCI, 9609 Med Ctr Dr,Room 6E602, Rockville, MD 20850 USA. EM purduem@mail.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD SEP PY 2016 VL 70 IS 3 BP 467 EP 468 DI 10.1016/j.eururo.2016.04.009 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA DS4MA UT WOS:000380754000023 PM 27130147 ER PT J AU Krakow, M Rogers, B AF Krakow, Melinda Rogers, Brian TI Collateral Damage and Critical Turning Points: Public Health Implications of HPV Vaccine News Coverage for Boys and Men in 2011 SO HEALTH COMMUNICATION LA English DT Article ID HUMAN-PAPILLOMAVIRUS VACCINATION; PROMISCUITY; NEWSPAPERS; CANCER; SAMPLE AB In 2009, the Food and Drug Administration (FDA) officially expanded approval of the Gardasil vaccine to include human papillomavirus (HPV) vaccination for boys and men, and in 2011, the Centers for Disease Control and Prevention (CDC) issued a formal recommendation for routine vaccination for this population. Despite these efforts, HPV vaccination rates for boys and men continue to fall short of public health targets. While news was breaking about the benefits of the HPV vaccine for boys and men, public attention shifted as a result of political debates concerning the vaccine. This study examines a pivotal time period for public health in which the vaccine became officially recommended for boys and men and at the same time became the center of political controversies in the lead-up to the 2012 presidential campaign. The current study extends previous research and presents a content analysis of newspaper articles (N=154) about the HPV vaccine for the year 2011. Results indicate that the lack of comprehensive coverage of HPV and the HPV vaccine found in previous studies continued in this year. Results shed light on key political events that may have functioned to overshadow the recommendation of the HPV vaccine for boys and men. The implications of this pattern of news coverage can inform public health efforts to address low rates of HPV vaccination uptake among boys and men in present day. C1 [Krakow, Melinda] NCI, Canc Prevent Fellowship Program, 9609 Med Ctr Dr,Room 2W-136, Rockville, MD 20850 USA. [Rogers, Brian] Univ Utah, Dept Commun, Salt Lake City, UT 84112 USA. RP Krakow, M (reprint author), NCI, Canc Prevent Fellowship Program, 9609 Med Ctr Dr,Room 2W-136, Rockville, MD 20850 USA. EM melinda.krakow@nih.gov NR 21 TC 1 Z9 1 U1 17 U2 17 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1041-0236 EI 1532-7027 J9 HEALTH COMMUN JI Health Commun. PD SEP PY 2016 VL 31 IS 9 BP 1081 EP 1088 DI 10.1080/10410236.2015.1038773 PG 8 WC Communication; Health Policy & Services SC Communication; Health Care Sciences & Services GA DR8LG UT WOS:000380148800004 PM 26799666 ER PT J AU Stolze, BR Gounden, V Gu, JH Elliott, EA Masika, LS Abel, BS Merke, DP Skarulis, MC Soldin, SJ AF Stolze, Brian R. Gounden, Verena Gu, Jianghong Elliott, Elizabeth A. Masika, Likhona S. Abel, Brent S. Merke, Deborah P. Skarulis, Monica C. Soldin, Steven J. TI An improved micro-method for the measurement of steroid profiles by APPI-LC-MS/MS and its use in assessing diurnal effects on steroid concentrations and optimizing the diagnosis and treatment of adrenal insufficiency and CAH SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Review DE Micro-method atmospheric pressure; photoionization LC-MS/MS; Steroids; Diurnal variation; Dehydroepiandrosterone ID TANDEM MASS-SPECTROMETRY; LIQUID-CHROMATOGRAPHY; TESTOSTERONE; MEN; HORMONES; SERUM; HYPERPLASIA; CORTISOL; 5-ALPHA-ANDROSTANE-3-ALPHA,17-BETA-DIOL; RADIOIMMUNOASSAY AB Our goals were to (1) develop an improved micro-method usable for neonates for steroid profile measurements and a method to measure androsterone, a key steroid in the recently described androgen backdoor pathway together, with dehydroepiandrosterone and (2) to assess if dehydroepiandrosterone diurnal concentration fluctuations exist potentially necessitating strict adherence to time of blood sample draw and requirement of separate time-dependent reference intervals. Liquid chromatography tandem mass spectrometry was performed with an atmospheric pressure photoionization source [1]. For each sample 50 mu L (100 mu L for the backdoor pathway) of serum was deproteinized by adding 75 mu L (150 mu L for the backdoor pathway) of acetonitrile containing the internal standards. After centrifugation, 75 mu L (150 mu L for the backdoor pathway) of supernatant was diluted with 250 mu L of water and injected onto a Poroshell 120 EC-C8 column (SB-C8 column for the backdoor pathway). Within-run coefficients of variation ranged from 2.4 to 10.4% and between-day coefficients of variation from 2.9 to 11.2%. Comparison studies yielded correlation coefficient between 0.97 and 1.00 with recoveries of 90% or greater. Our methods analyze a 9 steroid profile and an additional 2 steroid profile (backdoor pathway) with minimal sample volume (usable in neonates optimizing early diagnosis of endocrinopathies and genetic diseases). Low limits of quantitation make these methods ideal for steroid measurement in women and prepubertal children. As diurnal variations of dehydroepiandrosterone and other steroids [2] concentrations are clinically significant we recommend that separate reference intervals be developed for 8 am, 8 pm, and midnight sample draws. The use of this approach in improving the diagnosis of patients with adrenal insufficiency and congenital adrenal hyperplasia is discussed. Published by Elsevier Ltd. C1 [Stolze, Brian R.; Gounden, Verena; Gu, Jianghong; Elliott, Elizabeth A.; Masika, Likhona S.; Soldin, Steven J.] NIH, Dept Lab Med, 10 Ctr Dr,Bldg 10,Room 2C-306, Bethesda, MD 20814 USA. [Abel, Brent S.; Skarulis, Monica C.] NIDDK, NIH, 10Ctr Dr,Bldg 10,Room 6-3940, Bethesda, MD 20814 USA. [Soldin, Steven J.] Georgetown Univ, Div Endocrinol & Metab, Dept Med, 3700 O St NW, Washington, DC 20057 USA. [Merke, Deborah P.] NIH, Ctr Clin, 10 Ctr Dr,Bldg 10,Room 1-2740, Bethesda, MD 20814 USA. [Merke, Deborah P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, 10 Ctr Dr,Bldg 10,Room 1-2740, Bethesda, MD 20814 USA. RP Soldin, SJ (reprint author), NIH, Dept Lab Med, 10 Ctr Dr,Bldg 10,Room 2C-306, Bethesda, MD 20814 USA. EM steven.soldin@nih.gov OI Elliott, Elizabeth/0000-0001-7743-4526 FU Intramural program of the NIH FX This research has been supported (in part) by the Intramural program of the NIH. NR 32 TC 1 Z9 1 U1 4 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD SEP PY 2016 VL 162 SI SI BP 110 EP 116 DI 10.1016/j.jsbmb.2015.12.024 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA DS1XM UT WOS:000380418500010 PM 26721696 ER PT J AU Tetrault, JM Tate, JP Edelman, EJ Gordon, AJ Lo Re, V Lim, JK Rimland, D Goulet, J Crystal, S Gaither, JR Gibert, CL Rodriguez-Barradas, MC Fiellin, LE Bryant, K Justice, AC Fiellin, DA AF Tetrault, Jeanette M. Tate, Janet P. Edelman, E. Jennifer Gordon, Adam J. Lo Re, Vincent, III Lim, Joseph K. Rimland, David Goulet, Joseph Crystal, Stephen Gaither, Julie R. Gibert, Cynthia L. Rodriguez-Barradas, Maria C. Fiellin, Lynn E. Bryant, Kendall Justice, Amy C. Fiellin, David A. TI Hepatic Safety of Buprenorphine in HIV-Infected and Uninfected Patients With Opioid Use Disorder: The Role of HCV-Infection SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE Buprenorphine; HIV; Hepatitis C; Drug induced liver injury ID LIVER-ENZYME ELEVATION; DEPENDENT PATIENTS; NALOXONE TREATMENT; INDIVIDUALS; THERAPY; HEALTH; TRIAL; RISK AB Introduction: Individuals with HIV and hepatitis C (HCV) infection, alcohol use disorder, or who are prescribed potentially hepatotoxic medications may be at increased risk for buprenorphine (BUP) associated hepatotoxicity. Materials and methods: We examined a cohort of HIV-infected and uninfected patients receiving an initial BUP prescription between 2003 and 2012. We compared changes in alanine and aspartate aminotransferases (ALT and AST) and total bilirubin (TB) stratified by HIV status. We identified cases of liver enzyme elevation (LEE), TB elevation (TBE), and conducted chart review to assess for cases of drug induced liver injury (DILI) and death. We examined associations between age, sex, race, HIV-infection, HCV-infection, alcohol use disorder, and prescription of other potentially heptatotoxic medications with the composite endpoint of LEE, TBE, and DILI. Results: Of 666 patients prescribed BUP, 36% were HIV-infected, 98% were male, 60% had RNA-confirmed HCV infection, 50% had a recent diagnosis of alcohol use disorder, and 64% were prescribed other potentially hepatotoxic medications. No clinically significant changes were observed in median ALT, AST and TB and these changes did not differ between HIV-infected and uninfected patients. Compared with uninfected patients, HIV-infected (OR 73, 95% CI 2.1-26.1, p = 0.002), HCV-infected (OR 4.9 95% CI 1.6-15.2, p = 0.007) or HIV/HCV co-infected patients (OR 6.9, 95%CI 2.1-22.2, p = 0.001) were more likely to have the composite endpoint of LEE, TB elevation or DILI, in analyses that excluded 60 patients with evidence of pre-existing liver injury. 31 patients had LEE, 14/187 HIV-infected and 17/340 uninfected (p = 0.25); 11 had TBE, including 9/186 HIV-infected and 2/329 uninfected (p = 0.002); 8 experienced DILI, 4/202 HIV-infected and 4/204 uninfected (p = 0.45). There were no significant associations with alcohol use disorder or prescription of other potentially hepatotoxic medications after adjustment for HIV/HCV status. Conclusions: Liver enzymes and TB are rarely elevated in HIV-infected and uninfected patients receiving BUP. Risk of hepatotoxicity was greater in individuals infected with HIV, HCV, or HIV/HCV co-infection, who may benefit from increased monitoring. (C) 2016 Elsevier Inc. All rights reserved. C1 [Tetrault, Jeanette M.; Tate, Janet P.; Edelman, E. Jennifer; Lim, Joseph K.; Fiellin, Lynn E.; Justice, Amy C.; Fiellin, David A.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Tate, Janet P.; Lim, Joseph K.; Justice, Amy C.] VA Connecticut Hlth Care Syst, West Haven, CT USA. [Gordon, Adam J.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Gordon, Adam J.] Univ Pittsburgh, Pittsburgh, PA USA. [Lo Re, Vincent, III] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Rimland, David] VA Med Ctr, Atlanta, GA USA. [Rimland, David] Emory Univ, Sch Med, Atlanta, GA USA. [Goulet, Joseph] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Crystal, Stephen] Rutgers State Univ, Inst Hlth, Ctr Hlth Serv Res, New Brunswick, NJ USA. [Gaither, Julie R.; Justice, Amy C.; Fiellin, David A.] Yale Univ, Sch Publ Hlth, Ctr Interdisciplinary Res AIDS, New Haven, CT USA. [Gibert, Cynthia L.] VA Med Ctr, Washington, DC USA. [Gibert, Cynthia L.] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20052 USA. [Rodriguez-Barradas, Maria C.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Rodriguez-Barradas, Maria C.] Baylor Coll, Sch Med, Houston, TX USA. [Bryant, Kendall] NIAAA, Bethesda, MD USA. RP Tetrault, JM (reprint author), 367 Cedar St,Suite 305, New Haven, CT 06510 USA. EM jeanette.tetrault@yale.edu OI Fiellin, David/0000-0002-4006-010X; Goulet, Joseph/0000-0002-0842-804X FU Department of Veterans Affairs, Veterans Health Administration, and Office of Research and Development; [U10 AA013566]; [U24 AA020794]; [U01 AA020790]; [U19 HS021112]; [R01 HS018372] FX This material is based upon work supported by the Department of Veterans Affairs, Veterans Health Administration, and Office of Research and Development We must disclaim that the views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs.; Supported by. U10 AA013566, U24 AA020794, U01 AA020790, U19 HS021112, R01 HS018372 NR 25 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD SEP PY 2016 VL 68 BP 62 EP 67 DI 10.1016/j.jsat.2016.06.002 PG 6 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA DS2GB UT WOS:000380579300008 PM 27431048 ER PT J AU Strickland, J Zang, QD Kleinstreuer, N Paris, M Lehmann, DM Choksi, N Matheson, J Jacobs, A Lowit, A Allen, D Casey, W AF Strickland, Judy Zang, Qingda Kleinstreuer, Nicole Paris, Michael Lehmann, David M. Choksi, Neepa Matheson, Joanna Jacobs, Abigail Lowit, Anna Allen, David Casey, Warren TI Integrated decision strategies for skin sensitization hazard SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Article DE skin sensitization; allergic contact dermatitis; integrated decision strategy; machine learning; LLNA; DPRA; KeratinoSens; h-CLAT; support vector machine ID LYMPH-NODE ASSAY; LINE ACTIVATION TEST; TEST H-CLAT; SCREENING CONTACT ALLERGENS; PEPTIDE REACTIVITY ASSAY; NONANIMAL TEST METHODS; PIG MAXIMIZATION TEST; RISK-ASSESSMENT MODEL; IN-VITRO METHODS; PREDICTIVE PERFORMANCE AB One of the top priorities of the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM) is the identification and evaluation of non-animal alternatives for skin sensitization testing. Although skin sensitization is a complex process, the key biological events of the process have been well characterized in an adverse outcome pathway (AOP) proposed by the Organisation for Economic Co-operation and Development (OECD). Accordingly, ICCVAM is working to develop integrated decision strategies based on the AOP using in vitro, in chemico and in silico information. Data were compiled for 120 substances tested in the murine local lymph node assay (LLNA), direct peptide reactivity assay (DPRA), human cell line activation test (h-CLAT) and KeratinoSens assay. Data for six physicochemical properties, which may affect skin penetration, were also collected, and skin sensitization read-across predictions were performed using OECD QSAR Toolbox. All data were combined into a variety of potential integrated decision strategies to predict LLNA outcomes using a training set of 94 substances and an external test set of 26 substances. Fifty-four models were built using multiple combinations of machine learning approaches and predictor variables. The seven models with the highest accuracy (89-96% for the test set and 96-99% for the training set) for predicting LLNA outcomes used a support vector machine (SVM) approach with different combinations of predictor variables. The performance statistics of the SVM models were higher than any of the non-animal tests alone and higher than simple test battery approaches using these methods. These data suggest that computational approaches are promising tools to effectively integrate data sources to identify potential skin sensitizers without animal testing. Published 2016. This article has been contributed to by US Government employees and their work is in the public domain in the USA. The Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM) evaluated a non-animal decision strategies to predict skin sensitization. Machine learning approaches integrated in vitro, in chemico and in silico data and six physicochemical properties for 120 substances to predict murine local lymph node assay (LLNA) outcomes. The seven models with the highest accuracy used a support vector machine with different combinations of predictor variables. The models outperformed individual non-animal methods and test batteries. This suggests that computational approaches are promising tools to effectively integrate data to identify potential skin sensitizers without animal testing. C1 [Strickland, Judy; Zang, Qingda; Kleinstreuer, Nicole; Paris, Michael; Choksi, Neepa; Allen, David] ILS, Res Triangle Pk, NC 27709 USA. [Lehmann, David M.] US EPA, NHEERL, EPHD, CIB, Res Triangle Pk, NC 27709 USA. [Matheson, Joanna] US Consumer Prod Safety Commiss, Bethesda, MD 20814 USA. [Jacobs, Abigail] US FDA, CDER, Silver Spring, MD 20993 USA. [Lowit, Anna] US EPA, OCSPP, OPP, HED, Washington, DC 20460 USA. [Casey, Warren] NIEHS, NIH, DNTP, NICEATM, Res Triangle Pk, NC 27709 USA. RP Casey, W (reprint author), NIEHS, NIH, DNTP, NICEATM, POB 12233, Res Triangle Pk, NC 27709 USA. EM warren.casey@nih.gov OI Kleinstreuer, Nicole/0000-0002-7914-3682 FU federal funds from the NIEHS, NIH of NICEATM [HHSN273201500010C] FX The authors thank Drs D. Germolec, B.A. Merrick, R. Luebke and M. Ward for their thoughtful critical review of this manuscript. This project was funded in whole or in part with federal funds from the NIEHS, NIH under contract HHSN273201500010C to ILS in support of NICEATM. NR 77 TC 8 Z9 8 U1 3 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0260-437X EI 1099-1263 J9 J APPL TOXICOL JI J. Appl. Toxicol. PD SEP PY 2016 VL 36 IS 9 BP 1150 EP 1162 DI 10.1002/jat.3281 PG 13 WC Toxicology SC Toxicology GA DR5PD UT WOS:000379954000008 PM 26851134 ER PT J AU He, ZJ Wan, XM Schulz, A Bludau, H Dobrovolskaia, MA Stern, ST Montgomery, SA Yuan, H Li, ZB Alakhova, D Sokolsky, M Darr, DB Perou, CM Jordan, R Luxenhofer, R Kabanov, AV AF He, Zhijian Wan, Xiaomeng Schulz, Anita Bludau, Herdis Dobrovolskaia, Marina A. Stern, Stephan T. Montgomery, Stephanie A. Yuan, Hong Li, Zibo Alakhova, Dania Sokolsky, Marina Darr, David B. Perou, Charles M. Jordan, Rainer Luxenhofer, Robert Kabanov, Alexander V. TI A high capacity polymeric micelle of paclitaxel: Implication of high dose drug therapy to safety and in vivo anti-cancer activity SO BIOMATERIALS LA English DT Article DE Polyoxazolines; Paclitaxel nanoformulation; In vitro; In vivo; Efficacy; Multi-drug resistant cancer ID BREAST-CANCER; DELIVERY-SYSTEMS; NANOPARTICLE FORMULATION; CREMOPHOR-FREE; PHASE-II; POLY(2-OXAZOLINE); EFFICACY; TUMORS; NK105; TAXOL AB The poor solubility of paclitaxel (PTX), the commercially most successful anticancer drug, has long been hampering the development of suitable formulations. Here, we present translational evaluation of a nanoformulation of PTX, which is characterized by a facile preparation, extraordinary high drug loading of 50% wt. and PTX solubility of up to 45 g/L, excellent shelf stability and controllable, sub-100 nm size. We observe favorable in vitro and in vivo safety profiles and a higher maximum tolerated dose compared to clinically approved formulations. Pharmacokinetic analysis reveals that the higher dose administered leads to a higher exposure of the tumor to PTX. As a result, we observed improved therapeutic outcome in orthotopic tumor models including particularly faithful and aggressive "T11" mouse claudin-low breast cancer orthotopic, syngeneic transplants. The promising preclinical data on the presented PTX nanoformulation showcase the need to investigate new excipients and is a robust basis to translate into clinical trials. (C) 2016 Elsevier Ltd. All rights reserved. C1 [He, Zhijian; Wan, Xiaomeng; Alakhova, Dania; Sokolsky, Marina; Kabanov, Alexander V.] Univ N Carolina, Eshelman Sch Pharm, Ctr Nanotechnol Drug Delivery, Genet Med Bldg,Room 1094,Campus Box 7362, Chapel Hill, NC 27599 USA. [He, Zhijian; Wan, Xiaomeng; Alakhova, Dania; Sokolsky, Marina; Kabanov, Alexander V.] Univ N Carolina, Eshelman Sch Pharm, Div Mol Pharmaceut, Chapel Hill, NC 27599 USA. [Schulz, Anita; Bludau, Herdis; Jordan, Rainer] Tech Univ Dresden, Dept Chem, Makromol Chem, Mommsenstr 4, D-01069 Dresden, Germany. [Dobrovolskaia, Marina A.; Stern, Stephan T.] Leidos Biomed Res Inc, Nanotechnol Characterizat Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. [Montgomery, Stephanie A.] Univ N Carolina, Dept Pathol & Lab Med, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Yuan, Hong; Li, Zibo] Univ N Carolina, Sch Med, Dept Radiol, Chapel Hill, NC 27599 USA. [Darr, David B.; Perou, Charles M.] Univ N Carolina, Anim Study Core, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Luxenhofer, Robert] Univ Wurzburg, Funct Polymer Mat, Chair Chem Technol Mat Synth, Rontgenring 11, D-97070 Wurzburg, Germany. [Kabanov, Alexander V.] Moscow MV Lomonosov State Univ, Lab Chem Design Bionanomat, Fac Chem, Moscow, Russia. RP Kabanov, AV (reprint author), Univ N Carolina, Eshelman Sch Pharm, Ctr Nanotechnol Drug Delivery, Genet Med Bldg,Room 1094,Campus Box 7362, Chapel Hill, NC 27599 USA.; Luxenhofer, R (reprint author), Univ Wurzburg, Funct Polymer Mat, Chair Chem Technol Mat Synth, Rontgenring 11, D-97070 Wurzburg, Germany. EM robert.luxenhofer@uni-wuerzburg.de; kabanov@email.unc.edu RI Jordan, Rainer/B-6542-2008; Nanotechnology Characterization Lab, NCL/K-8454-2012; Luxenhofer, Robert/C-2825-2008 OI Jordan, Rainer/0000-0002-9414-1597; Luxenhofer, Robert/0000-0001-5567-7404 FU Cancer Nanotechnology Platform Partnership grant of the National Cancer Institute Alliance for Nanotechnology in Cancer [U01 CA116591]; UNC Eshelman School of Pharmacy; University Cancer Research Fund through the Lineberger Comprehensive Cancer Center; NCI Breast SPORE program [P50-CA58223-09A1]; [RO1-CA148761] FX This work was supported by a Cancer Nanotechnology Platform Partnership grant (U01 CA116591) of the National Cancer Institute Alliance for Nanotechnology in Cancer awarded to A.V.K. and the The Carolina Partnership, a strategic partnership between the, UNC Eshelman School of Pharmacy and The University Cancer Research Fund through the Lineberger Comprehensive Cancer Center. C.M.P was supported by NCI Breast SPORE program (P50-CA58223-09A1), and RO1-CA148761. NR 45 TC 6 Z9 6 U1 44 U2 96 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 SEP PY 2016 VL 101 BP 296 EP 309 DI 10.1016/j.biomaterials.2016.06.002 PG 14 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA DR0YJ UT WOS:000379632500027 PM 27315213 ER PT J AU Liu, LJ Fissel, JA Tasnim, A Borzan, J Gocke, A Calabresi, PA Farah, MH AF Liu, Lijuan Fissel, John A. Tasnim, Aniqa Borzan, Jasenka Gocke, Anne Calabresi, Peter A. Farah, Mohamed H. TI Increased TNFR1 expression and signaling in injured peripheral nerves of mice with reduced BACE1 activity SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Neuroinflammation; Macrophages in the PNS; Nervous system injury ID NECROSIS-FACTOR-ALPHA; MOUSE SCIATIC-NERVE; IMMUNE-MEDIATED DEMYELINATION; CHRONIC CONSTRICTION INJURY; AMYLOID PRECURSOR PROTEIN; BETA-SECRETASE BACE1; WALLERIAN DEGENERATION; FUNCTIONAL RECOVERY; CYTOKINE EXPRESSION; AXON REGENERATION AB Hematogenous macrophages remove myelin debris from injured peripheral nerves to provide a micro environment conducive to axonal regeneration. Previously, we observed that injured peripheral nerves from Beta-site APP Cleaving Enzyme 1 (BACE1) knockout (KO) mice displayed earlier influx of and enhanced phagocytosis by macrophages when compared to wild-type (WT) mice. These observations suggest that BACE1 might regulate macrophage influx into distal stumps of injured nerves. To determine through which pathway BACE1 influences macrophage influx, we used a mouse inflammation antibody array to assay the expression of inflammation-related proteins in injured nerves of BACE1 KO and WT mice. The most significant change was in expression of tumor necrosis factor receptor 1 (TNFR1) in the distal stump of injured BACE1 KO nerves. Western blotting of protein extracts confirmed increased expression of TNFR1 and its downstream transcriptional factor NF kappa B in the BACE1 KO distal stumps. Additionally, treatment of WT mice with a BACE1 inhibitor resulted in increased TNFR1 expression and signaling in the distal stump of injured nerves. Exogenous TNF alpha increased nuclear translocation of p65 NF kappa B in BACE1 KO tissue and cultured fibroblasts compared with control WT. BACE1 regulates TNFR1 expression at the level of gene expression and not through proteolytic processing. The accelerated macrophage influx in injured nerves of BACE1 KO mice correlates with increased expression and signaling via TNFR1, indicating a link between BACE1 activity and TNFR1 expression/signaling that might contribute to repair of the injured nervous system. (C) 2016 Elsevier Inc All rights reserved. C1 [Liu, Lijuan; Fissel, John A.; Tasnim, Aniqa; Gocke, Anne; Calabresi, Peter A.; Farah, Mohamed H.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Borzan, Jasenka] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. [Tasnim, Aniqa] Harvard Univ, Cambridge, MA 02138 USA. [Borzan, Jasenka] NIH, Bldg 10, Bethesda, MD 20892 USA. RP Farah, MH (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurol, Neuromuscular Div, John G Rangos Sr Bldg,Room 239,855 N Wolfe St, Baltimore, MD 21205 USA. EM mfarah2@jhmi.edu FU Muscular Dystrophy Association [MDA 254860]; National Institutes of Neurological Disease and Stroke of the National Institutes of Health [R01NS079339] FX This work was supported by the Muscular Dystrophy Association (MDA 254860) and R01NS079339 from the National Institutes of Neurological Disease and Stroke of the National Institutes of Health. We thank Carol Cooke, Justin Glenn, Lori Lebson, Zoe Rammelkamp, and Parisa Moghaddam-Taaheri for technical assistance. NR 53 TC 1 Z9 1 U1 7 U2 10 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 SEP PY 2016 VL 93 BP 21 EP 27 DI 10.1016/j.nbd.2016.04.002 PG 7 WC Neurosciences SC Neurosciences & Neurology GA DQ8IE UT WOS:000379452600003 PM 27080468 ER PT J AU Srivastava, S Reid, BJ Ghosh, S Kramer, BS AF Srivastava, Sudhir Reid, Brian J. Ghosh, Sharmistha Kramer, Barnett S. TI Research Needs for Understanding the Biology of Overdiagnosis in Cancer Screening SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Review ID PROSTATE-CANCER; BREAST-CANCER; FOLLOW-UP; BARRETTS-ESOPHAGUS; EVOLUTION; MUTATIONS; CELLS; ADENOCARCINOMA; KERATINOCYTES; MAMMOGRAPHY AB Many cancers offer an extended window of opportunity for early detection and therapeutic intervention that could lead to a reduction in cause-specific mortality. The pursuit of early detection in screening settings has resulted in decreased incidence and mortality for some cancers (e.g., colon and cervical cancers), and increased incidence with only modest or no effect on cause-specific mortality in others (e.g., breast and prostate). Whereas highly sensitive screening technologies are better at detecting a number of suspected "cancers" that are indolent and likely to remain clinically unimportant in the lifetime of a patient, defined as overdiagnosis, they often miss cancers that are aggressive and tend to present clinically between screenings, known as interval cancers. Unrecognized overdiagnosis leads to overtreatment with its attendant (often long-lasting) side effects, anxiety, and substantial financial harm. Existing methods often cannot differentiate indolent lesions from aggressive ones or understand the dynamics of neoplastic progression. To correctly identify the population that would benefit the most from screening and identify the lesions that would benefit most from treatment, the evolving genomic and molecular profiles of individual cancers during the clinical course of progression or indolence must be investigated, while taking into account an individual's genetic susceptibility, clinical and environmental risk factors, and the tumor microenvironment. Practical challenges lie not only in the lack of access to tissue specimens that are appropriate for the study of natural history, but also in the absence of targeted research strategies. This commentary summarizes the recommendations from a diverse group of scientists with expertise in basic biology, translational research, clinical research, statistics, and epidemiology and public health professionals convened to discuss research directions. (C) 2015 Wiley Periodicals, Inc. C1 [Srivastava, Sudhir; Ghosh, Sharmistha; Kramer, Barnett S.] NCI, Canc Prevent Div, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Reid, Brian J.] Univ Washington, Fred Hutchinson Canc Res Ctr, Dept Genome Sci, Div Human Biol, Seattle, WA 98195 USA. [Reid, Brian J.] Univ Washington, Fred Hutchinson Canc Res Ctr, Dept Genome Sci, Div Publ Hlth Sci, Seattle, WA 98195 USA. [Reid, Brian J.] Univ Washington, Fred Hutchinson Canc Res Ctr, Dept Med, Div Human Biol, Seattle, WA 98195 USA. Univ Washington, Fred Hutchinson Canc Res Ctr, Dept Med, Div Publ Hlth Sci, Seattle, WA 98195 USA. RP Srivastava, S (reprint author), NCI, Canc Prevent Div, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM srivasts@mail.nih.gov FU NCI NIH HHS [P01 CA091955] NR 51 TC 3 Z9 3 U1 3 U2 26 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9541 EI 1097-4652 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD SEP PY 2016 VL 231 IS 9 BP 1870 EP 1875 DI 10.1002/jcp.25227 PG 6 WC Cell Biology; Physiology SC Cell Biology; Physiology GA DQ4FJ UT WOS:000379159100004 PM 26505642 ER PT J AU Salinas, AG Davis, MI Lovinger, DM Mateo, Y AF Salinas, Armando G. Davis, Margaret I. Lovinger, David M. Mateo, Yolanda TI Dopamine dynamics and cocaine sensitivity differ between striosome and matrix compartments of the striatum SO NEUROPHARMACOLOGY LA English DT Article DE Patch; Voltammetry; Nucleus accumbens; Dopamine transporter; Dopamine D2 receptor ID SIZED SPINY NEURONS; CAT CAUDATE-NUCLEUS; RAT STRIATUM; DORSAL STRIATUM; CHOLINERGIC INTERNEURONS; PROJECTION SYSTEMS; SINGLE-AXON; RELEASE; ACCUMBENS; HETEROGENEITY AB The striatum is typically classified according to its major output pathways, which consist of dopamine D1 and D2 receptor-expressing neurons. The striatum is also divided into striosome and matrix compartments, based on the differential expression of a number of proteins, including the mu opioid receptor, dopamine transporter (DAT), and Nr4a1 (nuclear receptor subfamily 4, group A, member 1). Numerous functional differences between the striosome and matrix compartments are implicated in dopamine related neurological disorders including Parkinson's disease and addiction. Using Nr4a1-eGFP mice, we provide evidence that electrically evoked dopamine release differs between the striosome and matrix compartments in a regionally-distinct manner. We further demonstrate that this difference is not due to differences in inhibition of dopamine release by dopamine autoreceptors or nicotinic acetylcholine receptors. Furthermore, cocaine enhanced extracellular dopamine in striosomes to a greater degree than in the matrix and concomitantly inhibited dopamine uptake in the matrix to a greater degree than in striosomes. Importantly, these compartment differences in cocaine sensitivity were limited to the dorsal striatum. These findings demonstrate a level of exquisite microanatomical regulation of dopamine by the DAT in striosomes relative to the matrix. Published by Elsevier Ltd. C1 [Salinas, Armando G.] George Mason Univ, Krasnow Inst Adv Study, Fairfax, VA 22030 USA. [Salinas, Armando G.; Davis, Margaret I.; Lovinger, David M.; Mateo, Yolanda] NIAAA, Lab Integrat Neurosci, Sect Synapt Pharmacol, Rockville, MD 20852 USA. RP Mateo, Y (reprint author), NIAAA, Lab Integrat Neurosci, Sect Synapt Pharmacol, NIH, 5625 Fishers Lane, Rockville, MD 20852 USA. EM mateoy@mail.nih.gov FU NIAAA [R01 AA016022]; National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Division of Intramural Clinical and Biomedical Research [ZIA AA000407] FX This work was supported by NIAAA R01 AA016022 (AGS) and the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Division of Intramural Clinical and Biomedical Research (MID, YM, and DML) (Grant Number: ZIA AA000407). NR 59 TC 4 Z9 4 U1 4 U2 14 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 SEP PY 2016 VL 108 BP 275 EP 283 DI 10.1016/j.neuropharm.2016.03.049 PG 9 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DQ1IA UT WOS:000378953500027 PM 27036891 ER PT J AU Kocarnik, JM Chan, AT Slattery, ML Potter, JD Meyerhardt, J Phipps, A Nan, HM Harrison, T Rohan, TE Qi, LH Hou, LF Caan, B Kroenke, CH Strickler, H Hayes, RB Schoen, RE Chong, DQ White, E Berndt, SI Peters, U Newcomb, PA AF Kocarnik, Jonathan M. Chan, Andrew T. Slattery, Martha L. Potter, John D. Meyerhardt, Jeffrey Phipps, Amanda Nan, Hongmei Harrison, Tabitha Rohan, Thomas E. Qi, Lihong Hou, Lifang Caan, Bette Kroenke, Candyce H. Strickler, Howard Hayes, Richard B. Schoen, Robert E. Chong, Dawn Q. White, Emily Berndt, Sonja I. Peters, Ulrike Newcomb, Polly A. TI Relationship of prediagnostic body mass index with survival after colorectal cancer: Stage-specific associations SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE body mass index (BMI); cancer stage; colorectal cancer (CRC); mortality; survival ID OBESITY PARADOX; WOMENS HEALTH; COLON-CANCER; SUSCEPTIBILITY LOCI; PROSPECTIVE COHORT; PHYSICAL-ACTIVITY; MORTALITY; DIAGNOSIS; OVERWEIGHT; DEATH AB Higher body mass index (BMI) is a well-established risk factor for colorectal cancer (CRC), but is inconsistently associated with CRC survival. In 6 prospective studies participating in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), 2,249 non-Hispanic white CRC cases were followed for a median 4.5 years after diagnosis, during which 777 died, 554 from CRC-related causes. Associations between prediagnosis BMI and survival (overall and CRC-specific) were evaluated using Cox regression models adjusted for age at diagnosis, sex, study and smoking status (current/former/never). The association between BMI category and CRC survival varied by cancer stage at diagnosis (I-IV) for both all-cause (p-interaction=0.03) and CRC-specific mortality (p-interaction=0.04). Compared to normal BMI (18.5-24.9 kg/m(2)), overweight (BMI 25.0-29.9) was associated with increased mortality among those with Stage I disease, and decreased mortality among those with Stages II-IV disease. Similarly, obesity (BMI >= 30) was associated with increased mortality among those with Stages I-II disease, and decreased mortality among those with Stages III-IV disease. These results suggest the relationship between BMI and survival after CRC diagnosis differs by stage at diagnosis, and may emphasize the importance of adequate metabolic reserves for colorectal cancer survival in patients with late-stage disease. C1 [Kocarnik, Jonathan M.; Phipps, Amanda; White, Emily; Peters, Ulrike; Newcomb, Polly A.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Kocarnik, Jonathan M.; Potter, John D.; Phipps, Amanda; Harrison, Tabitha; White, Emily; Peters, Ulrike; Newcomb, Polly A.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Chan, Andrew T.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Chan, Andrew T.; Chong, Dawn Q.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Slattery, Martha L.] Univ Utah, Dept Internal Med, Hlth Sci Ctr, Salt Lake City, UT 84112 USA. [Meyerhardt, Jeffrey] Dana Farber Canc Inst, Boston, MA 02115 USA. [Meyerhardt, Jeffrey] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Nan, Hongmei] Indiana Univ, Richard M Fairbanks Sch Publ Hlth, Dept Epidemiol, Indianapolis, IN 46204 USA. [Nan, Hongmei] Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. [Rohan, Thomas E.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Qi, Lihong] Univ Calif Davis, Sch Med, Dept Publ Hlth Sci, Davis, CA 95616 USA. [Hou, Lifang] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Hou, Lifang] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Caan, Bette; Kroenke, Candyce H.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Hayes, Richard B.] NYU, Div Epidemiol, Sch Med, New York, NY USA. [Schoen, Robert E.] Univ Pittsburgh, Med Ctr, Dept Med & Epidemiol, Pittsburgh, PA USA. [Chong, Dawn Q.] Natl Canc Ctr Singapore, Div Med Oncol, Singapore, Singapore. [Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Kocarnik, JM (reprint author), Kocarnik 1100 Fairview Ave N Mailstop M4-B402, Seattle, WA 98199 USA. EM jkocarni@fredhutch.org OI Hayes, Richard/0000-0002-0918-661X; Kocarnik, Jonathan/0000-0001-8084-1608 FU National Center for Advancing Translational Sciences (National Institutes of Health) [KL2 TR000421]; National Cancer Institute [K05 CA152715, T32 CA 09168, U01 CA137088, R01 CA059045, P01 CA055075, UM1 CA167552, R01 CA137178, R01 CA151993, P50 CA127003, UM1 CA186107, P01 CA87969, R01 CA042182, K05 CA154337]; Division of Cancer Epidemiology; Division of Cancer Prevention (PLCO); National Heart, Lung, and Blood Institute, National Institutes of Health [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C] FX Grant sponsor: National Center for Advancing Translational Sciences (National Institutes of Health); Grant number: KL2 TR000421; Grant sponsor: National Cancer Institute; Grant numbers: K05 CA152715, T32 CA 09168; U01 CA137088 and R01 CA059045 (GECCO); P01 CA055075, UM1 CA167552, R01 CA137178, R01 CA151993 and P50 CA127003 (HPFS); UM1 CA186107, R01 CA137178, P01 CA87969, R01 CA151993 and P50 CA127003 (NHS); R01 CA042182 (PHS); K05 CA154337 (VITAL); Intramural Research Program of the Division of Cancer Epidemiology and contracts from the Division of Cancer Prevention (PLCO); Grant sponsor: National Heart, Lung, and Blood Institute, National Institutes of Health; Grant numbers: HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C (WHI) NR 47 TC 2 Z9 2 U1 2 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD SEP 1 PY 2016 VL 139 IS 5 BP 1065 EP 1072 DI 10.1002/ijc.30163 PG 8 WC Oncology SC Oncology GA DP3TR UT WOS:000378418800011 PM 27121247 ER PT J AU Xi, LF Schiffman, M Koutsky, LA Hughes, JP Hulbert, A Shen, ZP Galloway, DA Kiviat, NB AF Xi, Long Fu Schiffman, Mark Koutsky, Laura A. Hughes, James P. Hulbert, Ayaka Shen, Zhenping Galloway, Denise A. Kiviat, Nancy B. TI Variant-specific persistence of infections with human papillomavirus Types 31, 33, 45, 56 and 58 and risk of cervical intraepithelial neoplasia SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE human papillomavirus; variants; persistence; cervical intraepithelial neoplasia ID NATURAL-HISTORY; YOUNG-WOMEN; LESIONS; HPV; POLYMORPHISM; POPULATION; CANCER; COHORT; CLASSIFICATION AB In our previous study of the etiologic role of oncogenic human papillomavirus (HPV) types other than HPV16 and 18, we observed a significantly higher risk of cervical intraepithelial neoplasia Grades 2-3 (CIN2/3) associated with certain lineages of HPV types 31/33/45/56/58 [called high-risk (HR) variants] compared with non-HR variants. This study was to examine whether these intra-type variants differ in persistence of the infection and persistence-associated risk of CIN2/3. Study subjects were women who had any of HPV types 31/33/45/56/58 newly detected during a 2-year follow-up with 6-month intervals. For each type, the first positive sample was used for variant characterization. The association of reverting-to-negativity with group of the variants and CIN2/3 with length of positivity was assessed using discrete Cox regression and logistic regression, respectively. Of the 598 newly detected, type-specific HPV infections, 312 became undetectable during follow-up. Infections with HR, compared with non-HR, variants were marginally more likely to become negative [adjusted hazard ratio=1.3; 95% confidence interval (CI), 0.9-1.8]. The adjusted odds ratio associating with the development of CIN2/3 was 3.0 (95% CI, 1.2-7.4) for persistent infections with HR variants for 6 months and 10.0 (95% CI, 3.8-38.0) for persistent infections with HR variants for 12-18 months as compared with the first positive detection of HR variants. Among women with non-HR variants, there were no appreciable differences in risk of CIN2/3 by length of positivity. Findings suggest that the lineage-associated risk of CIN2/3 was not mediated through a prolonged persistent infection, but oncogenic heterogeneity of the variants. C1 [Xi, Long Fu; Hulbert, Ayaka; Shen, Zhenping; Kiviat, Nancy B.] Univ Washington, Sch Med, Dept Pathol, NJB Ste 1187,325 9th Ave, Seattle, WA 98104 USA. [Xi, Long Fu; Koutsky, Laura A.] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, NJB Ste 1187,325 9th Ave, Seattle, WA 98104 USA. [Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Hughes, James P.] Univ Washington, Sch Publ Hlth & Community Med, Dept Biostat, NJB Ste 1187,325 9th Ave, Seattle, WA 98104 USA. [Galloway, Denise A.] Fred Hutchinson Canc Res Ctr, Div Human Biol, 1124 Columbia St, Seattle, WA 98104 USA. RP Xi, LF (reprint author), Univ Washington, Harborview Med Ctr, Dept Pathol, NJB Ste 1187,325 9th Ave, Seattle, WA 98104 USA. EM longfu@u.washington.edu FU National Cancer Institute of the National Institutes of Health [CA133569] FX This study was part of the project ancillary to the ALTS clinical trial but does not represent the views of the ALTS Group. The authors would like to thank the ALTS Group Investigators for their planning and conducting the trial and for providing the biological specimens and data to the present study. We also thank Information Management Services, Calverton, MD for data management and programming support. The research reported in this publication was supported by National Cancer Institute of the National Institutes of Health under award number CA133569. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. All authors have no commercial or other associations that might pose a conflict of interest. NR 38 TC 0 Z9 0 U1 7 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD SEP 1 PY 2016 VL 139 IS 5 BP 1098 EP 1105 DI 10.1002/ijc.30164 PG 8 WC Oncology SC Oncology GA DP3TR UT WOS:000378418800015 PM 27121353 ER PT J AU Liow, JS Zoghbi, SS Hu, S Hall, MD Hines, CS Shetty, HU Araneta, MD Page, EM Pike, VW Kreisl, WC Herscovitch, P Gottesman, MM Theodore, WH Innis, RB AF Liow, Jeih-San Zoghbi, Sami S. Hu, Shuo Hall, Matthew D. Hines, Christina S. Shetty, H. Umesha Araneta, Maria D. Page, Emily M. Pike, Victor W. Kreisl, William C. Herscovitch, Peter Gottesman, Michael M. Theodore, William H. Innis, Robert B. TI F-18-FCWAY, a serotonin 1A receptor radioligand, is a substrate for efflux transport at the human blood-brain barrier SO NEUROIMAGE LA English DT Article DE PET; Efflux transporter; P-gp; Blood brain barrier; 5-HT1A ID TEMPORAL-LOBE EPILEPSY; P-GLYCOPROTEIN; 5-HT1A RECEPTORS; RODENT BRAIN; PET; DEFLUORINATION; METABOLITES; INHIBITION; WAY-100635; EXPRESSION AB Efflux transporters at the blood-brain barrier can decrease the entry of drugs and increase the removal of those molecules able to bypass the transporter. We previously hypothesized that F-18-FCWAY, a radioligand for the serotonin 5-HT1A receptor, is a weak substrate for permeability glycoprotein (P-gp) based on its very early peak and rapid washout from human brain. To determine whether F-18-FCWAY is a substrate for P-gp, breast cancer resistance protein (BCRP), and multidrug resistance protein (MRP1) - the three most prevalent efflux transporters at the blood-brain barrier - we performed three sets of experiments. In vitro, we conducted fluorescence-activated cell sorting (FACS) flow cytometry studies in cells over-expressing P-gp, BCRP, and MRP1 treated with inhibitors specific to each transporter and with FCWAY. Ex vivo, we measured F-18-FCWAY concentration in plasma and brain homogenate of transporter knockout mice using gamma-counter and radio-HPLC. In vivo, we conducted positron emission tomography (PET) studies to assess changes in humans who received F-18-FCWAY during an infusion of tariquidar (2-4mg/kg iv), a potent and selective P-gp inhibitor. In vitro studies showed that FCWAY allowed fluorescent substrates to get into the cell by competitive inhibition of all three transporters at the cell membrane. Ex vivo measurements in knockout mice indicate that F-18-FCWAY is a substrate only for P-gp and not BCRP. In vivo, tariquidar increased F-18-FCWAY brain uptake in seven of eight subjects by 60-100% compared to each person's baseline. Tariquidar did not increase brain uptake via some peripheral mechanism, given that it did not significantly alter concentrations in plasma of the parent radioligand F-18-FCWAY or its brain-penetrant radiometabolite F-18-FC. These results show that F-18-FCWAY is a weak substrate for efflux transport at the blood-brain barrier; some radioligand can enter brain, but its removal is hastened by P-gp. Although F-18-FCWAY is not ideal for measuring 5-HT1A receptors, it demonstrates that weak substrate radioligands can be useful for measuring both increased and decreased function of efflux transporters, which is not possible with currently available radioligands such as C-11-loperamide and C-11-verapamil that are avid substrates for transporters. Published by Elsevier Inc. C1 [Liow, Jeih-San; Zoghbi, Sami S.; Shetty, H. Umesha; Araneta, Maria D.; Page, Emily M.; Pike, Victor W.; Innis, Robert B.] NIMH, Mol Imaging Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. [Hu, Shuo] Cent S Univ, Xiang Ya Hosp, PET Ctr, Changsha, Hunan, Peoples R China. [Hall, Matthew D.] NCATS Chem Genom Ctr, Rockville, MD USA. [Hines, Christina S.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Kreisl, William C.] Columbia Univ, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA. [Herscovitch, Peter] NIH, PET Dept, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Gottesman, Michael M.] NCI, Multidrug Resistance Sect, NIH, Bethesda, MD 20892 USA. [Theodore, William H.] NINDS, Clin Epilepsy Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Liow, JS (reprint author), NIMH, Mol Imaging Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM liowj@mail.nih.gov FU Intramural Research Program of the National Institute Mental Health, NIH [ZIAMH002852, ZIAMH002793, NCT01386476] FX This study was funded by the Intramural Research Program of the National Institute Mental Health, NIH: projects ZIAMH002852 and ZIAMH002793, under clinical protocol NCT01386476. All authors have no conflicts of interest to disclose. NR 25 TC 0 Z9 0 U1 6 U2 10 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 SEP PY 2016 VL 138 BP 134 EP 140 DI 10.1016/j.neuroimage.2016.05.045 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DP5ET UT WOS:000378519500011 PM 27211474 ER PT J AU Huo, Y Plassard, AJ Carass, A Resnick, SM Pham, DL Prince, JL Landman, BA AF Huo, Yuankai Plassard, Andrew J. Carass, Aaron Resnick, Susan M. Pham, Dzung L. Prince, Jerry L. Landman, Bennett A. TI Consistent cortical reconstruction and multi-atlas brain segmentation SO NEUROIMAGE LA English DT Article DE Multi-atlas segmentation; Magnetic resonance imaging; Cerebral cortex; Cortical reconstruction ID HUMAN CEREBRAL-CORTEX; MAGNETIC-RESONANCE IMAGES; AUTOMATED 3-D EXTRACTION; SURFACE-BASED ANALYSIS; TISSUE CLASSIFICATION; COORDINATE SYSTEM; OLDER-ADULTS; LABEL FUSION; MR-IMAGES; THICKNESS AB Whole brain segmentation and cortical surface reconstruction are two essential techniques for investigating the human brain. Spatial inconsistences, which can hinder further integrated analyses of brain structure, can result due to these two tasks typically being conducted independently of each other. FreeSurfer obtains selfconsistent whole brain segmentations and cortical surfaces. It starts with subcortical segmentation, then carries out cortical surface reconstruction, and ends with cortical segmentation and labeling. However, this "segmentation to surface to parcellation" strategy has shown limitations in various cohorts such as older populations with large ventricles. In this work, we propose a novel "multi-atlas segmentation to surface" method calledMulti-atlas CRUISE (MaCRUISE), which achieves self-consistent whole brain segmentations and cortical surfaces by combining multi-atlas segmentation with the cortical reconstruction method CRUISE. A modification called MaCRUISE(+) is designed to perform well when white matter lesions are present. Comparing to the benchmarks CRUISE and FreeSurfer, the surface accuracy of MaCRUISE and MaCRUISE+ is validated using two independent datasets with expertly placed cortical landmarks. A third independent dataset with expertly delineated volumetric labels is employed to compare segmentation performance. Finally, 200MR volumetric images from an older adult sample are used to assess the robustness of MaCRUISE and FreeSurfer. The advantages of MaCRUISE are: (1) MaCRUISE constructs self-consistent voxelwise segmentations and cortical surfaces, while MaCRUISE(+) is robust to white matter pathology. (2) MaCRUISE achieves more accurate whole brain segmentations than independently conducting the multi-atlas segmentation. (3) MaCRUISE is comparable in accuracy to FreeSurfer (when FreeSurfer does not exhibit global failures) while achieving greater robustness across an older adult population. MaCRUISE has been made freely available in open source. (C) 2016 Elsevier Inc. All rights reserved. C1 [Huo, Yuankai; Landman, Bennett A.] Vanderbilt Univ, Elect Engn, EECS 2301,Vanderbilt Pl,POB 351679 Stn B, Nashville, TN 37235 USA. [Plassard, Andrew J.; Landman, Bennett A.] Vanderbilt Univ, Comp Sci, EECS 2301,Vanderbilt Pl,POB 351679 Stn B, Nashville, TN 37235 USA. [Carass, Aaron; Prince, Jerry L.] Johns Hopkins Univ, Image Anal & Commun Lab, Baltimore, MD USA. [Resnick, Susan M.] Natl Inst Aging, Lab Behav Neurosci, Baltimore, MD USA. [Pham, Dzung L.] Henry Jackson Fdn, Ctr Neurosci & Regenerat Med, Bethesda, MD USA. [Landman, Bennett A.] Vanderbilt Univ, Inst Imaging Sci, EECS 2301,Vanderbilt Pl,POB 351679 Stn B, Nashville, TN 37235 USA. [Landman, Bennett A.] Vanderbilt Univ, Radiol & Radiol Sci, EECS 2301,Vanderbilt Pl,POB 351679 Stn B, Nashville, TN 37235 USA. RP Huo, Y (reprint author), Vanderbilt Univ, EECS 2301,Vanderbilt Pl,POB 351679 Stn B, Nashville, TN 37235 USA. EM yuankai.huo@vanderbilt.edu OI Huo, Yuankai/0000-0002-2096-8065; Carass, Aaron/0000-0003-4939-5085 FU NSF CAREER [1452485]; NIH [5R21EY024036, 1R21NS064534, 1R01NS070906, 5R01NS056307, 1R21NS096497, 2R01EB006136, 1R03EB012461, R01EB006193, 5R21NS082891]; Intramural Research Program, National Institute on Aging, NIH; National MS Society [RG-1507-05243]; Advanced Computing Center for Research and Education (ACCRE) at Vanderbilt University, Nashville, TN; ViSE/VICTR [VR3029]; National Center for Research Resources [UL1 RR024975-01]; National Center for Advancing Translational Sciences [2 UL1 TR000445-06]; Department of Defense in the Center for Neuroscience and Regenerative Medicine FX This research was supported by NSF CAREER 1452485 (Landman), NIH grants 5R21EY024036 (Landman), 1R21NS064534 (Prince/Landman), 1R01NS070906 (Pham), 5R01NS056307 (Prince), 1R21NS096497 (Prince), 2R01EB006136 (Dawant), 1R03EB012461 (Landman) and R01EB006193 (Dawant). This research was conducted with the support from Intramural Research Program, National Institute on Aging, NIH. This research was supported by National MS Society RG-1507-05243 (Pham). This study was also supported by NIH 5R01NS056307, 5R21NS082891 and in part using the resources of the Advanced Computing Center for Research and Education (ACCRE) at Vanderbilt University, Nashville, TN. This project was supported in part by ViSE/VICTR VR3029 and the National Center for Research Resources, Grant UL1 RR024975-01, and is now at the National Center for Advancing Translational Sciences, Grant 2 UL1 TR000445-06. Support for this work included funding from the Department of Defense in the Center for Neuroscience and Regenerative Medicine. The authors are responsible for the content. The content does not necessarily represent the official views of the NIH. We are grateful for the assistance of Naresh Nandakumar in helping prepare this manuscript. NR 92 TC 1 Z9 1 U1 6 U2 10 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 SEP PY 2016 VL 138 BP 197 EP 210 DI 10.1016/j.neuroimage.2016.05.030 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DP5ET UT WOS:000378519500017 PM 27184203 ER PT J AU Guo, AL Xu, YF Mowery, J Nagy, A Bauchan, G Nou, XW AF Guo, Ailing Xu, Yunfeng Mowery, Joseph Nagy, Attila Bauchan, Gary Nou, Xiangwu TI Ralstonia insidiosa induces cell aggregation of Listeria monocytogenes SO FOOD CONTROL LA English DT Article DE Listeria monocytogenes; Ralstonia insidiosa; Cell aggregation; Biofilms; TEM ID ESCHERICHIA-COLI O157H7; BIOFILM FORMATION; STRAINS; COAGGREGATION; PREVALENCE; CANTALOUPE; PICKETTII; OUTBREAK; GROWTH; LEVEL AB Biofilm formation is an important strategy for foodborne bacterial pathogens to survive in stressful environments such as fresh produce processing facilities. Bacterial cell aggregation strongly promotes the initiation of microcolonies and the formation of biofilms on abiological surfaces. We previously showed that Ralstonia insidiosa, an environmental bacterial species frequently isolated from fresh produce facilities, may serve as a "bridge bacterium" that strongly enhanced the incorporation of several foodborne bacterial pathogens into dual species biofilms. While the R. insidiosa strain exhibited moderate cell aggregation in liquid culture, co-culturing Listeria monocytogenes with R. insidiosa resulted in significant augmentation of cell aggregation. Electron microscopy indicated that L. monocytogenes cells were initially attracted to the R. insidiosa aggregates and formed large dual species aggregates that were predominately composed of L. monocytogenes cells. The predominant presence of L. monocytogenes in the dual species aggregates was also confirmed by differential plating. These findings suggest that bridge bacteria such as R. insidiosa play critical roles in the survival of foodborne bacterial pathogens, such as L. monocytogenes and Escherichia coli, by promoting multispecies biofilm formation. The implications of such bridge bacteria on food safety need to be further evaluated. Published by Elsevier Ltd. C1 [Guo, Ailing] Huazhong Agr Univ, Natl Res & Dev Ctr Egg Proc, Wuhan 430070, Peoples R China. [Xu, Yunfeng; Nagy, Attila; Nou, Xiangwu] ARS, Environm Microbial & Food Safety Lab, Beltsville Agr Res Ctr, USDA, Beltsville, MD 20705 USA. [Mowery, Joseph; Bauchan, Gary] ARS, Electron & Confocal Microscopy Unit, Beltsville Agr Res Ctr, USDA, Beltsville, MD 20705 USA. [Nagy, Attila] NIAID, NIH, Vaccine Res Ctr, Gaithersburg, MD 20878 USA. RP Nou, XW (reprint author), ARS, Environm Microbial & Food Safety Lab, Beltsville Agr Res Ctr, USDA, Beltsville, MD 20705 USA. EM Xiangwu.nou@ars.usda.gov FU Huazhong Agricultural University; China Scholarship Council FX Authors wish to thank Dr. T. Ward for providing L.monocytogenes strains used in this study. Ailing Guo was a visiting scientist to USDA ARS EMFSL from and supported by Huazhong Agricultural University, and Yunfeng Xu is predoctoral student from Northwest A&F University, China, and is supported by China Scholarship Council. NR 37 TC 0 Z9 0 U1 6 U2 16 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-7135 EI 1873-7129 J9 FOOD CONTROL JI Food Control PD SEP PY 2016 VL 67 BP 303 EP 309 DI 10.1016/j.foodcont.2016.03.006 PG 7 WC Food Science & Technology SC Food Science & Technology GA DK8FY UT WOS:000375163800039 ER PT J AU Wang, YC Chin, KH Tu, ZL He, J Jones, CJ Sanchez, DZ Yildiz, FH Galperin, MY Chou, SH AF Wang, Yu-Chuan Chin, Ko-Hsin Tu, Zhi-Le He, Jin Jones, Christopher J. Sanchez, David Zamorano Yildiz, Fitnat H. Galperin, Michael Y. Chou, Shan-Ho TI Nucleotide binding by the widespread high-affinity cyclic di-GMP receptor MshEN domain SO NATURE COMMUNICATIONS LA English DT Article ID II SECRETION SYSTEM; MOLECULAR DISCRIMINATION; MECHANISTIC INSIGHTS; STRUCTURAL BASIS; YDAO RIBOSWITCH; PILZ-DOMAIN; PROTEIN; DATABASE; AMP; 2ND-MESSENGER AB C-di-GMP is a bacterial second messenger regulating various cellular functions. Many bacteria contain c-di-GMP-metabolizing enzymes but lack known c-di-GMP receptors. Recently, two MshE-type ATPases associated with bacterial type II secretion system and type IV pilus formation were shown to specifically bind c-di-GMP. Here we report crystal structure of the MshE N-terminal domain (MshEN(1-145)) from Vibrio cholerae in complex with c-di-GMP at a 1.37 resolution. This structure reveals a unique c-di-GMP-binding mode, featuring a tandem array of two highly conserved binding motifs, each comprising a 24-residue sequence RLGxx(L/V/I)(L/V/I)xxG(L/V/I)(L/V/I)xxxxLxxxLxxQ that binds half of the c-di-GMP molecule, primarily through hydrophobic interactions. Mutating these highly conserved residues markedly reduces c-di-GMP binding and biofilm formation by V. cholerae. This c-di-GMP-binding motif is present in diverse bacterial proteins exhibiting binding affinities ranging from 0.5 mu M to as low as 14 nM. The MshEN domain contains the longest nucleotide-binding motif reported to date. C1 [Wang, Yu-Chuan; Tu, Zhi-Le; Chou, Shan-Ho] Natl Chung Hsing Univ, Inst Biochem, Taichung 40227, Taiwan. [Chin, Ko-Hsin; Chou, Shan-Ho] Natl Chung Hsing Univ, Agr Biotechnol Ctr, Taichung 40227, Taiwan. [He, Jin] Huazhong Agr Univ, Coll Life Sci & Technol, State Key Lab Agr Microbiol, Wuhan 430070, Hubei, Peoples R China. [Jones, Christopher J.; Sanchez, David Zamorano; Yildiz, Fitnat H.] Univ Calif Santa Cruz, Dept Microbiol & Environm Toxicol, Santa Cruz, CA 95064 USA. [Galperin, Michael Y.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Chou, SH (reprint author), Natl Chung Hsing Univ, Inst Biochem, Taichung 40227, Taiwan.; Chou, SH (reprint author), Natl Chung Hsing Univ, Agr Biotechnol Ctr, Taichung 40227, Taiwan. EM shchou@nchu.edu.tw OI Galperin, Michael/0000-0002-2265-5572 FU Ministry of Education, Taiwan, ROC under the ATU plan; Ministry of Science and Technology, Taiwan, ROC [102-2113-M-005 -006 -MY3]; NIH [RO1 AI102584]; NIH Intramural Research Program at the US National Library of Medicine FX This work was supported in part by the Ministry of Education, Taiwan, ROC under the ATU plan, and by the Ministry of Science and Technology, Taiwan, ROC (102-2113-M-005 -006 -MY3) to S.-H.C. and NIH award RO1 AI102584 to F.H.Y. M.Y.G. was supported by the NIH Intramural Research Program at the US National Library of Medicine. We would also like to thank the National Synchrotron Radiation Research Center (NSRRC) in Taiwan, and the SPring-8 Synchrotron facility in Japan for assistance of the X-ray data collections. NR 51 TC 2 Z9 2 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD AUG 31 PY 2016 VL 7 AR 12481 DI 10.1038/ncomms12481 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH6FY UT WOS:000391869500001 PM 27578558 ER PT J AU Wen, PJ Grenklo, S Arpino, G Tan, XY Liao, HS Heureaux, J Peng, SY Chiang, HC Hamid, E Zhao, WD Shin, W Nareoja, T Evergren, E Jin, YH Karlsson, R Ebert, SN Jin, A Liu, AP Shupliakov, O Wu, LG AF Wen, Peter J. Grenklo, Staffan Arpino, Gianvito Tan, Xinyu Liao, Hsien-Shun Heureaux, Johanna Peng, Shi-Yong Chiang, Hsueh-Cheng Hamid, Edaeni Zhao, Wei-Dong Shin, Wonchul Naereoja, Tuomas Evergren, Emma Jin, Yinghui Karlsson, Roger Ebert, Steven N. Jin, Albert Liu, Allen P. Shupliakov, Oleg Wu, Ling-Gang TI Actin dynamics provides membrane tension to merge fusing vesicles into the plasma membrane SO NATURE COMMUNICATIONS LA English DT Article ID ADRENAL CHROMAFFIN CELLS; KISS-AND-RUN; CROSS-LINKED PROFILIN; DENSE-CORE VESICLES; REGULATED EXOCYTOSIS; F-ACTIN; COMPENSATORY ENDOCYTOSIS; NEUROENDOCRINE CELLS; STRUCTURAL-CHANGES; SYNAPTIC VESICLES AB Vesicle fusion is executed via formation of an Omega-shaped structure (Omega-profile), followed by closure (kiss-and-run) or merging of the Omega-profile into the plasma membrane (full fusion). Although Omega-profile closure limits release but recycles vesicles economically, Omega-profile merging facilitates release but couples to classical endocytosis for recycling. Despite its crucial role in determining exocytosis/endocytosis modes, how Omega-profile merging is mediated is poorly understood in endocrine cells and neurons containing small similar to 30-300 nm vesicles. Here, using confocal and super-resolution STED imaging, force measurements, pharmacology and gene knockout, we show that dynamic assembly of filamentous actin, involving ATP hydrolysis, N-WASP and formin, mediates Omega-profile merging by providing sufficient plasma membrane tension to shrink the Omega-profile in neuroendocrine chromaffin cells containing similar to 300 nm vesicles. Actin-directed compounds also induce Omega-profile accumulation at lamprey synaptic active zones, suggesting that actin may mediate Omega-profile merging at synapses. These results uncover molecular and biophysical mechanisms underlying Omega-profile merging. C1 [Wen, Peter J.; Arpino, Gianvito; Peng, Shi-Yong; Chiang, Hsueh-Cheng; Hamid, Edaeni; Zhao, Wei-Dong; Shin, Wonchul; Jin, Yinghui; Wu, Ling-Gang] Natl Inst Neurol Disorders & Stroke, 35 Convent Dr,Bldg 35,Room 2B 1012, Bethesda, MD 20892 USA. [Grenklo, Staffan; Arpino, Gianvito; Naereoja, Tuomas; Evergren, Emma; Shupliakov, Oleg] Karolinska Inst, Ctr Excellence Dev Biol, Dept Neurosci, S-17177 Stockholm, Sweden. [Grenklo, Staffan; Karlsson, Roger] Stockholm Univ, WGI, Dept Cell Biol, S-10691 Stockholm, Sweden. [Tan, Xinyu; Heureaux, Johanna; Liu, Allen P.] Univ Michigan, Dept Mech Engn, Ann Arbor, MI 48109 USA. [Liao, Hsien-Shun; Jin, Albert] NIBIB, Bethesda, MD 20892 USA. [Ebert, Steven N.] Univ Cent Florida, Burnett Sch Biomed Sci, Coll Med, 6900 Lake Nona Blvd, Orlando, FL 32827 USA. [Shupliakov, Oleg] St Petersburg State Univ, Inst Translat Biomed, St Petersburg 199034, Russia. [Chiang, Hsueh-Cheng] Natl Cheng Kung Univ, Coll Med, Dept Pharmacol, 1 Univ Rd, Tainan 701, Taiwan. [Evergren, Emma] Queens Univ Belfast, Ctr Canc Res & Cell Biol, Belfast BT9 7AE, Antrim, North Ireland. RP Wu, LG (reprint author), Natl Inst Neurol Disorders & Stroke, 35 Convent Dr,Bldg 35,Room 2B 1012, Bethesda, MD 20892 USA.; Shupliakov, O (reprint author), Karolinska Inst, Ctr Excellence Dev Biol, Dept Neurosci, S-17177 Stockholm, Sweden.; Shupliakov, O (reprint author), St Petersburg State Univ, Inst Translat Biomed, St Petersburg 199034, Russia. EM oleg.shupliakov@ki.se; wul@ninds.nih.gov RI Nareoja, Tuomas/K-3800-2014 OI Nareoja, Tuomas/0000-0002-2174-4434 FU National Institute of Neurological Disorders and Stroke Intramural Research Program [ZIA NS003009-13, ZIA NS003105-08]; Swedish Research Council [13473]; Parkinsonfonden; Hjarnfonden; Russian Science Foundation [16-15-10273] FX We thank Dr James Ervasti for providing Actbloxp mice. This work was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program (ZIA NS003009-13 and ZIA NS003105-08) to L.G.W. and by grants from the Swedish Research Council (project 13473), Parkinsonfonden, Hjarnfonden and the Russian Science Foundation (project number 16-15-10273) to O.S. NR 67 TC 2 Z9 2 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 AUG 31 PY 2016 VL 7 AR 12604 DI 10.1038/ncomms12604 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH6GO UT WOS:000391871100001 PM 27576662 ER PT J AU Zaslavsky, L Ciufo, S Fedorov, B Tatusova, T AF Zaslavsky, Leonid Ciufo, Stacy Fedorov, Boris Tatusova, Tatiana TI Clustering analysis of proteins from microbial genomes at multiple levels of resolution SO BMC BIOINFORMATICS LA English DT Article; Proceedings Paper CT 11th International Symposium on Bioinformatics Research and Applications (ISBRA) CY JUN 07-10, 2015 CL Old Domin Univ, Norfolk, VA HO Old Domin Univ DE Protein; Cluster; Clustering; Microbial; Procaryotic; Core-periphery; Multiscale; Multiresolution; Knowledge discovery; Data mining; Parallel processing; Parallel computing ID BACTERIAL PAN-GENOME; PARALLEL ALGORITHMS; SEARCH; ORTHOLOGS; ALIGNMENT; BLAST AB Background: Microbial genomes at the National Center for Biotechnology Information (NCBI) represent a large collection of more than 35,000 assemblies. There are several complexities associated with the data: a great variation in sampling density since human pathogens are densely sampled while other bacteria are less represented; different protein families occur in annotations with different frequencies; and the quality of genome annotation varies greatly. In order to extract useful information from these sophisticated data, the analysis needs to be performed at multiple levels of phylogenomic resolution and protein similarity, with an adequate sampling strategy. Results: Protein clustering is used to construct meaningful and stable groups of similar proteins to be used for analysis and functional annotation. Our approach is to create protein clusters at three levels. First, tight clusters in groups of closely-related genomes (species-level clades) are constructed using a combined approach that takes into account both sequence similarity and genome context. Second, clustroids of conservative in-clade clusters are organized into seed global clusters. Finally, global protein clusters are built around the the seed clusters. We propose filtering strategies that allow limiting the protein set included in global clustering. The in-clade clustering procedure, subsequent selection of clustroids and organization into seed global clusters provides a robust representation and high rate of compression. Seed protein clusters are further extended by adding related proteins. Extended seed clusters include a significant part of the data and represent all major known cell machinery. The remaining part, coming from either non-conservative (unique) or rapidly evolving proteins, from rare genomes, or resulting from low-quality annotation, does not group together well. Processing these proteins requires significant computational resources and results in a large number of questionable clusters. Conclusion: The developed filtering strategies allow to identify and exclude such peripheral proteins limiting the protein dataset in global clustering. Overall, the proposed methodology allows the relevant data at different levels of details to be obtained and data redundancy eliminated while keeping biologically interesting variations. C1 [Zaslavsky, Leonid; Ciufo, Stacy; Fedorov, Boris; Tatusova, Tatiana] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Zaslavsky, L (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM zaslavsk@ncbi.nlm.nih.gov NR 43 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD AUG 31 PY 2016 VL 17 SU 8 AR 276 DI 10.1186/s12859-016-1112-8 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA DW5AV UT WOS:000383655300001 PM 27586436 ER PT J AU Kim, DA Benjamin, EJ Fowler, JH Christakis, NA AF Kim, David A. Benjamin, Emelia J. Fowler, James H. Christakis, Nicholas A. TI Social connectedness is associated with fibrinogen level in a human social network SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE social networks; social epidemiology; fibrinogen; social hierarchy; stress response ID CORONARY-HEART-DISEASE; MORTALITY; HEALTH; DETERMINANTS; SPREAD; LONELINESS; INEQUALITY; FRIENDSHIP; DYNAMICS; WOMEN AB Socially isolated individuals face elevated rates of illness and death. Conventional measures of social connectedness reflect an individual's perceived network and can be subject to bias and variation in reporting. In this study of a large human social network, we find that greater indegree, a sociocentric measure of friendship and familial ties identified by a subject's social connections rather than by the subject, predicts significantly lower concentrations of fibrinogen (a biomarker of inflammation and cardiac risk), after adjusting for demographics, education, medical history and known predictors of cardiac risk. The association between fibrinogen and social isolation, as measured by low indegree, is comparable to the effect of smoking, and greater than that of low education, a conventional measure of socioeconomic disadvantage. By contrast, outdegree, which reflects an individual's perceived connectedness, displays a significantly weaker association with fibrinogen concentrations. C1 [Kim, David A.] Stanford Univ, Dept Emergency Med, 300 Pasteur Dr MC 5119, Stanford, CA 94305 USA. [Benjamin, Emelia J.] Natl Heart Lung & Blood Inst, 73 Mt Wayte Ave, Framingham, MA 01702 USA. [Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. [Fowler, James H.] Univ Calif San Diego, Dept Med, 9500 Gilman Dr 0521, La Jolla, CA 92093 USA. [Fowler, James H.] Univ Calif San Diego, Dept Polit Sci, 9500 Gilman Dr 0521, La Jolla, CA 92093 USA. [Christakis, Nicholas A.] Yale Univ, Dept Med, POB 208263, New Haven, CT 06520 USA. [Christakis, Nicholas A.] Yale Univ, Dept Ecol & Evolutionary Biol, POB 208263, New Haven, CT 06520 USA. [Christakis, Nicholas A.] Yale Univ, Dept Sociol, POB 208263, New Haven, CT 06520 USA. RP Christakis, NA (reprint author), Yale Univ, Dept Med, POB 208263, New Haven, CT 06520 USA.; Christakis, NA (reprint author), Yale Univ, Dept Ecol & Evolutionary Biol, POB 208263, New Haven, CT 06520 USA.; Christakis, NA (reprint author), Yale Univ, Dept Sociol, POB 208263, New Haven, CT 06520 USA. EM nicholas.christakis@yale.edu OI Kim, David/0000-0003-0151-5121 FU NIH [P01AG31093]; National Institute on Aging; Canadian Institutes of Health Research; [HHSN268201500001I]; [N01-HC 25195] FX This work was supported by NIH grant no. P01AG31093 and by the National Institute on Aging. D.A.K. was supported by the Canadian Institutes of Health Research. The FHS is supported by HHSN268201500001I and N01-HC 25195. NR 48 TC 0 Z9 0 U1 5 U2 5 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 AUG 31 PY 2016 VL 283 IS 1837 AR 20160958 DI 10.1098/rspb.2016.0958 PG 7 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA DY4FY UT WOS:000385055600018 ER PT J AU Pugacheva, EM Teplyakov, E Wu, QF Li, JJ Chen, C Meng, CC Liu, J Robinson, S Loukinov, D Boukaba, A Hutchins, AP Lobanenkov, V Strunnikov, A AF Pugacheva, Elena M. Teplyakov, Evgeny Wu, Qiongfang Li, Jingjing Chen, Cheng Meng, Chengcheng Liu, Jian Robinson, Susan Loukinov, Dmitry Boukaba, Abdelhalim Hutchins, Andrew Paul Lobanenkov, Victor Strunnikov, Alexander TI The cancer-associated CTCFL/BORIS protein targets multiple classes of genomic repeats, with a distinct binding and functional preference for humanoid-specific SVA transposable elements SO EPIGENETICS & CHROMATIN LA English DT Article ID DNA METHYLATION; CTCF BINDING; SOMATIC RETROTRANSPOSITION; ENDOGENOUS RETROVIRUSES; EXPANSION DISORDERS; PLURIPOTENT CELLS; GENE PROMOTERS; FACTOR BORIS; STEM-CELLS; EXPRESSION AB Background: A common aberration in cancer is the activation of germline-specific proteins. The DNA-binding proteins among them could generate novel chromatin states, not found in normal cells. The germline-specific transcription factor BORIS/CTCFL, a paralog of chromatin architecture protein CTCF, is often erroneously activated in cancers and rewires the epigenome for the germline-like transcription program. Another common feature of malignancies is the changed expression and epigenetic states of genomic repeats, which could alter the transcription of neighboring genes and cause somatic mutations upon transposition. The role of BORIS in transposable elements and other repeats has never been assessed. Results: The investigation of BORIS and CTCF binding to DNA repeats in the K562 cancer cells dependent on BORIS for self-renewal by ChIP-chip and ChIP-seq revealed three classes of occupancy by these proteins: elements cohabited by BORIS and CTCF, CTCF-only bound, or BORIS-only bound. The CTCF-only enrichment is characteristic for evolutionary old and inactive repeat classes, while BORIS and CTCF co-binding predominately occurs at uncharacterized tandem repeats. These repeats form staggered cluster binding sites, which are a prerequisite for CTCF and BORIS co-binding. At the same time, BORIS preferentially occupies a specific subset of the evolutionary young, transcribed, and mobile genomic repeat family, SVA. Unlike CTCF, BORIS prominently binds to the VNTR region of the SVA repeats in vivo. This suggests a role of BORIS in SVA expression regulation. RNA-seq analysis indicates that BORIS largely serves as a repressor of SVA expression, alongside DNA and histone methylation, with the exception of promoter capture by SVA. Conclusions: Thus, BORIS directly binds to, and regulates SVA repeats, which are essentially movable CpG islands, via clusters of BORIS binding sites. This finding uncovers a new function of the global germline-specific transcriptional regulator BORIS in regulating and repressing the newest class of transposable elements that are actively transposed in human genome when activated. This function of BORIS in cancer cells is likely a reflection of its roles in the germline. C1 [Teplyakov, Evgeny; Wu, Qiongfang; Li, Jingjing; Chen, Cheng; Meng, Chengcheng; Liu, Jian; Boukaba, Abdelhalim; Strunnikov, Alexander] Guangzhou Inst Biomed & Hlth, Mol Epigenet Lab, Guangzhou 510530, Guangdong, Peoples R China. [Pugacheva, Elena M.; Robinson, Susan; Loukinov, Dmitry; Lobanenkov, Victor] NIAID, Lab Immunogenet, NIH, Rockville, MD 20852 USA. [Hutchins, Andrew Paul] Southern Univ Sci & Technol China, Dept Biol, Shenzhen 518055, Guangdong, Peoples R China. RP Strunnikov, A (reprint author), Guangzhou Inst Biomed & Hlth, Mol Epigenet Lab, Guangzhou 510530, Guangdong, Peoples R China. EM alex@gibh.org FU PRC government's "1000 Talents Program" grant; Guangdong provincial government's "Guangdong High Talent" award; Intramural Program of the National Institute of Allergy and Infectious Diseases FX This work was supported by the PRC government's "1000 Talents Program" grant to AS, the Guangdong provincial government's "Guangdong High Talent" award to AS, and the Intramural Program of the National Institute of Allergy and Infectious Diseases for VL. NR 117 TC 1 Z9 1 U1 10 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-8935 J9 EPIGENET CHROMATIN JI Epigenetics Chromatin PD AUG 31 PY 2016 VL 9 AR 35 DI 10.1186/s13072-016-0084-2 PG 20 WC Genetics & Heredity SC Genetics & Heredity GA DV8CR UT WOS:000383165600001 PM 27588042 ER PT J AU Yu, LD Ham, K Gao, XH Castro, L Yan, YT Kissling, GE Tucker, CJ Flagler, N Dong, R Archer, TK Dixon, D AF Yu, Linda Ham, Kyle Gao, Xiaohua Castro, Lysandra Yan, Yitang Kissling, Grace E. Tucker, Charles J. Flagler, Norris Dong, Ray Archer, Trevor K. Dixon, Darlene TI Epigenetic regulation of transcription factor promoter regions by low-dose genistein through mitogen-activated protein kinase and mitogen-and-stress activated kinase 1 nongenomic signaling SO CELL COMMUNICATION AND SIGNALING LA English DT Article DE Epigenetic; Histone H3; Leiomyoma; MAPK(p44/42); MSK1 ID HISTONE H3 PHOSPHORYLATION; ESTROGEN-RECEPTOR-ALPHA; BREAST-CANCER CELLS; HUMAN UTERINE LEIOMYOMAS; MATCHED MYOMETRIUM; GROWTH-FACTORS; ER-ALPHA; PATHWAY; CHROMATIN; TRANSDUCTION AB Background: The phytoestrogen, genistein at low doses nongenomically activates mitogen-activated protein kinase p44/42 (MAPK(p44/42)) via estrogen receptor alpha (ER alpha) leading to proliferation of human uterine leiomyoma cells. In this study, we evaluated if MAPK(p44/42) could activate downstream effectors such as mitogen-and stress-activated protein kinase 1 (MSK1), which could then epigenetically modify histone H3 by phosphorylation following a low dose (1 mu g/ml) of genistein. Results: Using hormone-responsive immortalized human uterine leiomyoma (ht-UtLM) cells, we found that genistein activated MAPK(p44/42) and MSK1, and also increased phosphorylation of histone H3 at serine10 (H3S10ph) in ht-UtLM cells. Colocalization of phosphorylated MSK1 and H3S10ph was evident by confocal microscopy in ht-UtLM cells (r = 0.8533). Phosphorylation of both MSK1 and H3S10ph was abrogated by PD98059 (PD), a MEK1 kinase inhibitor, thereby supporting genistein's activation of MSK1 and Histone H3 was downstream of MAPK(p44/42). In proliferative (estrogenic) phase human uterine fibroid tissues, phosphorylated MSK1 and H3S10ph showed increased immunoexpression compared to normal myometrial tissues, similar to results observed in in vitro studies following low-dose genistein administration. Real-time RT-PCR arrays showed induction of growth-related transcription factor genes, EGR1, Elk1, ID1, and MYB (cMyb) with confirmation by western blot, downstream of MAPK in response to low-dose genistein in ht-UtLM cells. Additionally, genistein induced associations of promoter regions of the above transcription factors with H3S10ph as evidenced by Chromatin Immunoprecipitation (ChIP) assays, which were inhibited by PD. Therefore, genistein epigenetically modified histone H3 by phosphorylation of serine 10, which was regulated by MSK1 and MAPK activation. Conclusion: Histone H3 phosphorylation possibly represents a mechanism whereby increased transcriptional activation occurs following low-dose genistein exposure. C1 [Yu, Linda; Ham, Kyle; Gao, Xiaohua; Castro, Lysandra; Yan, Yitang; Dong, Ray; Dixon, Darlene] NIEHS, Mol Pathogenesis Grp, Toxicol Program NTP Lab, Div NTP DNTP,NIH,US Dept Hlth & Human Serv HHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Kissling, Grace E.] NIEHS, Biostat & Computat Biol Branch, DIR, NIH,HHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Tucker, Charles J.] NIEHS, Signal Transduct Lab, DIR, NIH,HHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Flagler, Norris] NIEHS, Cellular & Mol Pathol Branch, DNTP, NIH,HHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Archer, Trevor K.] NIEHS, Chromatin & Gene Express Grp, Epigenet & Stem Cell Biol Lab, DIR,NIH,HHS, POB 12233, Res Triangle Pk, NC 27709 USA. RP Dixon, D (reprint author), NIEHS, Mol Pathogenesis Grp, Toxicol Program NTP Lab, Div NTP DNTP,NIH,US Dept Hlth & Human Serv HHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM dixon@niehs.nih.gov FU Intramural Research Program of the NIH; NIEHS; DNTP FX The authors kindly thank Drs. Wei Qu and Kyathanahalli Janardhan for their critical review of this manuscript. The authors would also like to thank Alicia B. Moore for her excellent assistance with formatting the manuscript. This research was supported by the Intramural Research Program of the NIH, NIEHS and DNTP. NR 44 TC 0 Z9 0 U1 4 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-811X J9 CELL COMMUN SIGNAL JI Cell Commun. Signal. PD AUG 31 PY 2016 VL 14 AR 18 DI 10.1186/s12964-016-0141-2 PG 13 WC Cell Biology SC Cell Biology GA DV3IV UT WOS:000382815400001 PM 27582276 ER PT J AU Segade, F Cota, C Famiglietti, A Cha, A Davidson, B AF Segade, Fernando Cota, Christina Famiglietti, Amber Cha, Anna Davidson, Brad TI Fibronectin contributes to notochord intercalation in the invertebrate chordate, Ciona intestinalis SO EVODEVO LA English DT Article DE Chordate evolution; Tunicates; Extracellular matrix; Fibronectin; Notochord; Convergent extension ID GENE REGULATORY NETWORK; CONVERGENT EXTENSION; TRANSCRIPTION FACTORS; EXTRACELLULAR-MATRIX; FUNCTIONAL GENOMICS; ASCIDIAN NOTOCHORD; TISSUE MECHANICS; CELL MOTILITY; EVOLUTION; HEART AB Background: Genomic analysis has upended chordate phylogeny, placing the tunicates as the sister group to the vertebrates. This taxonomic rearrangement raises questions about the emergence of a tunicate/vertebrate ancestor. Results: Characterization of developmental genes uniquely shared by tunicates and vertebrates is one promising approach for deciphering developmental shifts underlying acquisition of novel, ancestral traits. The matrix glycoprotein Fibronectin (FN) has long been considered a vertebrate-specific gene, playing a major instructive role in vertebrate embryonic development. However, the recent computational prediction of an orthologous "vertebrate-like" Fn gene in the genome of a tunicate, Ciona savignyi, challenges this viewpoint suggesting that Fn may have arisen in the shared tunicate/vertebrate ancestor. Here we verify the presence of a tunicate Fn ortholog. Transgenic reporter analysis was used to characterize a Ciona Fn enhancer driving expression in the notochord. Targeted knockdown in the notochord lineage indicates that FN is required for proper convergent extension. Conclusions: These findings suggest that acquisition of Fn was associated with altered notochord morphogenesis in the vertebrate/tunicate ancestor. C1 [Segade, Fernando] Univ Penn, Sch Dent Med, Dept Anat & Cell Biol, Philadelphia, PA 19104 USA. [Cota, Christina; Davidson, Brad] Swarthmore Coll, Dept Biol, 500 Coll Ave, Swarthmore, PA 19081 USA. [Famiglietti, Amber] Natl Inst Dent & Craniofacial Res, Sect Biol Chem, NIH, Bethesda, MD 20892 USA. [Cha, Anna] Harvard Med Sch, Dept Syst Biol, Boston, MA USA. RP Davidson, B (reprint author), Swarthmore Coll, Dept Biol, 500 Coll Ave, Swarthmore, PA 19081 USA. EM bdavids1@swarthmore.edu OI Cota, Christina/0000-0003-1307-903X FU Swarthmore College; NIH [1R01HL091027, R15 HD080525-01]; American Heart Association Postdoctoral Award [16POST27250075] FX Funding was also provided by Swarthmore College and the NIH (1R01HL091027, R15 HD080525-01). CC was supported by an American Heart Association Postdoctoral Award (16POST27250075). NR 83 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 2041-9139 J9 EVODEVO JI EvoDevo PD AUG 31 PY 2016 VL 7 AR 21 DI 10.1186/s13227-016-0056-4 PG 16 WC Evolutionary Biology; Developmental Biology SC Evolutionary Biology; Developmental Biology GA DU7ZX UT WOS:000382434200001 PM 27583126 ER PT J AU Vargas-Inchaustegui, DA Ying, O Demberg, T Robert-Guroff, M AF Vargas-Inchaustegui, Diego A. Ying, Olivia Demberg, Thorsten Robert-Guroff, Marjorie TI Evaluation of Functional NK Cell Responses in Vaccinated and SIV-Infected Rhesus Macaques SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE NK cell; SIV; rhesus macaque; cytokine; cytotoxicity ID NATURAL-KILLER-CELLS; IMMUNODEFICIENCY-VIRUS-INFECTION; VIREMIC HIV-1 INFECTION; EXPRESSION; INNATE; INTERLEUKIN-15; MEMORY; CYTOTOXICITY; INDIVIDUALS; ACTIVATION AB NK cells are crucial components of the innate immune system due to their capacity to exert rapid cytotoxic and immunomodulatory function in the absence of prior sensitization. NK cells can become activated by exposure to target cells and/or by cytokines produced by antigen-presenting cells. In this study, we examined the effects of a simian immunodeficiency virus (SIV) vaccine regimen and subsequent SIV infection on the cytotoxic and immunomodulatory functions of circulatory NK cells. While vaccination did not significantly impact the capacity of NK cells to kill MHC-devoid 721.221 target cells, Sly-infection led to a significant decrease in target cell killing. NK cells from uninfected macaques were responsive to a low dose (5 ng/ml) of IL-15 pre-activation, leading to significant increases in their cytotoxic potential, however, NK cells from SIV-infected macaques required a higher dose (50 ng/ml) of IL-15 pre-activation in order to significantly increase their cytotoxic potential. By contrast, no differences were observed in the capacity of NK cells from vaccinated and SIV-infected macaques to respond to IL-12 and IL-18. Similarly, NK cells both before and after infection exhibited equivalent responses to Fc-mediated activation. Collectively, our results show that early SIV-infection impairs the natural cytotoxic capacity of circulatory NK cells without affecting Fc-mediated or cytokine-producing function. C1 [Vargas-Inchaustegui, Diego A.; Ying, Olivia; Demberg, Thorsten; Robert-Guroff, Marjorie] NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Vargas-Inchaustegui, Diego A.] NIAID, Mol Struct Sect, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Vargas-Inchaustegui, DA; Robert-Guroff, M (reprint author), NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM vargasinchausda@mail.nih.gov; guroffm@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute FX We gratefully acknowledge the animal caretakers at Advanced BioScience Laboratories, Inc. We thank Katherine McKinnon and Sophia Brown (Vaccine Branch Flow Core, NCI) for expert advice in Flow Cytometry; the NIIA/NCRR Resource for Non-human Primate Immune Reagents (Emory University, Atlanta, GA, USA) for the macaque recombinant proteins; and Dr. Bernard A. P. Lafont (Laboratory of Molecular Microbiology, MAID) for providing 721.221 cells. The following reagent was obtained through the NIH Non-human Primate Reagent Resource: QD0t605 anti-CD4. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute. NR 41 TC 0 Z9 0 U1 0 U2 0 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD AUG 31 PY 2016 VL 7 AR 340 DI 10.3389/fimmu.2016.00340 PG 10 WC Immunology SC Immunology GA DU5DO UT WOS:000382232600001 PM 27630641 ER PT J AU Lehmann, ML Cooper, HA Maric, D Herkenham, M AF Lehmann, Michael L. Cooper, Hannah A. Maric, Dragan Herkenham, Miles TI Social defeat induces depressive-like states and microglial activation without involvement of peripheral macrophages SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Stress; Microglia; Depression; Neuroimmune; Macrophage; Microglial proliferation ID ANXIETY-LIKE BEHAVIOR; BLOOD-BRAIN-BARRIER; MEDIAL PREFRONTAL CORTEX; MARROW-DERIVED MICROGLIA; CENTRAL-NERVOUS-SYSTEM; ENVIRONMENTAL ENRICHMENT; NEUROTROPHIC FACTOR; IMMUNE INTERACTIONS; ADULT NEUROGENESIS; RAT-BRAIN AB Background: We are interested in the causal interactions between psychological stress and activity within different compartments of the immune system. Psychosocial stress has been reported to not only alter microglia morphology but also produce anxiety-like and depressive-like effects by triggering CNS infiltration of macrophages from the periphery. We sought to test these phenomena in a somewhat different but standardized model of chronic social defeat (SD) stress. Methods: We used a paradigm of dyadic home pairing of dominant and subordinate mice that has been validated to induce powerful anxiety-like and depressive-like effects manifested by behavior assessed in social tasks. We administered the SD stress for 3 days (acute SD) or 14 days (chronic SD) and looked for monocyte entry into the brain by three independent means, including CD45 activation states assessed by flow cytometry and tracking fluorescently tagged peripheral cells from Ccr2(wt/rfp) and Ubc(gfp/gfp) reporter mice. We further characterized the effects of SD stress on microglia using quantitative morphometric analysis, ex vivo phagocytosis assays, flow cytometry, and immunochemistry. Results: We saw no evidence of stress-induced macrophage entry after acute or chronic defeat stress. In comparison, brain infiltration of peripheral cells did occur after endotoxin administration. Furthermore, mutant mice lacking infiltrating macrophages due to CCR2 knockout developed the same degree of chronic SD-induced depressive behavior as wildtype mice. We therefore focused more closely on the intrinsic immune cells, the microglia. Using Cx3cr1(wt/gpf) microglial reporter mice, we saw by quantitative methods that microglial morphology was not altered by stress at either time point. However, chronic SD mice had elevated numbers of CD68(hi) microglia examined by flow cytometry. CD68 is a marker for phagocytic activity. Indeed, these cells ex vivo showed elevated phagocytosis, confirming the increased activation status of chronic SD microglia. Finally, acute SD but not chronic SD increased microglial proliferation, which occurred selectively in telencephalic stress-related brain areas. Conclusions: In the SD paradigm, changes in CNS-resident microglia numbers and activation states might represent the main immunological component of the psychosocial stress-induced depressive state. C1 [Lehmann, Michael L.; Cooper, Hannah A.; Herkenham, Miles] NIMH, Funct Neuroanat Sect, Intramural Res Program, NIH, Bldg 35,Rm 1C911, Bethesda, MD 20892 USA. [Maric, Dragan] NINDS, Flow Cytometry Core Facil, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Lehmann, ML (reprint author), NIMH, Funct Neuroanat Sect, Intramural Res Program, NIH, Bldg 35,Rm 1C911, Bethesda, MD 20892 USA. EM michael.lehmann@nih.gov FU NIMH Intramural Research Program [ZIA MH001090] FX The work was supported by the NIMH Intramural Research Program, ZIA MH001090. NR 89 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 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD AUG 31 PY 2016 VL 13 AR 224 DI 10.1186/s12974-016-0672-x PG 19 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA DV4EX UT WOS:000382879300001 PM 27581371 ER PT J AU Puppala, AK French, RL Matthies, D Baxa, U Subramaniam, S Simonovic, M AF Puppala, Anupama K. French, Rachel L. Matthies, Doreen Baxa, Ulrich Subramaniam, Sriram Simonovic, Miljan TI Structural basis for early-onset neurological disorders caused by mutations in human selenocysteine synthase SO SCIENTIFIC REPORTS LA English DT Article ID PROGRESSIVE CEREBELLOCEREBRAL ATROPHY; CAUSE PONTOCEREBELLAR HYPOPLASIA; SCATTERING DATA-ANALYSIS; SELENOPROTEIN BIOSYNTHESIS; RNA; SYSTEM; GENE; DIFFRACTION; CLEARANCE; MECHANISM AB Selenocysteine synthase (SepSecS) catalyzes the terminal reaction of selenocysteine, and is vital for human selenoproteome integrity. Autosomal recessive inheritance of mutations in SepSecS-Ala239Thr, Thr325Ser, Tyr334Cys and Tyr429*-induced severe, early-onset, neurological disorders in distinct human populations. Although harboring different mutant alleles, patients presented remarkably similar phenotypes typified by cerebellar and cerebral atrophy, seizures, irritability, ataxia, and extreme spasticity. However, it has remained unclear how these genetic alterations affected the structure of SepSecS and subsequently elicited the development of a neurological pathology. Herein, our biophysical and structural characterization demonstrates that, with the exception of Tyr429*, pathogenic mutations decrease protein stability and trigger protein misfolding. We propose that the reduced stability and increased propensity towards misfolding are the main causes for the loss of SepSecS activity in afflicted patients, and that these factors contribute to disease progression. We also suggest that misfolding of enzymes regulating protein synthesis should be considered in the diagnosis and study of childhood neurological disorders. C1 [Puppala, Anupama K.; French, Rachel L.; Simonovic, Miljan] Univ Illinois, Dept Biochem & Mol Genet, Chicago, IL 60607 USA. [Matthies, Doreen; Baxa, Ulrich; Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. [French, Rachel L.] St Louis Univ, Dept Biochem & Mol Biol, St Louis, MO 63104 USA. RP Simonovic, M (reprint author), Univ Illinois, Dept Biochem & Mol Genet, Chicago, IL 60607 USA. EM msimon5@uic.edu RI ID, BioCAT/D-2459-2012 FU National Institute of General Medical Sciences of the National Institutes of Health [R01 GM097042, P41 GM103622]; National Cancer Institute, NIH; DOE Office of Science [DE-AC02-06CH11357]; Michigan Economic Development Corporation; Michigan Technology Tri-Corridor [085P1000817] FX We are grateful to the staff of LS-CAT beam line at APS-ANL for their help during X-ray data collection and processing, and Dr. Srinivas Chakravarthy for help during SAXS data collection and processing. We thank Kaitlyn Holman for help with protein purification. This work was supported by a grant from the National Institute of General Medical Sciences of the National Institutes of Health R01 GM097042 (to MS) and from the intramural program of the National Cancer Institute, NIH (to SS). 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. BioCAT is supported by grant from the National Institute of General Medical Sciences of the National Institutes of Health (P41 GM103622). Use of the LS-CAT Sector 21 is supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (Grant 085P1000817). NR 42 TC 0 Z9 0 U1 3 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 AUG 31 PY 2016 VL 6 AR 32563 DI 10.1038/srep32563 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DU5JD UT WOS:000382247100001 PM 27576344 ER PT J AU Pavlatou, MG Remaley, AT Gold, PW AF Pavlatou, M. G. Remaley, A. T. Gold, P. W. TI Klotho: a humeral mediator in CSF and plasma that influences longevity and susceptibility to multiple complex disorders, including depression SO TRANSLATIONAL PSYCHIATRY LA English DT Review ID VITAMIN-D METABOLISM; CORONARY-ARTERY-DISEASE; CHRONIC KIDNEY-DISEASE; CHRONIC-RENAL-FAILURE; ENDOTHELIAL DYSFUNCTION; ALPHA-KLOTHO; PARATHYROID-HORMONE; FUNCTIONAL VARIANT; BLOOD-PRESSURE; MUTANT MICE AB Klotho is a hormone secreted into human cerebrospinal fluid (CSF), plasma and urine that promotes longevity and influences the onset of several premature senescent phenotypes in mice and humans, including atherosclerosis, cardiovascular disease, stroke and osteoporosis. Preliminary studies also suggest that Klotho possesses tumor suppressor properties. Klotho's roles in these phenomena were first suggested by studies demonstrating that a defect in the Klotho gene in mice results in a significant decrease in lifespan. The Klotho-deficient mouse dies prematurely at 8-9 weeks of age. At 4-5 weeks of age, a syndrome resembling human ageing emerges consisting of atherosclerosis, osteoporosis, cognitive disturbances and alterations of hippocampal architecture. Several deficits in Klotho-deficient mice are likely to contribute to these phenomena. These include an inability to defend against oxidative stress in the central nervous system and periphery, decreased capacity to generate nitric oxide to sustain normal endothelial reactivity, defective Klotho-related mediation of glycosylation and ion channel regulation, increased insulin/insulin-like growth factor signaling and a disturbed calcium and phosphate homeostasis accompanied by altered vitamin D levels and ectopic calcification. Identifying the mechanisms by which Klotho influences multiple important pathways is an emerging field in human biology that will contribute significantly to understanding basic physiologic processes and targets for the treatment of complex diseases. Because many of the phenomena seen in Klotho-deficient mice occur in depressive illness, major depression and bipolar disorder represent illnesses potentially associated with Klotho dysregulation. Klotho's presence in CSF, blood and urine should facilitate its study in clinical populations. C1 [Pavlatou, M. G.; Gold, P. W.] NIMH, Clin Neuroendocrinol Branch, NIH, Bethesda, MD 20892 USA. [Remaley, A. T.] Natl Inst Heart Lung & Blood Inst, Lipoprotein Metab Sect, Cardiovasc & Pulm Branch, Bethesda, MD USA. RP Gold, PW (reprint author), NIMH, Intramural NIH Res Program, NIH, Ctr Clin, Bldg 10,Room 2D-46,10 Ctr Dr MSC 1284, Bethesda, MD 20892 USA. EM philipgold@mail.nih.gov NR 110 TC 0 Z9 1 U1 0 U2 0 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 AUG 30 PY 2016 VL 6 AR e876 DI 10.1038/tp.2016.135 PG 9 WC Psychiatry SC Psychiatry GA DW1SR UT WOS:000383423400002 PM 27576165 ER PT J AU Ha, HL Kwon, T Bak, IS Erikson, RL Kim, BY Yu, DY AF Ha, Hye-Lin Kwon, Taeho Bak, In Seon Erikson, Raymond L. Kim, Bo Yeon Yu, Dae-Yeul TI IGF-II induced by hepatitis B virus X protein regulates EMT via SUMO mediated loss of E- cadherin in mice SO ONCOTARGET LA English DT Article DE hepatocellular carcinoma; hepatitis B virus X protein; IGF-II; epithelial-mesenchymal transition; SUMOylation ID GROWTH-FACTOR-II; EPITHELIAL-MESENCHYMAL TRANSITION; HEPATOCELLULAR-CARCINOMA; CANCER CELLS; GENE-EXPRESSION; BREAST-CANCER; IN-VITRO; EXTRACELLULAR CLEAVAGE; MOLECULAR-MECHANISMS; TUMOR PROGRESSION AB Hepatocellular carcinoma (HCC) is one of the most common cancers and a leading cause of cancer mortality. Prognosis of this disease largely depends on its stage. An Enlarged liver, due to dysplasia, may be a critical point in the multi-step progression to HCC. The mechanism underlying hepatomegaly in human and mouse models are poorly understood. We previously reported we observed enlarged liver in hepatitis B virus X protein (HBx) expressing mice (HBx mice). Here we identify the critical role of HBx induced IGF-II in hepatomegaly in mice and abnormal cell growth in human hepatoma cells. We found that HBx induced IGF-II is essential to induce epithelial-mesenchymal transition (EMT) through loss of E-cadherin. In mouse liver, loss of E-cadherin was mediated by post-translational regulation, at least in part, by protease and SUMOylation not by transcriptional regulation. In contrast, in hepatoma cell line (HepG2 cells) Akt signal pathway controls the mRNA expression level of EMT-related transcription factors, especially Twist, in addition to post-translational modification through SUMOylation. Thus, IGF-II-mediated loss of E-cadherin is central in developing hepatomegaly in mice and abnormal cell growth in the hepatoma cell line. HBx induced IGF-II represents a potential biomarker, which is also a therapeutic target in HCC. C1 [Ha, Hye-Lin; Kwon, Taeho; Bak, In Seon; Yu, Dae-Yeul] Korea Res Inst Biosci & Biotechnol, Genome Editing Res Ctr, Dis Model Res Lab, Daejeon, South Korea. [Ha, Hye-Lin; Yu, Dae-Yeul] Univ Sci & Technol, Dept Funct Genom, Daejeon, South Korea. [Erikson, Raymond L.] Harvard Univ, Dept Mol & Cellular Biol, 16 Divin Ave, Cambridge, MA 02138 USA. [Kim, Bo Yeon] Korea Res Inst Biosci & Biotechnol, Anticanc Agents Res Ctr, Ochang, Cheongwon, South Korea. [Ha, Hye-Lin] NIAID, Immune Activat Sect, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Yu, DY (reprint author), Korea Res Inst Biosci & Biotechnol, Genome Editing Res Ctr, Dis Model Res Lab, Daejeon, South Korea.; Yu, DY (reprint author), Univ Sci & Technol, Dept Funct Genom, Daejeon, South Korea.; Kim, BY (reprint author), Korea Res Inst Biosci & Biotechnol, Anticanc Agents Res Ctr, Ochang, Cheongwon, South Korea. EM bykim@kribb.re.kr; dyyu10@kribb.re.kr FU R&D Convergence Program of the National Research Council of Science & Technology (NST) of the Republic of Korea [CAP-15-03-KRIBB, CAP-16-03-KRIBB]; Bio and Medical Technology Development Program of the Ministry of Science, ICT and Future Planning (MSIP) of Korea [NRF-2014M3A9B5073938] FX The authors thank Dr. SM Kim for meaningful discussion. This work was supported by the R&D Convergence Program (CAP-15-03-KRIBB and CAP-16-03-KRIBB) of the National Research Council of Science & Technology (NST) of the Republic of Korea and by the Bio and Medical Technology Development Program (NRF-2014M3A9B5073938) of the Ministry of Science, ICT and Future Planning (MSIP) of Korea. NR 55 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 AUG 30 PY 2016 VL 7 IS 35 BP 56944 EP 56957 DI 10.18632/oncotarget.10922 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EA8TL UT WOS:000386911600080 PM 27486970 ER PT J AU Hannah-Shmouni, F Faucz, FR Stratakis, CA AF Hannah-Shmouni, Fady Faucz, Fabio R. Stratakis, Constantine A. TI Alterations of Phosphodiesterases in Adrenocortical Tumors SO FRONTIERS IN ENDOCRINOLOGY LA English DT Review DE phosphodiesterases; adrenocortical tumors; adrenal hyperplasia; Cushing syndrome; genetics; Carney complex; cAMP ID MACRONODULAR ADRENAL-HYPERPLASIA; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES; MCCUNE-ALBRIGHT-SYNDROME; CUSHINGS-SYNDROME; CARNEY COMPLEX; GENETIC-HETEROGENEITY; ACTIVATING MUTATIONS; MOLECULAR-GENETICS; SEQUENCE VARIANTS; 11A4 PDE11A AB Alterations in the cyclic (c) AMP-dependent signaling pathway have been implicated in the majority of benign adrenocortical tumors (ACTs) causing Cushing syndrome (CS). Phosphodiesterases (PDEs) are enzymes that regulate cyclic nucleotide levels, including cyclic adenosine monophosphate (cAMP). Inactivating mutations and other functional variants in PDE11A and PDE8B, two cAMP-binding PDEs, predispose to ACTs. The involvement of these two genes in ACTs was initially revealed by a genome-wide association study in patients with micronodular bilateral adrenocortical hyperplasia. Thereafter, PDE11A or PDE8B genetic variants have been found in other ACTs, including macronodular adrenocortical hyperplasias and cortisol-producing adenomas. In addition, downregulation of PDE11A expression and inactivating variants of the gene have been found in hereditary and sporadic testicular germ cell tumors, as well as in prostatic cancer. PDEs confer an increased risk of ACT formation probably through, primarily, their action on cAMP levels, but other actions might be possible. In this report, we review what is known to date about PDE11A and PDE8B and their involvement in the predisposition to ACTs. C1 [Hannah-Shmouni, Fady; Faucz, Fabio R.; Stratakis, Constantine A.] NICHD, Program Dev Endocrinol & Genet PDEGEN, Sect Endocrinol & Genet SEGEN, NIH, Bethesda, MD 20817 USA. RP Stratakis, CA (reprint author), NICHD, Program Dev Endocrinol & Genet PDEGEN, Sect Endocrinol & Genet SEGEN, NIH, Bethesda, MD 20817 USA. EM fady.hannah-shmouni@nih.gov; stratakc@mail.nih.gov FU intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH) [HD008920] FX This work was supported by the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), protocol HD008920. NR 58 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 AUG 30 PY 2016 VL 7 AR 111 DI 10.3389/fendo.2016.00111 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DY7ML UT WOS:000385313300001 PM 27625633 ER PT J AU Smith, A Calley, J Mathur, S Qian, HR Wu, H Farmen, M Caiment, F Bushel, PR Li, JY Fisher, C Kirby, P Koenig, E Hall, DG Watson, DE AF Smith, Aaron Calley, John Mathur, Sachin Qian, Hui-Rong Wu, Han Farmen, Mark Caiment, Florian Bushel, Pierre R. Li, Jianying Fisher, Craig Kirby, Patrick Koenig, Erik Hall, David G. Watson, David E. TI The Rat microRNA body atlas; Evaluation of the microRNA content of rat organs through deep sequencing and characterization of pancreas enriched miRNAs as biomarkers of pancreatic toxicity in the rat and dog SO BMC GENOMICS LA English DT Article DE microRNA; Biomarkers; Deep sequencing; Tissue specific; Tissue enriched; Pancreatic toxicity AB Background: MicroRNAs (miRNA) are similar to 19-25 nucleotide long RNA molecules that fine tune gene expression through the inhibition of translation or degradation of the mRNA through incorporation into the RNA induced silencing complex (RISC). MicroRNAs are stable in the serum and plasma, are detectable in a wide variety of body fluids, are conserved across veterinary species and humans and are expressed in a tissue specific manner. They can be detected at low concentrations in circulation in animals and humans, generating interest in the utilization of miRNAs as serum and/or plasma based biomarkers of tissue injury. MicroRNA tissue profiling in rodents has been published, but sample an insufficient number of organs of toxicologic interest using microarray or qPCR technologies for miRNA detection. Here we impart an improved rat microRNA body atlas consisting of 21 and 23 tissues of toxicologic interest from male and female Sprague Dawley rats respectively, using Illumina miRNA sequencing. Several of the authors created a dog miRNA body atlas and we collaborated to test miRNAs conserved in rat and dog pancreas in caerulein toxicity studies utilizing both species. Results: A rich data set is presented that more robustly defines the tissue specificity and enrichment profiles of previously published and undiscovered rat miRNAs. We generated 1,927 sequences that mapped to mature miRNAs in rat, mouse and human from miRBase and discovered an additional 1,162 rat miRNAs as compared to the current number of rat miRNAs in miRBase version 21. Tissue specific and enriched miRNAs were identified and a subset of these miRNAs were validated by qPCR for tissue specificity or enrichment. As an example of the power of this approach, we have conducted rat and dog pancreas toxicity studies and examined the levels of some tissue specific and enriched miRNAs conserved between rat and dog in the serum of each species. The studies demonstrate that conserved tissue specific/ enriched miRs-216a-5p, 375-3p, 148a-3p, 216b-5p and 141-3p are candidate biomarkers of pancreatic injury in the rat and dog. Conclusions: A microRNA body atlas for rat and dog was useful in identifying new candidate miRNA biomarkers of organ toxicity in 2 toxicologically relevant species. C1 [Smith, Aaron; Watson, David E.] Lilly Corp Ctr, Dept Investigat Toxicol Non Clin Safety Assessmen, Lilly Res Labs, Indianapolis, IN 46285 USA. [Calley, John; Mathur, Sachin] Lilly Corp Ctr, Dept TTX Bioinformat, Lilly Res Labs, Indianapolis, IN 46285 USA. [Qian, Hui-Rong; Wu, Han; Farmen, Mark] Lilly Corp Ctr, Dept Discovery & Dev Stat, Lilly Res Labs, Indianapolis, IN 46285 USA. [Caiment, Florian] Maastricht Univ, Univ Single, Dept Toxicogen, Maastricht, Netherlands. [Bushel, Pierre R.] NIEHS, Biostat Branch, Durham, NC USA. [Li, Jianying] Kelly Govt Solut, Durham, NC 27709 USA. [Fisher, Craig; Kirby, Patrick] Takeda Pharmaceut Int Co, Drug Safety Evaluat, Deerfield, IL USA. [Koenig, Erik] Takeda Pharmaceut Int Co, Mol Pathol, Deerfield, IL USA. [Hall, David G.] Lilly Corp Ctr, Dept Investigat Pathol, Lilly Res Labs, Indianapolis, IN 46285 USA. RP Smith, A (reprint author), Lilly Corp Ctr, Dept Investigat Toxicol Non Clin Safety Assessmen, Lilly Res Labs, Indianapolis, IN 46285 USA. EM smithat@lilly.com FU Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS); HESI FX This research was supported, in part, by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS).; This HESI scientific initiative is primarily supported by in-kind contributions (from public and private sector participants) of time, expertise, and experimental effort. These contributions are supplemented by direct funding (that largely supports program infrastructure and management) that was provided by HESI's corporate sponsors. A list of supporting organizations (public and private) is available at http://www.hesiglobal.org/i4a/pages/index.cfm?pageid=3311. NR 45 TC 1 Z9 1 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD AUG 30 PY 2016 VL 17 AR 694 DI 10.1186/s12864-016-2956-z PG 19 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DY3HG UT WOS:000384980800008 PM 27576563 ER PT J AU Woo, HJ Yu, CG Kumar, K Gold, B Reifman, J AF Woo, Hyung Jun Yu, Chenggang Kumar, Kamal Gold, Bert Reifman, Jaques TI Genotype distribution-based inference of collective effects in genome-wide association studies: insights to age-related macular degeneration disease mechanism SO BMC GENOMICS LA English DT Article DE Genome-wide association; Machine learning; Epistasis; Single-nucleotide polymorphism; Age-related macular degeneration ID COMPLEMENT FACTOR-H; PENALIZED LOGISTIC-REGRESSION; DISCRIMINANT-ANALYSIS; VARIABLE SELECTION; GENE INTERACTIONS; CANDIDATE GENE; BREAST-CANCER; SUSCEPTIBILITY; EPISTASIS; APOPTOSIS AB Background: Genome-wide association studies provide important insights to the genetic component of disease risks. However, an existing challenge is how to incorporate collective effects of interactions beyond the level of independent single nucleotide polymorphism (SNP) tests. While methods considering each SNP pair separately have provided insights, a large portion of expected heritability may reside in higher-order interaction effects. Results: We describe an inference approach (discrete discriminant analysis; DDA) designed to probe collective interactions while treating both genotypes and phenotypes as random variables. The genotype distributions in case and control groups are modeled separately based on empirical allele frequency and covariance data, whose differences yield disease risk parameters. We compared pairwise tests and collective inference methods, the latter based both on DDA and logistic regression. Analyses using simulated data demonstrated that significantly higher sensitivity and specificity can be achieved with collective inference in comparison to pairwise tests, and with DDA in comparison to logistic regression. Using age-related macular degeneration (AMD) data, we demonstrated two possible applications of DDA. In the first application, a genome-wide SNP set is reduced into a small number (similar to 100) of variants via filtering and SNP pairs with significant interactions are identified. We found that interactions between SNPs with highest AMD association were epigenetically active in the liver, adipocytes, and mesenchymal stem cells. In the other application, multiple groups of SNPs were formed from the genome-wide data and their relative strengths of association were compared using cross-validation. This analysis allowed us to discover novel collections of loci for which interactions between SNPs play significant roles in their disease association. In particular, we considered pathway-based groups of SNPs containing up to similar to 10,000 variants in each group. In addition to pathways related to complement activation, our collective inference pointed to pathway groups involved in phospholipid synthesis, oxidative stress, and apoptosis, consistent with the AMD pathogenesis mechanism where the dysfunction of retinal pigment epithelium cells plays central roles. Conclusions: The simultaneous inference of collective interaction effects within a set of SNPs has the potential to reveal novel aspects of disease association. C1 [Woo, Hyung Jun; Yu, Chenggang; Kumar, Kamal; Reifman, Jaques] US Army Med Res & Mat Command, Biotechnol High Performance Comp Software Applica, Telemed & Adv Technol Res Ctr, Ft Detrick, MD 21702 USA. [Gold, Bert] NCI, Lab Genom Div, Frederick, MD 21701 USA. RP Reifman, J (reprint author), US Army Med Res & Mat Command, Biotechnol High Performance Comp Software Applica, Telemed & Adv Technol Res Ctr, Ft Detrick, MD 21702 USA. EM jaques.reifman.civ@mail.mil OI Kumar, Kamal/0000-0002-9470-6682 FU U.S. Army Medical Research and Materiel Command (Ft. Detrick, Maryland) FX This work was supported by the U.S. Army Medical Research and Materiel Command (Ft. Detrick, Maryland). The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Army or of the U.S. Department of Defense. This paper has been approved for public release with unlimited distribution. NR 71 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 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD AUG 30 PY 2016 VL 17 AR 695 DI 10.1186/s12864-016-2871-3 PG 20 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DY3HG UT WOS:000384980800009 PM 27576376 ER PT J AU Vaid, R Dev, K Lichten, M Sourirajan, A AF Vaid, Rajni Dev, Kamal Lichten, Michael Sourirajan, Anuradha TI Generation of an inducible system to express polo-like kinase, Cdc5 as TAP fusion protein during meiosis in Saccharomyces cerevisiae SO 3 BIOTECH LA English DT Article DE Tandem affinity purification; Fusion protein; Saccharomyces cerevisiae; Meiosis; Polo-like kinase; Cdc5; Kinase dead; Estrogen inducible; Pachytene; Meiotic recombination; Joint molecules (JM); Substrates ID BUDDING YEAST; SEGREGATION; DIVISION; GENE; RECOMBINATION; PURIFICATION; CHROMOSOMES; MECHANISMS; REGULATORS; PACHYTENE AB Tandem affinity purification (TAP) is a highly efficient method for isolation of protein complexes from endogenous biological macromolecules. TAP system consists of dual affinity tags that facilitates the sequential purification of the desired proteins expressed at their low levels in vivo. Polo-like kinases (PLK) are serine/threonine protein kinases that are the crucial regulators of cell cycle. Cdc5, the solitary PLK in budding yeast Saccharomyces cerevisiae, has diverse array of targets in cell cycle. The present study was undertaken to construct an estrogen-inducible system for expression of Cdc5-TAP to isolate the substrates of Cdc5 during meiosis, particularly, pachytene stage of meiosis I. Two yeast strains were constructed CDC5-IN (ndt80 Delta pGAL1-CDC5-TAP) and Cdc5-kinase inactive mutant (ndt80 Delta pGAL1-cdc5-N209A-TAP). The estrogen-inducible expression of Cdc5-TAP and cdc5-N209A-TAP was validated by Western analysis. The systems would serve as a valuable tool for purification of substrates binding to Cdc5-TAP by TAP affinity chromatography. C1 [Vaid, Rajni; Dev, Kamal; Sourirajan, Anuradha] Shoolini Univ, Fac Appl Sci & Biotechnol, Solan 173212, Himachal Prades, India. [Lichten, Michael] NCI, Lab Biochem & Mol Biol, Ctr Canc Res, Bethesda, MD 20892 USA. RP Sourirajan, A (reprint author), Shoolini Univ, Fac Appl Sci & Biotechnol, Solan 173212, Himachal Prades, India. EM mlichten@helix.nih.gov; asourirajan@gmail.com FU Department of Biotechnology (DBT), Government of India [BT/Bio-CARe/01/616] FX We thank Dr. Wolfgang Zachariae, Max Planck Institute of Molecular Cell Biology and Genetics, Germany for providing genomic-tagged CDC5-TAP yeast strains. We acknowledge the research funding to Dr. Sourirajan and research fellowship to Ms. Vaid provided by the Department of Biotechnology (DBT), Government of India under the project BT/Bio-CARe/01/616. The authors would like to acknowledge Shoolini University for infrastructural support in the research work. NR 29 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 2190-5738 EI 2190-572X J9 3 BIOTECH JI 3 Biotech PD AUG 30 PY 2016 VL 6 AR 185 DI 10.1007/s13205-016-0503-x PG 6 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DV0YR UT WOS:000382647200001 PM 28330257 ER PT J AU St Laurent, B Oy, K Miller, B Gasteiger, EB Lee, E Sovannaroth, S Gwadz, RW Anderson, JM Fairhurst, RM AF St Laurent, Brandyce Oy, Kolthida Miller, Becky Gasteiger, Elizabeth B. Lee, Eunjae Sovannaroth, Siv Gwadz, Robert W. Anderson, Jennifer M. Fairhurst, Rick M. TI Cow-baited tents are highly effective in sampling diverse Anopheles malaria vectors in Cambodia SO MALARIA JOURNAL LA English DT Article DE Anopheles; Cambodia; Trap; Outdoor transmission; Malaria; Vector ID PLASMODIUM-FALCIPARUM MALARIA; HUMAN LANDING CATCHES; MOSQUITOS DIPTERA; WESTERN THAILAND; SOUTHEAST-ASIA; ENDEMIC AREA; IDENTIFICATION; TRANSMISSION; POPULATIONS; RESISTANCE AB Background: The accurate monitoring and evaluation of malaria vectors requires efficient sampling. The objective of this study was to compare methods for sampling outdoor-biting Anopheles mosquitoes in Cambodia. Methods: In the Cambodian provinces of Pursat, Preah Vihear, and Ratanakiri, six different mosquito trapping methods were evaluated: human landing collection (HLC), human-baited tent (HBT), cow-baited tent (CBT), CDC miniature light trap (LT), CDC miniature light trap baited with molasses and yeast (LT-M), and barrier fence (F) in a Latin square design during four or six consecutive nights at the height of the malaria transmission season. Results: Using all traps, a total of 507, 1175, and 615 anophelines were collected in Pursat, Preah Vihear, and Ratanakiri, respectively. CBTs captured 10- to 20-fold more anophelines per night than the other five sampling methods. All 2297 Anopheles mosquitoes were morphologically identified and molecularly typed using standard morphological keys and sequencing the rDNA ITS2 region to distinguish cryptic species, respectively. Overall, an extremely diverse set of 27 known Anopheles species was sampled. CBTs captured the same molecular species that HLCs and the other four traps did, as well as additional species. Nine specimens representing five Anopheles species (Anopheles hyrcanus, Anopheles barbirostris sensu stricto, Anopheles barbirostris clade III, Anopheles nivipes, and Anopheles peditaeniatus) were infected with Plasmodium falciparum and were exclusively captured in CBTs. Conclusions: These data indicate that cow-baited tents are highly effective in sampling diverse Anopheles malaria vectors in Cambodia. This sampling method captured high numbers of anophelines with limited sampling effort and greatly reduced human exposure to mosquito bites compared to the gold-standard human landing collection. C1 [St Laurent, Brandyce; Miller, Becky; Gasteiger, Elizabeth B.; Lee, Eunjae; Gwadz, Robert W.; Anderson, Jennifer M.; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Oy, Kolthida; Sovannaroth, Siv] Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh 12101, Cambodia. RP St Laurent, B; Fairhurst, RM (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM brandyce.stlaurent@nih.gov; rfairhurst@niaid.nih.gov OI St. Laurent, Brandyce/0000-0002-2957-5364 FU Intramural Research Program, National Institute of Allergy and Infectious Diseases, US National Institutes of Health FX This study was funded by the Intramural Research Program, National Institute of Allergy and Infectious Diseases, US National Institutes of Health. NR 34 TC 0 Z9 0 U1 3 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD AUG 30 PY 2016 VL 15 AR 440 DI 10.1186/s12936-016-1488-y PG 11 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DU9KM UT WOS:000382535900001 PM 27577697 ER PT J AU Langenfurth, A Gu, S Bautze, V Zhang, CY Neumann, JE Schuller, U Stock, K Wolf, SA Maier, AM Mastrella, G Pak, A Cheng, HW Kalin, RE Holmbeck, K Strotmann, J Kettenmann, H Glass, R AF Langenfurth, Anika Gu, Song Bautze, Verena Zhang, Caiyi Neumann, Julia E. Schueller, Ulrich Stock, Kristin Wolf, Susanne A. Maier, Anna-Maria Mastrella, Giorgia Pak, Andrew Cheng, Hongwei Kaelin, Roland E. Holmbeck, Kenn Strotmann, Joerg Kettenmann, Helmut Glass, Rainer TI Decreased demand for olfactory periglomerular cells impacts on neural precursor cell viability in the rostral migratory stream SO SCIENTIFIC REPORTS LA English DT Article ID ADULT MAMMALIAN BRAIN; SUBVENTRICULAR ZONE; BULB NEUROGENESIS; STEM-CELLS; MICE; RAT; HIPPOCAMPAL; DEATH; PLASTICITY; NEURONS AB The subventricular zone (SVZ) provides a constant supply of new neurons to the olfactory bulb (OB). Different studies have investigated the role of olfactory sensory input to neural precursor cell (NPC) turnover in the SVZ but it was not addressed if a reduced demand specifically for periglomerular neurons impacts on NPC-traits in the rostral migratory stream (RMS). We here report that membrane type-1 matrix metalloproteinase (MT1-MMP) deficient mice have reduced complexity of the nasal turbinates, decreased sensory innervation of the OB, reduced numbers of olfactory glomeruli and reduced OB-size without alterations in SVZ neurogenesis. Large parts of the RMS were fully preserved in MT1-MMP-deficient mice, but we detected an increase in cell death-levels and a decrease in SVZ-derived neuroblasts in the distal RMS, as compared to controls. BrdU-tracking experiments showed that homing of NPCs specifically to the glomerular layer was reduced in MT1-MMP-deficient mice in contrast to controls while numbers of tracked cells remained equal in other OB-layers throughout all experimental groups. Altogether, our data show the demand for olfactory interneurons in the glomerular layer modulates cell turnover in the RMS, but has no impact on subventricular neurogenesis. C1 [Langenfurth, Anika; Stock, Kristin; Wolf, Susanne A.; Kettenmann, Helmut] Helmholtz Assoc, Max Delbruck Ctr Mol Med, Cellular Neurosci, Robert Rossle Str 10, Berlin, Germany. [Langenfurth, Anika] Charite, Dept Psychiat & Psychotherapy Neuropsychiat, Charitepl 1, Berlin, Germany. [Gu, Song; Zhang, Caiyi; Mastrella, Giorgia; Kaelin, Roland E.; Glass, Rainer] Univ Munich, Neurosurg Res, Marchioninistr 15, Munich, Germany. [Gu, Song; Cheng, Hongwei] Anhui Med Univ, Affiliated Hosp 1, Dept Neurosurg, Hefei 230022, Anhui, Peoples R China. [Bautze, Verena; Maier, Anna-Maria; Strotmann, Joerg] Univ Hohenheim, Inst Physiol, Garbenstr 30, Hohenheim, Germany. [Neumann, Julia E.; Schueller, Ulrich] Univ Munich, Ctr Neuropathol, Feodor Lynen Str 23, Munich, Germany. [Neumann, Julia E.; Schueller, Ulrich] Univ Med Ctr, Inst Neuropathol, Hamburg, Germany. [Neumann, Julia E.; Schueller, Ulrich] Res Inst Childrens Canc Ctr, Hamburg, Germany. [Schueller, Ulrich] Univ Med Ctr Hamburg Eppendorf, Dept Pediat Hematol & Oncol, D-20264 Hamburg, Germany. [Pak, Andrew; Holmbeck, Kenn] NIDCR, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. RP Glass, R (reprint author), Univ Munich, Neurosurg Res, Marchioninistr 15, Munich, Germany. EM rainer.glass@med.uni-muenchen.de FU Klinisches Ausbildungsprogramm (KAP); Neurocure; DFG [Str 619/5-1, SPP1392, GL691/2, SFB824]; Wilhelm Sander Stiftung; Anni-Hofmann Stiftung; Verein zur Forderung von Wissenschaft und Forschung an der Medizinischen Fakultat (WiFoMed) der LMU Munchen; Curt Bohnewandt Fonds; Friedrich-Baur-Stiftung; Familie Mehdorn Stiftung FX We are thankful to Kazuaki Yoshikawa (Osaka University, Osaka, Japan) for providing us with the guinea pig anti-Dlx2 antibody. A.L. was supported by a scholarship from the "Klinisches Ausbildungsprogramm (KAP)". This research was supported by Neurocure. J.S. R.G. and R.E.K. gratefully acknowledge funding by the DFG (Str 619/5-1; SPP1392; GL691/2; SFB824), the Wilhelm Sander Stiftung, the Anni-Hofmann Stiftung, Verein zur Forderung von Wissenschaft und Forschung an der Medizinischen Fakultat (WiFoMed) der LMU Munchen, the Curt Bohnewandt Fonds, the Friedrich-Baur-Stiftung and the Familie Mehdorn Stiftung. NR 45 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 AUG 30 PY 2016 VL 6 AR 32203 DI 10.1038/srep32203 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DU5PH UT WOS:000382263300001 PM 27573347 ER PT J AU van der Laan, SW Fall, T Soumare, A Teumer, A Sedaghat, S Baumert, J Zabaneh, D van Setten, J Isgum, I Galesloot, TE Arpegard, J Amouyel, P Trompet, S Waldenberger, M Dorr, M Magnusson, PK Giedraitis, V Larsson, A Morris, AP Felix, JF Morrison, AC Franceschini, N Bis, JC Kavousi, M O'Donnell, C Drenos, F Tragante, V Munroe, PB Malik, R Dichgans, M Worrall, BB Erdmann, J Nelson, CP Samani, NJ Schunkert, H Marchini, J Patel, RS Hingorani, AD Lind, L Pedersen, NL de Graaf, J Kiemeney, LALM Baumeister, SE Franco, OH Hofman, A Uitterlinden, AG Koenig, W Meisinger, C Peters, A Thorand, B Jukema, JW Eriksen, BO Toft, I Wilsgaard, T Onland-Moret, NC van der Schouw, YT Debette, S Kumari, M Svensson, P van der Harst, P Kivimaki, M Keating, BJ Sattar, N Dehghan, A Reiner, AP Ingelsson, E den Ruijter, HM de Bakker, PIW Pasterkamp, G Arnlov, J Holmes, MV Asselbergs, FW AF van der Laan, Sander W. Fall, Tove Soumare, Aicha Teumer, Alexander Sedaghat, Sanaz Baumert, Jens Zabaneh, Delilah van Setten, Jessica Isgum, Ivana Galesloot, Tessel E. Arpegard, Johannes Amouyel, Philippe Trompet, Stella Waldenberger, Melanie Doerr, Marcus Magnusson, Patrik K. Giedraitis, Vilmantas Larsson, Anders Morris, Andrew P. Felix, Janine F. Morrison, Alanna C. Franceschini, Nora Bis, Joshua C. Kavousi, Maryam O'Donnell, Christopher Drenos, Fotios Tragante, Vinicius Munroe, Patricia B. Malik, Rainer Dichgans, Martin Worrall, Bradford B. Erdmann, Jeanette Nelson, Christopher P. Samani, Nilesh J. Schunkert, Heribert Marchini, Jonathan Patel, Riyaz S. Hingorani, Aroon D. Lind, Lars Pedersen, Nancy L. de Graaf, Jacqueline Kiemeney, Lambertus A. L. M. Baumeister, Sebastian E. Franco, Oscar H. Hofman, Albert Uitterlinden, Andre G. Koenig, Wolfgang Meisinger, Christa Peters, Annette Thorand, Barbara Jukema, J. Wouter Eriksen, Bjorn Odvar Toft, Ingrid Wilsgaard, Tom Onland-Moret, N. Charlotte van der Schouw, Yvonne T. Debette, Stephanie Kumari, Meena Svensson, Per van der Harst, Pim Kivimaki, Mika Keating, Brendan J. Sattar, Naveed Dehghan, Abbas Reiner, Alex P. Ingelsson, Erik den Ruijter, Hester M. de Bakker, Paul I. W. Pasterkamp, Gerard Arnlov, Johan Holmes, Michael V. Asselbergs, Folkert W. TI Cystatin C and Cardiovascular Disease A Mendelian Randomization Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE coronary heart disease; genetics; heart failure; ischemic stroke ID CHRONIC KIDNEY-DISEASE; GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; INCIDENT HEART-FAILURE; BODY-MASS INDEX; SUSCEPTIBILITY LOCI; CHARGE CONSORTIUM; COMMON VARIANTS; ISCHEMIC-STROKE; RISK AB BACKGROUND Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation. OBJECTIVES The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. METHODS We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure. RESULTS Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 x 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 x 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence fora causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0,994), which was statistically different from the observational estimate (p = 1.6 x 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD. CONCLUSIONS Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD. (C) 2016 The Authors. Published by Elsevier Inc. on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license. C1 [van der Laan, Sander W.; van Setten, Jessica; den Ruijter, Hester M.; Pasterkamp, Gerard] Univ Med Ctr Utrecht, Div Heart & Lungs, Lab Expt Cardiol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands. [Fall, Tove; Arnlov, Johan] Uppsala Univ, Dept Med Sci, Cardiovasc Epidemiol, Uppsala, Sweden. [Soumare, Aicha; Debette, Stephanie] Univ Bordeaux, INSERM, U1219, Team Vintage, Bordeaux, France. [Teumer, Alexander; Baumeister, Sebastian E.] Univ Med Greifswald, Inst Community Med, Dept SHIP KEF, Greifswald, Germany. [Teumer, Alexander; Doerr, Marcus; Koenig, Wolfgang; Peters, Annette] German Ctr Cardiovasc Res, DZHK, Partner Site, Greifswald, Germany. [Sedaghat, Sanaz; Felix, Janine F.; Kavousi, Maryam; Franco, Oscar H.; Hofman, Albert; Dehghan, Abbas] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Baumert, Jens; Waldenberger, Melanie; Meisinger, Christa; Peters, Annette; Thorand, Barbara] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Zabaneh, Delilah] UCL, Dept Genet Environm & Evolut, London, England. [Zabaneh, Delilah] UCL, Genet Inst, London, England. [Isgum, Ivana] Univ Med Ctr Utrecht, Image Sci Inst, Utrecht, Netherlands. [Galesloot, Tessel E.; de Graaf, Jacqueline; Kiemeney, Lambertus A. L. M.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Nijmegen, Netherlands. [Arpegard, Johannes; Svensson, Per] Karolinska Univ Hosp Solna, Dept Emergency Med, Stockholm, Sweden. [Arpegard, Johannes; Svensson, Per] Karolinska Inst, Dept Med Solna, Stockholm, Sweden. [Amouyel, Philippe] Univ Lille, INSERM, Lille, France. [Amouyel, Philippe] Inst Pasteur, Lille, France. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol P C5, Leiden, Netherlands. [Trompet, Stella] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands. [Waldenberger, Melanie] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany. [Doerr, Marcus] Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany. [Magnusson, Patrik K.; Pedersen, Nancy L.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Giedraitis, Vilmantas] Uppsala Univ, Dept Publ Health Geriatr, Uppsala, Sweden. [Larsson, Anders; Lind, Lars] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England. [Morris, Andrew P.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Morrison, Alanna C.] Univ Texas Hlth Sci Ctr Houston, Dept Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA. [Franceschini, Nora] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Bis, Joshua C.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [O'Donnell, Christopher] Boston Vet Adm Healthcare, Dept Cardiol, West Roxbury, MA USA. [O'Donnell, Christopher] NHLBI, Framingham Heart Study, Framingham, MA USA. [Drenos, Fotios] UCL, Inst Cardiovasc Sci, Ctr Cardiovasc Genet, London, England. [Drenos, Fotios] Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol, Avon, England. [Tragante, Vinicius; Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands. [Munroe, Patricia B.] Queen Mary Univ London, William Harvey Res Inst, Natl Inst Hlth Res, Cardiovasc Biomed Res Unit, London, England. [Malik, Rainer; Dichgans, Martin] Univ Munich, Klinikum Univ Munchen, Inst Stroke & Dementia Res, Munich, Germany. [Dichgans, Martin] Munich Cluster Syst Neurol SyNergy, Munich, Germany. [Worrall, Bradford B.] Univ Virginia, Dept Neurol, Charlottesville, VA USA. [Worrall, Bradford B.] Univ Virginia, Dept Hlth Evaluat Sci, Charlottesville, VA USA. [Erdmann, Jeanette] Univ Lubeck, Inst Integrat & Expt Genom, Lubeck, Germany. [Nelson, Christopher P.; Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, British Heart Fdn Cardiovasc, Res Ctr,Dept Cardiovasc Sci, Leicester, Leics, England. [Nelson, Christopher P.; Samani, Nilesh J.] Glenfield Hosp, Natl Inst Hlth Res Leicester, Cardiovasc Biomed Res Unit, Leicester, Leics, England. [Schunkert, Heribert; Koenig, Wolfgang] Tech Univ Munich, Deutsch Herzzentrum Munchen, Munich, Germany. [Schunkert, Heribert] German Ctr Cardiovasc Res, DZHK, Munich Heart Alliance, Partner Site, Munich, Germany. [Marchini, Jonathan] Univ Oxford, Dept Stat, Oxford, England. [Patel, Riyaz S.; Hingorani, Aroon D.] UCL, Inst Cardiovasc Sci, Genet Epidemiol Res Grp, London, England. [Patel, Riyaz S.] Barts Heart Ctr, London, England. [Patel, Riyaz S.] UCL, Farr Inst Hlth Informat, London, England. [de Graaf, Jacqueline] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, Nijmegen, Netherlands. [Baumeister, Sebastian E.] Univ Regensburg, Inst Epidemiol & Prevent Med, Regensburg, Germany. [Uitterlinden, Andre G.] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Koenig, Wolfgang] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, Ulm, Germany. [Jukema, J. Wouter; van der Harst, Pim; Asselbergs, Folkert W.] ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands. [Eriksen, Bjorn Odvar] UiT Arctic Univ Norway, Metab & Renal Res Grp, Tromso, Norway. [Eriksen, Bjorn Odvar; Toft, Ingrid] Univ Hosp North Norway, Nephrol Sect, Tromso, Norway. [Wilsgaard, Tom] UiT Arctic Univ Norway, Dept Community Med, Tromso, Norway. [Onland-Moret, N. Charlotte; van der Schouw, Yvonne T.; de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Kumari, Meena] Univ Essex, Biol & Social Epidemiol, Inst Social & Econ Res, Colchester CO4 3SQ, Essex, England. [van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Kivimaki, Mika] UCL, Dept Epidemiol & Publ Hlth, London, England. [Keating, Brendan J.] Univ Penn, Dept Surg, Div Transplantat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Sattar, Naveed] Univ Glasgow, Glasgow, Lanark, Scotland. [Reiner, Alex P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 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. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Ctr Mol Med, Dept Med Genet, Utrecht, Netherlands. [Pasterkamp, Gerard] Univ Med Ctr Utrecht, Div Labs & Pharm, Lab Clin Chem & Hematol, Utrecht, Netherlands. [Holmes, Michael V.] Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Richard Doll Bldg,Old Rd Campus,Roosevelt Dr, Oxford OX3 7LF, England. [Holmes, Michael V.] Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit CTSU, Richard Doll Bldg,Old Rd Campus,Roosevelt Dr, Oxford OX3 7LF, England. [Asselbergs, Folkert W.] UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, London, England. RP van der Laan, SW (reprint author), Univ Med Ctr Utrecht, Div Heart & Lungs, Lab Expt Cardiol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands.; Asselbergs, FW (reprint author), Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands.; Holmes, MV (reprint author), Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Richard Doll Bldg,Old Rd Campus,Roosevelt Dr, Oxford OX3 7LF, England.; Holmes, MV (reprint author), Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit CTSU, Richard Doll Bldg,Old Rd Campus,Roosevelt Dr, Oxford OX3 7LF, England. EM s.w.vanderlaan-2@umcutrecht.nl; michael.holmes@ndph.ox.ac.uk; f.w.asselbergs@umcutrecht.nl RI Waldenberger, Melanie/B-5355-2014; Peters, Annette/A-6117-2011; Onland-Moret, N. Charlotte/G-9185-2011; Magnusson, Patrik/C-4458-2017; OI Waldenberger, Melanie/0000-0003-0583-5093; van der Laan, Sander W./0000-0001-6888-1404; Kumari, Meena/0000-0001-9716-1035; Svensson, Per/0000-0003-0372-6272; Peters, Annette/0000-0001-6645-0985 FU Pie Medical Imaging; 3Mensio Medical Imaging B.V.; NWO and Foundation for Technological Sciences [12726]; Stockholm County Council (combined clinical residency and PhD training program); Servier; Hoffman Laroche; Total; Genoscreen; Alzprotect; Fondation Plan Alzheimer; Takeda; Wellcome Trust Senior Fellow in Basic Biomedical Science [WT098017]; National Institute of Neurological Disorders and Stroke [U-01 N5069208]; National Human Genome Research Institute [U-01 HG005160]; British Heart Foundation (BHF); National Institute for Health Research Senior Investigator; BHF; Nestle Nutrition (Nestec Ltd.); Metagenics Inc.; AXA; BHF Intermediate Fellowship; NGFNplus [01GS0834]; Abbott; Roche Diagnostics; Beckmann; Singulex; Netherlands Heart Foundation [2001 D 032]; Swedish Society of Medicine [SLS-412071]; Medical Research Council [K013351]; Economic and Social Research Council; National Institutes of Health [HL36310]; Netherlands Organization for Scientific Research (NWO) [916.12.154]; EUR Fellowship; Goran Gustafsson Foundation; Swedish Heart-Lung Foundation [20140422]; Knut and Alice Wallenberg Foundation; European Research Council [ERC-StG-335395]; Swedish Diabetes Foundation (Diabetesfonden) [2013-024]; Swedish Research Council [2012-1397, 2012-1727, 2012-2215]; Swedish Heart-Lung Foundation; Thureus Foundation; Marianne and Marcus Wallenberg Foundation; Dalarna University; Uppsala University; Dekker scholarship-Junior Staff Member [2014T001]; European Union Seventh Framework Programme FP7 [HEALTH-F2-2013-601456]; Netherlands Heart Foundation; UCL Hospitals National Institute for Health Research Biomedical Research Centre FX The individual study sponsor(s) had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Dr. Isgum is supported by research grants from Pie Medical Imaging, 3Mensio Medical Imaging B.V., the NWO and Foundation for Technological Sciences under Project 12726, The Netherlands Organization for Health Research and Development, and the Dutch Cancer Society. Dr. Arpegard has received funding through the Stockholm County Council (combined clinical residency and PhD training program). Dr. Amouyel has received personal fees from Servier, Hoffman Laroche, Total, Genoscreen, Alzprotect, Fondation Plan Alzheimer, and Takeda outside of the submitted work; and has shares in Genoscreen. Dr. Morris is a Wellcome Trust Senior Fellow in Basic Biomedical Science under grant number WT098017. Dr. Worrall has received compensation for his role as deputy editor of the Journal of Neurology; and has received National Institutes of Health funding through the National Institute of Neurological Disorders and Stroke (U-01 N5069208) and National Human Genome Research Institute (U-01 HG005160). Dr. Samani is supported by the British Heart Foundation (BHF); and is a National Institute for Health Research Senior Investigator. Dr. Nelson is supported by the BHF. Dr. Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestle Nutrition (Nestec Ltd.), Metagenics Inc., and AXA; Nestle Nutrition (Nestec Ltd.), Metagenics Inc., and AXA had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Dr. Patel is supported by a BHF Intermediate Fellowship. Dr. Koenig has received funds through NGFNplus, project number 01GS0834; has received research grants from Abbott, Roche Diagnostics, Beckmann, and Singulex; has received honorarium for lectures from AstraZeneca, Novartis, Merck Sharp & Dohme, Amgen, and Actavis; and has served as a consultant for Novartis, Pfizer, The Medicines Company, Amgen, AstraZeneca, Merck Sharp & Dohme, and GlaxoSmithKline. Dr. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Dr. Svensson has received a grant from the Swedish Society of Medicine (SLS-412071). Dr. Kivimaki has received funding through the Medical Research Council (K013351), Economic and Social Research Council, and National Institutes of Health (HL36310). Dr. Dehghan is supported by a Netherlands Organization for Scientific Research (NWO) grant (VENI, 916.12.154) and the EUR Fellowship; and has received consultancy and research support from Metagenics Inc. (outside the scope of this work). Dr. Ingelsson is supported by grants from Goran Gustafsson Foundation, Swedish Heart-Lung Foundation (20140422), Knut and Alice Wallenberg Foundation (Knut och Alice Wallenbergs Stiftelse), European Research Council (ERC-StG-335395), Swedish Diabetes Foundation (Diabetesfonden; grant no. 2013-024), and the Swedish Research Council (VR; grant no. 2012-1397). Dr. de Bakker is an employee of Vertex Pharmaceuticals. Dr. Arnlov was funded by the Swedish Research Council (2012-1727, 2012-2215), Swedish Heart-Lung Foundation, Thureus Foundation, the Marianne and Marcus Wallenberg Foundation, Dalarna University, and Uppsala University. Dr.; Asselbergs is supported by a Dekker scholarship-Junior Staff Member 2014T001-Netherlands Heart Foundation and UCL Hospitals National Institute for Health Research Biomedical Research Centre. The research leading to these results has received funding from the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement no HEALTH-F2-2013-601456 (CVgenes-at-target). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 46 TC 1 Z9 1 U1 10 U2 11 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 AUG 30 PY 2016 VL 68 IS 9 BP 934 EP 945 DI 10.1016/j.jacc.2016.05.092 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DU6GS UT WOS:000382312900009 PM 27561768 ER PT J AU Nugent, AC Robinson, SE Coppola, R Zarate, CA AF Nugent, Allison C. Robinson, Stephen E. Coppola, Richard Zarate, Carlos A., Jr. TI Preliminary differences in resting state MEG functional connectivity pre- and post-ketamine in major depressive disorder SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Magnetoencephalography (MEG); Depression; Ketamine; Resting state; Connectivity; Independent components analysis (ICA) ID RAPID ANTIDEPRESSANT RESPONSE; TREATMENT-RESISTANT DEPRESSION; DEFAULT MODE NETWORK; ACTING ANTIDEPRESSANTS; HEALTHY-VOLUNTEERS; NEURAL ACTIVITY; CINGULATE; GLUTAMATE; CORTEX; FMRI AB Functional neuroimaging techniques including magnetoencephalography (MEG) have demonstrated that the brain is organized into networks displaying correlated activity. Group connectivity differences between healthy controls and participants with major depressive disorder (MDD) can be detected using temporal independent components analysis (ICA) on beta-bandpass filtered Hilbert envelope MEG data. However, the response of these networks to treatment is unknown. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, exerts rapid antidepressant effects. We obtained MEG recordings before and after open-label infusion of 0.5mg/kg ketamine in MDD subjects (N=13) and examined networks previously shown to differ between healthy individuals and those with MDD. Connectivity between the amygdala and an insulo-temporal component decreased post-ketamine in MDD subjects towards that observed in control subjects at baseline. Decreased baseline connectivity of the subgenual anterior cingulate cortex (sgACC) with a bilateral precentral network had previously been observed in MDD compared to healthy controls, and the change in connectivity post-ketamine was proportional to the change in sgACC glucose metabolism in a subset (N=8) of subjects receiving [11F]FDG-PET imaging. Ketamine appeared to reduce connectivity, regardless of whether connectivity was abnormally high or low compared to controls at baseline. These preliminary findings suggest that sgACC connectivity may be directly related to glutamate levels. Published by Elsevier Ireland Ltd. C1 [Nugent, Allison C.; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, 9000 Rockville Pike,MSC 1030, Bethesda, MD 20892 USA. [Robinson, Stephen E.; Coppola, Richard] NIMH, NIMH Magnetoencephalog Core Facil, NIH, Bethesda, MD 20892 USA. RP Nugent, AC (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, NIH, 9000 Rockville Pike,MSC 1030, Bethesda, MD 20892 USA. EM nugenta@mail.nih.gov FU Intramural Research Program at the National Institute of Mental Health; National Institutes of Health (IRP-NIMH-NIH) [ZIA-MH002927-04]; 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; Clinical Trials Identifier: NCT00024635 (ZIA-MH002927-04)), by a NARSAD Independent Investigator to Dr. Zarate, and by a Brain & Behavior Mood Disorders Research Award to Dr. Zarate. The authors thank the 7SE research unit and staff for their support. loline Henter, MA (NIMH) provided invaluable editorial assistance. NR 66 TC 3 Z9 3 U1 5 U2 8 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 AUG 30 PY 2016 VL 254 BP 56 EP 66 DI 10.1016/j.pscychresns.2016.06.006 PG 11 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DU6HU UT WOS:000382316000009 PM 27362845 ER PT J AU Szczepanik, J Nugent, AC Drevets, WC Khanna, A Zarate, CA Furey, ML AF Szczepanik, Joanna Nugent, Allison C. Drevets, Wayne C. Khanna, Ashish Zarate, Carlos A., Jr. Furey, Maura L. TI Amygdala response to explicit sad face stimuliat baseline predicts antidepressant treatment response to scopolamine in major depressive disorder SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Major depressive disorder; Amygdala; Rapid-acting antidepressants; Scopolamine; Stimulus processing; Functional magnetic resonance imaging (fMRI) ID EMOTIONAL FACES; MOOD-STATE; PERSONALIZED MEDICINE; SELECTIVE ATTENTION; FEARFUL FACES; BIOMARKERS; FMRI; SUPERSENSITIVITY; PATHOPHYSIOLOGY; ACETYLCHOLINE AB The muscarinic antagonist scopolamine produces rapid antidepressant effects in individuals with major depressive disorder (MDD). In healthy subjects, manipulation of acetyl-cholinergic transmission modulates attention in a stimulus-dependent manner. This study tested the hypothesis that baseline amygdalar activity in response to emotional stimuli correlates with antidepressant treatment response to scopolamine and could thus potentially predict treatment outcome. MDD patients and healthy controls performed an attention shifting task involving emotional faces while undergoing functional magnetic resonance imaging (fMRI). We found that blood oxygenation level dependent (BOLD) signal in the amygdala acquired while MDD patients processed sad face stimuli correlated positively with antidepressant response to scopolamine. Amygdalar response to sad faces in MDD patients who did not respond to scopolamine did not differ from that of healthy controls. This suggests that the pre-treatment task elicited amygdalar activity that may constitute a biomarker of antidepressant treatment response to scopolamine. Furthermore, in MDD patients who responded to scopolamine, we observed a post-scopolamine stimulus processing shift towards a pattern demonstrated by healthy controls, indicating a change in stimulus-dependent neural response potentially driven by attenuated cholinergic activity in the amygdala. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Szczepanik, Joanna; Nugent, Allison C.; Zarate, Carlos A., Jr.; Furey, Maura L.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bldg 10 CRC,Rm 7-5565, Bethesda, MD 20892 USA. [Drevets, Wayne C.] Johnson & Johnson Inc, Janssen Pharmaceut LLC, Titusville, NJ USA. [Khanna, Ashish] Brooklyn Hosp Ctr, Jewish Med Ctr, Phys Med & Rehabil, Brooklyn, NY USA. [Furey, Maura L.] Janssen Res & Dev, Neurosci Biomarkers Div, San Diego, CA USA. RP Szczepanik, J (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bldg 10 CRC,Rm 7-5565, Bethesda, MD 20892 USA. EM szczepaj@mail.nih.gov FU Intramural Research Program at the National Institute of Mental Health; National Institutes of Health (IRP-NIMH-NIH) [NCT00369915, ZIA MH002927]; NARSAD Independent Investigator; Brain & Behavior Mood Disorders Research Award FX Funding for this work was supported in part by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; NCT00369915, ZIA MH002927), by a NARSAD Independent Investigator to Dr. Zarate, and by a Brain & Behavior Mood Disorders Research Award to Dr. Zarate. These funding sources had no further role in study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. Dr. Zarate is listed as a co-inventor on a patent application for the use of ketamine and its metabolites in major depression, and Dr. Furey is identified as a co-inventor on a patent application for the use of scopolamine in mood disorders. Drs. Zarate and Furey have assigned their rights in these patents to the U.S. government but will share a percentage of any royalties that may be received by the government. Dr. Furey was a full-time employee of the NIMH at the time this study was conducted. All other authors have no conflict of interest to disclose, financial or otherwise. NR 53 TC 0 Z9 0 U1 6 U2 6 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 AUG 30 PY 2016 VL 254 BP 67 EP 73 DI 10.1016/j.pscychresns.2016.06.005 PG 7 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DU6HU UT WOS:000382316000010 PM 27366831 ER PT J AU Cai, XY Li, HY Liu, AY AF Cai, Xiaoyu Li, Huiyun Liu, Aiyi TI A marginal rank-based inverse normal transformation approach to comparing multiple clinical trial endpoints SO STATISTICS IN MEDICINE LA English DT Article DE clinical trials; multiple endpoints; power of test; rank-based transformation; ratio of dependent variables; type I error ID FUNCTIONAL LINEAR-MODELS; QUANTITATIVE TRAITS; FAMILY; ASSOCIATION; QUALITY; INDEX AB The increase in incidence of obesity and chronic diseases and their health care costs have raised the importance of quality diet on the health policy agendas. The healthy eating index is an important measure for diet quality which consists of 12 components derived from ratios of dependent variables with distributions hard to specify, measurement errors and excessive zero observations difficult to model parametrically. Hypothesis testing involving data of such nature poses challenges because the widely used multiple comparison procedures such as Hotelling's T-2 test and Bonferroni correction may suffer from substantial loss of efficiency. We propose a marginal rank-based inverse normal transformation approach to normalizing the marginal distribution of the data before employing a multivariate test procedure. Extensive simulation was conducted to demonstrate the ability of the proposed approach to adequately control the type I error rate as well as increase the power of the test, with data particularly from non-symmetric or heavy-tailed distributions. The methods are exemplified with data from a dietary intervention study for type I diabetic children. Published 2016. This article is a U.S. Government work and is in the public domain in the USA C1 [Cai, Xiaoyu] George Washington Univ, Dept Stat, Washington, DC 20052 USA. [Li, Huiyun] Beijing Inst Technol, Sch Management & Econ, Beijing 100081, Peoples R China. [Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Rockville, MD 20852 USA. RP Liu, AY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Rockville, MD 20852 USA. EM liua@mail.nih.gov OI Liu, Aiyi/0000-0002-6618-5082 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development Intramural Research Program [HHSN267200703434C, HHSN2752008000031/HHSN275002] FX Research of A. Liu was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Intramural Research Program (contract #HHSN267200703434C and #HHSN2752008000031/HHSN275002). The authors thank Drs. Ruzong Fan for helpful discussions and Tonja Nansel for providing the dietary quality data from the CHEF study. The authors thank two anonymous referees for their constructive comments that helped improve the manuscript. NR 15 TC 0 Z9 0 U1 5 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD AUG 30 PY 2016 VL 35 IS 19 BP 3259 EP 3271 DI 10.1002/sim.6928 PG 13 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA DS0YS UT WOS:000380323400002 PM 26990442 ER PT J AU Wu, MX Shu, Y Li, ZH Liu, AY AF Wu, Mixia Shu, Yu Li, Zhaohai Liu, Aiyi TI Repeated significance tests of linear combinations of sensitivity and specificity of a diagnostic biomarker SO STATISTICS IN MEDICINE LA English DT Article DE expected sample size; inference upon early stopping; sensitivity; sequential testing; specificity; two-stage designs; type I error; Youden's index ID II CLINICAL-TRIALS; SEQUENTIAL EVALUATION; 2-STAGE DESIGNS; ACCURACY; PREVALENCE; EFFICIENT; BIAS AB A sequential design is proposed to test whether the accuracy of a binary diagnostic biomarker meets the minimal level of acceptance. The accuracy of a binary diagnostic biomarker is a linear combination of the marker's sensitivity and specificity. The objective of the sequential method is to minimize the maximum expected sample size under the null hypothesis that the marker's accuracy is below the minimal level of acceptance. The exact results of two-stage designs based on Youden's index and efficiency indicate that the maximum expected sample sizes are smaller than the sample sizes of the fixed designs. Exact methods are also developed for estimation, confidence interval and p-value concerning the proposed accuracy index upon termination of the sequential testing. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. C1 [Wu, Mixia] Beijing Univ Technol, Coll Appl Sci, Beijing 100124, Peoples R China. [Shu, Yu] Abbott Labs Vasc Div, 3200 Lakeside Dr, Santa Clara, CA 95054 USA. [Li, Zhaohai] George Washington Univ, Dept Stat, 801 22nd St NW, Washington, DC 20052 USA. [Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, 6100 Execut Blvd, Rockville, MD 20852 USA. RP Liu, AY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, 6100 Execut Blvd, Rockville, MD 20852 USA. EM liua@mail.nih.gov OI Liu, Aiyi/0000-0002-6618-5082 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) FX Research of A. Liu is supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Institutes of Health (NIH). The authors thank two anonymous referees and an associate editor for their constructive comments that resulted in an improved manuscript. NR 31 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD AUG 30 PY 2016 VL 35 IS 19 BP 3397 EP 3412 DI 10.1002/sim.6932 PG 16 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA DS0YS UT WOS:000380323400011 PM 26947768 ER PT J AU Shaw, PA Fay, MP AF Shaw, Pamela A. Fay, Michael P. TI A rank test for bivariate time-to-event outcomes when one event is a surrogate SO STATISTICS IN MEDICINE LA English DT Article DE bivariate survival; composite outcome; interval censoring; semi-competing risks; surrogate endpoints; survival analysis ID INTERVAL-CENSORED-DATA; MULTIPLE END-POINTS; CLINICAL-TRIALS; SURVIVAL; FAILURE; NPMLE AB In many clinical settings, improving patient survival is of interest but a practical surrogate, such as time to disease progression, is instead used as a clinical trial's primary endpoint. A time-to-first endpoint (e.g., death or disease progression) is commonly analyzed but may not be adequate to summarize patient outcomes if a subsequent event contains important additional information. We consider a surrogate outcome very generally as one correlated with the true endpoint of interest. Settings of interest include those where the surrogate indicates a beneficial outcome so that the usual time-to-first endpoint of death or surrogate event is nonsensical. We present a new two-sample test for bivariate, interval-censored time-to-event data, where one endpoint is a surrogate for the second, less frequently observed endpoint of true interest. This test examines whether patient groups have equal clinical severity. If the true endpoint rarely occurs, the proposed test acts like a weighted logrank test on the surrogate; if it occurs for most individuals, then our test acts like a weighted logrank test on the true endpoint. If the surrogate is a useful statistical surrogate, our test can have better power than tests based on the surrogate that naively handles the true endpoint. In settings where the surrogate is not valid (treatment affects the surrogate but not the true endpoint), our test incorporates the information regarding the lack of treatment effect from the observed true endpoints and hence is expected to have a dampened treatment effect compared with tests based on the surrogate alone. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. C1 [Shaw, Pamela A.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Fay, Michael P.] NIAID, Biostat Res Branch, Rockville, MD USA. RP Shaw, PA (reprint author), Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. EM shawp@upenn.edu OI Fay, Michael P./0000-0002-8643-9625 FU Intramural NIH HHS [Z99 AI999999] NR 24 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD AUG 30 PY 2016 VL 35 IS 19 BP 3413 EP 3423 DI 10.1002/sim.6950 PG 11 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA DS0YS UT WOS:000380323400012 PM 27059817 ER PT J AU Brooks, AT Krumlauf, M Fryer, CS Beck, KH Yang, L Ramchandani, VA Wallen, GR AF Brooks, Alyssa Todaro Krumlauf, Michael Fryer, Craig S. Beck, Kenneth H. Yang, Li Ramchandani, Vijay A. Wallen, Gwenyth R. TI Critical Transitions: A Mixed Methods Examination of Sleep from Inpatient Alcohol Rehabilitation Treatment to the Community SO PLOS ONE LA English DT Article ID QUALITY INDEX; DAYTIME SLEEPINESS; DEPENDENT PATIENTS; INSOMNIA; SCALE; ABSTINENCE; DRINKING; DURATION; RELAPSE; DEPRESSION AB Aims This prospective, repeated measures study utilized a convergent parallel mixed methods approach to assess sleep experiences among individuals who were alcohol-dependent undergoing inpatient detoxification and treatment at a clinical research facility across the transition periods associated with the rehabilitation process: the initial adjustment to becoming an inpatient and the transition from inpatient to outpatient status. Methods This study included individual semi-structured interviews and quantitative measures relating to psychological distress, sleep quality, daytime sleepiness, and sleep-related beliefs and behavior (n = 33; 66.7% male). Interviews were conducted and questionnaires were administered within one week of participants' scheduled discharge date and again four to six weeks post-discharge when they returned for a follow-up visit (or via phone). Results Participants self-reported significant sleep disturbances at both study time points. Of those participants with valid data at both time points (n = 28), there were no significant changes in mean scores from pre- to post-discharge with the exception of self-efficacy for sleep (SE-S) being significantly higher post-discharge. Preliminary qualitative findings suggested differences between those with ongoing sleep disturbances, those whose sleep disturbances had resolved, and those with no sleep disturbances at either time point. Conclusions This analysis highlights individual variation in sleep throughout the process of inpatient treatment and transition to outpatient aftercare in individuals with alcohol dependence. Collecting quantitative and qualitative data concurrently and combining emerging themes from qualitative data with quantitative analyses allowed for a more thorough examination of this relatively novel area of research and provided information that can be utilized to inform future behavioral sleep interventions. C1 [Brooks, Alyssa Todaro; Krumlauf, Michael; Yang, Li; Wallen, Gwenyth R.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Brooks, Alyssa Todaro; Ramchandani, Vijay A.] NIAAA, Bethesda, MD 20892 USA. [Fryer, Craig S.; Beck, Kenneth H.] Univ Maryland, Sch Publ Hlth, Dept Behav & Community Hlth, College Pk, MD 20742 USA. RP Brooks, AT (reprint author), NIH, Ctr Clin, Bethesda, MD 20892 USA.; Brooks, AT (reprint author), NIAAA, Bethesda, MD 20892 USA. EM todaroad@mail.nih.gov; gwallen@cc.nih.gov FU National Institutes of Health, Clinical Center intramural research program FX This project has been funded in whole or in part with federal funds from the National Institutes of Health, Clinical Center intramural research program. 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 49 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 AUG 29 PY 2016 VL 11 IS 8 AR e0161725 DI 10.1371/journal.pone.0161725 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV4DZ UT WOS:000382876700030 PM 27571353 ER PT J AU Martinez, NJ Rai, G Yasgar, A Lea, WA Sun, HM Wang, YH Luci, DK Yang, SM Nishihara, K Takeda, S Sagor, M Earnshaw, I Okada, T Mori, K Wilson, K Riggins, GJ Xia, MH Grimaldi, M Jadhav, A Maloney, DJ Simeonov, A AF Martinez, Natalia J. Rai, Ganesha Yasgar, Adam Lea, Wendy A. Sun, Hongmao Wang, Yuhong Luci, Diane K. Yang, Shyh-Ming Nishihara, Kana Takeda, Shunichi Sagor, Mohiuddin Earnshaw, Irina Okada, Tetsuya Mori, Kazutoshi Wilson, Kelli Riggins, Gregory J. Xia, Menghang Grimaldi, Maurizio Jadhav, Ajit Maloney, David J. Simeonov, Anton TI A High-Throughput Screen Identifies 2,9-Diazaspiro[5.5]Undecanes as Inducers of the Endoplasmic Reticulum Stress Response with Cytotoxic Activity in 3D Glioma Cell Models SO PLOS ONE LA English DT Article ID UNFOLDED-PROTEIN RESPONSE; ER STRESS; MALIGNANT GLIOMA; DEATH; CA2+; CANCER; ACTIVATION; GRP78/BIP; AUTOPHAGY; XBP1 AB The endoplasmic reticulum (ER) is involved in Ca2+ signaling and protein folding. ER Ca2+ depletion and accumulation of unfolded proteins activate the molecular chaperone GRP78 (glucose-regulated protein 78) which in turn triggers the ER stress response (ERSR) pathway aimed to restore ER homeostasis. Failure to adapt to stress, however, results in apoptosis. We and others have shown that malignant cells are more susceptible to ERSR-induced apoptosis than their normal counterparts, implicating the ERSR as a potential target for cancer therapeutics. Predicated on these findings, we developed an assay that uses a GRP78 biosensor to identify small molecule activators of ERSR in glioma cells. We performed a quantitative high-throughput screen (qHTS) against a collection of similar to 425,000 compounds and a comprehensive panel of orthogonal secondary assays was formulated for stringent compound validation. We identified novel activators of ERSR, including a compound with a 2,9-diazaspiro[5.5]undecane core, which depletes intracellular Ca2+ stores and induces apoptosis-mediated cell death in several cancer cell lines, including patient-derived and 3D cultures of glioma cells. This study demonstrates that our screening platform enables the identification and profiling of ERSR inducers with cytotoxic activity and advocates for characterization of these compound in in vivo models. C1 [Martinez, Natalia J.; Rai, Ganesha; Yasgar, Adam; Lea, Wendy A.; Sun, Hongmao; Wang, Yuhong; Luci, Diane K.; Yang, Shyh-Ming; Nishihara, Kana; Wilson, Kelli; Xia, Menghang; Jadhav, Ajit; Maloney, David J.; Simeonov, Anton] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Nishihara, Kana; Sagor, Mohiuddin; Earnshaw, Irina] Kyoto Univ, Grad Sch Med, Dept Radiat Genet, Sakyo Ku, Kyoto 6068501, Japan. [Okada, Tetsuya; Mori, Kazutoshi] Kyoto Univ, Grad Sch Sci, Dept Biophys, Sakyo Ku, Kyoto 6068502, Japan. [Takeda, Shunichi; Wilson, Kelli; Riggins, Gregory J.] Johns Hopkins Univ, Dept Neurosurg, Baltimore, MD 21231 USA. [Grimaldi, Maurizio] Southern Res Inst, Dept Biochem & Mol Biol, Neuropharmacol Lab, Birmingham, AL 35205 USA. RP Maloney, DJ; Simeonov, A (reprint author), NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. EM maloneyd@mail.nih.gov; asimeono@mail.nih.gov OI Earnshaw, Irina/0000-0002-9546-6641 FU National Center for Advancing Translational Sciences; Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research [U54MH084681, DA031669] FX NJM, GR, AY, WAL, HS, YW, DKL, SMY, MX, AJ, DJM and AS were supported by the intramural research program of the National Center for Advancing Translational Sciences and the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research (U54MH084681 and DA031669). NR 45 TC 1 Z9 1 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 AUG 29 PY 2016 VL 11 IS 8 AR e0161486 DI 10.1371/journal.pone.0161486 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV4DZ UT WOS:000382876700021 PM 27570969 ER PT J AU Zhao, WT Pang, Q Xu, RX Liu, JW Liu, SF Li, J Su, XZ AF Zhao, Wenting Pang, Qin Xu, Ruixue Liu, Jianwen Liu, Shengfa Li, Jian Su, Xin-zhuan TI Monitoring the Prevalence of Leucocytozoon sabrazesi in Southern China and Testing Tricyclic Compounds against Gametocytes SO PLOS ONE LA English DT Article ID AVIAN BLOOD PARASITES; PCR-BASED DETECTION; HAEMOPROTEUS; PLASMODIUM; INFECTION; CHICKENS; SIMONDI; MALARIA; BIRDS; OWLS AB Leucocytozoon parasites infect many species of avian hosts, including domestic chicken, and can inflict heavy economic loss on the poultry industry. Two major species of Leucocytozoon parasites have been reported in China, L. sabrazesi and L. caulleryi, although L. sabrazesi appears to be more widespread than L. caulleryi in southern China. The traditional method for detecting Leucocytozoon infection is microscopic examination of blood smears for the presence of mature gametocytes in circulation, which may miss infections with low parasitemia (gametocytemia) or immature gametocytes. Here we developed a PCR-based method to monitor L. sabrazesi infections at seven sites in four provinces of China after testing two PCR primer pairs based on parasite mitochondrial cytochrome b (cytb) and cytochrome c oxidase III (coxIII) genes. We compared the results of PCR detection with those of microscopic observation. As expected, the PCR assays were more sensitive than microscope examination in detecting L. sabrazesi infection and were able to detect parasite DNA after gametocytes disappeared in the blood stream. Using these methods, we investigated monthly dynamics of L. sabrazesi in chickens from a free-range farm in Xiamen, Fujian province of China, over one year. Our results showed that chickens were infected with L. sabrazesi year-round in southern China. Finally, we tested several compounds for potential treatment of Leucocytozoon infections, including primaquine, ketotifen, clomipramine hydrochloride, desipramine hydrochloride, sulfaquinoxaline, and pyrimethamine. Only primaquine had activity against L. sabrazesi gametocytes. Our results provide important information for controlling parasite transmission in southern China and disease management. C1 [Zhao, Wenting; Pang, Qin; Xu, Ruixue; Liu, Jianwen; Liu, Shengfa; Li, Jian; Su, Xin-zhuan] Xiamen Univ, Sch Life Sci, Innovat Ctr Cell Signaling Network, State Key Lab Cellular Stress Biol, Xiamen 361005, Fujian, Peoples R China. [Su, Xin-zhuan] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Li, J; Su, XZ (reprint author), Xiamen Univ, Sch Life Sci, Innovat Ctr Cell Signaling Network, State Key Lab Cellular Stress Biol, Xiamen 361005, Fujian, Peoples R China.; Su, XZ (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. EM jianli_204@xmu.edu.cn; xsu@niaid.nih.gov OI Su, Xinzhuan/0000-0003-3246-3248 FU National Natural Science Foundation of China [81220108019, 81271858, 81572017]; Fundamental Research Funds for the Central Universities [20720160057]; Project 111 of the State Bureau of Foreign Experts and Ministry of Education of China [B06016]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the National Natural Science Foundation of China #81220108019, #81271858, and #81572017, by Fundamental Research Funds for the Central Universities (20720160057), by Project 111 of the State Bureau of Foreign Experts and Ministry of Education of China (B06016), and by 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 42 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 AUG 29 PY 2016 VL 11 IS 8 AR e0161869 DI 10.1371/journal.pone.0161869 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DV4DZ UT WOS:000382876700038 PM 27571513 ER PT J AU Banadyga, L Dolan, MA Ebihara, H AF Banadyga, Logan Dolan, Michael A. Ebihara, Hideki TI Rodent-Adapted Filoviruses and the Molecular Basis of Pathogenesis SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Review DE Filovirus; Ebola virus; Marburg virus; rodent adaptation; pathogenesis ID EBOLA-VIRUS VP24; MARBURG HEMORRHAGIC-FEVER; REVERSE GENETICS SYSTEM; SYRIAN GOLDEN-HAMSTER; VERVET MONKEY DISEASE; MATRIX PROTEIN VP40; DOUBLE-STRANDED-RNA; OUTBRED GUINEA-PIG; MOUSE MODEL; INTERFERON ANTAGONISM AB Ebola, Marburg, and Ravn viruses, all filoviruses, are the causative agents of severe hemorrhagic fever. Much of what we understand about the pathogenesis of filovirus disease is derived from work with animal models, including nonhuman primates, which are considered the "gold standard" filovirus model since they faithfully recapitulate the clinical hallmarks of filovirus disease. However, rodent models, including the mouse, guinea pig, and hamster, also exist for Ebola, Marburg, and Ravn viruses, and although they may not reproduce all the clinical signs of filovirus disease, thanks to their relative ease of use and low cost, they are often the first choice for initial descriptions of virus pathogenesis and evaluation of antiviral prophylactics and therapeutics. Since filoviruses do not cause significant disease in adult, immunocompetent rodents, these models rely on "rodent-adapted" viruses that have been passaged several times through their host until virulence and lethality are achieved. In the process of adaptation, the viruses acquire numerous nucleotide/amino acid mutations that contribute to virulence in their rodent host. Interestingly, virus protein 24 (VP24) and nucleoprotein (NP) appear to be major virulence factors for ebolaviruses in rodents, whereas VP40 appears to be the major virulence factor for marburgviruses. By characterizing these mutations and understanding the molecular mechanisms that lead to the acquisition of virulence, we can gain better insight into the pathogenic processes that underlie filovirus disease in humans. These processes, and the viral and/or cellular proteins that contribute to them, will make attractive targets for the development of novel therapeutics and counter-measures. Published by Elsevier Ltd. C1 [Banadyga, Logan; Ebihara, Hideki] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT 59840 USA. [Dolan, Michael A.] NIAID, Bioinformat & Computat Biosci Branch, NIH, Bethesda, MD 20892 USA. RP Ebihara, H (reprint author), 903 South 4th St, Hamilton, MT 59840 USA. EM ebiharah@niaid.nih.gov FU Division of Intramural Research, NIAID, NIH FX The authors are grateful to Ryan Kissinger and Austin Athman (Visual Medical Arts, Rocky Mountain Laboratories) for their technical assistance in preparing Fig. 2. We thank Heinz Feldmann for his critical review of this manuscript. The authors are supported 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 136 TC 3 Z9 3 U1 6 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD AUG 28 PY 2016 VL 428 IS 17 SI SI BP 3449 EP 3466 DI 10.1016/j.jmb.2016.05.008 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DW0FD UT WOS:000383315400008 PM 27189922 ER PT J AU Du, C Pusey, BN Adams, CJ Lau, CC Bone, WP Gahl, WA Markello, TC Adams, DR AF Du, Chen Pusey, Barbara N. Adams, Christopher J. Lau, C. Christopher Bone, William P. Gahl, William A. Markello, Thomas C. Adams, David R. TI Explorations to improve the completeness of exome sequencing SO BMC MEDICAL GENOMICS LA English DT Article DE Clinical exome sequencing; Analytical quality; Performance enhancement; Clinical genomics; Rare diseases; Completeness problem; False negative results ID HUMAN PHENOTYPE ONTOLOGY; UNDIAGNOSED DISEASES; HUMAN GENOME; INTRONIC MUTATION; CLINICAL EXOME; FRAMEWORK; VARIANTS; PROGRAM; POPULATION; DISCOVERY AB Background: Exome sequencing has advanced to clinical practice and proven useful for obtaining molecular diagnoses in rare diseases. In approximately 75 % of cases, however, a clinical exome study does not produce a definitive molecular diagnosis. These residual cases comprise a new diagnostic challenge for the genetics community. The Undiagnosed Diseases Program of the National Institutes of Health routinely utilizes exome sequencing for refractory clinical cases. Our preliminary data suggest that disease-causing variants may be missed by current standard-of-care clinical exome analysis. Such false negatives reflect limitations in experimental design, technical performance, and data analysis. Results: We present examples from our datasets to quantify the analytical performance associated with current practices, and explore strategies to improve the completeness of data analysis. In particular, we focus on patient ascertainment, exome capture, inclusion of intronic variants, and evaluation of medium-sized structural variants. Conclusions: The strategies we present may recover previously-missed, disease causing variants in second-pass exome analysis. Understanding the limitations of the current clinical exome search space provides a rational basis to improve methods for disease variant detection using genome-scale sequencing techniques. C1 [Du, Chen; Pusey, Barbara N.; Adams, Christopher J.; Lau, C. Christopher; Bone, William P.; Gahl, William A.; Markello, Thomas C.; Adams, David R.] NHGRI, Undiagnosed Dis Program, Common Fund, NIH, Bethesda, MD 20892 USA. RP Adams, DR (reprint author), NHGRI, Undiagnosed Dis Program, Common Fund, NIH, Bethesda, MD 20892 USA. EM dadams1@mail.nih.gov FU Intramural Research Program of the National Human Genome Research Institute; Common Fund of the National Institutes of Health FX This research is supported by the Intramural Research Program of the National Human Genome Research Institute and the Common Fund of the National Institutes of Health. NR 64 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 1755-8794 J9 BMC MED GENOMICS JI BMC Med. Genomics PD AUG 27 PY 2016 VL 9 AR 56 DI 10.1186/s12920-016-0216-3 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA DU4XE UT WOS:000382215400001 PM 27568008 ER PT J AU Freedhoff, Y Hall, KD AF Freedhoff, Yoni Hall, Kevin D. TI Weight loss diet studies: we need help not hype SO LANCET LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; LOW-FAT DIET; METAANALYSIS; ADHERENCE; OUTCOMES; ADULTS C1 [Freedhoff, Yoni] Bariatr Med Inst, Ottawa, ON, Canada. [Hall, Kevin D.] NIDDK, Integrat Physiol Sect, Lab Biol Modeling, Bethesda, MD 20892 USA. RP Hall, KD (reprint author), NIDDK, Integrat Physiol Sect, Lab Biol Modeling, Bethesda, MD 20892 USA. EM kevinh@niddk.nih.gov NR 13 TC 2 Z9 2 U1 7 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD AUG 27 PY 2016 VL 388 IS 10047 BP 849 EP 851 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DU0RI UT WOS:000381911800008 PM 27597452 ER PT J AU Zhao, YP Zhang, T Huo, HH Ye, YH Liu, YF AF Zhao, Yupeng Zhang, Ting Huo, Huanhuan Ye, Yihong Liu, Yanfen TI Lunapark Is a Component of a Ubiquitin Ligase Complex Localized to the Endoplasmic Reticulum Three-way Junctions SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE endoplasmic-reticulum-associated protein degradation (ERAD); protein misfolding; ubiquitin; ubiquitin ligase; ubiquitin-conjugating enzyme (E2 enzyme); Atlastin; ER three-way junction; Lunapark; Lnp; gp78; misfolded ID ER-ASSOCIATED DEGRADATION; MEMBRANE-PROTEINS; POLYUBIQUITIN CHAINS; GP78; REQUIRES; CYTOSOL; GENERATION; MORPHOLOGY; NETWORK; ENZYMES AB The endoplasmic reticulum (ER) network comprises sheets and tubules that are connected by dynamic three-way junctions. Lunapark (Lnp) localizes to and stabilizes ER three-way junctions by antagonizing the small GTPase Atlastin, but how Lnp shapes the ER network is unclear. Here, we used an affinity purification approach and mass spectrometry to identify Lnp as an interacting partner of the ER protein quality control ubiquitin ligase gp78. Accordingly, Lnp purified from mammalian cells has a ubiquitin ligase activity in vitro. Intriguingly, biochemical analyses show that this activity can be attributed not only to associated ubiquitin ligase, but also to an intrinsic ubiquitin ligase activity borne by Lnp itself. This activity is contained in the N-terminal 45 amino acids of Lnp although this segment does not share homology to any known ubiquitin ligase motifs. Despite its interaction with gp78, Lnp does not seem to have a broad function in degradation of misfolded ER proteins. On the other hand, the N-terminal ubiquitin ligase-bearing motif is required for the ER three-way junction localization of Lnp. Our study identifies a new type of ubiquitin ligase and reveals a potential link between ubiquitin and ER morphology regulation. C1 [Zhao, Yupeng; Huo, Huanhuan; Liu, Yanfen] ShanghaiTech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China. [Zhang, Ting; Ye, Yihong] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Liu, YF (reprint author), ShanghaiTech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China.; Ye, YH (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM yihongy@mail.nih.gov; liuyf@shanghaitech.edu.cn FU National Institutes of Health Intramural Research Program NIDDK Grant [1ZIADK033008-06]; National Natural Science Foundation of China [31570781] FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Program NIDDK Grant 1ZIADK033008-06 and National Natural Science Foundation of China Grant 31570781. The authors declare no conflict of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 48 TC 1 Z9 1 U1 3 U2 3 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 AUG 26 PY 2016 VL 291 IS 35 BP 18252 EP 18262 DI 10.1074/jbc.M116.737783 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV9EC UT WOS:000383241800018 PM 27387505 ER PT J AU Rosas-Hernandez, H Cuevas, E Lantz, SM Rice, KC Gannon, BM Fantegrossi, WE Gonzalez, C Paule, MG Ali, SF AF Rosas-Hernandez, Hector Cuevas, Elvis Lantz, Susan M. Rice, Kenner C. Gannon, Brenda M. Fantegrossi, William E. Gonzalez, Carmen Paule, Merle G. Ali, Syed F. TI Methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxypyrovalerone (MDPV) induce differential cytotoxic effects in bovine brain microvessel endothelial cells SO NEUROSCIENCE LETTERS LA English DT Article DE Methamphetamine; MDMA; MDPV; Blood-brain barrier; Cytotoxicity ID BARRIER DISRUPTION; OXIDATIVE STRESS; DOPAMINE TRANSPORTER; IN-VITRO; HYPERTHERMIA; ECSTASY; COCAINE; METHYLENEDIOXYPYROVALERONE; NEUROINFLAMMATION; VASOCONSTRICTION AB Designer drugs such as synthetic psychostimulants are indicative of a worldwide problem of drug abuse and addiction. In addition to methamphetamine (METH), these drugs include 3,4-methylenedioxy-methamphetamine (MDMA) and commercial preparations of synthetic cathinones including 3,4-methylenedioxypyrovalerone (MDPV), typically referred to as "bath salts." These psychostimulants exert neurotoxic effects by altering monoamine systems in the brain. Additionally, METH and MDMA adversely affect the integrity of the blood-brain barrier (BBB): there are no current reports on the effects of MDPV on the BBB. The aim of this study was to compare the effects of METH, MDMA and MDPV on bovine brain microvessel endothelial cells (bBMVECs), an accepted in vitro model of the BBB. Confluent bBMVEC monolayers were treated with METH, MDMA and MDPV (0.5 mM-2.5 mM) for 24 h. METH and MDMA increased lactate dehydrogenase release only at the highest concentration (2.5 mM), whereas MDPV induced cytotoxicity at all concentrations. MDMA and METH decreased cellular proliferation only at 2.5 mM, with similar effects observed after MDPV exposures starting at 1 mM. Only MDPV increased reactive oxygen species production at all concentrations tested whereas all 3 drugs increased nitric oxide production. Morphological analysis revealed different patterns of compound-induced cell damage. METH induced vacuole formation at 1 mM and disruption of the monolayer at 2.5 mM. MDMA induced disruption of the endothelial monolayer from 1 mM without vacuolization. On the other hand, MDPV induced monolayer disruption at doses >= 0.5 mM without vacuole formation; at 2.5 mM, the few remaining cells lacked endothelial morphology. These data suggest that even though these synthetic psychostimulants altermonoaminergic systems, they each induce BBB toxicity by different mechanisms with MDPV being the most toxic. Published by Elsevier Ireland Ltd. C1 [Rosas-Hernandez, Hector; Cuevas, Elvis; Lantz, Susan M.; Paule, Merle G.; Ali, Syed F.] US FDA, Neurochem Lab, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Rice, Kenner C.] NIAAA, Drug Design & Synth Sect, Mol Targets & Medicat Discovery Branch, NIDA, Bethesda, MD USA. [Gannon, Brenda M.; Fantegrossi, William E.] UAMS, Dept Pharmacol & Toxicol, Little Rock, AR USA. [Gonzalez, Carmen] UASLP, Fac Ciencias Quim, Slp, Mexico. RP Ali, SF (reprint author), US FDA, Neurochem Lab, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM Syed.Ali@fda.hhs.gov FU U.S. Department of Energy; U.S. Food and Drug Administration; Intramural Research Programs of the National Institute on Drug Abuse; National Institute on Alcoholism and Alcohol Abuse FX This research was supported in part by an appointment (H. R-H.) to the Research Participation Program at the National Center for Toxicological Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. A portion of this work was supported by the Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcoholism and Alcohol Abuse. The content is solely the responsibility of the authors and does not necessarily represent the official views of the US. Food and Drug Administration, the National Institute on Drug Abuse, the National Institute of Alcohol Abuse and Alcoholism, or the National Institutes of Health. NR 45 TC 0 Z9 0 U1 4 U2 4 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 AUG 26 PY 2016 VL 629 BP 125 EP 130 DI 10.1016/j.neulet.2016.06.029 PG 6 WC Neurosciences SC Neurosciences & Neurology GA DU7QF UT WOS:000382409000023 PM 27320055 ER PT J AU Dellibovi-Ragheb, TA AF Dellibovi-Ragheb, Teegan A. TI Next Gen PhD A Guide to Career Paths in Science SO SCIENCE LA English DT Book Review C1 [Dellibovi-Ragheb, Teegan A.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Dellibovi-Ragheb, TA (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM teegan.dellibovi-ragheb@nih.gov NR 1 TC 0 Z9 0 U1 4 U2 4 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD AUG 26 PY 2016 VL 353 IS 6302 BP 877 EP 877 DI 10.1126/science.aah3463 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DU0CA UT WOS:000381867700023 ER PT J AU Sherman, ME Ichikawa, L Pfeiffer, RM Miglioretti, DL Kerlikowske, K Tice, J Vacek, PM Gierach, GL AF Sherman, Mark E. Ichikawa, Laura Pfeiffer, Ruth M. Miglioretti, Diana L. Kerlikowske, Karla Tice, Jeffery Vacek, Pamela M. Gierach, Gretchen L. TI Relationship of Predicted Risk of Developing Invasive Breast Cancer, as Assessed with Three Models, and Breast Cancer Mortality among Breast Cancer Patients SO PLOS ONE LA English DT Article ID HORMONE-RECEPTOR STATUS; POSTMENOPAUSAL WOMEN; SCREENING-PROGRAM; MAMMOGRAPHY; VALIDATION; CONSORTIUM; PREVENTION; REDUCTION; PROGNOSIS; ONCOLOGY AB Purpose Breast cancer risk prediction models are used to plan clinical trials and counsel women; however, relationships of predicted risks of breast cancer incidence and prognosis after breast cancer diagnosis are unknown. Methods Using largely pre-diagnostic information from the Breast Cancer Surveillance Consortium (BCSC) for 37,939 invasive breast cancers (1996-2007), we estimated 5-year breast cancer risk (< 1%; 1-1.66%; >= 1.67%) with three models: BCSC 1-year risk model (BCSC-1; adapted to 5-year predictions); Breast Cancer Risk Assessment Tool (BCRAT); and BCSC 5-year risk model (BCSC-5). Breast cancer-specific mortality post-diagnosis (range: 1-13 years; median: 5.4-5.6 years) was related to predicted risk of developing breast cancer using unadjusted Cox proportional hazards models, and in age-stratified (35-44; 45-54; 55-69; 70-89 years) models adjusted for continuous age, BCSC registry, calendar period, income, mode of presentation, stage and treatment. Mean age at diagnosis was 60 years. Results Of 6,021 deaths, 2,993 (49.7%) were ascribed to breast cancer. In unadjusted case-only analyses, predicted breast cancer risk >= 1.67% versus < 1.0% was associated with lower risk of breast cancer death; BCSC-1: hazard ratio (HR) = 0.82 (95% CI = 0.75-0.90); BCRAT: HR = 0.72 (95% CI = 0.65-0.81) and BCSC-5: HR = 0.84 (95% CI = 0.75-0.94). Age-stratified, adjusted models showed similar, although mostly non-significant HRs. Among women ages 55-69 years, HRs approximated 1.0. Generally, higher predicted risk was inversely related to percentages of cancers with unfavorable prognostic characteristics, especially among women 35-44 years. Conclusions Among cases assessed with three models, higher predicted risk of developing breast cancer was not associated with greater risk of breast cancer death; thus, these models would have limited utility in planning studies to evaluate breast cancer mortality reduction strategies. Further, when offering women counseling, it may be useful to note that high predicted risk of developing breast cancer does not imply that if cancer develops it will behave aggressively. C1 [Sherman, Mark E.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Sherman, Mark E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Ichikawa, Laura; Miglioretti, Diana L.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Pfeiffer, Ruth M.; Gierach, Gretchen L.] Div Canc Epidemiol & Genet, Bethesda, MD USA. [Miglioretti, Diana L.] Univ Calif Davis, Dept Publ Hlth, Davis, CA 95616 USA. [Kerlikowske, Karla; Tice, Jeffery] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Kerlikowske, Karla] Univ Calif San Francisco, Dept Epidemiol Biostat, San Francisco, CA 94143 USA. [Vacek, Pamela M.] Univ Vermont, Sch Med, Dept Med Biostat, Burlington, VT 05405 USA. RP Sherman, ME (reprint author), NCI, Canc Prevent Div, Bethesda, MD 20892 USA.; Sherman, ME (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM ShermanM@mail.nih.gov RI Gierach, Gretchen/E-1817-2016 OI Gierach, Gretchen/0000-0002-0165-5522 FU Intramural Research Program of the National Cancer Institute [HHSN261201100031C]; several state public health departments and cancer registries throughout the US FX This was funded in part by the Intramural Research Program of the National Cancer Institute (HHSN261201100031C). The collection of cancer and vital status data used in this study was supported in part by several state public health departments and cancer registries throughout the US. For a full description of these sources, please see: http://breastscreening.cancer.gov/work/acknowledgement.html. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 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 AUG 25 PY 2016 VL 11 IS 8 AR e0160966 DI 10.1371/journal.pone.0160966 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DU5NN UT WOS:000382258600021 PM 27560501 ER PT J AU Lo, B Fritz, JM Su, HC Uzel, G Jordan, MB Lenardo, MJ AF Lo, Bernice Fritz, Jill M. Su, Helen C. Uzel, Gulbu Jordan, Michael B. Lenardo, Michael J. TI CHAI and LATAIE: new genetic diseases of CTLA-4 checkpoint insufficiency SO BLOOD LA English DT Article ID REGULATORY T-CELLS; IMMUNE DYSREGULATION; LRBA MUTATION; RHEUMATOID-ARTHRITIS; FOLLICULAR HELPER; DEFICIENCY; RESPONSES; PATIENT; HYDROXYCHLOROQUINE; TRANSPLANTATION AB CTLA-4 is a critical inhibitory "checkpoint" molecule of immune activation. Several recent reports have described patients with immune dysregulation and lymphoproliferative disease resulting from 2 different genetic diseases that directly or indirectly cause CTLA-4 deficiency. Numerous articles have also been published describing CTLA-4 blockade in cancer immunotherapy and its side effects, which are ultimately the consequence of treatment-induced CTLA-4 deficiency. Here, we review these 2 diseases and CTLA-4 blockade therapy, emphasizing the crucial role of CTLA-4 in immune checkpoint regulation. C1 [Lo, Bernice] Sidra Med & Res Ctr, Div Translat Med, POB 26999, Doha, Qatar. [Lo, Bernice; Fritz, Jill M.; Lenardo, Michael J.] NIAID, Mol Dev, Immune Syst Sect, Immunol Lab,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lo, Bernice; Fritz, Jill M.; Su, Helen C.; Lenardo, Michael J.] NIAID, Clin Genom Program, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Su, Helen C.] NIAID, Human Immunol Dis Sect, Lab Host Defenses, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Uzel, Gulbu] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Jordan, Michael B.] Univ Cincinnati, Dept Pediat, Div Bone Marrow Transplantat & Immune Deficiency, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Jordan, Michael B.] Univ Cincinnati, Div Immunobiol, Dept Pediat, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. RP Lo, B (reprint author), Sidra Med & Res Ctr, Div Translat Med, POB 26999, Doha, Qatar.; Lenardo, MJ (reprint author), Immunol Lab, 10 Ctr Dr,Bldg 10,Room 11D14, Bethesda, MD 20892 USA. EM blo@sidra.org; lenardo@nih.gov OI Lo, Bernice/0000-0002-1087-6845 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 48 TC 2 Z9 2 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 AUG 25 PY 2016 VL 128 IS 8 BP 1037 EP 1042 DI 10.1182/blood-2016-04-712612 PG 6 WC Hematology SC Hematology GA DW7LT UT WOS:000383832900010 PM 27418640 ER PT J AU Alvarnas, JC Le Rademacher, J Wang, YL Little, RF Akpek, G Ayala, E Devine, S Baiocchi, R Lozanski, G Kaplan, L Noy, A Popat, U Hsu, J Morris, LE Thompson, J Horowitz, MM Mendizabal, A Levine, A Krishnan, A Forman, SJ Navarro, WH Ambinder, R AF Alvarnas, Joseph C. Le Rademacher, Jennifer Wang, Yanli Little, Richard F. Akpek, Gorgun Ayala, Ernesto Devine, Steven Baiocchi, Robert Lozanski, Gerard Kaplan, Lawrence Noy, Ariela Popat, Uday Hsu, Jack Morris, Lawrence E., Jr. Thompson, Jason Horowitz, Mary M. Mendizabal, Adam Levine, Alexandra Krishnan, Amrita Forman, Stephen J. Navarro, Willis H. Ambinder, Richard TI Autologous hematopoietic cell transplantation for HIV-related lymphoma: results of the BMT CTN 0803/AMC 071 trial SO BLOOD LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIGH-DOSE THERAPY; ACTIVE ANTIRETROVIRAL THERAPY; AIDS-RELATED LYMPHOMA; NON-HODGKINS-LYMPHOMA; PROGNOSTIC-FACTORS; SALVAGE TREATMENT; INFECTION; DISEASE; CHEMOTHERAPY AB Autologous hematopoietic cell transplant (AHCT) for HIV-infected patients is largely limited to centers with HIV-specific expertise. The Blood and Marrow Transplant Clinical Trials Network 0803/AIDS Malignancy Consortium 071 trial is a multicenter phase 2 study of AHCT for patients with HIV-related lymphoma (HRL). Eligible patients had chemotherapy-sensitive relapsed/persistent HRL, were >15 years of age, and had treatable HIV infection. Patients were prepared using carmustine, etoposide, cytarabine, and melphalan and received consistent management of peritransplant antiretroviral treatment. The primary endpoint was 1-year overall survival. Forty-three patients were enrolled; 40 underwent AHCT. Pretransplant HIV viral load was undetectable (<50 copies/mL) in 32 patients (80%); the median CD4 count was 249/mu L (range, 39-797). At a median follow-up of 24.8 months, 1-year and 2-year overall survival probabilities were 87.3% (95% confidence interval [CI], 72.1-94.5) and82%(95% CI, 65.9-91), respectively. The probability of 2-year progression-free survival was 79.8% (95% CI, 63.7-89.4). One-year transplant-related mortality was 5.2%. Median time to neutrophil and platelet recovery was 11 days and 18 days, respectively. Nine patients experienced a total of 13 unexpected grade 3-5 adverse events posttransplant (10 grade 3 and 3 grade 4 events). Twenty-two patients had at least 1 infectious episode posttransplant. At 1 year post-AHCT, median CD4(+) T-cell count was 280.3 (range, 28.8-1148.0); 82.6% had an undetectable HIV viral load. Trial patients were compared with 151 matched Center for International Bone Marrow Transplant Research controls. Outcomes between HIV-infected patients and controls were not statistically significantly different. HRL patients should be considered candidates for AHCT if they meet standard transplant criteria. The trial was registered at www.clinicaltrials.gov as #NCT01141712. C1 [Alvarnas, Joseph C.; Krishnan, Amrita; Forman, Stephen J.] City Hope Natl Med Ctr, Dept Hematol Hematopoiet Cell Transplantat, 1500 E Duarte Rd, Duarte, CA 91010 USA. [Le Rademacher, Jennifer; Horowitz, Mary M.] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Wang, Yanli; Thompson, Jason; Mendizabal, Adam] Emmes Corp, Rockville, MD USA. [Little, Richard F.] NCI, Canc Therapy Evaluat Program, Rockville, MD USA. [Akpek, Gorgun] Univ Maryland Med Syst, Greenebaum Canc Ctr, Baltimore, MD USA. [Ayala, Ernesto] H Lee Moffitt Canc Ctr & Res Inst, Dept Blood & Marrow Transplantat, Tampa, FL USA. [Devine, Steven; Baiocchi, Robert; Lozanski, Gerard] Ohio State Univ, Arthur G James Canc Ctr Hosp, Dept Hematol, Columbus, OH 43210 USA. [Kaplan, Lawrence] Univ Calif San Francisco, Div Hematol Oncol, San Francisco, CA 94143 USA. [Noy, Ariela] Mem Sloan Kettering Canc Ctr, Div Hematol Oncol, 1275 York Ave, New York, NY 10021 USA. [Popat, Uday] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cellular Therapy, Houston, TX 77030 USA. [Hsu, Jack] Univ Florida, Hlth Canc Ctr, Bone Marrow Transplant Program, Gainesville, FL USA. [Morris, Lawrence E., Jr.] Northside Hosp Canc Inst, Blood & Marrow Transplant Grp Georgia, Atlanta, GA USA. [Levine, Alexandra] City Hope Natl Med Ctr, 1500 E Duarte Rd,MOB3001, Duarte, CA 91010 USA. [Navarro, Willis H.] Natl Marrow Donor Program, Minneapolis, MN USA. [Ambinder, Richard] Johns Hopkins Sch Med, Dept Oncol, Baltimore, MD USA. RP Alvarnas, JC (reprint author), City Hope Natl Med Ctr, 1500 E Duarte Rd,MOB3001, Duarte, CA 91010 USA. EM jalvarnas@coh.org FU National Institutes of Health National Cancer Institute (NCI) [HHSN21200622012C-009]; AMC through NCI [U01CA121947]; National Heart, Lung, and Blood Institute; NCI [U10HL069294] FX This work is supported by grants from the National Institutes of Health National Cancer Institute (NCI; grant HHSN21200622012C-009) and the AMC through NCI (grant U01CA121947). The Blood and Marrow Transplant Clinical Trials Network infrastructure is supported in part by the National Heart, Lung, and Blood Institute and NCI (grant U10HL069294). NR 41 TC 5 Z9 5 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 AUG 25 PY 2016 VL 128 IS 8 BP 1050 EP 1058 DI 10.1182/blood-2015-08-664706 PG 9 WC Hematology SC Hematology GA DW7LT UT WOS:000383832900012 PM 27297790 ER PT J AU Schmidt, J Gong, SY Marafioti, T Mankel, B Gonzalez-Farre, B Balague, O Mozos, A Cabecadas, J van der Walt, J Hoehn, D Rosenwald, A Ott, G Dojcinov, S Egan, C Nadeu, F Ramis-Zaldivar, JE Clot, G Barcena, C Perez-Alonso, V Endris, V Penzel, R Lome-Maldonado, C Bonzheim, I Fend, F Campo, E Jaffe, ES Salaverria, I Quintanilla-Martinez, L AF Schmidt, Janine Gong, Shunyou Marafioti, Teresa Mankel, Barbara Gonzalez-Farre, Blanca Balague, Olga Mozos, Ana Cabecadas, Jose van der Walt, Jon Hoehn, Daniela Rosenwald, Andreas Ott, German Dojcinov, Stefan Egan, Caoimhe Nadeu, Ferran Ramis-Zaldivar, Joan Enric Clot, Guillem Barcena, Carmen Perez-Alonso, Vanesa Endris, Volker Penzel, Roland Lome-Maldonado, Carmen Bonzheim, Irina Fend, Falko Campo, Elias Jaffe, Elaine S. Salaverria, Itziar Quintanilla-Martinez, Leticia TI Genome-wide analysis of pediatric-type follicular lymphoma reveals low genetic complexity and recurrent alterations of TNFRSF14 gene SO BLOOD LA English DT Article ID LYMPHOCYTIC-LEUKEMIA; CLINICAL-FEATURES; NODULAR LYMPHOMA; YOUNG-ADULTS; MUTATIONS; EXPRESSION; CHILDREN; RECEPTOR; BTLA; TRANSLOCATION AB Pediatric-type follicular lymphoma (PTFL) is a variant of follicular lymphoma (FL) with distinctive clinicopathological features. Patients are predominantly young males presenting with localized lymphadenopathy; the tumor shows high-grade cytology and lacks both BCL2 expression and t(14; 18) translocation. The genetic alterations involved in the pathogenesis of PTFL are unknown. Therefore, 42 PTFL (40 males and 2 females; mean age, 16 years; range, 5-31) were genetically characterized. For comparison, 11 cases of conventional t(14: 18)(-) FL in adults were investigated. Morphologically, PTFL cases had follicular growth pattern without diffuse areas and characteristic immunophenotype. All cases showed monoclonal immunoglobulin (IG) rearrangement. PTFL displays low genomic complexity when compared with t(14; 18)(-) FL (mean, 0.77 vs 9 copy number alterations per case; P <.001). Both groups presented 1p36 alterations including TNFRSF14, but copy-number neutral loss of heterozygosity (CNN-LOH) of this locus was more frequently observed in PTFL (40% vs 9%; P =.075). TNFRSF14 was the most frequently affected gene in PTFL (21 mutations and 2 deletions), identified in 54% of cases, followed by KMT2D mutations in 16%. Other histone-modifying genes were rarely affected. In contrast, t(14; 18)(-) FL displayed a mutational profile similar to t(14; 18)(+) FL. In 8 PTFL cases (19%), no genetic alterations were identified beyond IG monoclonal rearrangement. The genetic landscape of PTFL suggests that TNFRSF14 mutations accompanied by CNN-LOH of the 1p36 locus in over 70% of mutated cases, as additional selection mechanism, might play a key role in the pathogenesis of this disease. The genetic profiles of PTFL and t(14; 18)(-) FL in adults indicate that these are two different disorders. C1 [Schmidt, Janine; Mankel, Barbara; Bonzheim, Irina; Fend, Falko; Quintanilla-Martinez, Leticia] Univ Tubingen, Inst Pathol & Neuropathol, Tubingen, Germany. [Schmidt, Janine; Mankel, Barbara; Bonzheim, Irina; Fend, Falko; Quintanilla-Martinez, Leticia] Univ Hosp Tubingen, Ctr Comprehens Canc, Tubingen, Germany. [Gong, Shunyou; Egan, Caoimhe; Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, Bethesda, MD 20892 USA. [Marafioti, Teresa] Barts & London NHS Trust, Dept Cellular Pathol, London, England. [Gonzalez-Farre, Blanca; Balague, Olga; Nadeu, Ferran; Ramis-Zaldivar, Joan Enric; Clot, Guillem; Campo, Elias; Salaverria, Itziar] Hosp Clin Barcelona, Hematopathol Unit, Inst Invest Biomed August Pi & Sunyer, Barcelona, Spain. [Mozos, Ana] Hosp Santa Creu & Sant Pau, Dept Pathol, Barcelona, Spain. [Cabecadas, Jose] Inst Portugues Oncol Francisco Gentil, Dept Pathol, Lisbon, Portugal. [van der Walt, Jon] Guys & St Thomas Hosp, Dept Histopathol, London, England. [Hoehn, Daniela] Columbia Univ, Dept Pathol & Cell Biol, Med Ctr, New York, NY USA. [Rosenwald, Andreas] Univ Wurzburg, Inst Pathol, Wurzburg, Germany. [Rosenwald, Andreas] Comprehens Canc Ctr Mainfranken, Wurzburg, Germany. [Ott, German] Robert Bosch Krankenhaus, Dept Clin Pathol, Stuttgart, Germany. [Ott, German] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Dojcinov, Stefan] Univ Wales Hosp, Dept Pathol, All Wales Lymphoma Panel, Cardiff, S Glam, Wales. [Barcena, Carmen; Perez-Alonso, Vanesa] Hosp Univ 12 Octubre, Madrid, Spain. [Endris, Volker; Penzel, Roland] Univ Heidelberg Hosp, Inst Pathol, Heidelberg, Germany. [Lome-Maldonado, Carmen] Inst Nacl Cancerol, Dept Pathol, Mexico City, DF, Mexico. RP Quintanilla-Martinez, L (reprint author), Univ Tubingen, Inst Pathol, Univ Hosp Tubingen, Liebermeisterstr 8, D-72076 Tubingen, Germany.; Quintanilla-Martinez, L (reprint author), Ctr Comprehens Canc, Liebermeisterstr 8, D-72076 Tubingen, Germany.; Salaverria, I (reprint author), IDIBAPS, Rossello 153, Barcelona 08036, Spain. EM isalaver@clinic.ub.es; leticia.quintanilla-fend@med.uni-tuebingen.de RI Campo, elias/O-7192-2016; OI Campo, elias/0000-0001-9850-9793; Cabecadas, Jose/0000-0001-6232-1596 FU Fondo de Investigaciones Sanitarias; Instituto de Salud Carlos III (Miguel Servet) [CP13/00159, PI15/00580]; Generalitat de Catalunya Suport Grups de Recerca [2013-SGR-378]; European Regional Development Fund "Una manera de fer Europa"; Wilhelm-Sander-Stiftung [2015.058.1] FX This work was supported by Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III (Miguel Servet contract CP13/00159 and PI15/00580), Generalitat de Catalunya Suport Grups de Recerca (2013-SGR-378), the European Regional Development Fund "Una manera de fer Europa" and the Wilhelm-Sander-Stiftung (2015.058.1; L.Q.-M. and F.F.). This work was partially developed at the Centro Esther Koplowitz, Barcelona, Spain. NR 41 TC 1 Z9 1 U1 5 U2 5 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 AUG 25 PY 2016 VL 128 IS 8 BP 1101 EP 1111 DI 10.1182/blood-2016-03-703819 PG 11 WC Hematology SC Hematology GA DW7LT UT WOS:000383832900018 PM 27257180 ER PT J AU Gopich, IV Szabo, A AF Gopich, Irina V. Szabo, Attila TI Reversible Stochastically Gated Diffusion-Influenced Reactions SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID ASSOCIATION-DISSOCIATION REACTION; DEPENDENT RATE COEFFICIENTS; MICHAELIS-MENTEN KINETICS; INTEGRAL ENCOUNTER THEORY; MANY-PARTICLE TREATMENT; LONG-TIME ASYMPTOTICS; BIMOLECULAR REACTIONS; MULTISTAGE REACTIONS; LIQUID SOLUTIONS; REACTION-RATES AB An approximate but accurate theory is developed for the kinetics of reversible binding of a ligand to a macromolecule when either can stochastically fluctuate between reactive and unreactive conformations. The theory is based on a set of reaction-diffusion equations for the deviations of the pair distributions from their bulk values. The concentrations are shown to satisfy non-Markovian rate equations with memory kernels that are obtained by solving an irreversible geminate (i.e., two-particle) problem. The relaxation to equilibrium is not exponential but rather a power law. In the Markovian limit, the theory reduces to a set of ordinary rate equations with renormalized rate constants. C1 [Gopich, Irina V.; Szabo, Attila] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Szabo, A (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM attilas@niddk.nih.gov RI Szabo, Attila/H-3867-2012 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 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 (NIDDK), National Institutes of Health. NR 53 TC 1 Z9 1 U1 4 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD AUG 25 PY 2016 VL 120 IS 33 BP 8080 EP 8089 DI 10.1021/acs.jpcb.6b00152 PG 10 WC Chemistry, Physical SC Chemistry GA DU4JZ UT WOS:000382180200004 PM 26956646 ER PT J AU Zhang, X Xiao, WX Acencio, ML Lemke, N Wang, XJ AF Zhang, Xue Xiao, Wangxin Acencio, Marcio Luis Lemke, Ney Wang, Xujing TI An ensemble framework for identifying essential proteins SO BMC BIOINFORMATICS LA English DT Article DE Essential protein; Protein-protein interaction networks; Centrality measure; Ensemble learning; Gene expression ID SACCHAROMYCES-CEREVISIAE GENOME; ESSENTIAL GENE IDENTIFICATION; INTERACTION NETWORKS; PPI NETWORK; CENTRALITY; YEAST; DATABASE; INTEGRATION; EXPRESSION; DISCOVERY AB Background: Many centrality measures have been proposed to mine and characterize the correlations between network topological properties and protein essentiality. However, most of them show limited prediction accuracy, and the number of common predicted essential proteins by different methods is very small. Results: In this paper, an ensemble framework is proposed which integrates gene expression data and protein-protein interaction networks (PINs). It aims to improve the prediction accuracy of basic centrality measures. The idea behind this ensemble framework is that different protein-protein interactions (PPIs) may show different contributions to protein essentiality. Five standard centrality measures (degree centrality, betweenness centrality, closeness centrality, eigenvector centrality, and subgraph centrality) are integrated into the ensemble framework respectively. We evaluated the performance of the proposed ensemble framework using yeast PINs and gene expression data. The results show that it can considerably improve the prediction accuracy of the five centrality measures individually. It can also remarkably increase the number of common predicted essential proteins among those predicted by each centrality measure individually and enable each centrality measure to find more low-degree essential proteins. Conclusions: This paper demonstrates that it is valuable to differentiate the contributions of different PPIs for identifying essential proteins based on network topological characteristics. The proposed ensemble framework is a successful paradigm to this end. C1 [Zhang, Xue; Wang, Xujing] NHLBI, Syst Biol Core, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Xiao, Wangxin] XiangNan Univ, Dept Comp Sci, Eastern Wangxian Pk, Chenzhou 423000, Hunan, Peoples R China. [Acencio, Marcio Luis; Lemke, Ney] UNESP Sao Paulo State Univ, Dept Phys & Biophys, Inst Biosci Botucatu, BR-18618970 Botucatu, SP, Brazil. [Acencio, Marcio Luis] Norwegian Univ Sci & Technol NTNU, Dept Canc Res & Mol Med, PB 8905, N-7491 Trondheim, Norway. RP Wang, XJ (reprint author), NHLBI, Syst Biol Core, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Xiao, WX (reprint author), XiangNan Univ, Dept Comp Sci, Eastern Wangxian Pk, Chenzhou 423000, Hunan, Peoples R China. EM xiaozhangdoctor@126.com; xujing.wang@nih.gov RI Acencio, Marcio/D-9264-2012 OI Acencio, Marcio/0000-0002-8278-240X FU Intramural Research Program of the NIH, NHLBI; National Natural Science Foundation of China [61402423, 51378243, 61502343] FX This work was partially supported by the Intramural Research Program of the NIH, NHLBI; the National Natural Science Foundation of China under Grants No.61402423, No.51378243, and No. 61502343. 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 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD AUG 25 PY 2016 VL 17 AR 322 DI 10.1186/s12859-016-1166-7 PG 17 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA DV3OJ UT WOS:000382831900001 ER PT J AU Freed, EO AF Freed, Eric O. TI Getting IN on Viral RNA Condensation and Virion Maturation SO CELL LA English DT Editorial Material ID HIV-1 INTEGRASE AB The retroviral enzyme integrase plays an essential role in the virus replication cycle by catalyzing the covalent insertion of newly synthesized viral DNA into the host cell chromosome early after infection. Now, Kessl et al. report a second function of integrase: binding to the viral RNA genome in virion particles late in the virus replication cycle to promote particle maturation. C1 [Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Dynam & Replicat Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Freed, EO (reprint author), NCI, Virus Cell Interact Sect, HIV Dynam & Replicat Program, Ctr Canc Res, Frederick, MD 21702 USA. EM efreed@nih.gov NR 10 TC 0 Z9 0 U1 10 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD AUG 25 PY 2016 VL 166 IS 5 BP 1082 EP 1083 DI 10.1016/j.cell.2016.08.013 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DU5NW UT WOS:000382259500008 PM 27565339 ER PT J AU Clever, D Roychoudhuri, R Constantinides, MG Askenase, MH Sukumar, M Klebanoff, CA Eil, RL Hickman, HD Yu, ZY Pan, JH Palmer, DC Phan, AT Goulding, J Gattinoni, L Goldrath, AW Belkaid, Y Restifo, NP AF Clever, David Roychoudhuri, Rahul Constantinides, Michael G. Askenase, Michael H. Sukumar, Madhusudhanan Klebanoff, Christopher A. Eil, Robert L. Hickman, Heather D. Yu, Zhiya Pan, Jenny H. Palmer, Douglas C. Phan, Anthony T. Goulding, John Gattinoni, Luca Goldrath, Ananda W. Belkaid, Yasmine Restifo, Nicholas P. TI Oxygen Sensing by T Cells Establishes an Immunologically Tolerant Metastatic Niche SO CELL LA English DT Article ID HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; TRANSCRIPTION FACTOR; RESPIRATORY-TRACT; DENDRITIC CELLS; REG-CELLS; PROLYL HYDROXYLATION; METABOLIC CHECKPOINT; EXPRESSION; DIFFERENTIATION; INFLAMMATION AB Cancer cells must evade immune responses at distant sites to establish metastases. The lung is a frequent site for metastasis. We hypothesized that lung-specific immunoregulatory mechanisms create an immunologically permissive environment for tumor colonization. We found that T-cell-intrinsic expression of the oxygen-sensing prolyl-hydroxylase (PHD) proteins is required to maintain local tolerance against innocuous antigens in the lung but powerfully licenses colonization by circulating tumor cells. PHD proteins limit pulmonary type helper (Th)-1 responses, promote CD4(+)-regulatory T (Treg) cell induction, and restrain CD8(+) T cell effector function. Tumor colonization is accompanied by PHD-protein-dependent induction of pulmonary Treg cells and suppression of IFN-g-dependent tumor clearance. T-cell-intrinsic deletion or pharmacological inhibition of PHD proteins limits tumor colonization of the lung and improves the efficacy of adoptive cell transfer immunotherapy. Collectively, PHD proteins function in T cells to coordinate distinct immunoregulatory programs within the lung that are permissive to cancer metastasis. C1 [Clever, David; Roychoudhuri, Rahul; Sukumar, Madhusudhanan; Klebanoff, Christopher A.; Eil, Robert L.; Yu, Zhiya; Pan, Jenny H.; Palmer, Douglas C.; Restifo, Nicholas P.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Clever, David] Ohio State Univ, Coll Med, Med Scientist Training Program, Columbus, OH 43210 USA. [Roychoudhuri, Rahul] Babraham Inst, Lab Lymphocyte Signaling & Dev, Cambridge CB22 3AT, England. [Constantinides, Michael G.; Askenase, Michael H.; Belkaid, Yasmine] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Belkaid, Yasmine] NIAID, NIAID Microbiome Program Initiat, 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. [Hickman, Heather D.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Phan, Anthony T.; Goulding, John; Goldrath, Ananda W.] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA. [Gattinoni, Luca] NCI, Expt Transplantat Immunol Branch, NIH, Bethesda, MD 20892 USA. [Restifo, Nicholas P.] NCI, Ctr Cell Based Therapy, NIH, Bethesda, MD 20892 USA. RP Clever, D; Restifo, NP (reprint author), NCI, Surg Branch, NIH, Bethesda, MD 20892 USA.; Clever, D (reprint author), Ohio State Univ, Coll Med, Med Scientist Training Program, Columbus, OH 43210 USA.; Restifo, NP (reprint author), NCI, Ctr Cell Based Therapy, NIH, Bethesda, MD 20892 USA. EM david.clever@osumc.edu; restifo@nih.gov RI Gattinoni, Luca/A-2281-2008; Roychoudhuri, Rahul/A-7442-2010 OI Gattinoni, Luca/0000-0003-2239-3282; Roychoudhuri, Rahul/0000-0002-5392-1853 FU NCI; NIAID; Wellcome Trust/Royal Society [105663/Z/14/Z]; UK Biotechnology and Biological Sciences Research Council [BB/N007794/1]; Cancer Research Institute FX This research was supported by the Intramural Research Programs of the NCI and NIAID and by charitable gifts from Li Jinyuan and the Tiens Charitable Foundation and the Milstein Family Foundation. R.R. was supported by the Wellcome Trust/Royal Society (grant 105663/Z/14/Z) and the UK Biotechnology and Biological Sciences Research Council (grant BB/N007794/1). M.G.C. is a Cancer Research Institute Irvington Fellow supported by the Cancer Research Institute. We thank G.H. Fong for providing Egln1-3fl/fl mice, D. Haines for pathologic analysis of H&E-stained tissues, R. Johnson, A. Palazon, and P. Tyrakis for technical advice. NR 50 TC 9 Z9 9 U1 27 U2 28 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD AUG 25 PY 2016 VL 166 IS 5 BP 1117 EP + DI 10.1016/j.cell.2016.07.032 PG 29 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DU5NW UT WOS:000382259500011 PM 27565342 ER PT J AU Ryan, JF Schnitzler, CE Tamm, SL AF Ryan, Joseph F. Schnitzler, Christine E. Tamm, Sidney L. TI Meeting report of Ctenopalooza: the first international meeting of ctenophorologists SO EVODEVO LA English DT Article DE Ctenophora; Ctenophore; Ctenopalooza ID MNEMIOPSIS-LEIDYI; CTENOPHORES; FERTILIZATION; INVASION; ANIMALS; SYSTEMS; SUCCESS; ORIGIN AB Here we present a report on Ctenopalooza: A meeting of ctenophorologists held at the Whitney Laboratory for Marine Bioscience in St. Augustine, FL, USA, on March 14-15, 2016. In this report, we provide a summary of each of the sessions that occurred during this two-day meeting, which touched on most of the relevant areas of ctenophore biology. The report includes some major themes regarding the future of ctenophore research that emerged during Ctenopalooza. More information can be found at the meeting Web site: http://ctenopalooza.whitney.ufl.edu. C1 [Ryan, Joseph F.; Schnitzler, Christine E.] Univ Florida, Whitney Lab Marine Biosci, St Augustine, FL 32080 USA. [Ryan, Joseph F.; Schnitzler, Christine E.] Univ Florida, Dept Biol, Gainesville, FL 32611 USA. [Schnitzler, Christine E.] NHGRI, NIH, Bethesda, MD 20892 USA. [Tamm, Sidney L.] Marine Biol Lab, Bell Ctr, Woods Hole, MA 02543 USA. RP Ryan, JF (reprint author), Univ Florida, Whitney Lab Marine Biosci, St Augustine, FL 32080 USA. EM joseph.ryan@whitney.ufl.edu FU National Science Foundation's Division of Integrative Organismal Systems [1619712]; University of Florida's Office of Research to Joseph Ryan [00075235]; Whitney Laboratory for Marine Bioscience FX Ctenopalooza was sponsored by a grant from the National Science Foundation's Division of Integrative Organismal Systems to Joseph Ryan (#1619712). We also acknowledge funding was provided by a grant from the University of Florida's Office of Research to Joseph Ryan (Project #00075235). Additional funding was provided by The Whitney Laboratory for Marine Bioscience. Student and Postdoc prizes were provided by Harvard University Press. EvoDevo generously waived open-access fees for this report. NR 41 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 2041-9139 J9 EVODEVO JI EvoDevo PD AUG 25 PY 2016 VL 7 AR 19 DI 10.1186/s13227-016-0057-3 PG 6 WC Evolutionary Biology; Developmental Biology SC Evolutionary Biology; Developmental Biology GA DU7ZV UT WOS:000382434000001 ER PT J AU Kumar, V Bonifazi, A Ellenberger, MP Keck, TM Pommier, E Rais, R Slusher, BS Gardner, E You, ZB Xi, ZX Newman, AH AF Kumar, Vivek Bonifazi, Alessandro Ellenberger, Michael P. Keck, Thomas M. Pommier, Elie Rais, Rana Slusher, Barbara S. Gardner, Eliot You, Zhi-Bing Xi, Zheng-Xiong Newman, Amy Hauck TI Highly Selective Dopamine D-3 Receptor (D3R) Antagonists and Partial Agonists Based on Eticlopride and the D3R Crystal Structure: New Leads for Opioid Dependence Treatment SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CONDITIONED PLACE PREFERENCE; FUNCTIONALIZED LINKING CHAINS; KNOCKOUT MICE; BEHAVIORAL SENSITIZATION; HIGH-AFFINITY; ADDICTION; COCAINE; RATS; DISCOVERY; POTENT AB The recent and precipitous increase in opioid analgesic abuse and overdose has inspired investigation of the dopamine D-3 receptor (D3R) as a target for therapeutic intervention. Metabolic instability or predicted toxicity has precluded successful translation of previously reported D3R-selective antagonists to clinical use for cocaine abuse. Herein, we report a series of novel and D3R crystal structure-guided 4-phenylpiperazines with exceptionally high D3R affinities and/or selectivities with varying efficacies. Lead compound 19 was selected based on its in vitro profile: D3R K-i= 6.84 nM, 1700-fold D3R versus D2R binding selectivity, and its metabolic stability in mouse microsomes. Compound 19 inhibited oxycodone-induced hyperlocomotion in mice and reduced oxycodone-induced locomotor sensitization. In addition, pretreatment with 19 also dose-dependently inhibited the acquisition of oxycodone-induced conditioned place preference (CPP) in rats. These findings support the D3R as a target for opioid dependence treatment and compound 19 as a new lead molecule for development. C1 [Kumar, Vivek; Bonifazi, Alessandro; Ellenberger, Michael P.; Keck, Thomas M.; Pommier, Elie; Gardner, Eliot; You, Zhi-Bing; Xi, Zheng-Xiong; Newman, Amy Hauck] NIDA, Mol Targets & Medicat Discovery Branch, Intramural Res Program, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. [Keck, Thomas M.] Rowan Univ, Coll Sci & Math, Dept Biomed & Translat Sci, Dept Chem & Biochem, 201 Mullica Hill Rd, Glassboro, NJ 08028 USA. [Pommier, Elie; Rais, Rana; Slusher, Barbara S.] Johns Hopkins Univ, Sch Med, Johns Hopkins Drug Discovery, Dept Neurol, 855 North Wolfe St, Baltimore, MD 21205 USA. 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 - Intramural Research Program; NIDA Addiction Treatment Discovery Program [ADA151001]; Oregon Health & Science University; Johns Hopkins Drug Discovery [P30MH075673] FX Support for this research was provided by the National Institute on Drug Abuse - Intramural Research Program, NIDA Addiction Treatment Discovery Program contract (ADA151001) with Oregon Health & Science University and Johns Hopkins Drug Discovery (P30MH075673 to BSS). We thank Dr. Anerbasha Shaik for help with the TOC Graphic. NR 56 TC 2 Z9 2 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 AUG 25 PY 2016 VL 59 IS 16 BP 7634 EP 7650 DI 10.1021/acs.jmedchem.6b00860 PG 17 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DU4JP UT WOS:000382179200020 PM 27508895 ER PT J AU Huynh, L Kusnadi, A Park, SH Murata, K Park-Min, KH Ivashkiv, LB AF Huynh, Linda Kusnadi, Anthony Park, Sung Ho Murata, Koichi Park-Min, Kyung-Hyun Ivashkiv, Lionel B. TI Opposing regulation of the late phase TNF response by mTORC1-IL-10 signaling and hypoxia in human macrophages SO SCIENTIFIC REPORTS LA English DT Article ID TUMOR-NECROSIS-FACTOR; INNATE IMMUNE-RESPONSES; RHEUMATOID-ARTHRITIS; GENE-EXPRESSION; LISTERIA-MONOCYTOGENES; METABOLIC CHECKPOINT; IL-10 PRODUCTION; CUTTING EDGE; I INTERFERON; MICE LACKING AB Tumor necrosis factor (TNF) is best known for inducing a rapid but transient NF-kappa B-mediated inflammatory response. We investigated later phases of TNF signaling, after the initial transient induction of inflammatory genes has subsided, in primary human macrophages. TNF signaling induced expression of late response genes, including inhibitors of NF-kappa B and TLR signaling, with delayed and sustained kinetics 6-24 hr after TNF stimulation. A subset of late phase genes was expressed in rheumatoid arthritis synovial macrophages, confirming their expression under chronic inflammatory conditions in vivo. Expression of a subset of late phase genes was mediated by autocrine IL-10, which activated STAT3 with delayed kinetics. Hypoxia, which occurs at sites of infection or inflammation where TNF is expressed, suppressed this IL-10-STAT3 autocrine loop and expression of late phase genes. TNF-induced expression of IL-10 and downstream genes was also dependent on signaling by mTORC1, which senses the metabolic state of cells and is modulated by hypoxia. These results reveal an mTORC1-dependent IL-10- mediated late phase response to TNF by primary human macrophages, and identify suppression of IL-10 responses as a new mechanism by which hypoxia can promote inflammation. Thus, hypoxic and metabolic pathways may modulate TNF responses during chronic inflammation. C1 [Huynh, Linda; Kusnadi, Anthony; Ivashkiv, Lionel B.] Weill Cornell Grad Sch Med Sci, Grad Program Immunol & Microbial Pathogenesis, 1300 York Ave, New York, NY 10021 USA. [Huynh, Linda; Kusnadi, Anthony; Park, Sung Ho; Murata, Koichi; Park-Min, Kyung-Hyun; Ivashkiv, Lionel B.] Hosp Special Surg, Arthrit & Tissue Degenerat Program, 535 East 70th St, New York, NY 10021 USA. [Huynh, Linda; Kusnadi, Anthony; Park, Sung Ho; Murata, Koichi; Park-Min, Kyung-Hyun; Ivashkiv, Lionel B.] Hosp Special Surg, David Z Rosensweig Genom Res Ctr, 535 East 70th St, New York, NY 10021 USA. [Huynh, Linda] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, 31 Ctr Dr,Bldg 31, Bethesda, MD 20892 USA. RP Ivashkiv, LB (reprint author), Weill Cornell Grad Sch Med Sci, Grad Program Immunol & Microbial Pathogenesis, 1300 York Ave, New York, NY 10021 USA.; Ivashkiv, LB (reprint author), Hosp Special Surg, Arthrit & Tissue Degenerat Program, 535 East 70th St, New York, NY 10021 USA.; Ivashkiv, LB (reprint author), Hosp Special Surg, David Z Rosensweig Genom Res Ctr, 535 East 70th St, New York, NY 10021 USA. EM ivashkivl@hss.edu FU NIH [T32 AI007621] FX We thank Carl Nathan and Amy Cunningham Bussel for access to tissue culture incubators in which oxygen tension can be regulated. We also thank Rachael Gordon for pilot experiments showing IL-10 production downstream of TNF signaling, and Galina Grigoriev and Angela Lee for processing samples from RA synovial fluids. We thank Laura Donlin for helpful discussions and critical reading of the manuscript. This work was supported by grants from the NIH (to L.B.I.). L.H. was supported by the NIH Grant T32 AI007621 (to the Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences). NR 68 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 2045-2322 J9 SCI REP-UK JI Sci Rep PD AUG 25 PY 2016 VL 6 AR 31959 DI 10.1038/srep31959 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DU0KI UT WOS:000381891900001 PM 27558590 ER PT J AU Kim, MK Caplen, N Chakka, S Hernandez, L House, C Pongas, G Jordan, E Annunziata, CM AF Kim, Marianne K. Caplen, Natasha Chakka, Sirisha Hernandez, Lidia House, Carrie Pongas, Georgios Jordan, Elizabeth Annunziata, Christina M. TI Identification of therapeutic targets applicable to clinical strategies in ovarian cancer SO BMC CANCER LA English DT Article DE Ovarian cancer; PLK1; MAP3K7/TAK1; WEE1 ID GYNECOLOGIC-ONCOLOGY-GROUP; CARCINOMA; CELLS; ACTIVATION; INHIBITOR; SURVIVAL; CD133 AB Background: shRNA-mediated lethality screening is a useful tool to identify essential targets in cancer biology. Ovarian cancer (OC) is extremely heterogeneous and most cases are advanced stages at diagnosis. OC has a high response rate initially, but becomes resistant to standard chemotherapy. We previously employed high throughput global shRNA sensitization screens to identify NF-kB related pathways. Here, we re-analyzed our previous shRNA screens in an unbiased manner to identify clinically applicable molecular targets. Methods: We proceeded with siRNA lethality screening using the top 55 genes in an expanded set of 6 OC cell lines. We investigated clinical relevance of candidate targets in The Cancer Genome Atlas OC dataset. To move these findings towards the clinic, we chose four pharmacological inhibitors to recapitulate the top siRNA effects: Oxozeaenol (for MAP3K7/TAK1), BI6727 (PLK1), MK1775 (WEE1), and Lapatinib (ERBB2). Cytotoxic effects were measured by cellular viability assay, as single agents and in 2-way combinations. Co-treatments were evaluated in either sequential or simultaneous exposure to drug for short term and extended periods to simulate different treatment strategies. Results: Loss-of-function shRNA screens followed by short-term siRNA validation screens identified therapeutic targets in OC cells. Candidate genes were dysregulated in a subset of TCGA OCs although the alterations of these genes showed no statistical significance to overall survival. Pharmacological inhibitors such as Oxozeaenol, BI6727, and MK1775 showed cytotoxic effects in OC cells regardless of cisplatin responsiveness, while all OC cells tested were cytostatic to Lapatinib. Co-treatment with BI6727 and MK1775 at sub-lethal concentrations was equally potent to BI6727 alone at lethal concentrations without cellular re-growth after the drugs were washed off, suggesting the co-inhibition at reduced dosages may be more efficacious than maximal single-agent cytotoxic concentrations. Conclusions: Loss-of-function screen followed by in vitro target validation using chemical inhibitors identified clinically relevant targets. This approach has the potential to systematically refine therapeutic strategies in OC. These molecular target-driven strategies may provide additional therapeutic options for women whose tumors have become refractory to standard chemotherapy. C1 [Kim, Marianne K.; Hernandez, Lidia; House, Carrie; Pongas, Georgios; Jordan, Elizabeth; Annunziata, Christina M.] NCI, Womens Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Caplen, Natasha; Chakka, Sirisha] NCI, Gene Silencing Sect, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Annunziata, Christina M.] Natl Canc Inst, Womens Malignancies Branch, Ctr Canc Res, 10 Ctr Dr,Room 4B54, Bethesda, MD 20892 USA. RP Annunziata, CM (reprint author), NCI, Womens Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA.; Annunziata, CM (reprint author), Natl Canc Inst, Womens Malignancies Branch, Ctr Canc Res, 10 Ctr Dr,Room 4B54, Bethesda, MD 20892 USA. EM annunzic@mail.nih.gov OI Annunziata, Christina/0000-0003-2033-6532 FU Foundation of Women's cancer-Amgen Ovarian Cancer Research Grant; Intramural Research Program of the National Cancer Institute FX This work was supported by the Foundation of Women's cancer-Amgen Ovarian Cancer Research Grant (MK) and the Intramural Research Program of the National Cancer Institute (CMA). NR 21 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 1471-2407 J9 BMC CANCER JI BMC Cancer PD AUG 24 PY 2016 VL 16 AR 678 DI 10.1186/s12885-016-2675-5 PG 13 WC Oncology SC Oncology GA DX2JR UT WOS:000384195500001 PM 27558154 ER PT J AU Antignani, A Griner, LM Guha, R Simon, N Pasetto, M Keller, J Huang, M Angelus, E Pastan, I Ferrer, M FitzGerald, DJ Thomas, CJ AF Antignani, Antonella Griner, Lesley Mathews Guha, Rajarshi Simon, Nathan Pasetto, Matteo Keller, Jonathan Huang, Manjie Angelus, Evan Pastan, Ira Ferrer, Marc FitzGerald, David J. Thomas, Craig J. TI Chemical Screens Identify Drugs that Enhance or Mitigate Cellular Responses to Antibody-Toxin Fusion Proteins SO PLOS ONE LA English DT Article ID PHASE-I TRIAL; IMMUNOTOXIN RFB4(DSFV)-PE38 BL22; ADP-RIBOSYLATING TOXINS; ANTIMESOTHELIN IMMUNOTOXIN; PSEUDOMONAS EXOTOXIN; CANCER-CELLS; CLINICAL-EXPERIENCE; BREAST-CANCER; SS1P; COMBINATION AB The intersection of small molecular weight drugs and antibody-based therapeutics is rarely studied in large scale. Both types of agents are currently part of the cancer armamentarium. However, very little is known about how to combine them in optimal ways. Immunotoxins are antibody-toxin gene fusion proteins engineered to target cancer cells via antibody binding to surface antigens. For fusion proteins derived from Pseudomonas exotoxin (PE), potency relies on the enzymatic domain of the toxin which catalyzes the ADP-ribosylation of EF2 causing inhibition of protein synthesis leading to cell death. Candidate immunotoxins have demonstrated clear value in clinical trials but generally have not been curative as single agents. Therefore we undertook three screens to discover effective combinations that could act synergistically. From the MIPE-3 library of compounds we identified various enhancers of immunotoxin action and at least one major class of inhibitor. Follow-up experiments confirmed the screening data and suggested that immunotoxins when administered with everolimus or nilotinib exhibit favorable combinatory activity and would be candidates for preclinical development. Mechanistic studies revealed that everolimus-immunotoxin combinations acted synergistically on elements of the protein synthetic machinery, including S61 kinase and 4E-BP1 of the mTORC1 pathway. Conversely, PARP inhibitors antagonized immunotoxins and also blocked the toxicity due to native ADP-ribosylating toxins. Thus, our goal of investigating a chemical library was justified based on the identification of several approved compounds that could be developed preclinically as 'enhancers' and at least one class of mitigator to be avoided. C1 [Antignani, Antonella; Simon, Nathan; Pasetto, Matteo; Huang, Manjie; Angelus, Evan; Pastan, Ira; FitzGerald, David J.] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. [Griner, Lesley Mathews; Guha, Rajarshi; Keller, Jonathan; Ferrer, Marc; Thomas, Craig J.] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Pasetto, Matteo] Univ Verona, Dept Pathol, Verona, Italy. RP FitzGerald, DJ (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA.; Thomas, CJ (reprint author), NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. EM fitzgerd@helix.nih.gov; craigt@mail.nih.gov FU National Cancer Institute; National Center for Advancing Translational Sciences FX This work was funded by the intramural programs of the National Cancer Institute and the National Center for Advancing Translational Sciences. There are no grant or award numbers as the funding is "in-house". NR 38 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 AUG 24 PY 2016 VL 11 IS 8 AR e0161415 DI 10.1371/journal.pone.0161415 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DU5NI UT WOS:000382258100040 PM 27556570 ER PT J AU Horne, HN Chung, CC Zhang, H Yu, K Prokunina-Olsson, L Michailidou, K Bolla, MK Wang, Q Dennis, J Hopper, JL Southey, MC Schmidt, MK Broeks, A Muir, K Lophatananon, A Fasching, PA Beckmann, MW Fletcher, O Johnson, N Sawyer, EJ Tomlinson, I Burwinkel, B Marme, F Guenel, P Truong, T Bojesen, SE Flyger, H Benitez, J Gonzalez-Neira, A Anton-Culver, H Neuhausen, SL Brenner, H Arndt, V Meindl, A Schmutzler, RK Brauch, H Hamann, U Nevanlinna, H Khan, S Matsuo, K Iwata, H Dork, T Bogdanova, NV Lindblom, A Margolin, S Mannermaa, A Kosma, VM Chenevix-Trench, G Wu, AH den Berg, DV Smeets, A Zhao, H Chang-Claude, J Rudolph, A Radice, P Barile, M Couch, FJ Vachon, C Giles, GG Milne, RL Haiman, CA Le Marchand, L Goldberg, MS Teo, SH Taib, NAM Kristensen, V Borresen-Dale, AL Zheng, W Shrubsole, M Winqvist, R Jukkola-Vuorinen, A Andrulis, IL Knight, JA Devilee, P Seynaeve, C Garcia-Closas, M Czene, K Darabi, H Hollestelle, A Martens, JWM Li, JM Lu, W Shu, XO Cox, A Cross, SS Blot, W Cai, QY Shah, M Luccarini, C Baynes, C Harrington, P Kang, D Choi, JY Hartman, M Chia, KS Kabisch, M Torres, D Jakubowska, A Lubinski, J Sangrajrang, S Brennan, P Slager, S Yannoukakos, D Shen, CY Hou, MF Swerdlow, A Orr, N Simard, J Hall, P Pharoah, PDP Easton, DF Chanock, SJ Dunning, AM Figueroa, JD AF Horne, Hisani N. Chung, Charles C. Zhang, Han Yu, Kai Prokunina-Olsson, Ludmila Michailidou, Kyriaki Bolla, Manjeet K. Wang, Qin Dennis, Joe Hopper, John L. Southey, Melissa C. Schmidt, Marjanka K. Broeks, Annegien Muir, Kenneth Lophatananon, Artitaya Fasching, Peter A. Beckmann, Matthias W. Fletcher, Olivia Johnson, Nichola Sawyer, Elinor J. Tomlinson, Ian Burwinkel, Barbara Marme, Frederik Guenel, Pascal Truong, Therese Bojesen, Stig E. Flyger, Henrik Benitez, Javier Gonzalez-Neira, Anna Anton-Culver, Hoda Neuhausen, Susan L. Brenner, Hermann Arndt, Volker Meindl, Alfons Schmutzler, Rita K. Brauch, Hiltrud Hamann, Ute Nevanlinna, Heli Khan, Sofia Matsuo, Keitaro Iwata, Hiroji Dork, Thilo Bogdanova, Natalia V. Lindblom, Annika Margolin, Sara Mannermaa, Arto Kosma, Veli-Matti Chenevix-Trench, Georgia Wu, Anna H. den Berg, David Ven Smeets, Ann Zhao, Hui Chang-Claude, Jenny Rudolph, Anja Radice, Paolo Barile, Monica Couch, Fergus J. Vachon, Celine Giles, Graham G. Milne, Roger L. Haiman, Christopher A. Le Marchand, Loic Goldberg, Mark S. Teo, Soo H. Taib, Nur A. M. Kristensen, Vessela Borresen-Dale, Anne-Lise Zheng, Wei Shrubsole, Martha Winqvist, Robert Jukkola-Vuorinen, Arja Andrulis, Irene L. Knight, Julia A. Devilee, Peter Seynaeve, Caroline Garcia-Closas, Montserrat Czene, Kamila Darabi, Hatef Hollestelle, Antoinette Martens, John W. M. Li, Jingmei Lu, Wei Shu, Xiao-Ou Cox, Angela Cross, Simon S. Blot, William Cai, Qiuyin Shah, Mitul Luccarini, Craig Baynes, Caroline Harrington, Patricia Kang, Daehee Choi, Ji-Yeob Hartman, Mikael Chia, Kee Seng Kabisch, Maria Torres, Diana Jakubowska, Anna Lubinski, Jan Sangrajrang, Suleeporn Brennan, Paul Slager, Susan Yannoukakos, Drakoulis Shen, Chen-Yang Hou, Ming-Feng Swerdlow, Anthony Orr, Nick Simard, Jacques Hall, Per Pharoah, Paul D. P. Easton, Douglas F. Chanock, Stephen J. Dunning, Alison M. Figueroa, Jonine D. CA kConFab AOCS Investigators TI Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; COMMON VARIANTS; CONFER SUSCEPTIBILITY; GENETIC-VARIATION; 14Q24.1 RAD51L1; RISK; HETEROGENEITY; ALLELES; DISEASE AB The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Perallelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10(-21)). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P <= 8.41 x 10(-5)). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive. C1 [Horne, Hisani N.; Chung, Charles C.; Zhang, Han; Yu, Kai; Prokunina-Olsson, Ludmila; Garcia-Closas, Montserrat; Chanock, Stephen J.; Figueroa, Jonine D.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Horne, Hisani N.] US FDA, Silver Spring, MD USA. [Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Pharoah, Paul D. P.; Easton, Douglas F.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England. [Hopper, John L.; Giles, Graham G.; Milne, Roger L.] Univ Melbourne, Ctr Epidemiol & Biostat, Sch Populat & Global Hlth, Melbourne, Vic, Australia. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Schmidt, Marjanka K.; Broeks, Annegien] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Muir, Kenneth; Lophatananon, Artitaya] Univ Warwick, Div Hlth Sci, Warwick Med Sch, Coventry, W Midlands, England. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Fasching, Peter A.; Beckmann, Matthias W.] Univ Erlangen Nurnberg, Dept Obstet & Gynaecol, Univ Hosp Erlangen, Comprehens Canc Ctr Erlangen EMN, Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Fletcher, Olivia; Johnson, Nichola; Orr, Nick] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London, England. [Fletcher, Olivia; Johnson, Nichola; Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, London, England. [Sawyer, Elinor J.] Kings Coll London, Res Oncol, Guys Hosp, London, England. [Tomlinson, Ian] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Tomlinson, Ian] Univ Oxford, Oxford Biomed Res Ctr, Oxford, England. [Burwinkel, Barbara; Marme, Frederik] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany. [Marme, Frederik] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany. [Guenel, Pascal; Truong, Therese] INSERM, Environm Epidemiol Canc, Ctr Res Epidemiol & Populat Hlth, Villejuif, France. [Guenel, Pascal; Truong, Therese] Univ Paris 11, Villejuif, France. [Bojesen, Stig E.] Copenhagen Univ Hosp, Copenhagen Gen Populat Study, Herlev Hosp, Herlev, Denmark. [Bojesen, Stig E.] Copenhagen Univ Hosp, Dept Clin Biochem, Herlev Hosp, Herlev, Denmark. [Bojesen, Stig E.] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. [Flyger, Henrik] Copenhagen Univ Hosp, Dept Breast Surg, Herlev Hosp, Herlev, Denmark. [Benitez, Javier; Gonzalez-Neira, Anna] Spanish Natl Canc Res Ctr, Human Canc Genet Program, Madrid, Spain. [Benitez, Javier] Ctr Invest Red Enfermedades Raras, Valencia, Spain. [Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Neuhausen, Susan L.] Beckman Res Inst City Hope, Duarte, CA USA. [Brenner, Hermann; Arndt, Volker] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Brenner, Hermann; Brauch, Hiltrud] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Meindl, Alfons] Tech Univ Munich, Div Gynaecol & Obstet, Munich, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Dept Obstet & Gynaecol, Div Mol Gynecooncol, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Integrated Oncol, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Ctr Mol Med, Cologne, Germany. [Brauch, Hiltrud] Dr Margarete Fischer Bosch Institute Clin Pharmac, Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, Tubingen, Germany. [Hamann, Ute; Kabisch, Maria; Torres, Diana] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany. [Nevanlinna, Heli; Khan, Sofia] Univ Helsinki, Helsinki Univ Hosp, Dept Obstet & Gynecol, Helsinki, Finland. [Matsuo, Keitaro] Kyushu Univ, Dept Prevent Med, Fac Med Sci, Fukuoka, Japan. [Iwata, Hiroji] Aichi Canc Ctr Hosp, Dept Breast Oncol, Nagoya, Aichi, Japan. [Dork, Thilo] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. [Bogdanova, Natalia V.] Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Margolin, Sara] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Mannermaa, Arto; Kosma, Veli-Matti] Kuopio Univ Hosp, Ctr Canc, Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti] Kuopio Univ Hosp, Imaging Ctr, Dept Clin Pathol, Kuopio, Finland. [Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld, Australia. [kConFab AOCS Investigators] Univ Melbourne, Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Wu, Anna H.; den Berg, David Ven; Haiman, Christopher A.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Smeets, Ann] Univ Hosp Gashuisberg, Leuven, Belgium. [Zhao, Hui] Vesalius Res Ctr, Leuven, Belgium. [Zhao, Hui] Univ Leuven, Lab Translat Genet, Dept Oncol, Leuven, Belgium. [Chang-Claude, Jenny; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Chang-Claude, Jenny] Univ Med Ctr Hamburg Eppendorf, UCCH, Hamburg, Germany. [Radice, Paolo] Ist Nazl Tumori, Unit Mol Bases Genet Risk & Genet Testing, Dept Prevent & Predict Med, Fdn IRCCS Ist Ricovero & Cura Carattere Sci, Milan, Italy. [Barile, Monica] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Vachon, Celine; Slager, Susan] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Giles, Graham G.; Milne, Roger L.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Goldberg, Mark S.] McGill Univ, Dept Med, Montreal, PQ, Canada. [Goldberg, Mark S.] McGill Univ, Div Clin Epidemiol, Royal Victoria Hosp, Montreal, PQ, Canada. [Teo, Soo H.] Canc Res Initiat Fdn, Subang Jaya, Selangor, Malaysia. [Teo, Soo H.; Taib, Nur A. M.] Univ Malaya, Med Ctr, Breast Canc Res Unit, Canc Res Inst, Kuala Lumpur, Malaysia. [Kristensen, Vessela; Borresen-Dale, Anne-Lise] Oslo Univ Hosp, Dept Genet, Inst Canc Res, Radiumhosp, Oslo, Norway. [Kristensen, Vessela; Borresen-Dale, Anne-Lise] Univ Oslo, Inst Clin Med, Fac Med, Oslo, Norway. [Kristensen, Vessela] Univ Oslo, Oslo Univ Hosp, Dept Clin Mol Biol, Oslo, Norway. [Zheng, Wei; Shrubsole, Martha; Shu, Xiao-Ou; Blot, William; Cai, Qiuyin] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37212 USA. [Winqvist, Robert] Univ Oulu, Lab Canc Genet & Tumor Biol, Dept Clin Chem, Oulu, Finland. [Winqvist, Robert] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Winqvist, Robert] Northern Finland Lab Ctr NordLab, Lab Canc Genet & Tumor Biol, Oulu, Finland. [Jukkola-Vuorinen, Arja] Univ Oulu, Dept Oncol, Oulu Univ Hosp, Oulu, Finland. [Andrulis, Irene L.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Knight, Julia A.] Mt Sinai Hosp, Prosserman Ctr Hlth Res, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [Knight, Julia A.] Univ Toronto, Div Epidemiol, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Seynaeve, Caroline; Hollestelle, Antoinette; Martens, John W. M.] Erasmus MC Canc Inst, Dept Med Oncol, Family Canc Clin, Rotterdam, Netherlands. [Garcia-Closas, Montserrat; Swerdlow, Anthony] Inst Canc Res, Div Genet & Epidemiol, London, England. [Czene, Kamila; Darabi, Hatef; Li, Jingmei; Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Lu, Wei] Shanghai Ctr Dis Control & Prevent, Shanghai, Peoples R China. [Cox, Angela] Univ Sheffield, Sheffield Canc Res, Dept Oncol, Sheffield, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Acad Unit Pathol, Dept Neurosci, Sheffield, S Yorkshire, England. [Blot, William] Int Epidemiol Inst, Rockville, MD USA. [Shah, Mitul; Luccarini, Craig; Baynes, Caroline; Harrington, Patricia; Pharoah, Paul D. P.; Easton, Douglas F.; Dunning, Alison M.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England. [Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Kang, Daehee; Choi, Ji-Yeob] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea. [Kang, Daehee; Choi, Ji-Yeob] Seoul Natl Univ, Canc Res Inst, Seoul, South Korea. [Hartman, Mikael; Chia, Kee Seng] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. [Hartman, Mikael] Natl Univ Hlth Syst, Dept Surg, Singapore, Singapore. [Torres, Diana] Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia. [Jakubowska, Anna; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Sangrajrang, Suleeporn] Natl Canc Inst, Bangkok, Thailand. [Brennan, Paul] Int Agcy Res Canc, Lyon, France. [Yannoukakos, Drakoulis] Natl Ctr Sci Res Demokritos, Mol Diagnost Lab, IRRP, Athens, Greece. [Shen, Chen-Yang] China Med Univ, Sch Publ Hlth, Taichung, Taiwan. [Shen, Chen-Yang] Acad Sinica, Taiwan Biobank, Inst Biomed Sci, Taipei, Taiwan. [Hou, Ming-Feng] Kaohsiung Med Univ, Ctr Canc, Chung Ho Mem Hosp, Kaohsiung, Taiwan. [Hou, Ming-Feng] Kaohsiung Med Univ, Dept Surg, Chung Ho Mem Hosp, Kaohsiung, Taiwan. [Simard, Jacques] Univ Laval, Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ, Canada. [Figueroa, Jonine D.] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland. [Figueroa, Jonine D.] Univ Edinburgh, Edinburgh Canc Res UK Ctr, Edinburgh, Midlothian, Scotland. RP Figueroa, JD (reprint author), NCI, Div Canc Epidemiol & Genet, Rockville, MD USA.; Figueroa, JD (reprint author), Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland.; Figueroa, JD (reprint author), Univ Edinburgh, Edinburgh Canc Res UK Ctr, Edinburgh, Midlothian, Scotland. EM jonine.figueroa@ed.ac.uk RI Knight, Julia/A-6843-2012; Zheng, Wei/O-3351-2013; Dork, Thilo/J-8620-2012; Zhang, Han/K-2118-2016; Li, Jingmei/I-2904-2012; Brenner, Hermann/B-4627-2017; OI Zheng, Wei/0000-0003-1226-070X; Zhang, Han/0000-0001-7977-9616; Li, Jingmei/0000-0001-8587-7511; Brenner, Hermann/0000-0002-6129-1572; Khan, Sofia/0000-0003-4185-8882; Matsuo, Keitaro/0000-0003-1761-6314; Yannoukakos, Drakoulis/0000-0001-7509-3510; Dunning, Alison Margaret/0000-0001-6651-7166 FU Cancer Research UK [10124]; NCI NIH HHS [R01 CA176785] NR 43 TC 1 Z9 1 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 AUG 24 PY 2016 VL 11 IS 8 AR e0160316 DI 10.1371/journal.pone.0160316 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DU5NI UT WOS:000382258100011 PM 27556229 ER PT J AU Tunstall, BJ Carmack, SA AF Tunstall, Brendan J. Carmack, Stephanie A. TI Social Stress-Induced Alterations in CRF Signaling in the VTA Facilitate the Emergence of Addiction-like Behavior SO JOURNAL OF NEUROSCIENCE LA English DT Editorial Material ID CORTICOTROPIN-RELEASING-FACTOR; VENTRAL TEGMENTAL AREA; COCAINE SEEKING; BINDING-PROTEIN; INDUCED RELAPSE; FACTOR NEURONS; DOPAMINE; RATS; VASOPRESSIN; RECEPTORS C1 [Tunstall, Brendan J.; Carmack, Stephanie A.] NIDA, NIH, Baltimore, MD 21224 USA. RP Tunstall, BJ (reprint author), NIDA, Intramural Res Program, 251 Bayview Blvd,BRC 08A406-17, Baltimore, MD 21224 USA. EM brendan.tunstall@nih.gov NR 29 TC 0 Z9 0 U1 3 U2 3 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 AUG 24 PY 2016 VL 36 IS 34 BP 8780 EP 8782 DI 10.1523/JNEUROSCI.1815-16.2016 PG 3 WC Neurosciences SC Neurosciences & Neurology GA DW9SW UT WOS:000384004000002 PM 27559161 ER PT J AU Henriksen, S Read, JCA Cumming, BG AF Henriksen, Sid Read, Jenny C. A. Cumming, Bruce G. TI Neurons in Striate Cortex Signal Disparity in Half-Matched Random-Dot Stereograms SO JOURNAL OF NEUROSCIENCE LA English DT Article DE binocular; correspondence problem; disparity; half-matched; random dot stereogram; stereopsis ID STEREOSCOPIC DEPTH-PERCEPTION; SINGLE-NEURON; V1 NEURONS; HORIZONTAL-DISPARITY; BINOCULAR DISPARITY; VISUAL-CORTEX; AWAKE MONKEYS; ENERGY-MODEL; RESPONSES; MACAQUE AB Human stereopsis can operate in dense "cyclopean" images containing no monocular objects. This is believed to depend on the computation of binocular correlation by neurons in primary visual cortex (V1). The observation that humans perceive depth in half-matched random-dot stereograms, although these stimuli have no net correlation, has led to the proposition that human depth perception in these stimuli depends on a distinct "matching" computation possibly performed in extrastriate cortex. However, recording from disparity-selective neurons in V1 of fixating monkeys, we found that they are in fact able to signal disparity in half-matched stimuli. We present a simple model that explains these results. This reinstates the view that disparity-selective neurons in V1 provide the initial substrate for perception in dense cyclopean stimuli, and strongly suggests that separate correlation and matching computations are not necessary to explain existing data on mixed correlation stereograms. C1 [Henriksen, Sid; Read, Jenny C. A.] Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Henriksen, Sid; Cumming, Bruce G.] NEI, Lab Sensorimotor Res, NIH, Bethesda, MD 20892 USA. RP Henriksen, S (reprint author), NIH, 49 Convent Dr, Bethesda, MD 20892 USA. EM sid.henriksen@gmail.com OI Read, Jenny/0000-0002-9029-5185 FU Wellcome Trust/National Institutes of Health joint PhD Studentship [100931/Z/13/Z]; Intramural Research Program at the National Eye Institute/National Institutes of Health FX This work was supported by a Wellcome Trust/National Institutes of Health joint PhD Studentship (100931/Z/13/Z) to S.H., and by the Intramural Research Program at the National Eye Institute/National Institutes of Health to B.G.C. NR 37 TC 0 Z9 0 U1 1 U2 1 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 AUG 24 PY 2016 VL 36 IS 34 BP 8967 EP 8976 DI 10.1523/JNEUROSCI.0642-16.2016 PG 10 WC Neurosciences SC Neurosciences & Neurology GA DW9SW UT WOS:000384004000018 PM 27559177 ER PT J AU Serra-Musach, J Mateo, F Capdevila-Busquets, E de Garibay, GR Zhang, XH Guha, R Thomas, CJ Grueso, J Villanueva, A Jaeger, S Heyn, H Vizoso, M Perez, H Cordero, A Gonzalez-Suarez, E Esteller, M Moreno-Bueno, G Tjarnberg, A Lazaro, C Serra, V Arribas, J Benson, M Gustafsson, M Ferrer, M Aloy, P Pujana, MA AF Serra-Musach, Jordi Mateo, Francesca Capdevila-Busquets, Eva de Garibay, Gorka Ruiz Zhang, Xiaohu Guha, Raj Thomas, Craig J. Grueso, Judit Villanueva, Alberto Jaeger, Samira Heyn, Holger Vizoso, Miguel Perez, Hector Cordero, Alex Gonzalez-Suarez, Eva Esteller, Manel Moreno-Bueno, Gema Tjaernberg, Andreas Lazaro, Conxi Serra, Violeta Arribas, Joaquin Benson, Mikael Gustafsson, Mika Ferrer, Marc Aloy, Patrick Pujana, Miquel Angel TI Cancer network activity associated with therapeutic response and synergism SO GENOME MEDICINE LA English DT Article DE Cancer; Network; Therapy; Synergy ID PROTEIN-INTERACTION NETWORKS; BREAST-CANCER; DRUG-RESISTANCE; SIGNALING ENTROPY; SYSTEMS BIOLOGY; CELLS; COMBINATION; SENSITIVITY; ROBUSTNESS; EXPRESSION AB Background: Cancer patients often show no or only modest benefit from a given therapy. This major problem in oncology is generally attributed to the lack of specific predictive biomarkers, yet a global measure of cancer cell activity may support a comprehensive mechanistic understanding of therapy efficacy. We reasoned that network analysis of omic data could help to achieve this goal. Methods: A measure of "cancer network activity" (CNA) was implemented based on a previously defined network feature of communicability. The network nodes and edges corresponded to human proteins and experimentally identified interactions, respectively. The edges were weighted proportionally to the expression of the genes encoding for the corresponding proteins and relative to the number of direct interactors. The gene expression data corresponded to the basal conditions of 595 human cancer cell lines. Therapeutic responses corresponded to the impairment of cell viability measured by the half maximal inhibitory concentration (IC50) of 130 drugs approved or under clinical development. Gene ontology, signaling pathway, and transcription factor-binding annotations were taken from public repositories. Predicted synergies were assessed by determining the viability of four breast cancer cell lines and by applying two different analytical methods. Results: The effects of drug classes were associated with CNAs formed by different cell lines. CNAs also differentiate target families and effector pathways. Proteins that occupy a central position in the network largely contribute to CNA. Known key cancer-associated biological processes, signaling pathways, and master regulators also contribute to CNA. Moreover, the major cancer drivers frequently mediate CNA and therapeutic differences. Cell-based assays centered on these differences and using uncorrelated drug effects reveals novel synergistic combinations for the treatment of breast cancer dependent on PI3K-mTOR signaling. Conclusions: Cancer therapeutic responses can be predicted on the basis of a systems-level analysis of molecular interactions and gene expression. Fundamental cancer processes, pathways, and drivers contribute to this feature, which can also be exploited to predict precise synergistic drug combinations. C1 [Zhang, Xiaohu; Guha, Raj; Thomas, Craig J.; Ferrer, Marc] NIH, NCATS, Div Preclin Innovat, 9800 Med Ctr Dr Rockville, Bethesda, MD 20850 USA. [Capdevila-Busquets, Eva; Jaeger, Samira; Aloy, Patrick] Barcelona Inst Sci & Technol, IRB Barcelona, Joint IRB BSC CRG Program Computat Biol, Baldiri Reixac 10, Barcelona 08028, Catalonia, Spain. [Serra-Musach, Jordi; Mateo, Francesca; de Garibay, Gorka Ruiz; Villanueva, Alberto; Pujana, Miquel Angel] Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Program Canc Therapeut Resistance ProCURE, Breast Canc & Syst Biol Lab, Gran Via 199,Lhosp Llobregat, Barcelona 08908, Catalonia, Spain. [Grueso, Judit; Serra, Violeta] VHIO, Cellex Ctr, Expt Therapeut Grp, Natzaret 115-117, Barcelona 08035, Catalonia, Spain. [Heyn, Holger; Vizoso, Miguel; Perez, Hector; Cordero, Alex; Gonzalez-Suarez, Eva; Esteller, Manel] IDIBELL, Cancer Epigenet & Biol Program PEBC, Gran Via 199, Barcelona 08908, Catalonia, Spain. [Esteller, Manel] Univ Barcelona, Sch Med, Dept Physiol Sci 2, Feixa Llarga S-N, Barcelona 08908, Catalonia, Spain. [Esteller, Manel] Univ Barcelona, Sch Med, Dept Physiol Sci 2, Feixa Llarga S-N, Barcelona 08010, Catalonia, Spain. [Esteller, Manel; Arribas, Joaquin; Aloy, Patrick] ICREA, Passeig Lluis Companys 23, Barcelona 08010, Catalonia, Spain. [Moreno-Bueno, Gema] Autonomous Univ Madrid, Biomed Res Inst Alberto Sols, Spanish Natl Res Council CSIC, Hosp La Paz Inst Hlth Res IdiPAZ,Dept Biochem, Arzobispo Morcillo 4, E-28029 Madrid, Spain. [Moreno-Bueno, Gema] MD Anderson Int Fdn, Arturo Soria 270, Madrid 28033, Spain. [Tjaernberg, Andreas; Benson, Mikael; Gustafsson, Mika] Linkoping Univ, Ctr Individualized Med, Dept Clin & Expt Med, S-58183 Linkoping, Sweden. [Lazaro, Conxi] IDIBELL, ICO, Hereditary Canc Program, Gran Via 199, Barcelona 08908, Catalonia, Spain. [Arribas, Joaquin] VHIO, Cellex Ctr, Preclin Res Program, Natzaret 115-117, Barcelona 08035, Catalonia, Spain. [Arribas, Joaquin] Autonomous Univ Barcelona, Med Sch Bldg M, Dept Biochem & Mol Biol, Bellaterra 08193, Catalonia, Spain. RP Ferrer, M (reprint author), NIH, NCATS, Div Preclin Innovat, 9800 Med Ctr Dr Rockville, Bethesda, MD 20850 USA.; Aloy, P (reprint author), Barcelona Inst Sci & Technol, IRB Barcelona, Joint IRB BSC CRG Program Computat Biol, Baldiri Reixac 10, Barcelona 08028, Catalonia, Spain.; Pujana, MA (reprint author), Bellvitge Inst Biomed Res IDIBELL, Catalan Inst Oncol ICO, Program Canc Therapeut Resistance ProCURE, Breast Canc & Syst Biol Lab, Gran Via 199,Lhosp Llobregat, Barcelona 08908, Catalonia, Spain.; Aloy, P (reprint author), ICREA, Passeig Lluis Companys 23, Barcelona 08010, Catalonia, Spain. EM marc.ferrer@nih.gov; paloy@irbbarcelona.org; mapujana@iconcologia.net RI Moreno-Bueno, Gema/K-9354-2016; Mateo, Francesca/K-7746-2015; OI Moreno-Bueno, Gema/0000-0002-5030-6687; Mateo, Francesca/0000-0002-2342-7010; Heyn, Holger/0000-0002-3276-1889 FU Generalitat de Catalunya AGAUR SGR [364]; Spanish Ministry of Health ISCIII [PI12/01528, PI15/00854, RTICC RD12/0036/0007, 0008]; Spanish Ministry of Science and Innovation "Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa" [PIE13/00022-ONCOPROFILE]; Telemaraton "Todos Somos Raros, Todos Somos Unicos" [P35] FX This study was supported by Generalitat de Catalunya AGAUR SGR 2014 grant 364, Spanish Ministry of Health ISCIII grants PI12/01528, PI15/00854, RTICC RD12/0036/0007 and 0008, and PIE13/00022-ONCOPROFILE, Spanish Ministry of Science and Innovation "Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa", and the Telemaraton 2014 "Todos Somos Raros, Todos Somos Unicos" grant P35. NR 59 TC 1 Z9 1 U1 7 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-994X J9 GENOME MED JI Genome Med. PD AUG 24 PY 2016 VL 8 AR 88 DI 10.1186/s13073-016-0340-x PG 12 WC Genetics & Heredity SC Genetics & Heredity GA DU8HR UT WOS:000382454400002 PM 27553366 ER PT J AU Francis, WR Christianson, LM Powers, ML Schnitzler, CE Haddock, SHD AF Francis, Warren R. Christianson, Lynne M. Powers, Meghan L. Schnitzler, Christine E. Haddock, Steven H. D. TI Non-excitable fluorescent protein orthologs found in ctenophores SO BMC EVOLUTIONARY BIOLOGY LA English DT Article DE Fluorescent protein; Ctenophore; Siphonophore; Transcriptome; Fluorescence; Haeckelia ID GFP-LIKE PROTEINS; GENOMIC ORGANIZATION; EVOLUTION; AEQUOREA; CORAL; SEA; BIOLUMINESCENCE; EXPRESSION; VERSION; FAMILY AB Background: Fluorescent proteins are optically active proteins found across many clades in metazoans. A fluorescent protein was recently identified in a ctenophore, but this has been suggested to derive from a cnidarian, raising again the question of origins of this group of proteins. Results: Through analysis of transcriptome data from 30 ctenophores, we identified a member of an orthologous group of proteins similar to fluorescent proteins in each of them, as well as in the genome of Mnemiopsis leidyi. These orthologs lack canonical residues involved in chromophore formation, suggesting another function. Conclusions: The phylogenetic position of the ctenophore protein family among fluorescent proteins suggests that this gene was present in the common ancestor of all ctenophores and that the fluorescent protein previously found in a ctenophore actually derives from a siphonophore. C1 [Francis, Warren R.; Christianson, Lynne M.; Powers, Meghan L.; Haddock, Steven H. D.] Monterey Bay Aquarium Res Inst, 7700 Sandholdt Rd, Moss Landing, CA 95039 USA. [Schnitzler, Christine E.] NHGRI, NIH, 50 South Dr, Bethesda, MD 20892 USA. [Francis, Warren R.] Univ Munich, Munich, Germany. [Schnitzler, Christine E.] Univ Florida, Whitney Lab Marine Biosci, St Augustine, FL 32080 USA. RP Haddock, SHD (reprint author), Monterey Bay Aquarium Res Inst, 7700 Sandholdt Rd, Moss Landing, CA 95039 USA. EM haddock@mbari.org FU David and Lucile Packard Foundation; National Institute of General Medical Sciences at the National Institutes of Health [NIGMS:5-R01-GM087198]; Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health FX This work was supported by the David and Lucile Packard Foundation and funded by the National Institute of General Medical Sciences at the National Institutes of Health (NIGMS:5-R01-GM087198) to SHDH. This work was also supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health to CES. NR 49 TC 0 Z9 0 U1 14 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2148 J9 BMC EVOL BIOL JI BMC Evol. Biol. PD AUG 24 PY 2016 VL 16 AR 167 DI 10.1186/s12862-016-0738-5 PG 8 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA DT9JG UT WOS:000381814600002 PM 27557948 ER PT J AU Liu, JF Huang, SG Su, XZ Song, JP Lu, FL AF Liu, Jinfeng Huang, Shiguang Su, Xin-zhuan Song, Jianping Lu, Fangli TI Blockage of Galectin-receptor Interactions by alpha-lactose Exacerbates Plasmodium berghei-induced Pulmonary Immunopathology SO SCIENTIFIC REPORTS LA English DT Article ID PROTEIN DISULFIDE-ISOMERASE; ENTERICA SEROVAR TYPHIMURIUM; REGULATORY T-CELLS; ACUTE LUNG INJURY; MALARIA INFECTIONS; CEREBRAL MALARIA; MACROPHAGES; INFLAMMATION; TIM-3; INTERFERONS AB Malaria-associated acute lung injury (ALI) is a frequent complication of severe malaria that is often caused by "excessive" immune responses. To better understand the mechanism of ALI in malaria infection, here we investigated the roles of galectin (Gal)-1, 3, 8, 9 and the receptors of Gal-9 (Tim-3, CD44, CD137, and PDI) in malaria-induced ALI. We injected alpha (alpha)-lactose into mice-infected with Plasmodium berghei ANKA (PbANKA) to block galectins and found significantly elevated total proteins in bronchoalveolar lavage fluid, higher parasitemia and tissue parasite burden, and increased numbers of CD68(+) alveolar macrophages as well as apoptotic cells in the lungs after blockage. Additionally, mRNA levels of Gal-9, Tim-3, CD44, CD137, and PDI were significantly increased in the lungs at day 5 after infection, and the levels of CD137, IFN-alpha, IFN-beta, IFN-gamma, IL-4, and IL-10 in the lungs were also increased after alpha-lactose treatment. Similarly, the levels of Gal-9, Tim-3, IFN-alpha, IFN-beta, IFN-gamma, and IL-10 were all significantly increased in murine peritoneal macrophages co-cultured with PbANKA-infected red blood cells in vitro; but only IFN-alpha and IFN-beta were significantly increased after alpha-lactose treatment. Our data indicate that Gal-9 interaction with its multiple receptors play an important role in murine malaria-associated ALI. C1 [Liu, Jinfeng; Lu, Fangli] Sun Yat Sen Univ, Zhongshan Sch Med, Dept Parasitol, Guangzhou 510080, Guangdong, Peoples R China. [Liu, Jinfeng; Lu, Fangli] Sun Yat Sen Univ, Minist Educ, Key Lab Trop Dis Control, Guangzhou 510080, Guangdong, Peoples R China. [Huang, Shiguang] Jinan Univ, Sch Med, Guangzhou 510632, Guangdong, Peoples R China. [Su, Xin-zhuan] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Su, Xin-zhuan] Xiamen Univ, Sch Life Sci, Innovat Ctr Cell Signaling Network, State Key Lab Cellular Stress Biol, Xiamen 361005, Fujian, Peoples R China. [Song, Jianping] Guangzhou Univ Chinese Med, Inst Sci & Technol, 436 Chentai Rd, Guangzhou 510445, Guangdong, Peoples R China. RP Lu, FL (reprint author), Sun Yat Sen Univ, Zhongshan Sch Med, Dept Parasitol, Guangzhou 510080, Guangdong, Peoples R China.; Lu, FL (reprint author), Sun Yat Sen Univ, Minist Educ, Key Lab Trop Dis Control, Guangzhou 510080, Guangdong, Peoples R China.; Su, XZ (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA.; Su, XZ (reprint author), Xiamen Univ, Sch Life Sci, Innovat Ctr Cell Signaling Network, State Key Lab Cellular Stress Biol, Xiamen 361005, Fujian, Peoples R China. EM xsu@niaid.nih.gov; fanglilu@yahoo.com FU Natural Science Foundation of China [81271854, 81471973, 81273643]; Science and Technology Planning Project of Guangdong Province, China [2014A020212108, 2013B021800043, 2014A020212212, 2014B050502013]; Project 111 of the State Bureau of Foreign Experts and Ministry of Education of China [B06016]; Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, National Institutes of Health; Natural Science Foundation of Guangdong Province, China [S2013010016736] FX Research reported in this publication was supported in part by the Natural Science Foundation of China (Nos 81271854 and 81471973), the Science and Technology Planning Project of Guangdong Province, China (No. 2014A020212108), and the Project 111 of the State Bureau of Foreign Experts and Ministry of Education of China (B06016) (F. Lu); by the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, National Institutes of Health (X.-z. Su); by the Science and Technology Planning Project of Guangdong Province, China (Nos 2013B021800043 and 2014A020212212) (S. Huang); by the Natural Science Foundation of China (No. 81273643); the Natural Science Foundation of Guangdong Province, China (No. S2013010016736), and the Science and Technology Planning Project of Guangdong Province, China (No. 2014B050502013) (J. Song). The authors thank Cindy Clark, NIH Library Writing Center, for manuscript editing assistance. NR 59 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 AUG 24 PY 2016 VL 6 AR 32024 DI 10.1038/srep32024 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT9WM UT WOS:000381853000002 PM 27554340 ER PT J AU Hsu, DC Ma, YF Hur, S Li, D Rupert, A Scherzer, R Kalapus, SC Deeks, S Sereti, I Hsue, PY AF Hsu, Denise C. Ma, Yi Fei Hur, Sophia Li, Danny Rupert, Adam Scherzer, Rebecca Kalapus, S. C. Deeks, Steven Sereti, Irini Hsue, Priscilla Y. TI Plasma IL-6 levels are independently associated with atherosclerosis and mortality in HIV-infected individuals on suppressive antiretroviral therapy SO AIDS LA English DT Article DE atherosclerosis; CCR5; HIV; IL-6; immune activation ID INTIMA-MEDIA THICKNESS; CORONARY-HEART-DISEASE; T-CELL-ACTIVATION; SUBCLINICAL VASCULAR-DISEASE; CARDIOVASCULAR RISK-FACTORS; CAROTID ATHEROSCLEROSIS; MYOCARDIAL-INFARCTION; RHEUMATOID-ARTHRITIS; INFLAMMATORY MARKERS; MONOCYTE-ACTIVATION AB Objective: To determine the associations of markers of immune activation with atherosclerosis and mortality, in participants with treated and suppressed HIV infection. Design: Observational study of 149 HIV-infected participants with virologic suppression on antiretroviral therapy. Methods: Cryopreserved mononuclear cells and plasma were used to evaluate markers of T cell and monocyte activation, inflammation and coagulopathy. Carotid artery intima-media thickness (CIMT) was measured by high-resolution ultrasound at the common, bifurcation and internal carotid regions. Associations of immunologic markers with CIMT and all-cause mortality were assessed using multivariable linear regression and Cox proportional hazards regression. Results: The majority of participants were men (93%) and white (67%), median age of 48.5 years and median CD4(+) T-cell count of 522 cells/mu l. The median baseline IMT was 1.0 mm. Over a median of 8.3-year follow-up, 12 deaths occurred. In multivariate analysis, adjusted for traditional cardiovascular risk factors, higher monocyte C-C motif chemokine receptor 5 (CCR5) expression [5.4%, P = 0.001] was associated with greater common CIMT. Higher plasma IL-6 was associated with greater bifurcation [8.0%, P = 0.007] and overall mean IMT [5.2%, P = 0.026]. Finally, higher plasma IL-6 [hazard ratio 1.9, P = 0.030], internal carotid [hazard ratio 4.1, P = 0.022] and mean IMT [hazard ratio 5.2, P = 0.026] were individually associated with all-cause mortality. Conclusion: Higher monocyte CCR5 expression and plasma IL-6 were associated with atherosclerosis, independent of traditional cardiovascular risk factors. IL-6 and CIMT were individually associated with all-cause mortality. The impact of therapies targeting immune activation in cardiovascular disease in treated HIV infection merits additional investigation. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Hsu, Denise C.; Sereti, Irini] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Ma, Yi Fei; Hur, Sophia; Li, Danny; Kalapus, S. C.; Deeks, Steven; Hsue, Priscilla Y.] Univ Calif San Francisco, Room 5G1 Cardiol SFGH,1001 Potrero Ave, San Francisco, CA 94110 USA. [Rupert, Adam] Leidos Biomed Res Inc, Frederick, MD USA. [Scherzer, Rebecca] Vet Affairs Med Ctr, San Francisco, CA 94121 USA. RP Hsue, PY (reprint author), Univ Calif San Francisco, Room 5G1 Cardiol SFGH,1001 Potrero Ave, San Francisco, CA 94110 USA. EM Priscilla.Hsue@ucsf.edu FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases [K24AI112393]; NIAID/NIH; NIAID [K24AI069994]; UCSF/Gladstone Institute of Virology & Immunology CFAR [P30 AI027763]; UCSF Clinical and Translational Research Institute Clinical Research Center [UL1 RR024131]; CFAR Network of Integrated Systems [R24 AI067039] FX The project has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E (A.R.) and by the National Institute of Allergy and Infectious Diseases K24AI112393 (P.Y.H.). This project has also been funded in part by the intramural program of NIAID/NIH. The SCOPE cohort was supported in part by the NIAID (K24AI069994), the UCSF/Gladstone Institute of Virology & Immunology CFAR (P30 AI027763), the UCSF Clinical and Translational Research Institute Clinical Research Center (UL1 RR024131) and the CFAR Network of Integrated Systems (R24 AI067039). 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 76 TC 2 Z9 2 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD AUG 24 PY 2016 VL 30 IS 13 BP 2065 EP 2074 DI 10.1097/QAD.0000000000001149 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DS5HN UT WOS:000380812400007 PM 27177313 ER PT J AU Chan, ES Landay, AL Brown, TT Ribaudo, HJ Mirmonsef, P Ofotokun, I Weitzmann, MN Martinson, J Klingman, KL Eron, JJ Fichtenbaum, CJ Plants, J Taiwo, BO AF Chan, Ellen S. Landay, Alan L. Brown, Todd T. Ribaudo, Heather J. Mirmonsef, Paria Ofotokun, Igho Weitzmann, M. Neale Martinson, Jeffrey Klingman, Karin L. Eron, Joseph J. Fichtenbaum, Carl J. Plants, Jill Taiwo, Babafemi O. TI Differential CD4(+) cell count increase and CD4(+): CD8(+) ratio normalization with maraviroc compared with tenofovir SO AIDS LA English DT Article DE CD4 lymphocyte count; CD4: CD8 ratio; HIV; inflammation; maraviroc; tenofovir ID ANTIRETROVIRAL THERAPY; IMMUNE ACTIVATION; CLINICAL-TRIALS; HIV; INFLAMMATION; SUPPRESSION; INDIVIDUALS; RECOVERY; MARKERS; EVENTS AB Objective: Studies exploring the immunologic effects of maraviroc (MVC) have produced mixed results; hence, it remains unclear whether MVC has unique immunologic effects in comparison with other antiretroviral drugs. We sought to determine whether MVC has differential effects compared with tenofovir disoproxil fumarate (TDF) during initial antiretroviral therapy. Design: Prospective study in AIDS Clinical Trials Group A5303, a double-blind, placebo-controlled trial (N = 262) of MVC vs. TDF, each combined with boosted darunavir and emtricitabine. Methods: A total of 31 cellular and soluble biomarkers were assayed at weeks 0 and 48. Polychromatic flow cytometry was performed on cryopreserved peripheral blood mononuclear cells. Soluble markers were assayed in plasma using ELISA kits. Analyses were as treated. Results: Analyses included 230 participants (119 in MVC arm and 111 in TDF arm). Over 48 weeks of treatment, no significant differences were detected in declines in markers of inflammation and activation with MVC vs. TDF. A greater CD4(+) T-cell count increase (median +234 vs. +188 cells/mu l, P = 0.036), a smaller CD8(+) T-cell count decrease (-6 vs. -109 cells/mu l, P = 0.008), and a smaller CD4(+) : CD8(+) ratio increase (0.26 vs. 0.39, P = 0.003) occurred with MVC. Among participants with a baseline CD4(+) : CD8(+) ratio less than 1, a smaller proportion of MVC group normalized to a ratio greater than 1 at week 48 (15 and 36%, P < 0.001). Conclusion: MVC resulted in less improvement in the CD4(+) : CD8(+) ratio driven by greater increase in CD4(+) cell count but smaller decline in CD8(+) cell count. Changes in soluble or cellular biomarkers of inflammation and immune activation were not different between MVC and TDF. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Chan, Ellen S.; Ribaudo, Heather J.] Harvard Chan Sch Publ Hlth, Stat & Data Anal Ctr, 651 Huntington Ave,FXB 539, Boston, MA 02115 USA. [Landay, Alan L.; Mirmonsef, Paria; Martinson, Jeffrey; Plants, Jill] Rush Univ, Med Ctr, Dept Immunol & Microbiol, Chicago, IL 60612 USA. [Brown, Todd T.] Johns Hopkins Univ, Div Endocrinol Diabet & Metab, Baltimore, MD USA. [Ofotokun, Igho] Emory Univ, Div Infect Dis, Atlanta, GA 30322 USA. [Weitzmann, M. Neale] Emory Univ, Div Endocrinol & Metab & Lipids, Atlanta, GA 30322 USA. [Weitzmann, M. Neale] Atlanta VA Med Ctr, Decatur, GA USA. [Klingman, Karin L.] NIAID, HIV Res Branch, Div Aids, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Eron, Joseph J.] Univ N Carolina, Div Infect Dis, Chapel Hill, NC USA. [Fichtenbaum, Carl J.] Univ Cincinnati, Div Infect Dis, Cincinnati, OH USA. [Taiwo, Babafemi O.] Northwestern Univ, Div Infect Dis, Chicago, IL 60611 USA. RP Chan, ES (reprint author), Harvard Chan Sch Publ Hlth, Stat & Data Anal Ctr, 651 Huntington Ave,FXB 539, Boston, MA 02115 USA. EM echan@sdac.harvard.edu; echan@sdac.harvard.edu; echan@sdac.harvard.edu FU National Institute of Allergy and Infectious Diseases [U01AI068636]; National Institute of Mental Health (NIMH), National Institute of Dental and Craniofacial Research (NIDCR); NIH [AI068634, AI068636, AI69439, UM1 AI069496, 5UM1AI069412, UM1 AI069423, 1UL1TR001111, P30 AI50410, 2UMIA1069423-08, 2UM1AI069418-08, 2P30 AI 50409-10, UL1TR000454]; NIH (National Center for Advancing Translational Sciences/NIH) [UMAI069494, UMAI069432, UM1AI 069471, UM1AI069452, UM1 AI069501, 2UM1AI069432, UL1 TR001082, 1U01AI069477-01, P30AI073961, 5UM1 AI068636, 2UM1AI069503, UM1 AI069471, 2UM1AI06943908, UL1 TR000445]; National Institute of Health [AI069501, 5UM1AI069415-10, 2UM1AI069412-08, AI069424, UL1 RR025780, 2UM1-AI069470-08, UM1AI069472, 2UMAI069432, AI 69501, UM1AI069471, UM1A 068636-09, 5 P30 AI-045008-15, U01AI069447, NO1-HD-3-3345, UMI AI069511, UM1 AI069465, UL1TR001079, UL1 RR024160, UL1 TR000042] FX This work was supported by (Award Number U01AI068636) from the National Institute of Allergy and Infectious Diseases and supported by National Institute of Mental Health (NIMH), National Institute of Dental and Craniofacial Research (NIDCR). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. This work was also supported by grants from the NIH [(grant numbers AI068634 and AI068636) to the ACTG Statistical Data Analysis Center (to E.S.C. and H.J.R.), (grant number AI068636) to the Rush University Medical Center (to A.L.L., P.M,J.M, and J.P.), and to the research sites that participated in the study (grant numbers UMAI069494, UMAI069432, UM1AI 069471, UM1AI069452, UM1 AI069501, 2UM1AI069432, UL1 TR001082, 1U01AI069477-01, P30AI073961, 5UM1 AI068636, 2UM1AI069503, UM1 AI069471, 2UM1AI06943908, and UL1 TR000445 from the National Center for Advancing Translational Sciences/NIH, AI69439, UM1 AI069496, 5UM1AI069412, UM1 AI069423, 1UL1TR001111, P30 AI50410, 2UMIA1069423-08, 2UM1AI069418-08, 2P30 AI 50409-10, UL1TR000454, AI069501, 5UM1AI069415-10, 2UM1AI069412-08, AI069424, UL1 RR025780, 2UM1-AI069470-08, UM1AI069472, 2UMAI069432, AI 69501, UM1AI069471, UM1A 068636-09, 5 P30 AI-045008-15, U01AI069447, NO1-HD-3-3345, UMI AI069511, UM1 AI069465, UL1TR001079, UL1 RR024160, and UL1 TR000042)]. ViiV, Gilead, and AbbVie provided study drugs. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 14 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD AUG 24 PY 2016 VL 30 IS 13 BP 2091 EP 2097 DI 10.1097/QAD.0000000000001181 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DS5HN UT WOS:000380812400010 PM 27281061 ER PT J AU Khatami, M AF Khatami, Mahin TI Is cancer a severe delayed hypersensitivity reaction and histamine a blueprint? SO CLINICAL AND TRANSLATIONAL MEDICINE LA English DT Article DE Aging; Allergy; Angiogenesis; Branched amino acids; Bioenergetics; Cancer; Fetal growth; Histamine; Hypersensitivity; Immune-privileged and immune-responsive tissues; Mitochondria; Placenta; Taurine; Yin and Yang of inflammation ID SMALL-CELL-CARCINOMA; AGE-RELATED-CHANGES; NECROSIS-FACTOR-ALPHA; L-DOPA DECARBOXYLASE; MAST-CELLS; OXIDATIVE STRESS; CAENORHABDITIS-ELEGANS; AORTIC STIFFNESS; BLOOD-PRESSURE; IMMUNE-SYSTEM AB Longevity and accumulation of multiple context-dependent signaling pathways of long-standing inflammation (antigen-load or oxidative stress) are the results of decreased/altered regulation of immunity and loss of control switch mechanisms that we defined as Yin and Yang of acute inflammation or immune surveillance. Chronic inflammation is initiated by immune disruptors-induced progressive changes in physiology and function of susceptible host tissues that lead to increased immune suppression and multistep disease processes including carcinogenesis. The interrelated multiple hypotheses that are presented for the first time in this article are extension of author's earlier series of 'accidental' discoveries on the role of inflammation in developmental stages of immune dysfunction toward tumorigenesis and angiogenesis. Detailed analyses of data on chronic diseases suggest that nearly all age-associated illnesses, generally categorized as 'mild' (e.g., increased allergies), 'moderate' (e.g., hypertension, colitis, gastritis, pancreatitis, emphysema) or 'severe' (e.g., accelerated neurodegenerative and autoimmune diseases or site-specific cancers and metastasis) are variations of hypersensitivity responses of tissues that are manifested as different diseases in immune-responsive or immune-privileged tissues. Continuous release/presence of low level histamine (subclinical) in circulation could contribute to sustained oxidative stress and induction of 'mild' or 'moderate' or 'severe' (immune tsunami) immune disorders in susceptible tissues. Site-specific cancers are proposed to be 'severe' (irreversible) forms of cumulative delayed hypersensitivity responses that would induce immunological chaos in favor of tissue growth in target tissues. Shared or special features of growth from fetus development into adulthood and aging processes and carcinogenesis are briefly compared with regard to energy requirements of highly complex function of Yin and Yang. Features of Yang (growth-promoting) arm of acute inflammation during fetus and cancer growth will be compared for consuming low energy from glycolysis (Warburg effect). Growth of fetus and cancer cells under hypoxic conditions and impaired mitochondrial energy requirements of tissues including metabolism of essential branched amino acids (e.g., val, leu, isoleu) will be compared for proposing a working model for future systematic research on cancer biology, prevention and therapy. Presentation of a working model provides insightful clues into bioenergetics that are required for fetus growth (absence of external threat and lack of high energy-demands of Yin events and parasite-like survival in host), normal growth in adulthood (balance in Yin and Yang processes) or disease processes and carcinogenesis (loss of balance in Yin-Yang). Future studies require focusing on dynamics and promotion of natural/inherent balance between Yin (tumoricidal) and Yang (tumorigenic) of effective immunity that develop after birth. Lawless growth of cancerous cells and loss of cell contact inhibition could partially be due to impaired mitochondria (mitophagy) that influence metabolism of branched chain amino acids for biosynthesis of structural proteins. The author invites interested scientists with diverse expertise to provide comments, confirm, dispute and question and/or expand and collaborate on many components of the proposed working model with the goal to better understand cancer biology for future designs of cost-effective research and clinical trials and prevention of cancer. Initial events during oxidative stress-induced damages to DNA/RNA repair mechanisms and inappropriate expression of inflammatory mediators are potentially correctable, preventable or druggable, if future studies were to focus on systematic understanding of early altered immune response dynamics toward multistep chronic diseases and carcinogenesis. C1 [Khatami, Mahin] NCI, NIH, Bethesda, MD 20892 USA. RP Khatami, M (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mkgoodness@aol.com FU National Eye Institute-NEI FX The experimental studies on models of acute and chronic ocular inflammatory diseases were established at the University of Pennsylvania, School of Medicine, Department of Ophthalmology, Scheie Eye Institute, laboratory of John H. Rockey, MD, Ph.D. with a supportive team of scientists, funded by National Eye Institute-NEI. Analyses of original data and recent hypotheses on the extension of our 'accidental' discoveries were developed at the National Cancer Institute (NCI), the National Institutes of Health (NIH) since 1998, despite heavy opposition and denial of NCI decision makers to support the studies. Opinions presented in this article are the author's views and not those of the cancer establishment at NCI/NIH. NR 224 TC 1 Z9 1 U1 8 U2 10 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 AUG 23 PY 2016 VL 5 AR 35 DI 10.1186/s40169-016-0108-3 PG 23 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EH7KH UT WOS:000391951200001 PM 27558401 ER PT J AU Venugopalan, A Lee, MJ Niu, G Medina-Echeverz, J Tomita, Y Lizak, MJ Cultraro, CM Simpson, RM Chen, XY Trepel, JB Guha, U AF Venugopalan, Abhilash Lee, Min-Jung Niu, Gang Medina-Echeverz, Jose Tomita, Yusuke Lizak, Martin J. Cultraro, Constance M. Simpson, Robert Mark Chen, Xiaoyuan Trepel, Jane B. Guha, Udayan TI EGFR-targeted therapy results in dramatic early lung tumor regression accompanied by imaging response and immune infiltration in EGFR mutant transgenic mouse models SO ONCOTARGET LA English DT Article DE lung cancer; EGFR; TKI; imaging; immune-infiltration ID GROWTH-FACTOR RECEPTOR; TYROSINE KINASE INHIBITOR; RANDOMIZED-TRIAL; PHASE-III; CANCER; GEFITINIB; MUTATIONS; ADENOCARCINOMAS; CHEMOTHERAPY; ERLOTINIB AB Lung adenocarcinoma patients harboring kinase domain mutations in Epidermal growth factor receptor (EGFR) have significant clinical benefit from EGFR-targeted tyrosine kinase inhibitors (TKIs). Although a majority of patients experience clinical symptomatic benefit immediately, an objective response can only be demonstrated after 6-8 weeks of treatment. Evaluation of patient response by imaging shows that 30-40% of patients do not respond due to intrinsic resistance to these TKIs. We investigated immediate-early effects of EGFR-TKI treatment in mutant EGFR-driven transgenic mouse models by FDG-PET and MRI and correlated the effects on the tumor and the tumor microenvironment. Within 24 hours of erlotinib treatment we saw approximately 65% tumor regression in mice with TKI-sensitive EGFR(L858R) lung adenocarcinoma. However, mice with EGFR(L858R/T790M)-driven tumors did not respond to either erlotinib or afatinib monotherapy, but did show a significant tumor response to afatinib-cetuximab combination treatment. The imaging responses correlated with the inhibition of downstream EGFR signaling, increased apoptosis, and decreased proliferation in the tumor tissues. In EGFR(L858R)-driven tumors, we saw a significant increase in CD45(+) leukocytes, NK cells, dendritic cells, macrophages and lymphocytes, particularly CD8(+) T cells. In response to erlotinib, these dendritic cells and macrophages had significantly higher MHC class II expression, indicating increased antigen-presenting capabilities. Together, results of our study provide novel insight into the immediate-early therapeutic response to EGFR TKIs in vivo. C1 [Venugopalan, Abhilash; Medina-Echeverz, Jose; Cultraro, Constance M.; Guha, Udayan] NCI, Thorac & Gastrointestinal Oncol Branch, Bethesda, MD 20892 USA. [Lee, Min-Jung; Tomita, Yusuke; Trepel, Jane B.] NCI, Dev Therapeut Branch, Bethesda, MD 20892 USA. [Niu, Gang; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, Bethesda, MD USA. [Lizak, Martin J.] NINDS, Mouse Imaging Facil, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Simpson, Robert Mark] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Guha, U (reprint author), NCI, Thorac & Gastrointestinal Oncol Branch, Bethesda, MD 20892 USA. EM udayan.guha@nih.gov FU Intramural Research Program of the NIH / NCI / Center for Cancer Research (CCR); Lung Cancer Research Foundation (LCRF) FX This research was supported by the Intramural Research Program of the NIH / NCI / Center for Cancer Research (CCR) and a Lung Cancer Research Foundation (LCRF) grant (U. Guha). NR 51 TC 2 Z9 2 U1 3 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD AUG 23 PY 2016 VL 7 IS 34 BP 54137 EP 54156 DI 10.18632/oncotarget.11021 PG 20 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY9DY UT WOS:000385435000005 PM 27494838 ER PT J AU Inaguma, S Wang, ZF Lasota, JP Miettinen, MM AF Inaguma, Shingo Wang, Zengfeng Lasota, Jerzy P. Miettinen, Markku M. TI Expression of neural cell adhesion molecule L1 (CD171) in neuroectodermal and other tumors. An immunohistochemical study of 5155 tumors and critical evaluation of CD171 prognostic value in gastrointestinal stromal tumors SO ONCOTARGET LA English DT Article DE CD171 (NCAM-L1, L1CAM); immunohistochemistry; neuroectodermal tumor; gastrointestinal stromal tumor; mismatch repair deficiency ID IMMUNOGLOBULIN SUPERFAMILY; ENDOMETRIAL CARCINOMAS; RECOGNITION MOLECULES; MEDIATED RELEASE; AXON GUIDANCE; L1CAM; CANCER; L1-CAM; NEUROBLASTOMA; RECEPTOR AB The neural cell adhesion molecule L1 (CD171) is a multidomain type 1 membrane glycoprotein of the immunoglobulin superfamily important in the nervous system development, kidney morphogenesis, and maintenance of the immune system. Recent studies reported CD171 expression being associated with adverse clinical outcome in different types of cancer and there has been a growing interest in targeting this cell membrane molecule on neoplastic cells by chimeric antigen receptor redirected T lymphocytes or specific antibodies. Nevertheless, conflicting results regarding the prognostic value of CD171 expression in renal cell carcinomas and gastrointestinal stromal tumors were published. In this study, CD171 expression was immunohistochemically analyzed in 5155 epithelial, mesenchymal, melanocytic, and lymphohematopoietic tumors to assess its utility in diagnostic pathology and to pinpoint potential targets for CD171-targeting therapy. A newly developed anti-CD171 rabbit monoclonal antibody, clone 014, was selected from the panel of commercially available CD171 antibodies. Immunohistochemistry was performed using Leica Bond Max automation and multitumor blocks containing up to 60 tumor samples. CD171 was constitutively and strongly expressed in neuroectodermal tumors such as schwannoma, neuroblastoma, and paraganglioma, whereas other mesenchymal tumors including schwannoma mimics showed only rarely CD171 positivity. Frequent CD171-expression was also detected in ovarian serous carcinoma, malignant mesothelioma, and testicular embryonal carcinoma. CD171 immunohistochemistry may have some role in immunophenotypic differential diagnosis of neurogenic tumors and pinpointing potential candidates for anti-CD171 therapy. Though, because of its rare expression and lack of predictive value, CD171 is neither a diagnostic nor prognostic marker for gastrointestinal stromal tumors. C1 [Inaguma, Shingo; Wang, Zengfeng; Lasota, Jerzy P.; Miettinen, Markku M.] NCI, Pathol Lab, Bldg 10, Bethesda, MD 20892 USA. [Inaguma, Shingo] Aichi Med Univ, Dept Pathol, Sch Med, Nagakute, Aichi, Japan. RP Inaguma, S (reprint author), NCI, Pathol Lab, Bldg 10, Bethesda, MD 20892 USA.; Inaguma, S (reprint author), Aichi Med Univ, Dept Pathol, Sch Med, Nagakute, Aichi, Japan. EM inaguma@aichi-med-u.ac.jp FU National Cancer Institute's intramural research program FX This study was supported as a part of National Cancer Institute's intramural research program. The authors have disclosed that they have no relationships with, or financial interest in, any commercial companies pertaining to this article. NR 41 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 AUG 23 PY 2016 VL 7 IS 34 BP 55276 EP 55289 DI 10.18632/oncotarget.10527 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY9DY UT WOS:000385435000093 PM 27419370 ER PT J AU Fenerty, KE Folio, LR Patronas, NJ Marte, JL Gulley, JL Heery, CR AF Fenerty, Kathleen E. Folio, Les R. Patronas, Nicholas J. Marte, Jennifer L. Gulley, James L. Heery, Christopher R. TI Predicting clinical outcomes in chordoma patients receiving immunotherapy: a comparison between volumetric segmentation and RECIST SO BMC CANCER LA English DT Article DE Chordoma; Volumetric; RECIST; Radiologic; Response criteria ID RADIATION-THERAPY; RESPONSE CRITERIA; TUMOR RESPONSE; SOLID TUMORS; CT; LESIONS; FRONTS AB Background: The Response Evaluation Criteria in Solid Tumors (RECIST) are the current standard for evaluating disease progression or therapy response in patients with solid tumors. RECIST 1.1 calls for axial, longest-diameter (or perpendicular short axis of lymph nodes) measurements of a maximum of five tumors, which limits clinicians' ability to adequately measure disease burden, especially in patients with irregularly shaped tumors. This is especially problematic in chordoma, a disease for which RECIST does not always adequately capture disease burden because chordoma tumors are typically irregularly shaped and slow-growing. Furthermore, primary chordoma tumors tend to be adjacent to vital structures in the skull or sacrum that, when compressed, lead to significant clinical consequences. Methods: Volumetric segmentation is a newer technology that allows tumor burden to be measured in three dimensions on either MR or CT. Here, we compared the ability of RECIST measurements and tumor volumes to predict clinical outcomes in a cohort of 21 chordoma patients receiving immunotherapy. Results: There was a significant difference in radiologic time to progression Kaplan-Meier curves between clinical outcome groups using volumetric segmentation (P = 0.012) but not RECIST (P = 0.38). In several cases, changes in volume were earlier and more sensitive reflections of clinical status. Conclusion: RECIST is a useful evaluation method when obvious changes are occurring in patients with chordoma. However, in many cases, RECIST does not detect small changes, and volumetric assessment was capable of detecting changes and predicting clinical outcome earlier than RECIST. Although this study was small and retrospective, we believe our results warrant further research in this area. C1 [Fenerty, Kathleen E.; Heery, Christopher R.] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Room 13N208, Bethesda, MD 20892 USA. [Folio, Les R.; Patronas, Nicholas J.] NCI, Canc Imaging Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Marte, Jennifer L.; Gulley, James L.] NCI, Genitourinary Malignancies Branch, NIH, Bethesda, MD 20892 USA. RP Heery, CR (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Room 13N208, Bethesda, MD 20892 USA. EM heerycr@mail.nih.gov 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 18 TC 1 Z9 1 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD AUG 23 PY 2016 VL 16 AR 672 DI 10.1186/s12885-016-2699-x PG 9 WC Oncology SC Oncology GA DX2JL UT WOS:000384194700001 PM 27553491 ER PT J AU Felix, AS Lenz, P Pfeiffer, RM Hewitt, SM Morris, J Patel, DA Geller, B Vacek, PM Weaver, DL Chicoine, RE Shepherd, J Mahmoudzadeh, AP Wang, J Fan, B Malkov, S Herschorn, SD Johnson, JM Cora, RL Brinton, LA Sherman, ME Gierach, GL AF Felix, Ashley S. Lenz, Petra Pfeiffer, Ruth M. Hewitt, Stephen M. Morris, Jennifer Patel, Deesha A. Geller, Berta Vacek, Pamela M. Weaver, Donald L. Chicoine, Rachael E. Shepherd, John Mahmoudzadeh, Amir Pasha Wang, Jeff Fan, Bo Malkov, Serghei Herschorn, Sally D. Johnson, Jason M. Cora, Renata L. Brinton, Louise A. Sherman, Mark E. Gierach, Gretchen L. TI Relationships between mammographic density, tissue microvessel density, and breast biopsy diagnosis SO BREAST CANCER RESEARCH LA English DT Article DE Mammographic density; Breast neoplasms; Angiogenesis; Pathology; Lesional density ID BACKGROUND PARENCHYMAL ENHANCEMENT; CANCER RISK; FIBROGLANDULAR TISSUE; LOBULAR INVOLUTION; ADIPOSE-TISSUE; IN-SITU; ANGIOGENESIS; MRI; DISEASE; IMPACT AB Background: Women with high levels of mammographic density (MD) have a four-to six-fold increased risk of developing breast cancer; however, most neither have a prevalent tumor nor will they develop one. Magnetic resonance imaging (MRI) studies suggest that background parenchymal enhancement, an indicator of vascularity, is related to increased breast cancer risk. Correlations of microvessel density (MVD) in tissue, MD and biopsy diagnosis have not been defined, and we investigated these relationships among 218 women referred for biopsy. Methods: MVD was determined by counting CD31-positive vessels in whole sections of breast biopsies in three representative areas; average MVD was transformed to approximate normality. Using digital mammograms, we quantified MD volume with single X-ray absorptiometry. We used linear regression to evaluate associations between MVD and MD adjusted for age and body mass index (BMI) overall, and stratified by biopsy diagnosis: cases (in situ or invasive cancer, n = 44) versus non-cases (non-proliferative or proliferative benign breast disease, n = 174). Logistic regression adjusted for age, BMI, and MD was used to calculate odds ratios (ORs) and 95 % confidence intervals (CIs) for associations between MVD and biopsy diagnosis. We also assessed whether the MVD-breast cancer association varied by MD. Results: MVD and MD were not consistently associated. Higher MVD was significantly associated with higher odds of in situ/invasive disease (ORAdjusted = 1.69, 95 % CI = 1.17-2.44). MVD-breast cancer associations were strongest among women with greater non-dense volume. Conclusions: Increased MVD in tissues is associated with breast cancer, independently of MD, consistent with MRI findings suggestive of its possible value as a radiological cancer biomarker. C1 [Felix, Ashley S.; Pfeiffer, Ruth M.; Patel, Deesha A.; Cora, Renata L.; Brinton, Louise A.; Gierach, Gretchen L.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Felix, Ashley S.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Felix, Ashley S.] Ohio State Univ, Coll Publ Hlth, Div Epidemiol, 1841 Neil Ave,300C Cunz Hall, Columbus, OH 43210 USA. [Lenz, Petra] Leidos Biomed Res Inc, Clin Res Directorate, Clin Monitoring Res Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Hewitt, Stephen M.; Morris, Jennifer] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Geller, Berta] Univ Vermont, Dept Family Med, Burlington, VT USA. [Vacek, Pamela M.; Weaver, Donald L.] Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. [Chicoine, Rachael E.] Univ Vermont, Off Hlth Promot Res, Burlington, VT USA. [Shepherd, John; Mahmoudzadeh, Amir Pasha; Wang, Jeff; Fan, Bo; Malkov, Serghei] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Wang, Jeff] Hokkaido Univ, Grad Sch Med, Sapporo, Hokkaido, Japan. [Herschorn, Sally D.] Univ Vermont, Dept Radiol, Burlington, VT USA. [Johnson, Jason M.] Univ Texas MD Anderson Canc Ctr, Dept Diagnost Radiol, Neuroradiol Sect, Houston, TX 77030 USA. [Sherman, Mark E.] NCI, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. RP Felix, AS (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.; Felix, AS (reprint author), NCI, Canc Prevent Fellowship Program, Canc Prevent Div, NIH, Bethesda, MD 20892 USA.; Felix, AS (reprint author), Ohio State Univ, Coll Publ Hlth, Div Epidemiol, 1841 Neil Ave,300C Cunz Hall, Columbus, OH 43210 USA. EM Felix.20@osu.edu RI Gierach, Gretchen/E-1817-2016 OI Gierach, Gretchen/0000-0002-0165-5522 FU NCI NIH HHS [R01 CA166945] NR 38 TC 0 Z9 0 U1 2 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 AUG 23 PY 2016 VL 18 AR 88 DI 10.1186/s13058-016-0746-9 PG 12 WC Oncology SC Oncology GA DW1VK UT WOS:000383430900001 PM 27552842 ER PT J AU Cossio, P Hummer, G Szabo, A AF Cossio, Pilar Hummer, Gerhard Szabo, Attila TI Kinetic Ductility and Force-Spike Resistance of Proteins from Single-Molecule Force Spectroscopy SO BIOPHYSICAL JOURNAL LA English DT Article ID DYNAMICS SIMULATIONS; UNFOLDING PATHWAYS; ENERGY LANDSCAPES; ADHESION BONDS; TITIN; DOMAIN; DEFORMATION; MICROSCOPY; DIFFUSION; UBIQUITIN AB Ductile materials can absorb spikes in mechanical force, whereas brittle ones fail catastrophically. Here we develop a theory to quantify the kinetic ductility of single molecules from force spectroscopy experiments, relating force-spike resistance to the differential responses of the intact protein and the unfolding transition state to an applied mechanical force. We introduce a class of unistable one-dimensional potential surfaces that encompass previous models as special cases and continuously cover the entire range from ductile to brittle. Compact analytic expressions for force-dependent rates and rupture-force distributions allow us to analyze force-clamp and force-ramp pulling experiments. We find that the force-transmitting protein domains of filamin and titin are kinetically ductile when pulled from their two termini, making them resistant to force spikes. For the mechanostable muscle protein titin, a highly ductile model reconciles data over 10 orders of magnitude in force loading rate from experiment and simulation. C1 [Cossio, Pilar; Hummer, Gerhard] Max Planck Inst Biophys, Dept Theoret Biophys, Frankfurt, Germany. [Szabo, Attila] Natl Inst Diabet & Digest & Kidney Dis, Lab Chem Phys, NIH, Bethesda, MD USA. RP Hummer, G (reprint author), Max Planck Inst Biophys, Dept Theoret Biophys, Frankfurt, Germany. EM gerhard.hummer@biophys.mpg.de RI Hummer, Gerhard/A-2546-2013; Szabo, Attila/H-3867-2012 OI Hummer, Gerhard/0000-0001-7768-746X; FU Max Planck Society; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX P.C. and G.H. were supported by the Max Planck Society; and A.S. was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 47 TC 0 Z9 0 U1 8 U2 8 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 AUG 23 PY 2016 VL 111 IS 4 BP 832 EP 840 DI 10.1016/j.bpj.2016.05.054 PG 9 WC Biophysics SC Biophysics GA DU3GR UT WOS:000382099300016 PM 27558726 ER PT J AU Manago, F Mereu, M Mastwal, S Mastrogiacomo, R Scheggia, D Emanuele, M De Luca, MA Weinberger, DR Wang, KH Papaleo, F AF Manago, Francesca Mereu, Maddalena Mastwal, Surjeet Mastrogiacomo, Rosa Scheggia, Diego Emanuele, Marco De Luca, Maria A. Weinberger, Daniel R. Wang, Kuan Hong Papaleo, Francesco TI Genetic Disruption of Arc/Arg3.1 in Mice Causes Alterations in Dopamine and Neurobehavioral Phenotypes Related to Schizophrenia SO CELL REPORTS LA English DT Article ID VENTRAL TEGMENTAL AREA; AMPHETAMINE-INDUCED ACTIVITY; MEDIAL PREFRONTAL CORTEX; IMMEDIATE-EARLY GENE; TEMPORAL-ORDER; PREPULSE INHIBITION; SYNAPTIC PLASTICITY; RECOGNITION MEMORY; NUCLEUS-ACCUMBENS; PYRAMIDAL NEURONS AB Human genetic studies have recently suggested that the postsynaptic activity-regulated cytoskeleton-associated protein (Arc) complex is a convergence signal for several genes implicated in schizophrenia. However, the functional significance of Arc in schizophrenia-related neurobehavioral phenotypes and brain circuits is unclear. Here, we find that, consistent with schizophrenia-related phenotypes, disruption of Arc in mice produces deficits in sensorimotor gating, cognitive functions, social behaviors, and amphetamine-induced psychomotor responses. Furthermore, genetic disruption of Arc leads to concomitant hypoactive mesocortical and hyperactive mesostriatal dopamine pathways. Application of a D1 agonist to the prefrontal cortex or a D2 antagonist in the ventral striatumrescues Arc-dependent cognitive or psychomotor abnormalities, respectively. Our findings demonstrate a role for Arc in the regulation of dopaminergic neurotransmission and related behaviors. The results also provide initial biological support implicating Arc in dopaminergic and behavioral abnormalities related to schizophrenia. C1 [Manago, Francesca; Mastrogiacomo, Rosa; Scheggia, Diego; Emanuele, Marco; Papaleo, Francesco] Ist Italiano Tecnol, Dept Neurosci & Brain Technol, Via Morego 30, I-16163 Genoa, Italy. [Mereu, Maddalena] Univ Padua, Dipartimento Sci Farmaco, Largo Meneghetti 2, I-35131 Padua, Italy. [Mastwal, Surjeet; Wang, Kuan Hong] NIMH, Unit Neural Circuits & Adapt Behav, Clin & Translat Neurosci Branch, Bethesda, MD 20892 USA. [De Luca, Maria A.] Univ Cagliari, Dept Biomed Sci, I-09124 Cagliari, Italy. [Weinberger, Daniel R.] Johns Hopkins Univ, Lieber Inst Brain Dev, Med Campus, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. RP Papaleo, F (reprint author), Ist Italiano Tecnol, Dept Neurosci & Brain Technol, Via Morego 30, I-16163 Genoa, Italy.; Wang, KH (reprint author), NIMH, Unit Neural Circuits & Adapt Behav, Clin & Translat Neurosci Branch, Bethesda, MD 20892 USA. EM wkuan@mail.nih.gov; francesco.papaleo@iit.it RI Wang, Kuan Hong/J-1150-2016; OI Wang, Kuan Hong/0000-0002-2249-5417; Papaleo, Francesco/0000-0002-6326-0657 FU Istituto Italiano di Tecnologia, Marie Curie grant [268247]; Italian Ministry of Health [GR-2010-2315883]; NARSAD Independent Investigator grant [23234]; Intramural Research Program of the National Institute of Mental Health [ZIA MH002897] FX We thank Dr. G. Tanda, Dr. R. Gainetdinov, Dr. M. Morini, D. Cantatore, and C. Chiabrera for suggestions and technical assistance. We thank Dr. S. Tonegawa for donating the Arc mutant breeders. This research was supported by the Istituto Italiano di Tecnologia, Marie Curie grant 268247, Italian Ministry of Health grant GR-2010-2315883, and 2015 NARSAD Independent Investigator grant 23234 (to F.P.) and by the Intramural Research Program of the National Institute of Mental Health (ZIA MH002897 to D.R.W. and K.H.W.). NR 72 TC 1 Z9 1 U1 6 U2 6 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 AUG 23 PY 2016 VL 16 IS 8 BP 2116 EP 2128 DI 10.1016/j.celrep.2016.07.044 PG 13 WC Cell Biology SC Cell Biology GA DU6FQ UT WOS:000382310100009 PM 27524619 ER PT J AU Casagrande, SS Menke, A Cowie, CC AF Casagrande, Sarah S. Menke, Andy Cowie, Catherine C. TI Cardiovascular Risk Factors of Adults Age 20-49 Years in the United States, 1971-2012: A Series of Cross-Sectional Studies SO PLOS ONE LA English DT Article ID OBESITY; HEALTH; ASSOCIATION; BALTIMORE; EPIDEMIC; MARYLAND; TRENDS; BMI AB Background The health of younger adults in the U.S. has important public health and economic-related implications. However, previous literature is insufficient to fully understand how the health of this group has changed over time. This study examined generational differences in cardiovascular risk factors of younger adults over the past 40 years. Methods Data were from 6 nationally representative cross-sectional National Health and Nutrition Examination Surveys (1971-2012; N = 44,670). Participants were adults age 20-49 years who self-reported sociodemographic characteristics and health conditions, and had examination/laboratory measures for hypertension, hyperlipidemia, diabetes, obesity, and chronic kidney disease. Prevalences of sociodemographic characteristics and health status were determined by study period. Logistic regression was used to determine the odds [odds ratio (OR), 95% confidence interval] of health conditions by study period: models adjusted only for age, sex, and race, and fully adjusted models additionally adjusted for socioeconomic characteristics, smoking, BMI, diabetes, and/or hypertension (depending on the outcome) were assessed. Results Participants in 2009-2012 were significantly more likely to be obese and have diabetes compared to those in 1971-1975 (OR = 4.98, 3.57-6.97; OR = 3.49, 1.59-7.65, respectively, fully adjusted). Participants in 2009-2012 vs. 1988-1994 were significantly more likely to have had hypertension but uncontrolled hypertension was significantly less likely (OR = 0.67, 0.52-0.86, fully adjusted). There was no difference over time for high cholesterol, but uncontrolled high cholesterol was significantly less likely in 2009-2012 vs. 1988-1994 (OR = 0.80, 0.68-0.94, fully adjusted). The use of hypertensive and cholesterol medications increased while chronic kidney and cardiovascular diseases were relatively stable. Conclusions Cardiovascular risk factors of younger U.S. adults have worsened over the past 40 years, but treatment for hypertension and high cholesterol has improved. The sub-optimal and worsening health in younger adults may have a substantial impact on health care utilization and costs, and should be considered when developing health care practices. C1 [Casagrande, Sarah S.; Menke, Andy] Social & Sci Syst Inc, Publ Hlth Res, Silver Spring, MD 20910 USA. [Cowie, Catherine C.] NIDDK, Div Diabet Endocrinol & Metab Dis, Bethesda, MD 20892 USA. RP Casagrande, SS (reprint author), Social & Sci Syst Inc, Publ Hlth Res, Silver Spring, MD 20910 USA. EM scasagrande@s-3.com FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [GS-10F-0381L] FX The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (GS-10F-0381L) funded NHANES and oversaw its conduct and reporting with regard to diabetes-related data. As employees NIDDK (C. Cowie) or contractors of NIDDK (Social & Scientific Systems, Inc.; S. Casagrande, A. Menke), the authors had a direct role in the design and interpretation of the secondary analysis and the decision to submit the manuscript for publication. NR 51 TC 0 Z9 0 U1 15 U2 15 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 AUG 23 PY 2016 VL 11 IS 8 AR e0161770 DI 10.1371/journal.pone.0161770 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT8TR UT WOS:000381768800075 PM 27552151 ER PT J AU Liberman, Z Woodward, AL Sullivan, KR Kinzler, KD AF Liberman, Zoe Woodward, Amanda L. Sullivan, Kathleen R. Kinzler, Katherine D. TI Early emerging system for reasoning about the social nature of food SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE food; social cognition; infancy; cognitive development; disgust ID CHILDS CONCEPTION; CONTAMINATION SENSITIVITY; INDUCTIVE INFERENCES; INFANTS GENERALIZE; SHAPE SIMILARITY; YOUNG-CHILDREN; SHARED LABELS; PREFERENCES; EAT; CONSUMPTION AB Selecting appropriate foods is a complex and evolutionarily ancient problem, yet past studies have revealed little evidence of adaptations present in infancy that support sophisticated reasoning about perceptual properties of food. We propose that humans have an early-emerging system for reasoning about the social nature of food selection. Specifically, infants' reasoning about food choice is tied to their thinking about agents' intentions and social relationships. Whereas infants do not expect people to like the same objects, infants view food preferences as meaningfully shared across individuals. Infants' reasoning about food preferences is fundamentally social: They generalize food preferences across individuals who affiliate, or who speak a common language, but not across individuals who socially disengage or who speak different languages. Importantly, infants' reasoning about food preferences is flexibly calibrated to their own experiences: Tests of bilingual babies reveal that an infant's sociolinguistic background influences whether she will constrain her generalization of food preferences to people who speak the same language. Additionally, infants' systems for reasoning about food is differentially responsive to positive and negative information. Infants generalize information about food disgust across all people, regardless of those people's social identities. Thus, whereas food preferences are seen as embedded within social groups, disgust is interpreted as socially universal, which could help infants avoid potentially dangerous foods. These studies reveal an early-emerging system for thinking about food that incorporates social reasoning about agents and their relationships, and allows infants to make abstract, flexible, adaptive inferences to interpret others' food choices. C1 [Liberman, Zoe; Woodward, Amanda L.; Sullivan, Kathleen R.; Kinzler, Katherine D.] Univ Chicago, Dept Psychol, Chicago, IL 60642 USA. [Sullivan, Kathleen R.] NIH, Off Res Womens Hlth, Bldg 10, Bethesda, MD 20892 USA. [Kinzler, Katherine D.] Cornell Univ, Dept Psychol, Ithaca, NY 14853 USA. [Kinzler, Katherine D.] Cornell Univ, Dept Human Dev, Ithaca, NY 14853 USA. RP Liberman, Z (reprint author), Univ Chicago, Dept Psychol, Chicago, IL 60642 USA. EM zoeliberman@uchicago.edu FU NIH [R01 HD070890]; National Science Foundation Graduate Research Fellowship Program FX We thank Kristin Shutts for extremely helpful conversations about the intellectual direction of this project, and Alex Shaw and Susan Goldin-Meadow for comments on a previous version of this manuscript. This research was supported by NIH Grant R01 HD070890 (to K.D.K.) and by a National Science Foundation Graduate Research Fellowship Program (to Z.L.). NR 85 TC 0 Z9 0 U1 5 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 23 PY 2016 VL 113 IS 34 BP 9480 EP 9485 DI 10.1073/pnas.1605456113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT9ZK UT WOS:000381860800042 PM 27503878 ER PT J AU Wang, W Nguyen, LTT Burlak, C Chegini, F Guo, F Chataway, T Ju, SL Fisher, OS Miller, DW Datta, D Wu, F Wu, CX Landeru, A Wells, JA Cookson, MR Boxer, MB Thomas, CJ Gai, WP Ringe, D Petsko, GA Hoang, QQ AF Wang, Wei Nguyen, Linh T. T. Burlak, Christopher Chegini, Fariba Guo, Feng Chataway, Tim Ju, Shulin Fisher, Oriana S. Miller, David W. Datta, Debajyoti Wu, Fang Wu, Chun-Xiang Landeru, Anuradha Wells, James A. Cookson, Mark R. Boxer, Matthew B. Thomas, Craig J. Gai, Wei Ping Ringe, Dagmar Petsko, Gregory A. Hoang, Quyen Q. TI Caspase-1 causes truncation and aggregation of the Parkinson's disease-associated protein alpha-synuclein SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE synuclein; Parkinson's disease; caspase; inflammasome; aggregation ID TRAUMATIC BRAIN-INJURY; GROWTH-FACTOR-ALPHA; CEREBROSPINAL-FLUID; MOUSE MODEL; IN-VIVO; NEURODEGENERATION; INTERLEUKIN-1-BETA; NEUROINFLAMMATION; INFLAMMATION; PATHOGENESIS AB The aggregation of alpha-synuclein (aSyn) leading to the formation of Lewy bodies is the defining pathological hallmark of Parkinson's disease (PD). Rare familial PD-associated mutations in aSyn render it aggregation-prone; however, PD patients carrying wild type (WT) aSyn also have aggregated aSyn in Lewy bodies. The mechanisms by which WT aSyn aggregates are unclear. Here, we report that inflammation can play a role in causing the aggregation of WT aSyn. We show that activation of the inflammasome with known stimuli results in the aggregation of aSyn in a neuronal cell model of PD. The insoluble aggregates are enriched with truncated aSyn as found in Lewy bodies of the PD brain. Inhibition of the inflammasome enzyme caspase-1 by chemical inhibition or genetic knockdown with shRNA abated aSyn truncation. In vitro characterization confirmed that caspase-1 directly cleaves aSyn, generating a highly aggregation-prone species. The truncation-induced aggregation of aSyn is toxic to neuronal culture, and inhibition of caspase-1 by shRNA or a specific chemical inhibitor improved the survival of a neuronal PD cell model. This study provides a molecular link for the role of inflammation in aSyn aggregation, and perhaps in the pathogenesis of sporadic PD as well. C1 [Wang, Wei; Nguyen, Linh T. T.; Wu, Chun-Xiang; Landeru, Anuradha; Hoang, Quyen Q.] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. [Wang, Wei; Nguyen, Linh T. T.; Wu, Chun-Xiang; Landeru, Anuradha; Hoang, Quyen Q.] Indiana Univ Sch Med, Stark Neurosci Res Inst, Indianapolis, IN 46202 USA. [Burlak, Christopher] Univ Minnesota, Dept Surg, Schulze Diabet Inst, Box 242 UMHC, Minneapolis, MN 55455 USA. [Chegini, Fariba; Guo, Feng; Chataway, Tim; Gai, Wei Ping] Flinders Univ S Australia, Dept Human Physiol, Ctr Neurosci, Adelaide, SA 5001, Australia. [Ju, Shulin; Fisher, Oriana S.; Wu, Fang; Ringe, Dagmar; Petsko, Gregory A.] Brandeis Univ, Dept Chem, Rosenstiel Basic Med Sci Res Ctr, Waltham, MA 02454 USA. [Ju, Shulin; Fisher, Oriana S.; Wu, Fang; Ringe, Dagmar; Petsko, Gregory A.] Brandeis Univ, Dept Biochem, Rosenstiel Basic Med Sci Res Ctr, Waltham, MA 02454 USA. [Miller, David W.; Cookson, Mark R.] NIH, Neurogenet Lab, Bldg 10, Bethesda, MD 20892 USA. [Datta, Debajyoti; Wells, James A.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA. [Wells, James A.] Univ Calif San Francisco, Dept Cellular & Mol Physiol, San Francisco, CA 94143 USA. [Boxer, Matthew B.; Thomas, Craig J.] NIH, Natl Ctr Adv Translat Sci, Chem Genom Ctr, Bldg 10, Bethesda, MD 20892 USA. [Ringe, Dagmar; Petsko, Gregory A.] Harvard Med Sch, Dept Neurol, Cambridge, MA 02139 USA. [Ringe, Dagmar; Petsko, Gregory A.] Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02116 USA. [Hoang, Quyen Q.] Indiana Univ Sch Med, Dept Neurol, Indianapolis, IN 46202 USA. [Ju, Shulin] Wright State Univ, Dept Biol Sci, Dayton, OH 45435 USA. [Fisher, Oriana S.] Northwestern Univ, Dept Mol Biosci, Evanston, IL 60208 USA. [Wu, Fang; Petsko, Gregory A.] Univ Calif Berkeley, Dept Mol & Cell Biol, Calif Inst Quantitat Biol, 229 Stanley Hall, Berkeley, CA 94720 USA. [Petsko, Gregory A.; Hoang, Quyen Q.] Weill Cornell Med Coll, Dept Neurol & Neurosci, New York, NY 10065 USA. RP Hoang, QQ (reprint author), Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA.; Hoang, QQ (reprint author), Indiana Univ Sch Med, Stark Neurosci Res Inst, Indianapolis, IN 46202 USA.; Petsko, GA (reprint author), Brandeis Univ, Dept Chem, Rosenstiel Basic Med Sci Res Ctr, Waltham, MA 02454 USA.; Petsko, GA (reprint author), Brandeis Univ, Dept Biochem, Rosenstiel Basic Med Sci Res Ctr, Waltham, MA 02454 USA.; Petsko, GA (reprint author), Harvard Med Sch, Dept Neurol, Cambridge, MA 02139 USA.; Petsko, GA (reprint author), Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02116 USA.; Hoang, QQ (reprint author), Indiana Univ Sch Med, Dept Neurol, Indianapolis, IN 46202 USA.; Petsko, GA (reprint author), Univ Calif Berkeley, Dept Mol & Cell Biol, Calif Inst Quantitat Biol, 229 Stanley Hall, Berkeley, CA 94720 USA.; Petsko, GA; Hoang, QQ (reprint author), Weill Cornell Med Coll, Dept Neurol & Neurosci, New York, NY 10065 USA. EM gpetsko@med.cornell.edu; qqhoang@iu.edu RI Wells, Jim/O-9854-2016 FU Community Fast Track grant from Michael J. Fox Foundation; National Institutes of Health Grants [1R21NS079881-01, 5R01GM111639]; Indiana University School of Medicine Biomedical Research Grant; Indiana University-Purdue University Indianapolis Research Support Funds Grant; Fidelity Biosciences Research Initiative; Ellison Medical Foundation; McKnight Endowment for Neuroscience; Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research; Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health; Intramural Research Program of the National Institute on Aging, National Institutes of Health FX We thank S. Lindquist for the yeast expression vectors of aSyn, and Z. Y. Z. Zhang and L. Chen for their generous support and access to the Chemical Genomics Core Facility at Indiana University. Q.Q.H., D.R., and G.A.P. were supported through a Community Fast Track grant from the Michael J. Fox Foundation. Q.Q.H. was also supported by National Institutes of Health Grants 1R21NS079881-01 and 5R01GM111639, an Indiana University School of Medicine Biomedical Research Grant, and an Indiana University-Purdue University Indianapolis Research Support Funds Grant. D.R. and G.A.P. also acknowledge support from the Fidelity Biosciences Research Initiative (with much useful discussion from Dr. S. Weninger) and early support from the Ellison Medical Foundation and the McKnight Endowment for Neuroscience. M.B.B. and C.J.T. acknowledge support from the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. This research was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 50 TC 0 Z9 0 U1 8 U2 9 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 AUG 23 PY 2016 VL 113 IS 34 BP 9587 EP 9592 DI 10.1073/pnas.1610099113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT9ZK UT WOS:000381860800060 ER PT J AU Brinkmeyer-Langford, C Balog-Alvarez, C Cai, JJ Davis, BW Kornegay, JN AF Brinkmeyer-Langford, Candice Balog-Alvarez, Cynthia Cai, James J. Davis, Brian W. Kornegay, Joe N. TI Genome-wide association study to identify potential genetic modifiers in a canine model for Duchenne muscular dystrophy SO BMC GENOMICS LA English DT Article DE Muscular dystrophy; Duchenne muscular dystrophy; DMD; Golden retriever muscular dystrophy; GRMD; Modifier; Linear mixed-model analysis; Gene expression ID READING-FRAME RULE; NONSENSE MUTATION; POPULATION STRATIFICATION; MESSENGER-RNA; DOGS; DISEASE; EXPRESSION; MUSCLE; DMD; EXON AB Background: Duchenne muscular dystrophy (DMD) causes progressive muscle degeneration, cardiomyopathy and respiratory failure in approximately 1/5,000 boys. Golden Retriever muscular dystrophy (GRMD) resembles DMD both clinically and pathologically. Like DMD, GRMD exhibits remarkable phenotypic variation among affected dogs, suggesting the influence of modifiers. Understanding the role(s) of genetic modifiers of GRMD may identify genes and pathways that also modify phenotypes in DMD and reveal novel therapies. Therefore, our objective in this study was to identify genetic modifiers that affect discrete GRMD phenotypes. Results: We performed a linear mixed-model (LMM) analysis using 16 variably-affected dogs from our GRMD colony (8 dystrophic, 8 non-dystrophic). All of these dogs were either full or half-siblings, and phenotyped for 19 objective, quantitative biomarkers at ages 6 and 12 months. Each biomarker was individually assessed. Gene expression profiles of 59 possible candidate genes were generated for two muscle types: the cranial tibialis and medial head of the gastrocnemius. SNPs significantly associated with GRMD biomarkers were identified on multiple chromosomes (including the X chromosome). Gene expression levels for candidate genes located near these SNPs correlated with biomarker values, suggesting possible roles as GRMD modifiers. Conclusions: The results of this study enhance our understanding of GRMD pathology and represent a first step toward the characterization of GRMD modifiers that may be relevant to DMD pathology. Such modifiers are likely to be useful for DMD treatment development based on their relationships to GRMD phenotypes. C1 [Brinkmeyer-Langford, Candice; Balog-Alvarez, Cynthia; Cai, James J.; Kornegay, Joe N.] Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX USA. [Davis, Brian W.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Brinkmeyer-Langford, C (reprint author), Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX USA. EM cbrinkmeyer@cvm.tamu.edu OI Cai, James/0000-0002-8081-6725 FU NINDS grant [1U24NS059696-01A1]; Co-operative Program in Translational Research: Proposal for Establishment of the National Center for Canine Models of Duchenne Muscular Dystrophy; Muscular Dystrophy Association Infrastructure grant FX NINDS grant 1U24NS059696-01A1, the Co-operative Program in Translational Research: Proposal for Establishment of the National Center for Canine Models of Duchenne Muscular Dystrophy, and a Muscular Dystrophy Association Infrastructure grant to the Translational Research Advisory Committee (J.N.K.). NR 82 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 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD AUG 22 PY 2016 VL 17 AR 665 DI 10.1186/s12864-016-2948-z PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DY3GT UT WOS:000384979500002 PM 27549615 ER PT J AU Guerard, F Lee, YS Baidoo, K Gestin, JF Brechbiel, MW AF Guerard, Francois Lee, Yong-Sok Baidoo, Kwamena Gestin, Jean-Francois Brechbiel, Martin W. TI Unexpected Behavior of the Heaviest Halogen Astatine in the Nucleophilic Substitution of Aryliodonium Salts SO CHEMISTRY-A EUROPEAN JOURNAL LA English DT Article DE astatine; halogenation; iodonium salts; nucleophilic substitution; radiopharmaceuticals ID DIARYLIODONIUM SALTS; RADIOFLUORINATION; CHEMISTRY; THERAPY; TOSYLATES; SOLVENTS; ARENES; IODINE; ARYL AB Aryliodonium salts have become precursors of choice for the synthesis of F-18-labeled tracers for nuclear imaging. However, little is known on the reactivity of these compounds with heavy halides, that is, radioiodide and astatide, at the radiotracer scale. In the first comparative study of radiohalogenation of aryliodonium salts with I-125(-) and At-211(-), initial experiments on a model compound highlight the higher reactivity of astatide compared to iodide, which could not be anticipated from the trends previously observed within the halogen series. Kinetic studies indicate a significant difference in activation energy (E-a=23.5 and 17.1kcalmol(-1) with I-125(-) and At-211(-), respectively). Quantum chemical calculations suggest that astatination occurs via the monomeric form of an iodonium complex whereas iodination occurs via a heterodimeric iodonium intermediate. The good to excellent regioselectivity of halogenation and high yields achieved with diversely substituted aryliodonium salts indicate that this class of compounds is a promising alternative to the stannane chemistry currently used for heavy radiohalogen labeling of tracers in nuclear medicine. C1 [Guerard, Francois; Baidoo, Kwamena; Brechbiel, Martin W.] NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Guerard, Francois; Gestin, Jean-Francois] Univ Nantes, INSERM, U892, CNRS,UMR6299, Nantes, France. [Lee, Yong-Sok] NIH, Ctr Mol Modeling, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. RP Guerard, F (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA.; Guerard, F (reprint author), Univ Nantes, INSERM, U892, CNRS,UMR6299, Nantes, France. EM francois.guerard@univ-nantes.fr OI Guerard, Francois/0000-0001-9795-2785 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and Center for Information Technology; French National Agency for Research, called "Investissements d'Avenir" IRON Labex [ANR-11-LABX-0018-01]; ArronaxPlus Equipex [ANR-11-EQPX-0004] FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and Center for Information Technology and in part by grants from the French National Agency for Research, called "Investissements d'Avenir" IRON Labex (no. ANR-11-LABX-0018-01) and ArronaxPlus Equipex (no. ANR-11-EQPX-0004). The quantum chemical study utilized PC/linux clusters at the center for Molecular Modeling of the National Institutes of Health (http://cit.nih.gov). Lawrence Szajek, NIH, CC is thanked for his cyclotron operations and irradiation of bismuth targets for the production of 211At. Professor Vanelle is thanked for the input on radical mechanism investigations. NR 49 TC 0 Z9 0 U1 9 U2 9 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 0947-6539 EI 1521-3765 J9 CHEM-EUR J JI Chem.-Eur. J. PD AUG 22 PY 2016 VL 22 IS 35 BP 12332 EP 12339 DI 10.1002/chem.201600922 PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA DV4DX UT WOS:000382876500017 PM 27305065 ER PT J AU Hager, A Wu, MX Wang, HC Brown, NW Shears, SB Veiga, N Fiedler, D AF Hager, Anastasia Wu, Mingxuan Wang, Huanchen Brown, Nathaniel W., Jr. Shears, Stephen B. Veiga, Nicolas Fiedler, Dorothea TI Cellular Cations Control Conformational Switching of Inositol Pyrophosphate Analogues SO CHEMISTRY-A EUROPEAN JOURNAL LA English DT Article DE biological activity; conformation analysis; phosphorylation; protonation; signal transduction ID DIPHOSPHOINOSITOL-POLYPHOSPHATE PHOSPHOHYDROLASES; MYOINOSITOL HEXAKISPHOSPHATE; P-31 NMR; PROTEIN PYROPHOSPHORYLATION; SACCHAROMYCES-CEREVISIAE; PH MICRODOMAINS; TELOMERE LENGTH; KINASE; PENTAKISPHOSPHATE; METABOLISM AB The inositol pyrophosphate messengers (PP-InsPs) are emerging as an important class of cellular regulators. These molecules have been linked to numerous biological processes, including insulin secretion and cancer cell migration, but how they trigger such a wide range of cellular responses has remained unanswered in many cases. Here, we show that the PP-InsPs exhibit complex speciation behaviour and propose that a unique conformational switching mechanism could contribute to their multifunctional effects. We synthesised non-hydrolysable bisphosphonate analogues and crystallised the analogues in complex with mammalian PPIP5K2 kinase. Subsequently, the bisphosphonate analogues were used to investigate the protonation sequence, metal-coordination properties, and conformation in solution. Remarkably, the presence of potassium and magnesium ions enabled the analogues to adopt two different conformations near physiological pH. Understanding how the intrinsic chemical properties of the PP-InsPs can contribute to their complex signalling outputs will be essential to elucidate their regulatory functions. C1 [Brown, Nathaniel W., Jr.; Fiedler, Dorothea] Leibniz Inst Mol Pharmacol, Robert Rossle Str 10, D-13125 Berlin, Germany. [Hager, Anastasia; Wu, Mingxuan; Brown, Nathaniel W., Jr.; Fiedler, Dorothea] Princeton Univ, Dept Chem, Washington Rd, Princeton, NJ 08544 USA. [Wang, Huanchen; Shears, Stephen B.] NIH, Inositol Signaling Grp, Res Triangle Pk, NC 27709 USA. [Veiga, Nicolas] Univ Republica, Fac Quim, Catedra Quim Inorgan, Dept Estrella Campos, CC 1157, Montevideo, Uruguay. RP Fiedler, D (reprint author), Leibniz Inst Mol Pharmacol, Robert Rossle Str 10, D-13125 Berlin, Germany.; Fiedler, D (reprint author), Princeton Univ, Dept Chem, Washington Rd, Princeton, NJ 08544 USA.; Veiga, N (reprint author), Univ Republica, Fac Quim, Catedra Quim Inorgan, Dept Estrella Campos, CC 1157, Montevideo, Uruguay. EM nveiga@fq.edu.uy; fiedler@fmp-berlin.de FU Deutsche Forschungsgemeinschaft (DFG); NIH [DP2 CA186753]; Sidney Kimmel Foundation; Rita Allen Foundation; Princeton University FX We thank Dr. Istvan Pelczer, Ken Conover, and Dr. Peter Schmieder for guidance with the NMR experiments, and their helpful suggestions. We also thank Laura Wilson from Lotus Separations for assistance with the chiral SFC. Anastasia Hager gratefully acknowledges the Deutsche Forschungsgemeinschaft (DFG) for her postdoctoral fellowship. D.F. received funding from the NIH (DP2 CA186753), the Sidney Kimmel Foundation, the Rita Allen Foundation, and Princeton University. NR 63 TC 2 Z9 2 U1 4 U2 4 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 0947-6539 EI 1521-3765 J9 CHEM-EUR J JI Chem.-Eur. J. PD AUG 22 PY 2016 VL 22 IS 35 BP 12406 EP 12414 DI 10.1002/chem.201601754 PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA DV4DX UT WOS:000382876500026 PM 27460418 ER PT J AU Maul, RW MacCarthy, T Frank, EG Donigan, KA McLenigan, MP Yang, W Saribasak, H Huston, DE Lange, SS Woodgate, R Gearhart, PJ AF Maul, Robert W. MacCarthy, Thomas Frank, Ekaterina G. Donigan, Katherine A. McLenigan, Mary P. Yang, William Saribasak, Huseyin Huston, Donald E. Lange, Sabine S. Woodgate, Roger Gearhart, Patricia J. TI DNA polymerase iota functions in the generation of tandem mutations during somatic hypermutation of antibody genes SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID CLASS-SWITCH RECOMBINATION; IMMUNOGLOBULIN GENES; DEFICIENT MICE; ZETA; ETA; MOUSE; CELLS; EXPRESSION; PROTEINS; FIDELITY AB DNA polymerase iota (Pol iota) is an attractive candidate for somatic hypermutation in antibody genes because of its low fidelity. To identify a role for Pol iota, we analyzed mutations in two strains of mice with deficiencies in the enzyme: 129 mice with negligible expression of truncated Pol iota, and knock-in mice that express full-length Pol iota that is catalytically inactive. Both strains had normal frequencies and spectra of mutations in the variable region, indicating that loss of Pol iota did not change overall mutagenesis. We next examined if Pol iota affected tandem mutations generated by another error-prone polymerase, Pol zeta. The frequency of contiguous mutations was analyzed using a novel computational model to determine if they occur during a single DNA transaction or during two independent events. Analyses of 2,000 mutations from both strains indicated that Pol iota-compromised mice lost the tandem signature, whereas C57BL/6 mice accumulated significant amounts of double mutations. The results support a model where Pol iota occasionally accesses the replication fork to generate a first mutation, and Pol zeta extends the mismatch with a second mutation. C1 [Maul, Robert W.; Yang, William; Saribasak, Huseyin; Gearhart, Patricia J.] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. [MacCarthy, Thomas] SUNY Stony Brook, Dept Appl Math & Stat, Stony Brook, NY 11794 USA. [Frank, Ekaterina G.; Donigan, Katherine A.; McLenigan, Mary P.; Huston, Donald E.; Woodgate, Roger] NICHHD, Lab Genom Integr, NIH, Rockville, MD 20850 USA. [Lange, Sabine S.] Univ Texas MD Anderson Canc Ctr, Dept Mol Carcinogenesis, Sci Pk, Smithville, TX 78957 USA. RP Gearhart, PJ (reprint author), NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. EM gearhartp@mail.nih.gov FU National Institutes of Health (NIH) [GM111741]; Intramural Research Programs of the National Institute of Child Health and Human Development; National Institute on Aging FX This work was supported in part by National Institutes of Health (NIH) grant GM111741 to T. MacCarthy, and the Intramural Research Programs of the National Institute of Child Health and Human Development to R. Woodgate, and National Institute on Aging to P.J. Gearhart. NR 36 TC 3 Z9 3 U1 5 U2 5 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 AUG 22 PY 2016 VL 213 IS 9 BP 1675 EP 1683 DI 10.1084/jem.20151227 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DU9FE UT WOS:000382520900004 PM 27455952 ER PT J AU Liu, Y Betts, MJ Lei, J Wei, GC Bao, QY Kehl, T Russell, RB Lochelt, M AF Liu, Yang Betts, Matthew J. Lei, Janet Wei, Guochao Bao, Qiuying Kehl, Timo Russell, Robert B. Loechelt, Martin TI Mutagenesis of N-terminal residues of feline foamy virus Gag reveals entirely distinct functions during capsid formation, particle assembly, Gag processing and budding SO RETROVIROLOGY LA English DT Article DE Foamy virus; Feline foamy virus; Gag; Mutagenesis; Capsid formation; Assembly; Genome packaging; Particle budding and maturation; Transmission ID ENV LEADER PROTEIN; TARGETING-RETENTION SIGNAL; PERICENTRIOLAR REGION; VIRAL INFECTIVITY; POL POLYPROTEIN; RETROVIRAL GAG; HUMAN-CELLS; C-TERMINUS; DOMAIN; IDENTIFICATION AB Background: Foamy viruses (FVs) of the Spumaretrovirinae subfamily are distinct retroviruses, with many features of their molecular biology and replication strategy clearly different from those of the Orthoretroviruses, such as human immunodeficiency, murine leukemia, and human T cell lymphotropic viruses. The FV Gag N-terminal region is responsible for capsid formation and particle budding via interaction with Env. However, the critical residues or motifs in this region and their functional interaction are currently ill-defined, especially in non-primate FVs. Results: Mutagenesis of N-terminal Gag residues of feline FV (FFV) reveals key residues essential for either capsid assembly and/or viral budding via interaction with the FFV Env leader protein (Elp). In an in vitro Gag-Elp interaction screen, Gag mutations abolishing particle assembly also interfered with Elp binding, indicating that Gag assembly is a prerequisite for this highly specific interaction. Gradient sedimentation analyses of cytosolic proteins indicate that wild-type Gag is mostly assembled into virus capsids. Moreover, proteolytic processing of Gag correlates with capsid assembly and is mostly, if not completely, independent from particle budding. In addition, Gag processing correlates with the presence of packaging-competent FFV genomic RNA suggesting that Pol encapsidation via genomic RNA is a prerequisite for Gag processing. Though an appended heterogeneous myristoylation signal rescues Gag particle budding of mutants unable to form capsids or defective in interacting with Elp, it fails to generate infectious particles that co-package Pol, as evidenced by a lack of Gag processing. Conclusions: Changes in proteolytic Gag processing, intracellular capsid assembly, particle budding and infectivity of defined N-terminal Gag mutants highlight their essential, distinct and only partially overlapping roles during viral assembly and budding. Discussion of these findings will be based on a recent model developed for Gag-Elp interactions in prototype FV. C1 [Liu, Yang; Lei, Janet; Wei, Guochao; Bao, Qiuying; Kehl, Timo; Loechelt, Martin] German Canc Res Ctr, Dept Mol Diagnost Oncogen Infect, Res Program Infect & Canc, Neuenheimer Feld 242, D-69120 Heidelberg, Germany. [Betts, Matthew J.; Russell, Robert B.] Heidelberg Univ, CellNetworks, Bioquant, Neuenheimer Feld 267, D-69120 Heidelberg, Germany. [Russell, Robert B.] BZH, Neuenheimer Feld 328, D-69120 Heidelberg, Germany. [Liu, Yang] NCI, Ctr Canc Res, Frederick, MD 21701 USA. [Lei, Janet] Univ Oxford, Dept Oncol, Oxford, England. [Bao, Qiuying] East China Normal Univ, Dept Biol, Shanghai, Peoples R China. RP Lochelt, M (reprint author), German Canc Res Ctr, Dept Mol Diagnost Oncogen Infect, Res Program Infect & Canc, Neuenheimer Feld 242, D-69120 Heidelberg, Germany. EM m.loechelt@dkfz.de FU German Cancer Research Center, Heidelberg, Germany; Chinese Scholarship Council; Helmholtz International Graduate School for Cancer Research FX This work was funded in part by the German Cancer Research Center, Heidelberg, Germany. YL, GW, and QB are supported by PhD stipends from the Chinese Scholarship Council. JL is supported by a PhD stipend from the Helmholtz International Graduate School for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 0 Z9 0 U1 4 U2 4 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 AUG 22 PY 2016 VL 13 AR 57 DI 10.1186/s12977-016-0291-8 PG 20 WC Virology SC Virology GA DT8OR UT WOS:000381751000001 PM 27549192 ER PT J AU Thokala, R Olivares, S Mi, TJ Maiti, S Deniger, D Huls, H Torikai, H Singh, H Champlin, RE Laskowski, T McNamara, G Cooper, LJN AF Thokala, Radhika Olivares, Simon Mi, Tiejuan Maiti, Sourindra Deniger, Drew Huls, Helen Torikai, Hiroki Singh, Harjeet Champlin, Richard E. Laskowski, Tamara McNamara, George Cooper, Laurence J. N. TI Redirecting Specificity of T cells Using the Sleeping Beauty System to Express Chimeric Antigen Receptors by Mix-and-Matching of V-L and V-H Domains Targeting CD123(+) Tumors SO PLOS ONE LA English DT Article ID ACUTE MYELOID-LEUKEMIA; TOXIN-INTERLEUKIN-3 FUSION PROTEIN; ACUTE MYELOGENOUS LEUKEMIA; ADOPTIVE IMMUNOTHERAPY; INTERLEUKIN-3 RECEPTOR; CD28 COSTIMULATION; PHASE-I; VENOOCCLUSIVE DISEASE; CYTOTOXIC LYMPHOCYTES; ANTITUMOR EFFICACY AB Adoptive immunotherapy infusing T cells with engineered specificity for CD19 expressed on B-cell malignancies is generating enthusiasm to extend this approach to other hematological malignancies, such as acute myelogenous leukemia (AML). CD123, or interleukin 3 receptor alpha, is overexpressed on most AML and some lymphoid malignancies, such as acute lymphocytic leukemia (ALL), and has been an effective target for T cells expressing chimeric antigen receptors (CARs). The prototypical CAR encodes a V-H and V-L from one monoclonal antibody (mAb), coupled to a transmembrane domain and one or more cytoplasmic signaling domains. Previous studies showed that treatment of an experimental AML model with CD123-specific CAR T cells was therapeutic, but at the cost of impaired myelopoiesis, highlighting the need for systems to define the antigen threshold for CAR recognition. Here, we show that CARs can be engineered using V-H and V-L chains derived from different CD123-specific mAbs to generate a panel of CAR(+) T cells. While all CARs exhibited specificity to CD123, one V-H and V-L combination had reduced lysis of normal hematopoietic stem cells. This CAR's in vivo anti-tumor activity was similar whether signaling occurred via chimeric CD28 or CD137, prolonging survival in both AML and ALL models. Co-expression of inducible caspase 9 eliminated CAR(+) T cells. These data help support the use of CD123-specific CARs for treatment of CD123(+) hematologic malignancies. C1 [Thokala, Radhika; Olivares, Simon; Mi, Tiejuan; Maiti, Sourindra; Deniger, Drew; Torikai, Hiroki; Singh, Harjeet; Laskowski, Tamara; McNamara, George; Cooper, Laurence J. N.] Univ Texas MD Anderson Canc Ctr, Div Pediat, Houston, TX 77030 USA. [Thokala, Radhika] Univ Texas Houston, Grad Sch Biomed Sci, Houston, TX USA. [Champlin, Richard E.] Univ Texas MD Anderson Canc Ctr, Stem Cell Transplantat & Cellular Therapy, Houston, TX 77030 USA. [Cooper, Laurence J. N.] Ziopharm Oncol Inc, Boston, MA 02129 USA. [Huls, Helen] Intrexon Corp, Germantown, MD USA. [Deniger, Drew] NCI, Surg Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Cooper, LJN (reprint author), Univ Texas MD Anderson Canc Ctr, Div Pediat, Houston, TX 77030 USA.; Cooper, LJN (reprint author), Ziopharm Oncol Inc, Boston, MA 02129 USA. EM ljncooper@ziopharm.com FU Cancer Center Core Grant [CA16672]; SPORES [CA100632, CA136411, CA00632]; Albert J Ward Foundation; Alex's Lemonade Stand Foundation; Burroughs Wellcome Fund; Cancer Prevention and Research Institute of Texas; Charles B. Goddard Foundation of Texas; CLL Global Research Foundation; Energy Transfer Partners; Estate of Noelan L. Bibler; Gillson Longenbaugh Foundation; Harry T. Mangurian, Jr., Fund for Leukemia Immunotherapy; Khalifa Bin Zayed Al Nahyan Foundation; Kleberg Foundation; Leukemia and Lymphoma Society; Lymphoma Research Foundation; Miller Foundation; National Foundation for Cancer Research; Pediatric Cancer Research Foundation; Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy; University of Texas MD Anderson Cancer Center Sister Institution Network Fund; University of Texas MD Anderson Cancer Center Moon Shot Fund; William Lawrence and Blanche Hughes Children's Foundation; [CA124782]; [CA120956]; [CA141303]; [CA148600] FX This work was supported by: Cancer Center Core Grant (CA16672); RO1 (CA124782, CA120956, CA141303; CA141303); P01 (CA148600); SPORES (CA100632, CA136411, CA00632); Albert J Ward Foundation; Alex's Lemonade Stand Foundation; Burroughs Wellcome Fund; Cancer Prevention and Research Institute of Texas; Charles B. Goddard Foundation of Texas; CLL Global Research Foundation; Energy Transfer Partners; Estate of Noelan L. Bibler; Gillson Longenbaugh Foundation; Harry T. Mangurian, Jr., Fund for Leukemia Immunotherapy; Khalifa Bin Zayed Al Nahyan Foundation; Kleberg Foundation; Leukemia and Lymphoma Society; Lymphoma Research Foundation; Miller Foundation; Mr. Herb Simons; Mr. and Mrs. Joe H. Scales; Mr. Thomas Scott; National Foundation for Cancer Research; Pediatric Cancer Research Foundation; Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy; University of Texas MD Anderson Cancer Center Sister Institution Network Fund and Moon Shot Fund; William Lawrence and Blanche Hughes Children's Foundation. Dr. Cooper receives a salary as CEO of Ziopharm. The specific roles of the authors are articulated in the 'author contributions' section. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 70 TC 3 Z9 3 U1 2 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 22 PY 2016 VL 11 IS 8 AR e0159477 DI 10.1371/journal.pone.0159477 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT8TP UT WOS:000381768400006 PM 27548616 ER PT J AU Tong, X Srivatsan, A Jacobson, O Wang, Y Wang, ZT Yang, XY Niu, G Kiesewetter, DO Zheng, HR Chen, XY AF Tong, Xiao Srivatsan, Avinash Jacobson, Orit Wang, Yu Wang, Zhantong Yang, Xiangyu Niu, Gang Kiesewetter, Dale O. Zheng, Hairong Chen, Xiaoyuan TI Monitoring Tumor Hypoxia Using F-18-FMISO PET and Pharmacokinetics Modeling after Photodynamic Therapy SO SCIENTIFIC REPORTS LA English DT Article ID IN-VITRO; F-18 FLUOROMISONIDAZOLE; F-18-FLUOROMISONIDAZOLE PET; NECK-CANCER; MICROENVIRONMENT; RESPONSIVENESS; VASCULATURE; DETERMINES; HEAD; PDT AB Photodynamic therapy (PDT) is an efficacious treatment for some types of cancers. However, PDT-induced tumor hypoxia as a result of oxygen consumption and vascular damage can reduce the efficacy of this therapy. Measuring and monitoring intrinsic and PDT-induced tumor hypoxia in vivo during PDT is of high interest for prognostic and treatment evaluation. In the present study, static and dynamic F-18-FMISO PET were performed with mice bearing either U87MG or MDA-MB-435 tumor xenografts immediately before and after PDT at different time points. Significant difference in tumor hypoxia in response to PDT over time was found between the U87MG and MDA-MB-435 tumors in both static and dynamic PET. Dynamic PET with pharmacokinetics modeling further monitored the kinetics of F-18-FMISO retention to hypoxic sites after treatment. The K-i and k(3) parametric analysis provided information on tumor hypoxia by distinction of the specific tracer retention in hypoxic sites from its non-specific distribution in tumor. Dynamic F-18-FMISO PET with pharmacokinetics modeling, complementary to static PET analysis, provides a potential imaging tool for more detailed and more accurate quantification of tumor hypoxia during PDT. C1 [Tong, Xiao; Srivatsan, Avinash; Jacobson, Orit; Wang, Yu; Wang, Zhantong; Yang, Xiangyu; Niu, Gang; Kiesewetter, Dale O.; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. [Tong, Xiao; Zheng, Hairong] Chinese Acad Sci, Shenzhen Inst Adv Technol, Paul C Lauterbur Res Ctr Biomed Imaging, Inst Biomed & Hlth Engn, Shenzhen 518055, Peoples R China. RP Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA.; Zheng, HR (reprint author), Chinese Acad Sci, Shenzhen Inst Adv Technol, Paul C Lauterbur Res Ctr Biomed Imaging, Inst Biomed & Hlth Engn, Shenzhen 518055, Peoples R China. EM hr.zheng@siat.ac.cn; shawn.chen@nih.gov FU Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH); National High Technology Research and Development Program of China [2014AA020503] 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), and the National High Technology Research and Development Program of China (2014AA020503). NR 38 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 AUG 22 PY 2016 VL 6 AR 31551 DI 10.1038/srep31551 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT7WZ UT WOS:000381700300001 PM 27546160 ER PT J AU Zheng, G Zhang, W Xu, JF Yuan, A Li, QZ Gastwirth, JL AF Zheng, Gang Zhang, Wei Xu, Jinfeng Yuan, Ao Li, Qizhai Gastwirth, Joseph L. TI Genetic risks and genetic model specification SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE Case-control design; Genetic model; Genetic risk; Hardy-Weinberg equilibrium ID CASE-CONTROL ASSOCIATION; HARDY-WEINBERG DISEQUILIBRIUM; SAMPLE-SIZE; TREND TESTS; POWER; APPROXIMATIONS; SELECTION; GENOTYPES; MARKERS; MAX AB Genetic risks and genetic models are often used in design and analysis of genetic epidemiology studies. A genetic model is defined in terms of two genetic risk measures: genotype relative risk and odds ratio. The impacts of choosing a risk measure on the resulting genetic models are studied in the power to detect association and deviation from Hardy Weinberg equilibrium in cases using genetic relative risk. Extensive simulations demonstrate that the power of a study to detect associations using odds ratio is lower than that using relative risk with the same value when other parameters are fixed. When the Hardy Weinberg equilibrium holds in the general population, the genetic model can be inferred by the deviation from Hardy Weinberg equilibrium in only cases. Furthermore, it is more efficient than that based on the deviation from Hardy-Weinberg equilibrium in all cases and controls. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Zheng, Gang] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Zhang, Wei; Li, Qizhai] Chinese Acad Sci, Acad Math & Syst Sci, Key Lab Syst & Control, Beijing, Peoples R China. [Xu, Jinfeng] Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. [Yuan, Ao] Georgetown Univ, Washington, DC 20057 USA. [Gastwirth, Joseph L.] George Washington Univ, Washington, DC USA. RP Yuan, A (reprint author), Georgetown Univ, Washington, DC 20057 USA. EM yuanao@hotmail.com FU National Science Foundation of China [11371353, 61134013]; Chinese Academy of Sciences [XDB13040600] FX We would like to thank three anonymous reviewers for their careful reading and thoughtful comments, which greatly improved our manuscript. The authors would like to thank Ryo Yamada for some helpful discussions. Q. Li was supported in part by the National Science Foundation of China, (Grant nos. 11371353 and 61134013) and the Breakthrough Project of Strategic Priority Program of the Chinese Academy of Sciences, Grant no. XDB13040600. NR 19 TC 1 Z9 1 U1 5 U2 8 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 EI 1095-8541 J9 J THEOR BIOL JI J. Theor. Biol. PD AUG 21 PY 2016 VL 403 BP 68 EP 74 DI 10.1016/j.jtbi.2016.05.016 PG 7 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA DQ1UY UT WOS:000378987100008 PM 27181372 ER PT J AU Lazarus, HM Pavletic, SZ AF Lazarus, Hillard M. Pavletic, Steven Z. TI Umbilical Cord Blood-Derived Mesenchymal Stromal Cells for Reducing Chronic Graft-Versus-Host Disease After Haploidentical Transplantation: Just Another Labor-Intensive Strategy, or Showing the Way? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID HEMATOLOGIC MALIGNANCY PATIENTS; ACUTE MYELOID-LEUKEMIA; NATURAL-KILLER-CELLS; STEM-CELLS; COTRANSPLANTATION C1 [Lazarus, Hillard M.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Pavletic, Steven Z.] Natl Inst Hlth, Bethesda, MD USA. RP Lazarus, HM (reprint author), Case Western Reserve Univ, Cleveland, OH 44106 USA. NR 18 TC 0 Z9 1 U1 2 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2016 VL 34 IS 24 BP 2812 EP + DI 10.1200/JCO.2016.67.7344 PG 4 WC Oncology SC Oncology GA DU8MZ UT WOS:000382469100003 PM 27400943 ER PT J AU Lengacher, CA Reich, RR Paterson, CL Ramesar, S Park, JY Alinat, C Johnson-Mallard, V Moscoso, M Budhrani-Shani, P Miladinovic, B Jacobsen, PB Cox, CE Goodman, M Kip, KE AF Lengacher, Cecile A. Reich, Richard R. Paterson, Carly L. Ramesar, Sophia Park, Jong Y. Alinat, Carissa Johnson-Mallard, Versie Moscoso, Manolete Budhrani-Shani, Pinky Miladinovic, Branko Jacobsen, Paul B. Cox, Charles E. Goodman, Matthew Kip, Kevin E. TI Examination of Broad Symptom Improvement Resulting From Mindfulness-Based Stress Reduction in Breast Cancer Survivors: A Randomized Controlled Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID QUALITY-OF-LIFE; OLDER WOMEN; LONG-TERM; FOLLOW-UP; MEDITATION; RECURRENCE; FATIGUE; SLEEP; PREVALENCE; THERAPY AB Purpose The purpose of this randomized trial was to evaluate the efficacy of the Mindfulness-Based Stress Reduction for Breast Cancer (MBSR[BC]) program in improving psychological and physical symptoms and quality of life among breast cancer survivors (BCSs) who completed treatment. Outcomes were assessed immediately after 6 weeks of MBSR(BC) training and 6 weeks later to test efficacy over an extended timeframe. Patients and Methods A total of 322 BCSs were randomly assigned to either a 6-week MBSR(BC) program (n = 155) or a usual care group (n = 167). Psychological (depression, anxiety, stress, and fear of recurrence) and physical symptoms (fatigue and pain) and quality of life (as related to health) were assessed at baseline and at 6 and 12 weeks. Linear mixed models were used to assess MBSR(BC) effects over time, and participant characteristics at baseline were also tested as moderators of MBSR(BC) effects. Results Results demonstrated extended improvement for the MBSR(BC) group compared with usual care in both psychological symptoms of anxiety, fear of recurrence overall, and fear of recurrence problems and physical symptoms of fatigue severity and fatigue interference (P < .01). Overall effect sizes were largest for fear of recurrence problems (d = 0.35) and fatigue severity (d = 0.27). Moderation effects showed BCSs with the highest levels of stress at baseline experienced the greatest benefit from MBSR(BC). Conclusion The MBSR(BC) program significantly improved a broad range of symptoms among BCSs up to 6 weeks after MBSR(BC) training, with generally small to moderate overall effect sizes. C1 [Lengacher, Cecile A.; Ramesar, Sophia; Alinat, Carissa; Moscoso, Manolete; Kip, Kevin E.] Univ S Florida, Coll Nursing, MDC 22,12901 Bruce B Downs Blvd, Tampa, FL 33620 USA. [Park, Jong Y.; Jacobsen, Paul B.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Miladinovic, Branko; Cox, Charles E.] Univ S Florida, Morsani Coll Med, Tampa, FL USA. [Reich, Richard R.] Univ S Florida, Sarasota, FL USA. [Johnson-Mallard, Versie] Univ Florida, Coll Nursing, Gainesville, FL 32611 USA. [Paterson, Carly L.] NCI, Rockville, MD USA. [Budhrani-Shani, Pinky] Texas Womans Univ, Nelda C Stark Coll Nursing, Houston, TX USA. [Goodman, Matthew] Univ Virginia, Charlottesville, VA USA. RP Lengacher, CA (reprint author), Univ S Florida, Coll Nursing, MDC 22,12901 Bruce B Downs Blvd, Tampa, FL 33620 USA. EM clengach@health.usf.edu FU National Cancer Institute [1R01CA131080-01A2]; Survey Methods Core Facility at the H. Lee Moffitt Cancer Center and Research Institute FX Supported by Award No. 1R01CA131080-01A2 from the National Cancer Institute and in part by the Survey Methods Core Facility at the H. Lee Moffitt Cancer Center and Research Institute. NR 43 TC 3 Z9 3 U1 10 U2 10 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 AUG 20 PY 2016 VL 34 IS 24 BP 2827 EP + DI 10.1200/JCO.2015.65.7874 PG 9 WC Oncology SC Oncology GA DU8MZ UT WOS:000382469100006 PM 27247219 ER PT J AU Wentzensen, N Poole, EM Trabert, B White, E Arslan, AA Patel, AV Setiawan, VW Visvanathan, K Weiderpass, E Adami, HO Black, A Bernstein, L Brinton, LA Buring, J Butler, LM Chamosa, S Clendenen, TV Dossus, L Fortner, R Gapstur, SM Gaudet, MM Gram, IT Hartge, P Hoffman-Bolton, J Idahl, A Jones, M Kaaks, R Kirsh, V Koh, WP Lacey, JV Lee, IM Lundin, E Merritt, MA Onland-Moret, NC Peters, U Poynter, JN Rinaldi, S Robien, K Rohan, T Sandler, DP Schairer, C Schouten, LJ Sjoholm, LK Sieri, S Swerdlow, A Tjonneland, A Travis, R Trichopoulou, A van den Brandt, PA Wilkens, L Wolk, A Yang, HP Zeleniuch-Jacquotte, A Tworoger, SS AF Wentzensen, Nicolas Poole, Elizabeth M. Trabert, Britton White, Emily Arslan, Alan A. Patel, Alpa V. Setiawan, V. Wendy Visvanathan, Kala Weiderpass, Elisabete Adami, Hans-Olov Black, Amanda Bernstein, Leslie Brinton, Louise A. Buring, Julie Butler, Lesley M. Chamosa, Saioa Clendenen, Tess V. Dossus, Laure Fortner, Renee Gapstur, Susan M. Gaudet, Mia M. Gram, Inger T. Hartge, Patricia Hoffman-Bolton, Judith Idahl, Annika Jones, Michael Kaaks, Rudolf Kirsh, Victoria Koh, Woon-Puay Lacey, James V., Jr. Lee, I-Min Lundin, Eva Merritt, Melissa A. Onland-Moret, N. Charlotte Peters, Ulrike Poynter, Jenny N. Rinaldi, Sabina Robien, Kim Rohan, Thomas Sandler, Dale P. Schairer, Catherine Schouten, Leo J. Sjoholm, Louise K. Sieri, Sabina Swerdlow, Anthony Tjonneland, Anna Travis, Ruth Trichopoulou, Antonia van den Brandt, Piet A. Wilkens, Lynne Wolk, Alicja Yang, Hannah P. Zeleniuch-Jacquotte, Anne Tworoger, Shelley S. TI Ovarian Cancer Risk Factors by Histologic Subtype: An Analysis From the Ovarian Cancer Cohort Consortium SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID INDIVIDUAL PARTICIPANT METAANALYSIS; RANDOMIZED CONTROLLED-TRIAL; ASSOCIATION CONSORTIUM; POOLED ANALYSIS; WOMEN; PATHOGENESIS; INFLAMMATION; MORTALITY; PROSTATE; SMOKING AB Purpose An understanding of the etiologic heterogeneity of ovarian cancer is important for improving prevention, early detection, and therapeutic approaches. We evaluated 14 hormonal, reproductive, and lifestyle factors by histologic subtype in the Ovarian Cancer Cohort Consortium (OC3). Patients and Methods Among 1.3 million women from 21 studies, 5,584 invasive epithelial ovarian cancers were identified (3,378 serous, 606 endometrioid, 331 mucinous, 269 clear cell, 1,000 other). By using competing risks Cox proportional hazards regression stratified by study and birth year and adjusted for age, parity, and oral contraceptive use, we assessed associations for all invasive cancers by histology. Heterogeneity was evaluated by likelihood ratio test. Results Most risk factors exhibited significant heterogeneity by histology. Higher parity was most strongly associated with endometrioid (relative risk [RR] per birth, 0.78; 95% CI, 0.74 to 0.83) and clear cell (RR, 0.68; 95% CI, 0.61 to 0.76) carcinomas (P value for heterogeneity [P-het] < .001). Similarly, age at menopause, endometriosis, and tubal ligation were only associated with endometrioid and clear cell tumors (P-het <= .01). Family history of breast cancer (P-het = .008) had modest heterogeneity. Smoking was associated with an increased risk of mucinous (RR per 20 pack-years, 1.26; 95% CI, 1.08 to 1.46) but a decreased risk of clear cell (RR, 0.72; 95% CI, 0.55 to 0.94) tumors (P-het = .004). Unsupervised clustering by risk factors separated endometrioid, clear cell, and low-grade serous carcinomas from high-grade serous and mucinous carcinomas. Conclusion The heterogeneous associations of risk factors with ovarian cancer subtypes emphasize the importance of conducting etiologic studies by ovarian cancer subtypes. Most established risk factors were more strongly associated with nonserous carcinomas, which demonstrate challenges for risk prediction of serous cancers, the most fatal subtype. (C) 2016 by American Society of Clinical Oncology C1 [Wentzensen, Nicolas; Poole, Elizabeth M.; Trabert, Britton; Black, Amanda; Brinton, Louise A.; Hartge, Patricia; Schairer, Catherine; Yang, Hannah P.] NCI, Bethesda, MD 20892 USA. [Sandler, Dale P.] NIEHS, Bethesda, MD USA. [Poole, Elizabeth M.; Buring, Julie; Lee, I-Min; Tworoger, Shelley S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Poole, Elizabeth M.; Adami, Hans-Olov; Buring, Julie; Lee, I-Min; Tworoger, Shelley S.] Harvard Univ, Boston, MA 02115 USA. [White, Emily; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Arslan, Alan A.; Clendenen, Tess V.; Zeleniuch-Jacquotte, Anne] NYU, Sch Med, New York, NY 10003 USA. [Rohan, Thomas] Albert Einstein Coll Med, New York, NY USA. [Patel, Alpa V.; Gapstur, Susan M.; Gaudet, Mia M.] Amer Canc Soc, Atlanta, GA 30329 USA. [Setiawan, V. Wendy] Univ Southern Calif, Los Angeles, CA USA. [Bernstein, Leslie; Lacey, James V., Jr.] City Hope Natl Med Ctr, Duarte, CA USA. [Visvanathan, Kala; Hoffman-Bolton, Judith] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Weiderpass, Elisabete; Gram, Inger T.] Univ Tromso Arctic Univ Norway, Tromso, Norway. [Weiderpass, Elisabete] Canc Registry Norway, Oslo, Norway. [Weiderpass, Elisabete; Adami, Hans-Olov; Sjoholm, Louise K.; Wolk, Alicja] Karolinska Inst, Stockholm, Sweden. [Idahl, Annika; Lundin, Eva] Umea Univ, Umea, Sweden. [Weiderpass, Elisabete] Folkhalsan Res Ctr, Helsinki, Finland. [Butler, Lesley M.] Univ Pittsburgh, Pittsburgh, PA USA. [Chamosa, Saioa] BioDonostia Res Inst, San Sebastian, Spain. [Dossus, Laure] French Inst Hlth & Med Res, Paris, France. [Rinaldi, Sabina] Int Agcy Res Canc, Lyon, France. [Fortner, Renee; Kaaks, Rudolf] German Canc Res Ctr, Heidelberg, Germany. [Jones, Michael; Swerdlow, Anthony] Inst Canc Res, Sutton, Surrey, England. [Merritt, Melissa A.] Imperial Coll London, London, England. [Travis, Ruth] Univ Oxford, Oxford, England. [Kirsh, Victoria] Univ Toronto, Toronto, ON, Canada. [Koh, Woon-Puay] Duke Univ, Singapore, Singapore. [Onland-Moret, N. Charlotte] Univ Med Ctr Utrecht, Utrecht, Netherlands. [Schouten, Leo J.; van den Brandt, Piet A.] Maastricht Univ, Maastricht, Netherlands. [Poynter, Jenny N.] Univ Minnesota, Minneapolis, MN USA. [Robien, Kim] George Washington Univ, Washington, DC USA. [Sieri, Sabina] Natl Canc Inst, Rome, Italy. [Tjonneland, Anna] Danish Canc Soc, Copenhagen, Denmark. [Trichopoulou, Antonia] Hellenic Hlth Fdn, Athens, Greece. [Wilkens, Lynne] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. RP Wentzensen, N (reprint author), NCI, Div Canc Epidemiol & Genet, Room 7-E114,9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM wentzenn@mail.nih.gov RI Weiderpass, Elisabete/M-4029-2016; Trabert, Britton/F-8051-2015; Onland-Moret, N. Charlotte/G-9185-2011; OI Weiderpass, Elisabete/0000-0003-2237-0128; Fortner, Renee/0000-0002-1426-8505; Robien, Kim/0000-0002-2120-2280; Sandler, Dale/0000-0002-6776-0018; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303 FU Department of Defense Ovarian Cancer Research Program [W81XWH-12-1-0561]; Breakthrough Breast Cancer; Institute of Cancer Research; National Health Service; National Cancer Institute (NCI) [K05 CA154337]; Office of Dietary Supplements (VITAL [Vitamins and Lifestyle study cohort]); Iowa Women's Health Study [R01 CA39742]; National Institutes of Health/NCI grant [UM1 CA182876, CA047988, HL043851, HL080467, HL099355, CA164973, R01 CA77398, UM1 CA169417, UM1 CA186107, P01 CA87969, UM1 CA176726, R01 CA67262]; Swedish Cancer Society; Swedish Research Council; Intramural Research Program of the American Cancer Society; NCI Intramural Research Program; Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences [Z01ES044005]; European Commission (DG-SANCO); International Agency for Research on Cancer; Danish Cancer Society (Denmark); Ligue Contre le Cancer (France); Institut Gustave Roussy (France); Mutuelle Generale de l'Education Nationale (France); Institut National de la Sante et de la Recherche Medicale (France); German Cancer Aid (Germany); German Cancer Research Center (Germany); Federal Ministry of Education and Research (Germany); Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-Italy; National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (the Netherlands); Netherlands Cancer Registry (the Netherlands); LK Research Funds (the Netherlands); Dutch Prevention Funds (the Netherlands); Dutch Zorg Onderzoek Nederland (the Netherlands); World Cancer Research Fund (the Netherlands); Statistics Netherlands (the Netherlands); Nordic Centre of Excellence Programme on Food, Nutrition and Health (Norway); Health Research Fund (Spain) [PI13/00061]; Instituto San Carlos III Las Redes Tematicas de Investigacion Cooperativa en Salud (Spain) [RD06/0020]; regional government of Spain (Andalucia); regional government of Spain (Asturias); regional government of Spain (Basque Country); regional government of Spain (Murcia) [6236]; regional government of Spain (Navarra); Swedish Cancer Society (Sweden); Swedish Scientific Council (Sweden); County Council of Skane (Sweden); County Council of Vasterbotten (Sweden); Cancer Research UK (United Kingdom) [14136, C570/A16491]; Medical Research Council (United Kingdom) [1000143] FX Supported by Department of Defense Ovarian Cancer Research Program Grant No. W81XWH-12-1-0561. The UK Breakthrough Generations Study is supported by Breakthrough Breast Cancer and the Institute of Cancer Research. The Institute for Cancer Research is supported by National Health Service funding to the National Institute for Health Research Biomedical Research Centre. Also supported by K05 CA154337 from the National Cancer Institute (NCI) and Office of Dietary Supplements (VITAL [Vitamins and Lifestyle study cohort]); R01 CA39742 (Iowa Women's Health Study); National Institutes of Health/NCI grant UM1 CA182876 (Singapore Chinese Health Study); CA047988, HL043851, HL080467, and HL099355 (Women's Health Study); CA164973 (Multiethnic Cohort); R01 CA77398 and UM1 CA169417 (California Teachers Study); UM1 CA186107, P01 CA87969, UM1 CA176726, and R01 CA67262 (Nurses' Health Study, Nurses' Health Study II); grants from the Swedish Cancer Society and Swedish Research Council (Swedish Women's Lifestyle and Health cohort study); and the Swedish Research Council (Swedish Mammography Cohort). All aspects of the Cancer Prevention Study II were funded by the Intramural Research Program of the American Cancer Society and by the NCI Intramural Research Program, Intramural Research Program of the National Institutes of Health, and National Institute of Environmental Health Sciences (Z01ES044005; Sister Study). The coordination of European Prospective Investigation Into Cancer (EPIC) is supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by the Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, and Institut National de la Sante et de la Recherche Medicale (France); German Cancer Aid, German Cancer Research Center, and Federal Ministry of Education and Research (Germany); Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Dutch Zorg Onderzoek Nederland, World Cancer Research Fund, and Statistics Netherlands (the Netherlands); Nordic Centre of Excellence Programme on Food, Nutrition and Health (Norway); Health Research Fund, PI13/00061 to Granada, regional governments of Spain (Andalucia, Asturias, Basque Country, Murcia [No. 6236], and Navarra), and Instituto San Carlos III Las Redes Tematicas de Investigacion Cooperativa en Salud (RD06/0020; Spain); Swedish Cancer Society, Swedish Scientific Council, and County Councils of Skane and Vasterbotten (Sweden); and Cancer Research UK (14136 to EPIC-Norfolk, C570/A16491 to EPIC-Oxford) and Medical Research Council (1000143 to EPIC-Norfolk; United Kingdom). NR 38 TC 4 Z9 4 U1 13 U2 14 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 AUG 20 PY 2016 VL 34 IS 24 BP 2888 EP + DI 10.1200/JCO.2016.66.8178 PG 19 WC Oncology SC Oncology GA DU8MZ UT WOS:000382469100014 PM 27325851 ER PT J AU Wu, YC Chandris, P Winter, PW Kim, EY Jaumouille, V Kumar, A Guo, M Leung, JM Smith, C Rey-Suarez, I Liu, HF Waterman, CM Ramamurthi, KS La Riviere, PJ Shroff, H AF Wu, Yicong Chandris, Panagiotis Winter, Peter W. Kim, Edward Y. Jaumouille, Valentin Kumar, Abhishek Guo, Min Leung, Jacqueline M. Smith, Corey Rey-Suarez, Ivan Liu, Huafeng Waterman, Clare M. Ramamurthi, Kumaran S. La Riviere, Patrick J. Shroff, Hari TI Simultaneous multiview capture and fusion improves spatial resolution in wide-field and light-sheet microscopy SO OPTICA LA English DT Article ID PLANE ILLUMINATION MICROSCOPY; TOXOPLASMA-GONDII; BACILLUS-SUBTILIS; FLUORESCENCE MICROSCOPY; DECONVOLUTION; LOCALIZATION; SPORULATION; PROTEIN; 3D AB Most fluorescence microscopes are inefficient, collecting only a small fraction of the emitted light at any instant. Besides wasting valuable signal, this inefficiency also reduces spatial resolution and causes imaging volumes to exhibit significant resolution anisotropy. We describe microscopic and computational techniques that address these problems by simultaneously capturing and subsequently fusing and deconvolving multiple specimen views. Unlike previous methods that serially capture multiple views, our approach improves spatial resolution without introducing any additional illumination dose or compromising temporal resolution relative to conventional imaging. When applying our methods to single-view wide-field or dual-view light-sheet microscopy, we achieve a twofold improvement in volumetric resolution (similar to 235 nm x 235 nm x 340 nm) as demonstrated on a variety of samples including microtubules in Toxoplasma gondii, SpoVM in sporulating Bacillus subtilis, and multiple protein distributions and organelles in eukaryotic cells. In every case, spatial resolution is improved with no drawback by harnessing previously unused fluorescence. (C) 2016 Optical Society of America C1 [Wu, Yicong; Chandris, Panagiotis; Winter, Peter W.; Kumar, Abhishek; Guo, Min; Rey-Suarez, Ivan; Shroff, Hari] Natl Inst Biomed Imaging & Bioengn, Sect High Resolut Opt Imaging, NIH, Bethesda, MD 20892 USA. [Kim, Edward Y.; Ramamurthi, Kumaran S.] NCI, Mol Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. [Jaumouille, Valentin; Waterman, Clare M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Guo, Min; Liu, Huafeng] Zhejiang Univ, State Key Lab Modern Opt Instrumentat, Coll Opt Sci & Engn, Hangzhou 310027, Peoples R China. [Leung, Jacqueline M.] Indiana Univ, Dept Biol, Bloomington, IN 47405 USA. [Smith, Corey; La Riviere, Patrick J.] Univ Chicago, Dept Radiol, Chicago, IL 60637 USA. [La Riviere, Patrick J.; Shroff, Hari] Marine Biol Lab, Whitman Ctr, Woods Hole, MA 02543 USA. RP Wu, YC (reprint author), Natl Inst Biomed Imaging & Bioengn, Sect High Resolut Opt Imaging, NIH, Bethesda, MD 20892 USA. EM yicong.wu@nih.gov FU National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI); Marine Biological Laboratory (MBL) MBL-UChicago Exploratory Research Fund Research Award; National Institute of General Medical Sciences (NIGMS) [R25GM109439]; National Natural Science Foundation of China (NSFC) [61427807, 61271083, 61525106]; Colciencias-Fulbright Scholarship; March of Dimes Foundation (MODF) [6-FY15-198] FX National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI); Marine Biological Laboratory (MBL) MBL-UChicago Exploratory Research Fund Research Award; National Institute of General Medical Sciences (NIGMS) (R25GM109439); National Natural Science Foundation of China (NSFC) (61427807, 61271083, 61525106); Colciencias-Fulbright Scholarship; March of Dimes Foundation (MODF) (6-FY15-198). NR 40 TC 2 Z9 2 U1 17 U2 17 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2334-2536 J9 OPTICA JI Optica PD AUG 20 PY 2016 VL 3 IS 8 BP 897 EP 910 DI 10.1364/OPTICA.3.000897 PG 14 WC Optics SC Optics GA DU1YU UT WOS:000382007700019 PM 27761486 ER PT J AU Dacks, PA Armstrong, JJ Brannan, SK Carman, AJ Green, AM Kirkman, MS Krakoff, LR Kuller, LH Launer, LJ Lovestone, S Merikle, E Neumann, PJ Rockwood, K Shineman, DW Stefanacci, RG Velentgas, P Viswanathan, A Whitmer, RA Williamson, JD Fillit, HM AF Dacks, Penny A. Armstrong, Joshua J. Brannan, Stephen K. Carman, Aaron J. Green, Allan M. Kirkman, M. Sue Krakoff, Lawrence R. Kuller, Lewis H. Launer, Lenore J. Lovestone, Simon Merikle, Elizabeth Neumann, Peter J. Rockwood, Kenneth Shineman, Diana W. Stefanacci, Richard G. Velentgas, Priscilla Viswanathan, Anand Whitmer, Rachel A. Williamson, Jeff D. Fillit, Howard M. TI A call for comparative effectiveness research to learn whether routine clinical care decisions can protect from dementia and cognitive decline SO ALZHEIMERS RESEARCH & THERAPY LA English DT Review DE Comparative effectiveness; Dementia; Alzheimer's; Prevention; Cognitive decline; Cognitive aging; Comorbidity; Repurposing; Hypertension; Diabetes ID CALCIUM-CHANNEL BLOCKERS; ALZHEIMERS-DISEASE; ANTIHYPERTENSIVE DRUGS; HYPERTENSIVE PATIENTS; PROSPECTIVE COHORT; BLOOD-PRESSURE; HEART-FAILURE; OLDER-ADULTS; IMPAIRMENT; PREVENTION AB Common diseases like diabetes, hypertension, and atrial fibrillation are probable risk factors for dementia, suggesting that their treatments may influence the risk and rate of cognitive and functional decline. Moreover, specific therapies and medications may affect long-term brain health through mechanisms that are independent of their primary indication. While surgery, benzodiazepines, and anti-cholinergic drugs may accelerate decline or even raise the risk of dementia, other medications act directly on the brain to potentially slow the pathology that underlies Alzheimer's and other dementia. In other words, the functional and cognitive decline in vulnerable patients may be influenced by the choice of treatments for other medical conditions. Despite the importance of these questions, very little research is available. The Alzheimer's Drug Discovery Foundation convened an advisory panel to discuss the existing evidence and to recommend strategies to accelerate the development of comparative effectiveness research on how choices in the clinical care of common chronic diseases may protect from cognitive decline and dementia. C1 [Dacks, Penny A.; Carman, Aaron J.; Shineman, Diana W.; Fillit, Howard M.] Alzheimers Drug Discovery Fdn, 57 West 57th St Suite 901, New York, NY 10019 USA. [Armstrong, Joshua J.; Rockwood, Kenneth] Dalhousie Univ, Dept Med, Geriatr Med Res Unit, Halifax, NS, Canada. [Brannan, Stephen K.; Merikle, Elizabeth] Takeda Pharmaceut, Deerfield, IL USA. [Green, Allan M.] Attorney Law, Cambridge, MA USA. [Kirkman, M. Sue] Univ N Carolina, Div Endocrinol & Metab, Dept Med, Sch Med, Chapel Hill, NC USA. [Krakoff, Lawrence R.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Kuller, Lewis H.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Launer, Lenore J.] NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Lovestone, Simon] Univ Oxford, Dept Psychiat, Oxford, England. [Neumann, Peter J.] Tufts Med Ctr, Inst Clin Res & Hlth Policy Studies, Ctr Evaluat Value & Risk Hlth, Boston, MA USA. [Rockwood, Kenneth] DGI Clin, Halifax, NS, Canada. [Rockwood, Kenneth] Nova Scotia Hlth Author, Halifax, NS, Canada. [Stefanacci, Richard G.] Thomas Jefferson Coll Populat Hlth, Access Grp, Philadelphia, PA USA. [Velentgas, Priscilla] Quintiles Real World Late Phase Res, Sci Affairs, Cambridge, MA USA. [Viswanathan, Anand] Amer Heart Assoc, Boston, MA USA. [Viswanathan, Anand] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Stroke Res, Dept Neurol,Hemorrhag Stroke Res Program, Boston, MA USA. [Whitmer, Rachel A.] Kaiser Permanente Div Res Populat Sci & Brain Agi, Oakland, CA USA. [Williamson, Jeff D.] Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. RP Dacks, PA (reprint author), Alzheimers Drug Discovery Fdn, 57 West 57th St Suite 901, New York, NY 10019 USA. EM pdacks@alzdiscovery.org FU Alzheimer's Drug Discovery Foundation; Canadian Consortium on Neurodegeneration in Aging; Intramural Research Program, National Institute on Aging, NIH; NIH-NIA grants [K23 AG028726, R01AG047975] FX This position paper and the corresponding advisory panel were funded by the Alzheimer's Drug Discovery Foundation. Support for authors' time was provided by the Canadian Consortium on Neurodegeneration in Aging (JJA); the Intramural Research Program, National Institute on Aging, NIH (LJL); NIH-NIA grants K23 AG028726 and R01AG047975 (AV). Takeda Pharmaceuticals provided some support for the advisory panel; the American Heart Association supported the cost of travel for their representative (AV). NR 68 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 1758-9193 J9 ALZHEIMERS RES THER JI Alzheimers Res. Ther. PD AUG 20 PY 2016 VL 8 AR 33 DI 10.1186/s13195-016-0200-3 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DU9FR UT WOS:000382522300001 PM 27543171 ER PT J AU Berrigan, D Troiano, RP Graubard, BI AF Berrigan, David Troiano, Richard P. Graubard, Barry I. TI BMI and mortality: the limits of epidemiological evidence SO LANCET LA English DT Editorial Material ID BODY-MASS INDEX; ADULTS; INTERVENTIONS; DISEASE; LIFE C1 [Berrigan, David; Troiano, Richard P.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Graubard, Barry I.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Berrigan, D (reprint author), NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. EM berrigad@mail.nih.gov NR 15 TC 1 Z9 1 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD AUG 20 PY 2016 VL 388 IS 10046 BP 734 EP 736 DI 10.1016/S0140-6736(16)30949-7 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DT6UH UT WOS:000381619200005 PM 27423263 ER PT J AU Di Angelantonio, E Bhupathiraju, SN Wormser, D Gao, P Kaptoge, S de Gonzalez, AB Cairns, BJ Huxley, R Jackson, CL Joshy, G Lewington, S Manson, JE Murphy, N Patel, AV Samet, JM Woodward, M Zheng, W Zhou, M Bansal, N Barricarte, A Carter, B Cerhan, JR Collins, R Smith, GD Fang, X Franco, OH Green, J Halsey, J Hildebrand, JS Jung, KJ Korda, RJ McLerran, DF Moore, SC O'Keeff, LM Paige, E Ramond, A Reeves, GK Rolland, B Sacerdote, C Sattar, N Sofianopoulou, E Stevens, J Thun, M Ueshima, H Yang, L Yun, YD Willeit, P Banks, E Beral, V Chen, Z Gapstur, SM Gunter, MJ Hartge, P Jee, SH Lam, TH Peto, R Potter, JD Willett, WC Thompson, SG Danesh, J Hu, FB AF Di Angelantonio, Emanuele Bhupathiraju, Shilpa N. Wormser, David Gao, Pei Kaptoge, Stephen de Gonzalez, Amy Berrington Cairns, Benjamin J. Huxley, Rachel Jackson, Chandra L. Joshy, Grace Lewington, Sarah Manson, JoAnn E. Murphy, Neil Patel, Alpa V. Samet, Jonathan M. Woodward, Mark Zheng, Wei Zhou, Maigen Bansal, Narinder Barricarte, Aurelio Carter, Brian Cerhan, James R. Collins, Rory Smith, George Davey Fang, Xianghua Franco, Oscar H. Green, Jane Halsey, Jim Hildebrand, Janet S. Jung, Keum Ji Korda, Rosemary J. McLerran, Dale F. Moore, Steven C. O'Keeff, Linda M. Paige, Ellie Ramond, Anna Reeves, Gillian K. Rolland, Betsy Sacerdote, Carlotta Sattar, Naveed Sofianopoulou, Eleni Stevens, June Thun, Michael Ueshima, Hirotsugu Yang, Ling Yun, Young Duk Willeit, Peter Banks, Emily Beral, Valerie Chen, Zhengming Gapstur, Susan M. Gunter, Marc J. Hartge, Patricia Jee, Sun Ha Lam, Tai-Hing Peto, Richard Potter, John D. Willett, Walter C. Thompson, Simon G. Danesh, John Hu, Frank B. CA Global BMI Mortality Collaboration TI Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents SO LANCET LA English DT Article ID CARDIOVASCULAR-DISEASE; ABDOMINAL ADIPOSITY; RISK-FACTORS; OBESITY; ASSOCIATION; POPULATION; OVERWEIGHT; METHODOLOGY; TRENDS; COHORT AB Background Overweight and obesity are increasing worldwide. To help assess their relevance to mortality in different populations we conducted individual-participant data meta-analyses of prospective studies of body-mass index (BMI), limiting confounding and reverse causality by restricting analyses to never-smokers and excluding pre-existing disease and the first 5 years of follow-up. Methods Of 10 625 411 participants in Asia, Australia and New Zealand, Europe, and North America from 239 prospective studies (median follow-up 13.7 years, IQR 11.4-14.7), 3 951 455 people in 189 studies were never-smokers without chronic diseases at recruitment who survived 5 years, of whom 385 879 died. The primary analyses are of these deaths, and study, age, and sex adjusted hazard ratios (HRs), relative to BMI 22.5-<25.0 kg/m(2). Findings All-cause mortality was minimal at 20.0-25.0 kg/m(2) (HR 1.00, 95% CI 0.98-1.02 for BMI 20.0-<22.5 kg/m(2); 1.00, 0.99-1.01 for BMI 22.5-<25.0 kg/m(2)), and increased significantly both just below this range (1.13, 1.09-1.17 for BMI 18.5-<20.0 kg/m(2); 1.51, 1.43-1.59 for BMI 15.0-<18.5) and throughout the overweight range (1.07, 1.07-1.08 for BMI 25.0-<27.5 kg/m(2); 1.20, 1.18-1.22 for BMI 27.5-<30.0 kg/m(2)). The HR for obesity grade 1 (BMI 30.0-<35.0 kg/m(2)) was 1.45, 95% CI 1.41-1.48; the HR for obesity grade 2 (35.0-<40.0 kg/m(2)) was 1.94, 1.87-2.01; and the HR for obesity grade 3 (40.0-<60.0 kg/m(2)) was 2.76, 2.60-2.92. For BMI over 25.0 kg/m(2), mortality increased approximately log-linearly with BMI; the HR per 5 kg/m(2) units higher BMI was 1.39 (1.34-1.43) in Europe, 1.29 (1.26-1.32) in North America, 1.39 (1.34-1.44) in east Asia, and 1.31 (1.27-1.35) in Australia and New Zealand. This HR per 5 kg/m(2) units higher BMI (for BMI over 25 kg/m(2)) was greater in younger than older people (1.52, 95% CI 1.47-1.56, for BMI measured at 35-49 years vs 1.21, 1.17-1.25, for BMI measured at 70-89 years; p(heterogeneity) < 0.0001), greater in men than women (1.51, 1.46-1.56, vs 1.30, 1.26-1.33; p(heterogeneity) < 0.0001), but similar in studies with self-reported and measured BMI. Interpretation The associations of both overweight and obesity with higher all-cause mortality were broadly consistent in four continents. This finding supports strategies to combat the entire spectrum of excess adiposity in many populations. C1 [Di Angelantonio, Emanuele; Wormser, David; Gao, Pei; Kaptoge, Stephen; Bansal, Narinder; O'Keeff, Linda M.; Paige, Ellie; Ramond, Anna; Sofianopoulou, Eleni; Willeit, Peter; Thompson, Simon G.; Danesh, John] Univ Cambridge, Cambridge, England. [Bhupathiraju, Shilpa N.] Harvard Univ, Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Gao, Pei] Peking Univ, Beijing 100871, Peoples R China. [de Gonzalez, Amy Berrington; Hartge, Patricia] Natl Canc Inst, Bethesda, MD USA. [Cairns, Benjamin J.; Lewington, Sarah; Woodward, Mark; Collins, Rory; Green, Jane; Halsey, Jim; Reeves, Gillian K.; Yang, Ling; Beral, Valerie; Chen, Zhengming; Peto, Richard] Univ Oxford, S Parks Rd, Oxford, England. [Huxley, Rachel] Curtin Univ, Perth, WA 6845, Australia. [Jackson, Chandra L.] Harvard Univ, Sch Med, Boston, MA USA. [Joshy, Grace] Australian Natl Univ, GPO Box 4, Canberra, ACT, Australia. [Manson, JoAnn E.] Harvard Univ, Sch Med, Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Murphy, Neil] Imperial Coll London, London, England. [Patel, Alpa V.; Carter, Brian; Hildebrand, Janet S.; Thun, Michael; Gapstur, Susan M.] Amer Canc Soc, Atlanta, GA 30329 USA. [Samet, Jonathan M.] Univ So Calif, Los Angeles, CA USA. [Woodward, Mark] Univ Sydney, Sydney, NSW, Australia. [Woodward, Mark] Johns Hopkins Univ, Baltimore, MD USA. [Zheng, Wei] Vanderbilt Univ Sch Med, Nashville, TN USA. [Zhou, Maigen] Chinese Ctr Dis Control & Prevent, Beijing, Peoples R China. [Barricarte, Aurelio] Consortium Biomed Res Epidemiol & Publ Hlth, Navarre Publ Hlth Inst, Pamplona, Spain. [Cerhan, James R.] Mayo Clin, Rochester, MN USA. [Smith, George Davey] Univ Bristol, Bristol, Avon, England. [Fang, Xianghua] Capital Med Univ, Beijing, Peoples R China. [Franco, Oscar H.] Univ Med Ctr Rotterdam, Rotterdam, Netherlands. [Jung, Keum Ji; Jee, Sun Ha] Yonsei Univ, Seoul 120749, South Korea. [Korda, Rosemary J.] Australian Natl Univ, GPO Box 4, Canberra, ACT, Australia. [McLerran, Dale F.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Moore, Steven C.; Rolland, Betsy] Natl Canc Inst, Bethesda, MD USA. [Sacerdote, Carlotta] Univ Turin, Ctr Canc Prevent, Turin, Italy. [Sattar, Naveed] Univ Glasgow, Glasgow, Lanark, Scotland. [Stevens, June] Univ N Carolina, Chapel Hill, NC USA. [Ueshima, Hirotsugu] Shiga Univ, Med Sci, Shiga, Japan. [Yun, Young Duk] Hlth Insurance Policy Res Inst, Seoul, South Korea. [Willeit, Peter] Med Univ Innsbruck, A-6020 Innsbruck, Austria. [Banks, Emily] Australian Natl Univ Canberra, Canberra, ACT, Australia. [Gunter, Marc J.] Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon, France. [Lam, Tai-Hing] Univ Hong Kong, Hong Kong, Peoples R China. [Potter, John D.] Massey Univ, Wellington, New Zealand. [Willett, Walter C.; Hu, Frank B.] Harvard Univ, Sch Med, Harvard TH Chan Sch Publ Hlth, Boston, MA USA. RP Di Angelantonio, E (reprint author), Univ Cambridge, Cambridge, England. RI Huxley, Rachel/C-7032-2013; Zheng, Wei/O-3351-2013; Woodward, Mark/D-8492-2015; Moore, Steven/D-8760-2016; Jackson, Chandra/A-6291-2017; Murphy, Neil/E-1189-2017; Ulmer, Hanno/C-3488-2011; OI Huxley, Rachel/0000-0002-2705-6616; Zheng, Wei/0000-0003-1226-070X; Davey Smith, George/0000-0002-1407-8314; Moore, Steven/0000-0002-8169-1661; Jackson, Chandra/0000-0002-0915-8272; Murphy, Neil/0000-0003-3347-8249; Ulmer, Hanno/0000-0001-5911-1002; Ramond, Anna/0000-0002-9958-3693 FU UK Medical Research Council; British Heart Foundation; National Institute for Health Research; US National Institutes of Health FX UK Medical Research Council, British Heart Foundation, National Institute for Health Research, US National Institutes of Health. NR 43 TC 3 Z9 3 U1 11 U2 20 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD AUG 20 PY 2016 VL 388 IS 10046 BP 776 EP 786 DI 10.1016/S0140-6736(16)30175-1 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DT6UH UT WOS:000381619200026 ER PT J AU Koonin, EV AF Koonin, Eugene V. TI Viruses and mobile elements as drivers of evolutionary transitions SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Review DE evolutionary transitions; mobile genetic elements; parasites; viruses; antivirus defence; host-parasite coevolution ID RESTRICTION-MODIFICATION SYSTEMS; TOXIN-ANTITOXIN SYSTEMS; PROGRAMMED CELL-DEATH; CRISPR-CAS SYSTEMS; TRANSPOSABLE ELEMENTS; GENE-TRANSFER; AGGREGATIVE MULTICELLULARITY; REVERSE-TRANSCRIPTASE; DELETERIOUS MUTATIONS; COMPARATIVE GENOMICS AB The history of life is punctuated by evolutionary transitions which engender emergence of new levels of biological organization that involves selection acting at increasingly complex ensembles of biological entities. Major evolutionary transitions include the origin of prokaryotic and then eukaryotic cells, multicellular organisms and eusocial animals. All or nearly all cellular life forms are hosts to diverse selfish genetic elements with various levels of autonomy including plasmids, transposons and viruses. I present evidence that, at least up to and including the origin of multicellularity, evolutionary transitions are driven by the coevolution of hosts with these genetic parasites along with sharing of 'public goods'. Selfish elements drive evolutionary transitions at two distinct levels. First, mathematical modelling of evolutionary processes, such as evolution of primitive replicator populations or unicellular organisms, indicates that only increasing organizational complexity, e.g. emergence ofmulticellular aggregates, can prevent the collapse of the host-parasite system under the pressure of parasites. Second, comparative genomic analysis reveals numerous cases of recruitment of genes with essential functions in cellular life forms, including those that enable evolutionary transitions. This article is part of the themed issue 'The major synthetic evolutionary transitions'. C1 [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 US Department of Health and Human Services FX This research is supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). NR 189 TC 2 Z9 2 U1 20 U2 20 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 AUG 19 PY 2016 VL 371 IS 1701 AR 20150442 DI 10.1098/rstb.2015.0442 PG 13 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DX5ZF UT WOS:000384460600005 ER PT J AU Corona, A Desantis, J Massari, S Distinto, S Masaoka, T Sabatini, S Esposito, F Manfroni, G Maccioni, E Cecchetti, V Pannecouque, C Le Grice, SFJ Tramontano, E Tabarrini, O AF Corona, Angela Desantis, Jenny Massari, Serena Distinto, Simona Masaoka, Takashi Sabatini, Stefano Esposito, Francesca Manfroni, Giuseppe Maccioni, Elias Cecchetti, Violetta Pannecouque, Christophe Le Grice, Stuart F. J. Tramontano, Enzo Tabarrini, Oriana TI Studies on Cycloheptathiophene-3-carboxamide Derivatives as Allosteric HIV-1 RibonucleaseH Inhibitors SO CHEMMEDCHEM LA English DT Article; Proceedings Paper CT 23rd National Meeting of the Medicinal-Chemistry-Division of the Italian-Chemical-Society (DCF-SCI) CY 2015 CL Salerno, ITALY SP Italian Chem Soc, Med Chem Div DE allosterism antiviral agents inhibitors medicinal chemistry ribonucleases ID DIKETO ACID-DERIVATIVES; RNASE-H FUNCTION; IMMUNODEFICIENCY-VIRUS TYPE-1; REVERSE-TRANSCRIPTASE; DUAL INHIBITORS; COLORIMETRIC ASSAY; DNA-POLYMERASE; ACTIVE-SITE; IDENTIFICATION; RESIDUES AB Despite the significant progress achieved with combination antiretroviral therapy in the fight against human immunodeficiency virus (HIV) infection, the difficulty to eradicate the virus together with the rapid emergence of multidrug-resistant strains clearly underline a pressing need for innovative agents, possibly endowed with novel mechanisms of action. In this context, owing to its essential role in HIV genome replication, the reverse transcriptase associated ribonucleaseH (RNaseH) has proven to be an appealing target. To identify new RNaseH inhibitors, an in-house cycloheptathiophene-3-carboxamide library was screened; this led to compounds endowed with inhibitory activity, the structural optimization of which led to the catechol derivative 2-(3,4-dihydroxybenzamido)-N-(pyridin-2-yl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide (compound 33) with an IC50 value on the RNaseH activity in the nanomolar range. Mechanistic studies suggested selective inhibition of the RNaseH through binding to an innovative allosteric site, which could be further exploited to enrich this class of inhibitors. C1 [Corona, Angela; Distinto, Simona; Esposito, Francesca; Maccioni, Elias; Tramontano, Enzo] Cittadella Univ Monserrato, Dipartimento Sci Vita & Ambiente, SS554, I-09042 Monserrato, Italy. [Desantis, Jenny; Massari, Serena; Sabatini, Stefano; Manfroni, Giuseppe; Cecchetti, Violetta; Tabarrini, Oriana] Univ Perugia, Dipartimento Sci Farmaceut, Via Liceo 1, I-06123 Perugia, Italy. [Masaoka, Takashi; Le Grice, Stuart F. J.] NCI, Basic Res Lab, Frederick, MD 21702 USA. [Pannecouque, Christophe] Katholieke Univ Leuven, Lab Virol & Chemotherapy, Dept Microbiol & Immunol, Rega Inst Med Res, Minderbroedersstr 10, B-3000 Leuven, Belgium. RP Tramontano, E (reprint author), Cittadella Univ Monserrato, Dipartimento Sci Vita & Ambiente, SS554, I-09042 Monserrato, Italy.; Tabarrini, O (reprint author), Univ Perugia, Dipartimento Sci Farmaceut, Via Liceo 1, I-06123 Perugia, Italy. EM tramon@unica.it; oriana.tabarrini@unipg.it RI Esposito, Francesca/I-8879-2012; OI Esposito, Francesca/0000-0001-9725-7977; Corona, Angela/0000-0002-6630-8636 NR 52 TC 0 Z9 0 U1 3 U2 3 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 AUG 19 PY 2016 VL 11 IS 16 SI SI BP 1709 EP 1720 DI 10.1002/cmdc.201600015 PG 12 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DW3YT UT WOS:000383579700007 PM 26990134 ER PT J AU Mammoli, V Bonifazi, A Dal Ben, D Giannella, M Giorgioni, G Piergentili, A Pigini, M Quaglia, W Thomas, A Newman, AH Ferre, S Sanchez-Soto, M Keck, TM Del Bello, F AF Mammoli, Valerio Bonifazi, Alessandro Dal Ben, Diego Giannella, Mario Giorgioni, Gianfabio Piergentili, Alessandro Pigini, Maria Quaglia, Wilma Thomas, Ajiroghene Newman, Amy H. Ferre, Sergi Sanchez-Soto, Marta Keck, Thomas M. Del Bello, Fabio TI A Novel Class of Dopamine D-4 Receptor Ligands Bearing an Imidazoline Nucleus SO CHEMMEDCHEM LA English DT Article; Proceedings Paper CT 23rd National Meeting of the Medicinal-Chemistry-Division of the Italian-Chemical-Society (DCF-SCI) CY 2015 CL Salerno, ITALY SP Italian Chem Soc, Med Chem Div DE D4 receptor antagonists; dopamine; drug design; imidazolines; privileged structures ID D3 RECEPTOR; PSYCHIATRIC-DISORDERS; PRIVILEGED STRUCTURES; ERECTILE DYSFUNCTION; CURRENT PERSPECTIVES; MORPHINE-DEPENDENCE; FORCE-FIELD; RATS; AGONIST; ANTAGONIST AB Over the years, the 2-substituted imidazoline nucleus has been demonstrated to be a bioversatile structural motif. In this study, novel imidazoline derivatives bearing a 3- and/or 4-hydroxy- or methoxy-substituted phenyl ring, linked by an ethylene bridge to position2 of an N-benzyl- or N-phenethyl-substituted imidazoline nucleus, were prepared and studied against D-2-like receptor subtypes. Binding studies highlighted that a set of N-phenethylimidazoline compounds are selective for D-4 over D-2 and D-3 receptors. In functional assays, the 3-methoxy-substituted derivative, endowed with the highest D-4 affinity value, and its 3-hydroxy analogue behaved as partial agonists with low intrinsic efficacy and as competitive D-4 antagonists when tested in the presence of the D-2-like receptor agonist quinpirole. Molecular docking analysis, performed using a homology model of the human D-4 receptor developed using the X-ray crystal structure of the antagonist-bound human D-3 receptor as a template, was in accordance with the binding results and provided useful information for the design of novel imidazoline D-4 receptor ligands based on this new scaffold. C1 [Mammoli, Valerio; Bonifazi, Alessandro; Dal Ben, Diego; Giannella, Mario; Giorgioni, Gianfabio; Piergentili, Alessandro; Pigini, Maria; Quaglia, Wilma; Thomas, Ajiroghene; Del Bello, Fabio] Univ Camerino, Sch Pharm, Med Chem Unit, Via S Agostino 1, I-62032 Camerino, Italy. [Bonifazi, Alessandro; Newman, Amy H.; Keck, Thomas M.] NIDA, Med Chem Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program, 333 Cassell Dr, Baltimore, MD 21224 USA. [Ferre, Sergi; Sanchez-Soto, Marta] NIDA, Integrat Neurobiol Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program, 333 Cassell Dr, Baltimore, MD 21224 USA. [Keck, Thomas M.] Rowan Univ, Dept Chem & Biochem, Dept Biomed & Translat Sci, Coll Sci & Math, 201 Mullica Hill Rd, Glassboro, NJ 08028 USA. RP Del Bello, F (reprint author), Univ Camerino, Sch Pharm, Med Chem Unit, Via S Agostino 1, I-62032 Camerino, Italy. EM fabio.delbello@unicam.it RI Ferre, Sergi/K-6115-2014; OI Ferre, Sergi/0000-0002-1747-1779; Thomas, Ajiroghene/0000-0003-1852-6716 FU Intramural NIH HHS [ZIA DA000424-17] NR 54 TC 0 Z9 0 U1 3 U2 3 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 AUG 19 PY 2016 VL 11 IS 16 SI SI BP 1819 EP 1828 DI 10.1002/cmdc.201600022 PG 10 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DW3YT UT WOS:000383579700018 PM 26990230 ER PT J AU Lauer, MS AF Lauer, Michael S. TI Heart Rate Recovery: Coming Back Full-Circle to the Baroreceptor Reflex SO CIRCULATION RESEARCH LA English DT Editorial Material DE Editorials; blood pressure; cohort studies; dogs; heart rate; myocardial infarction ID TREADMILL EXERCISE; SUDDEN-DEATH; MORTALITY; PREDICTOR; DISEASE C1 [Lauer, Michael S.] NIH, Off Extramural Res, One Ctr Dr,Bldg 1,Room 144, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), NIH, Off Extramural Res, One Ctr Dr,Bldg 1,Room 144, Bethesda, MD 20892 USA. EM michael.lauer@nih.gov FU Intramural NIH HHS [Z99 OD999999] NR 13 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 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD AUG 19 PY 2016 VL 119 IS 5 BP 582 EP 583 DI 10.1161/CIRCRESAHA.116.309392 PG 2 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA DV9RN UT WOS:000383279000005 PM 27539969 ER PT J AU Maric-Bilkan, C Galis, ZS AF Maric-Bilkan, Christine Galis, Zorina S. TI Trends in NHLBI-Funded Research on Sex Differences in Hypertension SO CIRCULATION RESEARCH LA English DT Article DE blood pressure; cardiovascular disease; hypertension; research; sex hormones ID AMERICAN-HEART-ASSOCIATION; II-INDUCED HYPERTENSION; T-CELL; DISEASE; UPDATE AB Although sex differences in blood pressure levels and the prevalence of hypertension are well recognized, the mechanisms responsible for this sexual dimorphism remain poorly understood. To gain a better understanding of the research funding trends in the field of sex differences related to hypertension and the main research topics funded by the National Heart, Lung, and Blood Institute (NHLBI), we analyzed the entire NHLBI award portfolio between fiscal years (FYs) 1991 to 2014. Using specific search terms to define "sex differences," we interrogated the publicly available list of NHLBI-funded awards active in FY1991 to FY2014 in the National Institutes of Health (NIH) Research Portfolio Online Reporting (RePORTER) database. We further analyzed and categorized awards according to a disease focus and whether each award was directly focused on comparing males versus females, or examining the effects of sex hormones in either sex. The number of NHLBI awards related to " sex differences in hypertension" progressively increased from FY1991 to FY2014, for a cumulative total of 486 awards during the entire period analyzed. The overall dollar investment has also progressively increased from $0.5 million (FY1991) to $18.3 million (FY2014), for a cumulative total of $187 million during FY1991 to FY2014. When compared with global funding trends, NHLBI seems to be the largest funder of research on " sex differences in hypertension" in the world. Importantly, the increased NHLBI investment in sex differences in hypertension research has enabled the investigation of an increased diversity of scientific topics. Although NHLBI is funding an increasing number of awards related to " sex differences in hypertension," there are still many unanswered questions related to the mechanisms underlying this disparity. C1 [Maric-Bilkan, Christine; Galis, Zorina S.] NHLBI, NIH, Div Cardiovasc Sci, Vasc Biol & Hypertens Branch, 6701 Rockledge Dr,Room 8110, Bethesda, MD 20892 USA. RP Maric-Bilkan, C (reprint author), NHLBI, NIH, Div Cardiovasc Sci, Vasc Biol & Hypertens Branch, 6701 Rockledge Dr,Room 8110, Bethesda, MD 20892 USA. EM christine.maric-bilkan@nih.gov NR 12 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD AUG 19 PY 2016 VL 119 IS 5 BP 591 EP 595 DI 10.1161/CIRCRESAHA.116.308963 PG 5 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA DV9RN UT WOS:000383279000008 PM 27539972 ER PT J AU Schmidt, T Ye, F Situ, AJ An, W Ginsberg, MH Ulmer, TS AF Schmidt, Thomas Ye, Feng Situ, Alan J. An, Woojin Ginsberg, Mark H. Ulmer, Tobias S. TI A Conserved Ectodomain-Transmembrane Domain Linker Motif Tunes the Allosteric Regulation of Cell Surface Receptors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE allosteric regulation; cytokine; integrin; isothermal titration calorimetry (ITC); nuclear magnetic resonance (NMR); protein dynamics; receptor signaling; transmembrane cell surface receptors ID GROWTH-FACTOR RECEPTOR; INTEGRIN ACTIVATION; DIPOLAR COUPLINGS; PROTEIN STRUCTURES; MEMBRANE-PROTEINS; CRYSTAL-STRUCTURE; NMR-SPECTROSCOPY; CHEMICAL-SHIFTS; ALPHA-SUBUNIT; COMPLEX AB In many families of cell surface receptors, a single transmembrane (TM) -helix separates ecto- and cytosolic domains. A defined coupling of ecto- and TM domains must be essential to allosteric receptor regulation but remains little understood. Here, we characterize the linker structure, dynamics, and resulting ecto-TM domain coupling of integrin IIb in model constructs and relate it to other integrin subunits by mutagenesis. Cellular integrin activation assays subsequently validate the findings in intact receptors. Our results indicate a flexible yet carefully tuned ecto-TM coupling that modulates the signaling threshold of integrin receptors. Interestingly, a proline at the N-terminal TM helix border, termed NBP, is critical to linker flexibility in integrins. NBP is further predicted in 21% of human single-pass TM proteins and validated in cytokine receptors by the TM domain structure of the cytokine receptor common subunit and its P441A-substituted variant. Thus, NBP is a conserved uncoupling motif of the ecto-TM domain transition and the degree of ecto-TM domain coupling represents an important parameter in the allosteric regulation of diverse cell surface receptors. C1 [Schmidt, Thomas; Situ, Alan J.; Ulmer, Tobias S.] Univ Southern Calif, Keck Sch Med, Dept Biochem & Mol Biol, Los Angeles, CA 90033 USA. [Schmidt, Thomas; Situ, Alan J.; Ulmer, Tobias S.] Univ Southern Calif, Keck Sch Med, Zilkha Neurogenet Inst, Los Angeles, CA 90033 USA. [Ye, Feng; Ginsberg, Mark H.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [An, Woojin] Univ Southern Calif, Dept Biochem & Mol Biol, Los Angeles, CA 90033 USA. [An, Woojin] Univ Southern Calif, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Schmidt, Thomas] NIDDK, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. RP Ulmer, TS (reprint author), 1501 San Pablo St,ZNI 111, Los Angeles, CA 90033 USA. EM tulmer@usc.edu FU American Heart Association [15GRNT23200010]; National Institutes of Health [HL31950, HL078784, HL117807] FX This work was supported by American Heart Association Grant 15GRNT23200010 (to T. S. U.) and National Institutes of Health Grants HL31950, HL078784, and HL117807 (to M. H. G.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 60 TC 3 Z9 3 U1 3 U2 3 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 AUG 19 PY 2016 VL 291 IS 34 BP 17536 EP 17546 DI 10.1074/jbc.M116.733683 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV9DX UT WOS:000383241300006 PM 27365391 ER PT J AU Zhou, BY Ritt, DA Morrison, DK Der, CJ Cox, AD AF Zhou, Bingying Ritt, Daniel A. Morrison, Deborah K. Der, Channing J. Cox, Adrienne D. TI Protein Kinase CK2 Maintains Extracellular Signal-regulated Kinase (ERK) Activity in a CK2 Kinase-independent Manner to Promote Resistance to Inhibitors of RAF and MEK but Not ERK in BRAF Mutant Melanoma SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE drug resistance; dual specificity phosphoprotein phosphatase; extracellular signal-regulated kinase (ERK); melanoma; Ras protein; CK2; kinase suppressor of RAS 1 (KSR1) ID PANCREATIC-CANCER; ACTIVATION; CK2-ALPHA; CELLS; PHOSPHORYLATES; CARCINOMA; SURVIVAL; LEUKEMIA; COMPLEX AB The protein kinase casein kinase 2 (CK2) is a pleiotropic and constitutively active kinase that plays crucial roles in cellular proliferation and survival. Overexpression of CK2, particularly the catalytic subunit (CK2, CSNK2A1), has been implicated in a wide variety of cancers and is associated with poorer survival and resistance to both conventional and targeted anticancer therapies. Here, we found that CK2 protein is elevated in melanoma cell lines compared with normal human melanocytes. We then tested the involvement of CK2 in drug resistance to Food and Drug Administration-approved single agent targeted therapies for melanoma. In BRAF mutant melanoma cells, ectopic CK2 decreased sensitivity to vemurafenib (BRAF inhibitor), dabrafenib (BRAF inhibitor), and trametinib (MEK inhibitor) by a mechanism distinct from that of mutant NRAS. Conversely, knockdown of CK2 sensitized cells to inhibitor treatment. CK2-mediated RAF-MEK kinase inhibitor resistance was tightly linked to its maintenance of ERK phosphorylation. We found that CK2 post-translationally regulates the ERK-specific phosphatase dual specificity phosphatase 6 (DUSP6) in a kinase dependent-manner, decreasing its abundance. However, we unexpectedly showed, by using a kinase-inactive mutant of CK2, that RAF-MEK inhibitor resistance did not rely on CK2 kinase catalytic function, and both wild-type and kinase-inactive CK2 maintained ERK phosphorylation upon inhibition of BRAF or MEK. That both wild-type and kinase-inactive CK2 bound equally well to the RAF-MEK-ERK scaffold kinase suppressor of Ras 1 (KSR1) suggested that CK2 increases KSR facilitation of ERK phosphorylation. Accordingly, CK2 did not cause resistance to direct inhibition of ERK by the ERK1/2-selective inhibitor SCH772984. Our findings support a kinase-independent scaffolding function of CK2 that promotes resistance to RAF- and MEK-targeted therapies. C1 [Zhou, Bingying; Der, Channing J.; Cox, Adrienne D.] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Der, Channing J.; Cox, Adrienne D.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Cox, Adrienne D.] Univ N Carolina, Dept Radiat Oncol, Chapel Hill, NC 27599 USA. [Ritt, Daniel A.; Morrison, Deborah K.] NCI, Lab Cell & Dev Signaling, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Cox, AD (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. EM adrienne_cox@med.unc.edu FU National Institutes of Health [CA042978, CA179193, CA199235]; NCI [ZIA BC 010329]; Pancreatic Cancer Action Network-American Association for Cancer Research FX This work was supported by National Institutes of Health Grants CA042978, CA179193, and CA199235 (to A. D. C. and C. J. D.) and ZIA BC 010329 from the NCI (to D. K. M. and D. A. R.) and by the Pancreatic Cancer Action Network-American Association for Cancer Research (to A. D. C. and C. J. D.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 40 TC 0 Z9 0 U1 7 U2 7 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 AUG 19 PY 2016 VL 291 IS 34 BP 17804 EP 17815 DI 10.1074/jbc.M115.712885 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV9DX UT WOS:000383241300027 PM 27226552 ER PT J AU Atwood, BL Woolnough, JL Lefevre, GM Ribeiro, MS Felsenfeld, G Giles, KE AF Atwood, Blake L. Woolnough, Jessica L. Lefevre, Gaelle M. Ribeiro, Mariana Saint Just Felsenfeld, Gary Giles, Keith E. TI Human Argonaute 2 Is Tethered to Ribosomal RNA through MicroRNA Interactions SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Argonaute; ChIP-sequencing (ChIP-seq); Dicer; microRNA (miRNA); ribosomal ribonucleic acid (rRNA) (ribosomal RNA); miRNA; par-clip; rRNA ID HUMAN-CELLS; GENE-EXPRESSION; BINDING-SITES; POLYMERASE I; PAR-CLIP; TARGET; NUCLEOLUS; PROTEIN; HETEROCHROMATIN; DICER AB The primary role of the RNAi machinery is to promote mRNA degradation within the cytoplasm in a microRNA-dependent manner. However, both Dicer and the Argonaute protein family have expanded roles in gene regulation within the nucleus. To further our understanding of this role, we have identified chromatin binding sites for AGO2 throughout the 45S region of the human rRNA gene. The location of these sites was mirrored by the positions of AGO2 cross-linking sites identified via PAR-CLIP-seq. AGO2 binding to the rRNA within the nucleus was confirmed by RNA immunoprecipitation and quantitative-PCR. To explore a possible mechanism by which AGO2 could be recruited to the rRNA, we identified 1174 regions within the 45S rRNA transcript that have the ability to form a perfect duplex with position 2-6 (seed sequence) of each microRNA expressed in HEK293T cells. Of these potential AGO2 binding sites, 479 occurred within experimentally verified AGO2-rRNA cross-linking sites. The ability of AGO2 to cross-link to rRNA was almost completely lost in a DICER knock-out cell line. The transfection of miR-92a-2-3p into the noDICE cell line facilitated AGO2 cross-linking at a region of the rRNA that has a perfect seed match at positions 3-8, including a single G-U base pair. Knockdown of AGO2 within HEK293T cells causes a slight, but statistically significant increase in the overall rRNA synthesis rate but did not impact the ratio of processing intermediates or the recruitment of the Pol I transcription factor UBTF. C1 [Atwood, Blake L.; Woolnough, Jessica L.; Ribeiro, Mariana Saint Just; Giles, Keith E.] Univ Alabama Birmingham, UAB Stem Cell Inst, Dept Biochem & Mol Genet, Birmingham, AL 35209 USA. [Lefevre, Gaelle M.; Felsenfeld, Gary] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Giles, KE (reprint author), Univ Alabama Birmingham, UAB Stem Cell Inst, Dept Biochem & Mol Genet, Birmingham, AL 35209 USA. EM kegiles@uab.edu FU National Institutes of Health, NIDDK Intramural Research Program FX This work was supported in part by the National Institutes of Health, NIDDK Intramural Research Program. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 60 TC 0 Z9 0 U1 6 U2 6 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 AUG 19 PY 2016 VL 291 IS 34 BP 17919 EP 17928 DI 10.1074/jbc.M116.725051 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV9DX UT WOS:000383241300035 PM 27288410 ER PT J AU Tatusova, T DiCuccio, M Badretdin, A Chetvernin, V Nawrocki, EP Zaslavsky, L Lomsadze, A Pruitt, K Borodovsky, M Ostell, J AF Tatusova, Tatiana DiCuccio, Michael Badretdin, Azat Chetvernin, Vyacheslav Nawrocki, Eric P. Zaslavsky, Leonid Lomsadze, Alexandre Pruitt, Kimd. Borodovsky, Mark Ostell, James TI NCBI prokaryotic genome annotation pipeline SO NUCLEIC ACIDS RESEARCH LA English DT Article ID MICROBIAL GENOMES; PAN-GENOME; DATABASE; PREDICTION; CLASSIFICATION; RESOURCES AB Recent technological advances have opened unprecedented opportunities for large-scale sequencing and analysis of populations of pathogenic species in disease outbreaks, as well as for large-scale diversity studies aimed at expanding our knowledge across the whole domain of prokaryotes. To meet the challenge of timely interpretation of structure, function and meaning of this vast genetic information, a comprehensive approach to automatic genome annotation is critically needed. In collaboration with Georgia Tech, NCBI has developed a new approach to genome annotation that combines alignment based methods with methods of predicting protein-coding and RNA genes and other functional elements directly from sequence. A new gene finding tool, GeneMarkS+, uses the combined evidence of protein and RNA placement by homology as an initial map of annotation to generate and modify ab initio gene predictions across the whole genome. Thus, the new NCBI's Prokaryotic Genome Annotation Pipeline (PGAP) relies more on sequence similarity when confident comparative data are available, while it relies more on statistical predictions in the absence of external evidence. The pipeline provides a framework for generation and analysis of annotation on the full breadth of prokaryotic taxonomy. For additional information on PGAP see https://www.ncbi.nlm.nih.gov/genome/annotation prok/ and the NCBI Handbook, https://www.ncbi.nlm.nih.gov/books/NBK174280/. C1 [Tatusova, Tatiana; DiCuccio, Michael; Badretdin, Azat; Chetvernin, Vyacheslav; Nawrocki, Eric P.; Zaslavsky, Leonid; Pruitt, Kimd.; Ostell, James] US Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Lomsadze, Alexandre; Borodovsky, Mark] Georgia Tech, Wallace H Coulter Dept Biomed Engn, Atlanta, GA 30332 USA. [Borodovsky, Mark] Georgia Tech, Sch Computat Sci & Engn, Atlanta, GA 30332 USA. RP Borodovsky, M (reprint author), Georgia Tech, Wallace H Coulter Dept Biomed Engn, Atlanta, GA 30332 USA.; Borodovsky, M (reprint author), Georgia Tech, Sch Computat Sci & Engn, Atlanta, GA 30332 USA. EM borodovsky@gatech.edu FU Intramural Research Program of the NIH National Library of Medicine; NIH [HG000783] FX Intramural Research Program of the NIH National Library of Medicine (in part); the work of M.B. and A.L. was supported in part by NIH grant HG000783 to M.B. Funding for open access charge: Intramural Research Program of the NIH National Library of Medicine. NR 36 TC 15 Z9 15 U1 6 U2 7 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 AUG 19 PY 2016 VL 44 IS 14 BP 6614 EP 6624 DI 10.1093/nar/gkw569 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV5VX UT WOS:000382999900013 PM 27342282 ER PT J AU Arbel-Goren, R Tal, A Parasar, B Dym, A Costantino, N Munoz-Garcia, J Court, DL Stavans, J AF Arbel-Goren, Rinat Tal, Asaf Parasar, Bibudha Dym, Alvah Costantino, Nina Munoz-Garcia, Javier Court, Donald L. Stavans, Joel TI Transcript degradation and noise of small RNA-controlled genes in a switch activated network in Escherichia coli SO NUCLEIC ACIDS RESEARCH LA English DT Article ID BACTERIAL SMALL RNAS; RYHB SMALL RNA; SMALL REGULATORY RNAS; MESSENGER-RNA; NONCODING RNA; PHENOTYPIC NOISE; IRON HOMEOSTASIS; HFQ-BINDING; EXPRESSION; TARGETS AB Post-transcriptional regulatory processes may change transcript levels and affect cell-to-cell variability or noise. We study small-RNA downregulation to elucidate its effects on noise in the iron homeostasis network of Escherichia coli. In this network, the small-RNA RyhB undergoes stoichiometric degradation with the transcripts of target genes in response to iron stress. Using single-molecule fluorescence in situ hybridization, we measured transcript numbers of the RyhB-regulated genes sodB and fumA in individual cells as a function of iron deprivation. We observed a monotonic increase of noise with iron stress but no evidence of theoretically predicted, enhanced stoichiometric fluctuations in transcript numbers, nor of bistable behavior in transcript distributions. Direct detection of RyhB in individual cells shows that its noise is much smaller than that of these two targets, when RyhB production is significant. A generalized two-state model of bursty transcription that neglects RyhB fluctuations describes quantitatively the dependence of noise and transcript distributions on iron deprivation, enabling extraction of in vivo RyhB-mediated transcript degradation rates. The transcripts' threshold-linear behavior indicates that the effective in vivo interaction strength between RyhB and its two target transcripts is comparable. Strikingly, the bacterial cell response exhibits Furdependent, switch-like activation instead of a graded response to iron deprivation. C1 [Arbel-Goren, Rinat; Tal, Asaf; Parasar, Bibudha; Dym, Alvah; Munoz-Garcia, Javier; Stavans, Joel] Weizmann Inst Sci, Dept Phys Complex Syst, IL-76100 Rehovot, Israel. [Costantino, Nina; Court, Donald L.] NCI, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. [Munoz-Garcia, Javier] Univ Carlos III Madrid, Dept Matemat, Ave Univ 30, Madrid 28911, Spain. [Munoz-Garcia, Javier] Univ Carlos III Madrid, GISC, Ave Univ 30, Madrid 28911, Spain. RP Stavans, J (reprint author), Weizmann Inst Sci, Dept Phys Complex Syst, IL-76100 Rehovot, Israel.; Court, DL (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. EM courtd@mail.nih.gov; joel.stavans@weizmann.ac.il RI Munoz-Garcia, Javier/C-1135-2011 OI Munoz-Garcia, Javier/0000-0002-7594-9507 FU Israel Science Foundation [514415]; Feinberg Foundation Visiting Faculty Program; MICINN (Spain) [FIS2012-32349]; Intramural Research Program of the National Institutes of Health; National Cancer Institute; Center for Cancer Research; Siegfried and Irma Ullman Professorial Chair FX Israel Science Foundation [514415 to J.S.]; Feinberg Foundation Visiting Faculty Program (to J.M.-G.); MICINN (Spain) [FIS2012-32349 to J.M.-G.]; Intramural Research Program of the National Institutes of Health (to D.L.C.); National Cancer Institute (to D.L.C.); Center for Cancer Research (to D.L.C.); Siegfried and Irma Ullman Professorial Chair (to J.S.). Funding for open access charge: Israel Science Foundation. NR 73 TC 1 Z9 1 U1 5 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD AUG 19 PY 2016 VL 44 IS 14 BP 6707 EP 6720 DI 10.1093/nar/gkw273 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV5VX UT WOS:000382999900020 PM 27085802 ER PT J AU Ni, T Yang, WJ Han, M Zhang, YB Shen, T Nie, HB Zhou, ZH Dai, YL Yang, YQ Liu, PC Cui, KR Zeng, ZH Tian, Y Zhou, B Wei, G Zhao, KJ Peng, WQ Zhu, J AF Ni, Ting Yang, Wenjing Han, Miao Zhang, Yubo Shen, Ting Nie, Hongbo Zhou, Zhihui Dai, Yalei Yang, Yanqin Liu, Poching Cui, Kairong Zeng, Zhouhao Tian, Yi Zhou, Bin Wei, Gang Zhao, Keji Peng, Weiqun Zhu, Jun TI Global intron retention mediated gene regulation during CD4(+) T cell activation SO NUCLEIC ACIDS RESEARCH LA English DT Article ID CO-TRANSCRIPTIONAL REGULATION; HUMAN GENOME; DNA METHYLATION; COORDINATED REGULATION; HISTONE MODIFICATION; CHROMATIN-STATE; RNA; DIFFERENTIATION; EXPRESSION; PATHWAYS AB T cell activation is a well-established model for studying cellular responses to exogenous stimulation. Using strand-specific RNA-seq, we observed that intron retention is prevalent in polyadenylated transcripts in resting CD4(+) T cells and is significantly reduced upon T cell activation. Several lines of evidence suggest that intron-retained transcripts are less stable than fully spliced transcripts. Strikingly, the decrease in intron retention (IR) levels correlate with the increase in steady-state mRNA levels. Further, the majority of the genes upregulated in activated T cells are accompanied by a significant reduction in IR. Of these 1583 genes, 185 genes are predominantly regulated at the IR level, and highly enriched in the proteasome pathway, which is essential for proper T cell proliferation and cytokine release. These observations were corroborated in both human and mouse CD4(+) T cells. Our study revealed a novel post-transcriptional regulatory mechanism that may potentially contribute to coordinated and/or quick cellular responses to extracellular stimuli such as an acute infection. C1 [Ni, Ting; Han, Miao; Shen, Ting; Nie, Hongbo; Zhou, Bin; Wei, Gang] Fudan Univ, Sch Life Sci, Collaborat Innovat Ctr Genet & Dev, State Key Lab Genet Engn, Shanghai 200438, Peoples R China. [Ni, Ting; Han, Miao; Shen, Ting; Nie, Hongbo; Zhou, Bin; Wei, Gang] Fudan Univ, Sch Life Sci, Collaborat Innovat Ctr Genet & Dev, MOE Key Lab Contemporary Anthropol, Shanghai 200438, Peoples R China. [Yang, Wenjing; Zhang, Yubo; Yang, Yanqin; Liu, Poching; Cui, Kairong; Zhao, Keji; Zhu, Jun] NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Zhou, Zhihui; Dai, Yalei] Tongji Univ, Sch Med, Dept Immunol, Shanghai 200092, Peoples R China. [Zeng, Zhouhao; Tian, Yi; Peng, Weiqun] George Washington Univ, Dept Phys, Washington, DC 20052 USA. [Tian, Yi] Third Mil Med Univ, PLA, Inst Immunol, Chongqing 400038, Peoples R China. RP Ni, T (reprint author), Fudan Univ, Sch Life Sci, Collaborat Innovat Ctr Genet & Dev, State Key Lab Genet Engn, Shanghai 200438, Peoples R China.; Ni, T (reprint author), Fudan Univ, Sch Life Sci, Collaborat Innovat Ctr Genet & Dev, MOE Key Lab Contemporary Anthropol, Shanghai 200438, Peoples R China.; Zhu, J (reprint author), NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA.; Peng, WQ (reprint author), George Washington Univ, Dept Phys, Washington, DC 20052 USA. EM tingni@fudan.edu.cn; wpeng@gwu.edu; jun.zhu@nih.gov FU National Institute of Health (NIH) [Division of Intramural Research of National Heart Lung and Blood Institute] [1R21AI113806]; National Key Basic Research Program of China [973 programs] [2013CB530700, 2015CB943000, 2012CB518700]; National Science Foundation of China [31271348, 31471192]; Innovation Project of Shanghai Municipal Education Commission [14ZZ007]; Thousand Talents Plan of China; 111 Project of China [B13016] FX National Institute of Health (NIH) [Division of Intramural Research of National Heart Lung and Blood Institute to K. Z. and J. Z.; 1R21AI113806 to W. P.]; National Key Basic Research Program of China [973 programs: 2013CB530700 and 2015CB943000 to T. N., 2012CB518700 to Y. D.]; National Science Foundation of China [31271348 and 31471192 to T. N.]; Innovation Project of Shanghai Municipal Education Commission [14ZZ007 to T. N.]; Thousand Talents Plan of China and the 111 Project of China (B13016). NR 61 TC 2 Z9 2 U1 8 U2 9 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 AUG 19 PY 2016 VL 44 IS 14 BP 6817 EP 6829 DI 10.1093/nar/gkw591 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV5VX UT WOS:000382999900029 PM 27369383 ER PT J AU Metifiot, M Johnson, BC Kiselev, E Marler, L Zhao, XZ Burke, TR Marchand, C Hughes, SH Pommier, Y AF Metifiot, Mathieu Johnson, Barry C. Kiselev, Evgeny Marler, Laura Zhao, Xue Zhi Burke, Terrence R., Jr. Marchand, Christophe Hughes, Stephen H. Pommier, Yves TI Selectivity for strand-transfer over 3 '-processing and susceptibility to clinical resistance of HIV-1 integrase inhibitors are driven by key enzyme-DNA interactions in the active site SO NUCLEIC ACIDS RESEARCH LA English DT Article ID VIRAL-DNA; MOLECULAR-DYNAMICS; CROSS-RESISTANCE; FLEXIBLE LOOP; IN-VITRO; RALTEGRAVIR; ELVITEGRAVIR; BINDING; MUTANTS; DOLUTEGRAVIR AB Integrase strand transfer inhibitors (INSTIs) are highly effective against HIV infections. Co-crystal structures of the prototype foamy virus intasome have shown that all three FDA-approved drugs, raltegravir (RAL), elvitegravir and dolutegravir (DTG), act as interfacial inhibitors during the strand transfer (ST) integration step. However, these structures give only a partial sense for the limited inhibition of the 3'-processing reaction by INSTIs and how INSTIs can be modified to overcome drug resistance, notably against the G140S-Q148H double mutation. Based on biochemical experiments with modified oligonucleotides, we demonstrate that both the viral DNA + 1 and -1 bases, which flank the 3'-processing site, play a critical role for 3'-processing efficiency and inhibition by RAL and DTG. In addition, the G140S-Q148H (SH) mutant integrase, which has a reduced 3'-processing activity, becomes more active and more resistant to inhibition of 3'-processing by RAL and DTG in the absence of the -1 and + 1 bases. Molecular modeling of HIV-1 integrase, together with biochemical data, indicate that the conserved residue Q146 in the flexible loop of HIV-1 integrase is critical for productive viral DNA binding through specific contacts with the virus DNA ends in the 3'-processing and ST reactions. The potency of integrase inhibitors against 3'-processing and their ability to overcome resistance is discussed. C1 [Metifiot, Mathieu; Kiselev, Evgeny; Marler, Laura; Marchand, Christophe; Pommier, Yves] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. [Metifiot, Mathieu; Kiselev, Evgeny; Marler, Laura; Marchand, Christophe; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. [Johnson, Barry C.; Hughes, Stephen H.] NCI, HIV Dynam & Replicat Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Zhao, Xue Zhi; Burke, Terrence R., Jr.] NCI, Biol Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Metifiot, Mathieu] Univ Bordeaux, Lab Microbiol Fondamentale & Pathogen, CNRS UMR 5234, 146 Rue Leo Saignat, F-33076 Bordeaux, France. RP Metifiot, M; Pommier, Y (reprint author), NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, 37 Convent Dr, Bethesda, MD 20892 USA.; Metifiot, M; Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, 37 Convent Dr, Bethesda, MD 20892 USA.; Metifiot, M (reprint author), Univ Bordeaux, Lab Microbiol Fondamentale & Pathogen, CNRS UMR 5234, 146 Rue Leo Saignat, F-33076 Bordeaux, France. EM mathieu.metifiot@u-bordeaux.fr; pommier@nih.gov FU Intramural Program of the National Cancer Institute; Center for Cancer Research [Z01 BC 007333, ZIA BC 007363]; Intramural AIDS Targeted Antiviral Program (IATAP); National Institutes of Health; Developmental Therapeutics Branch; Laboratory of Molecular Pharmacology; CCR/NCI/NIH FX Intramural Program of the National Cancer Institute; Center for Cancer Research [Z01 BC 007333, ZIA BC 007363]; Intramural AIDS Targeted Antiviral Program (IATAP); National Institutes of Health. Funding for open access charge: Developmental Therapeutics Branch; Laboratory of Molecular Pharmacology; CCR/NCI/NIH. NR 47 TC 0 Z9 0 U1 5 U2 5 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 AUG 19 PY 2016 VL 44 IS 14 BP 6896 EP 6906 DI 10.1093/nar/gkw592 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV5VX UT WOS:000382999900035 PM 27369381 ER PT J AU Lee, HJ Gottesman, S AF Lee, Hyun-Jung Gottesman, Susan TI sRNA roles in regulating transcriptional regulators: Lrp and SoxS regulation by sRNAs SO NUCLEIC ACIDS RESEARCH LA English DT Article ID TRANSPORTER MESSENGER-RNAS; OXIDATIVE STRESS REGULON; BINDING SMALL RNAS; GCVB SMALL RNA; COLI CRP GENE; ESCHERICHIA-COLI; H-NS; GLOBAL REGULATOR; LIPOPOLYSACCHARIDE MODIFICATION; POSTTRANSCRIPTIONAL REGULATION AB Post-transcriptional regulation of transcription factors contributes to regulatory circuits. We created translational reporter fusions for multiple central regulators in Escherichia coli and examined the effect of Hfq-dependent non-coding RNAs on these fusions. This approach yields an 'RNA landscape,' identifying Hfq-dependent sRNAs that regulate a given fusion. No significant sRNA regulation of crp or fnr was detected. hns was regulated only by DsrA, as previously reported. Lrp and SoxS were both found to be regulated post-transcriptionally. Lrp, 'leucineresponsive regulatory protein,' regulates genes involved in amino acid biosynthesis and catabolism and other cellular functions. sRNAs DsrA, MicF and GcvB each independently downregulate thelrp translational fusion, confirming previous reports for MicF and GcvB. MicF and DsrA interact with an overlapping site early in the lrp ORF, while GcvB acts upstream at two independent sites in the long lrp leader. Surprisingly, GcvB was found to be responsible for significant downregulation of lrp after oxidative stress; MicF also contributed. SoxS, an activator of genes used to combat oxidative stress, is negatively regulated by sRNA MgrR. This study demonstrates that while not all global regulators are subject to sRNA regulation, post-transcriptional control by sRNAs allows multiple environmental signals to affect synthesis of the transcriptional regulator. C1 [Lee, Hyun-Jung; Gottesman, Susan] NCI, Mol Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. [Lee, Hyun-Jung] Ajou Univ, Sch Med, Dept Biomed Sci, Suwon 443380, South Korea. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM Gottesms@helix.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. Funding for open access charge: Center for Cancer Research intramural funding. NR 83 TC 4 Z9 4 U1 5 U2 5 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 AUG 19 PY 2016 VL 44 IS 14 BP 6907 EP 6923 DI 10.1093/nar/gkw358 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV5VX UT WOS:000382999900036 PM 27137887 ER PT J AU Hao, Y Updegrove, TB Livingston, NN Storz, G AF Hao, Yue Updegrove, Taylor B. Livingston, Natasha N. Storz, Gisela TI Protection against deleterious nitrogen compounds: role of sigma(S)-dependent small RNAs encoded adjacent to sdiA SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SMALL NONCODING RNA; ESCHERICHIA-COLI; MESSENGER-RNA; SOLUBLE-RNA; OUTER-MEMBRANE; REGULATORY RNAS; GENE-EXPRESSION; E. COLI; HFQ; RPOS AB Here, we report the characterization of a set of small, regulatory RNAs (sRNAs) expressed from an Escherichia coli locus we have denoted sdsN located adjacent to the LuxR-homolog gene sdiA. Two longer sRNAs, SdsN(137) and SdsN(178) are transcribed from two sigma(S)-dependent promoters but share the same terminator. Low temperature, rich nitrogen sources and the Crl and NarP transcription factors differentially affect the levels of the SdsN transcripts. Whole genome expression analysis after pulse overexpression of SdsN(137) and assays of lacZ fusions revealed that the SdsN(137) directly represses the synthesis of the nitroreductase NfsA, which catalyzes the reduction of the nitrogroup (NO2) in nitroaromatic compounds and the flavohemoglobin HmpA, which has aerobic nitric oxide (NO) dioxygenase activity. Consistent with this regulation, SdsN(137) confers resistance to nitrofurans. In addition, SdsN(137) negatively regulates synthesis of NarP. Interestingly, SdsN(178) is defective at regulating the above targets due to unusual binding to the Hfq protein, but cleavage leads to a shorter form, SdsN(124), able to repress nfsA and hmpA. C1 [Hao, Yue; Updegrove, Taylor B.; Livingston, Natasha N.; Storz, Gisela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Mol & Cellular Biol, Bethesda, MD 20892 USA. [Hao, Yue] Chinese Acad Agr Sci, Inst Apicultural Res, Beijing 100093, Peoples R China. [Updegrove, Taylor B.] NCI, Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA. [Livingston, Natasha N.] US FDA, Ctr Tobacco Prod, Silver Spring, MD 20993 USA. RP Storz, G (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Mol & Cellular Biol, Bethesda, MD 20892 USA. EM storz@helix.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ZIA [HD001608] FX Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Funding for open access charge: ZIA [HD001608]. NR 51 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 AUG 19 PY 2016 VL 44 IS 14 BP 6935 EP 6948 DI 10.1093/nar/gkw404 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV5VX UT WOS:000382999900038 PM 27166377 ER PT J AU Agrawal, AS Ying, TL Tao, XR Garron, T Algaissi, A Wang, YP Wang, LL Peng, BH Jiang, SB Dimitrov, DS Tseng, CTK AF Agrawal, Anurodh Shankar Ying, Tianlei Tao, Xinrong Garron, Tania Algaissi, Abdullah Wang, Yanping Wang, Lili Peng, Bi-Hung Jiang, Shibo Dimitrov, Dimiter S. Tseng, Chien-Te K. TI Passive Transfer of A Germline-like Neutralizing Human Monoclonal Antibody Protects Transgenic Mice Against Lethal Middle East Respiratory Syndrome Coronavirus Infection SO SCIENTIFIC REPORTS LA English DT Article ID RECEPTOR-BINDING DOMAIN; PIPISTRELLUS BAT CORONAVIRUS; MERS-COV INFECTION; SPIKE PROTEIN; MOUSE MODEL; POSTEXPOSURE EFFICACY; DROMEDARY CAMELS; SAUDI-ARABIA; BETACORONAVIRUS; TRANSMISSION AB Middle East Respiratory Syndrome coronavirus (MERS-CoV) has repeatedly caused outbreaks in the Arabian Peninsula. To date, no approved medical countermeasures (MCM) are available to combat MERS-CoV infections. Several neutralizing human monoclonal antibodies (mAbs), including m336, a germline-like human mAb, have been chosen as promising MCM for MERS-CoV. However, their clinical development has been hindered by the lack of a robust animal model that recapitulate the morbidity and mortality of human infections. We assessed the prophylactic and therapeutic efficacy of m336 by using well-characterized transgenic mice shown to be highly sensitive to MERS-CoV infection and disease. We found that mice treated with m336 prior to or post lethal MERS-CoV challenging were fully protected, compared to control mice which sufferered from profound weight loss and uniform death within days after infection. Taken together, these results support further development of m336 and other human monoclonal antibodies as potential therapeutics for MERS-CoV infection. C1 [Agrawal, Anurodh Shankar; Tao, Xinrong; Garron, Tania; Algaissi, Abdullah; Tseng, Chien-Te K.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. [Ying, Tianlei] Fudan Univ, Sch Basic Med Sci, Key Lab Med Mol Virol, Minist Educ, Shanghai 200032, Peoples R China. [Ying, Tianlei] Fudan Univ, Sch Basic Med Sci, Key Lab Med Mol Virol, Minist Hlth, Shanghai 200032, Peoples R China. [Algaissi, Abdullah; Jiang, Shibo] Jazan Univ, Dept Med Labs Technol, Coll Appl Med Sci, Jazan, Saudi Arabia. [Wang, Yanping; Wang, Lili; Dimitrov, Dimiter S.] NCI, Prot Interact Sect, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Peng, Bi-Hung] Univ Texas Med Branch, Neurosci & Cell Biol, Galveston, TX 77555 USA. RP Tseng, CTK (reprint author), Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. EM sktseng@utmb.edu FU National Institutes of Health Grant [R21AI113206-01]; Center for Biodefense and Emerging Infectious Diseases and from the Galveston National Laboratory [5UC7AI094660-05]; University of Texas Medical Branch, Galveston, TX; NCI; National Natural Science Foundation of China [31570936]; T32 Biodefense Training Program by NIH [5 T32 AI 60549-12] FX We thank Dr. Heinz Feldmann, National Institute of Health at Hamilton, Montana, and Dr. Ron A. Fouchier, Erasmus Medical Center at Rotterdam, The Netherlands for the MERS-CoV. This research was supported in part by a National Institutes of Health Grant, R21AI113206-01 (to C-T.K.T), and pilot grants from the Center for Biodefense and Emerging Infectious Diseases and from the Galveston National Laboratory (Grant Number: 5UC7AI094660-05. Project Title: National Biocontainment Laboratories (NBLs) Operations Support), University of Texas Medical Branch, Galveston, TX (to C-T.K.T.), intramural funding of NCI (to DSD), and the National Natural Science Foundation of China (#31570936 to SJ, #31570936 to TY). T.G was supported in part by a T32 Biodefense Training Program (5 T32 AI 60549-12) awarded to UTMB by NIH. NR 46 TC 3 Z9 3 U1 0 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 AUG 19 PY 2016 VL 6 AR 31629 DI 10.1038/srep31629 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT7KX UT WOS:000381666600001 PM 27538452 ER PT J AU Ghazizadeh, A Griggs, W Hikosaka, O AF Ghazizadeh, Ali Griggs, Whitney Hikosaka, Okihide TI Ecological Origins of Object Salience: Reward, Uncertainty, Aversiveness, and Novelty SO FRONTIERS IN NEUROSCIENCE LA English DT Article DE object salience; reward; uncertainty; aversiveness; novelty ID BASAL GANGLIA CIRCUITS; LONG-TERM-MEMORY; RECOGNITION MEMORY; DOPAMINE NEURONS; ORBITOFRONTAL CORTEX; ATTENTIONAL CAPTURE; SIGNALS; INFORMATION; MONKEYS; STIMULI AB Among many objects around us, some are more salient than others (i.e., attract our attention automatically). Some objects may be inherently salient (e.g., brighter), while others may become salient by virtue of their ecological relevance through experience. However, the role of ecological experience in automatic attention has not been studied systematically. To address this question, we let subjects (macaque monkeys) view a large number of complex objects (>300), each experienced repeatedly (>5 days) with rewarding, aversive or no outcome association (mere-perceptual exposure). Test of salience was done on separate days using free viewing with no outcome. We found that gaze was biased among the objects from the outset, affecting saccades to objects or fixations within objects. When the outcome was rewarding, gaze preference was stronger (i.e., positive) for objects with larger or equal but uncertain rewards. The effects of aversive outcomes were variable. Gaze preference was positive for some outcome associations airpuff), but negative for others (e.g., time-out), possibly due to differences in threat levels. Finally, novel objects attracted gaze, but mere perceptual exposure of objects reduced their salience (learned negative salience). Our results show that, in primates, object salience is strongly influenced by previous ecological experience and is supported by a large memory capacity. Owing to such high capacity for learned salience, the ability to rapidly choose important objects can grow during the entire life to promote biological fitness. C1 [Ghazizadeh, Ali; Griggs, Whitney; Hikosaka, Okihide] NEI, Sensorimotor Res Lab, Natl Inst Hlth Bethesda, Bldg 10, Bethesda, MD 20892 USA. [Hikosaka, Okihide] NIDA, NIH, Baltimore, MD USA. RP Ghazizadeh, A (reprint author), NEI, Sensorimotor Res Lab, Natl Inst Hlth Bethesda, Bldg 10, Bethesda, MD 20892 USA. EM alieghazizadeh@gmail.com FU Intramural Research Program at the National Institutes of Health, National Eye Institute FX This research was supported by the Intramural Research Program at the National Institutes of Health, National Eye Institute. We thank H. Kim, H. Amita, D. McMahon for valuable discussions and S. Hong for providing technical assistance. We thank O. Dal Monte for providing the monkey face library. NR 69 TC 1 Z9 1 U1 9 U2 9 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD AUG 19 PY 2016 VL 10 AR 378 DI 10.3389/fnins.2016.00378 PG 16 WC Neurosciences SC Neurosciences & Neurology GA DT9FO UT WOS:000381801500002 PM 27594825 ER PT J AU Speer, SD Pierson, TC AF Speer, Scott D. Pierson, Theodore C. TI Diagnostics for Zika virus on the horizon SO SCIENCE LA English DT Editorial Material ID WEST-NILE-VIRUS; INFECTION; ANTIBODY C1 [Speer, Scott D.; Pierson, Theodore C.] NIAID, Viral Pathogenesis Sect, Bethesda, MD 20892 USA. RP Pierson, TC (reprint author), NIAID, Viral Pathogenesis Sect, Bethesda, MD 20892 USA. EM piersontc@niaid.nih.gov FU Intramural NIH HHS NR 15 TC 2 Z9 3 U1 71 U2 84 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD AUG 19 PY 2016 VL 353 IS 6301 BP 750 EP 751 DI 10.1126/science.aah6187 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT5ZE UT WOS:000381561400020 PM 27540152 ER PT J AU Russo, MV McGavern, DB AF Russo, Matthew V. McGavern, Dorian B. TI Inflammatory neuroprotection following traumatic brain injury SO SCIENCE LA English DT Editorial Material ID SPINAL-CORD; T-CELLS AB Traumatic brain injury (TBI) elicits an inflammatory response in the central nervous system (CNS) that involves both resident and peripheral immune cells. Neuroinflammation can persist for years following a single TBI and may contribute to neurodegeneration. However, administration of anti-inflammatory drugs shortly after injury was not effective in the treatment of TBI patients. Some components of the neuroinflammatory response seem to play a beneficial role in the acute phase of TBI. Indeed, following CNS injury, early inflammation can set the stage for proper tissue regeneration and recovery, which can, perhaps, explain why general immunosuppression in TBI patients is disadvantageous. Here, we discuss some positive attributes of neuroinflammation and propose that inflammation be therapeutically guided in TBI patients rather than globally suppressed. C1 [Russo, Matthew V.; McGavern, Dorian B.] NINDS, Viral Immunol & Intravital Imaging Sect, NIH, Bethesda, MD 20852 USA. RP McGavern, DB (reprint author), NINDS, Viral Immunol & Intravital Imaging Sect, NIH, Bethesda, MD 20852 USA. EM mcgavernd@mail.nih.gov FU Intramural NIH HHS [, ZIA NS003112-07] NR 15 TC 3 Z9 4 U1 14 U2 14 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD AUG 19 PY 2016 VL 353 IS 6301 BP 783 EP 785 DI 10.1126/science.aaf6260 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT5ZE UT WOS:000381561400036 PM 27540166 ER PT J AU Malecki, M Sabo, C Foorohar, A Tombokan, X AF Malecki, Marek Sabo, Chelsea Foorohar, Afsoon Tombokan, Xenia TI Novel paradigm for immunotherapy of breast cancer by engaging prophylactic immunity against hepatitis B SO CLINICAL AND TRANSLATIONAL MEDICINE LA English DT Article DE Breast cancer; Immunotherapy; Trastuzumab; Cancer; Vaccine; HER-2; Erb-B2; Mimotope; Hepatitis B ID VIRUS SURFACE-ANTIGEN; MECHANISM; CELLS; IMMUNOASSAY; ANTIBODIES; HERCEPTIN; SURVIVAL; SINGLE; YEAST AB Background: Immunotherapy of patients suffering from the human epidermal growth factor receptor 2 overexpressing (HER-2(+)) breast cancers with the anti-HER-2 antibodies results in increase of the patients' overall survival. However, no prophylactic vaccine is available against HER-2+ breast cancers. Although, prophylactic vaccine for human hepatitis B virus (HBV) is very effective. Specific aim: The specific aim of this work was to design, synthesize, and test bio-molecules which would engage prophylactic immunity against hepatitis B virus towards killing breast cancers cells. Methods and Results: By biomolecular engineering, we have created a novel family of biomolecules: antibody (anti-HER-2) x vaccine (HBsAg) engineered constructs (AVEC: anti-HER-2 x HBsAg). These biomolecules were utilized for redirecting, accelerating, and amplifying of the vaccination-induced, prophylactic immunity originally targeted against HBV as therapeutic immunity, newly targeted against HER-2+ breast cancers. Treatment of the HER-2+ breast cancer cells with AVEC: anti-HER-2 x HBsAg in blood of the patients, vaccinated with HBsAg, rapidly increased efficacy of killing of HER-2+ breast cancer cells over that attained with the naked anti-HER-2 antibodies. Conclusion: Novel antibody-vaccine engineered constructs (AVEC) facilitate redirecting, accelerating, and amplifying of prophylactic, HBV vaccination-induced immunity as immunotherapy (RAAVIIT) of HER-2+ breast cancer. We currently streamline this novel therapeutic paradigm into clinical trials of breast and other cancers. C1 [Malecki, Marek] Phoenix Biomol Engn Fdn, San Francisco, CA 94119 USA. [Malecki, Marek] Univ Wisconsin, Madison, WI 53706 USA. [Malecki, Marek] NIH, Madison, WI 20892 USA. [Sabo, Chelsea] Sutter Hlth Ctr, San Francisco, CA USA. [Foorohar, Afsoon] Univ Sheffield, Sheffield, S Yorkshire, England. [Tombokan, Xenia] Bruker Corp, The Woodlands, TX USA. RP Malecki, M (reprint author), Phoenix Biomol Engn Fdn, San Francisco, CA 94119 USA.; Malecki, M (reprint author), Univ Wisconsin, Madison, WI 53706 USA.; Malecki, M (reprint author), NIH, Madison, WI 20892 USA. EM mm@pbmef.org FU PBMEF [2006070101]; NSF [9420056, 9522771, 9902020, 0094016]; NIH [P41 RR000570, P41 RR002301] FX Parts of this work were supported by the funds from the PBMEF (2006070101), the NSF (9420056, 9522771, 9902020, and 0094016), the NIH (P41 RR000570 and P41 RR002301); to Marek Malecki MD Ph.D.-the principal investigator. Administrators of the funding institutions had no influence on the data acquisition and the IP. NR 22 TC 0 Z9 0 U1 6 U2 9 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 AUG 18 PY 2016 VL 5 AR 32 DI 10.1186/s40169-016-0111-8 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EH7KG UT WOS:000391951100001 PM 27539579 ER PT J AU Ferre, EMN Rose, SR Rosenzweig, SD Burbelo, PD Romito, KR Niemela, JE Rosen, LB Break, TJ Gu, WJ Hunsberger, S Browne, SK Hsu, AP Rampertaap, S Swamydas, M Collar, AL Kong, HH Lee, CCR Chascsa, D Simcox, T Pham, A Bondici, A Natarajan, M Monsale, J Kleiner, DE Quezado, M Alevizos, I Moutsopoulos, NM Yockey, L Frein, C Soldatos, A Calvo, KR Adjemian, J Similuk, MN Lang, DM Stone, KD Uzel, G Kopp, JB Bishop, RJ Holland, SM Olivier, KN Fleisher, TA Heller, T Winer, KK Lionakis, MS AF Ferre, Elise M. N. Rose, Stacey R. Rosenzweig, Sergio D. Burbelo, Peter D. Romito, Kimberly R. Niemela, Julie E. Rosen, Lindsey B. Break, Timothy J. Gu, Wenjuan Hunsberger, Sally Browne, Sarah K. Hsu, Amy P. Rampertaap, Shakuntala Swamydas, Muthulekha Collar, Amanda L. Kong, Heidi H. Lee, Chyi-Chia Richard Chascsa, David Simcox, Thomas Pham, Angela Bondici, Anamaria Natarajan, Mukil Monsale, Joseph Kleiner, David E. Quezado, Martha Alevizos, Ilias Moutsopoulos, Niki M. Yockey, Lynne Frein, Cathleen Soldatos, Ariane Calvo, Katherine R. Adjemian, Jennifer Similuk, Morgan N. Lang, David M. Stone, Kelly D. Uzel, Gulbu Kopp, Jeffrey B. Bishop, Rachel J. Holland, Steven M. Olivier, Kenneth N. Fleisher, Thomas A. Heller, Theo Winer, Karen K. Lionakis, Michail S. TI Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy SO JCI INSIGHT LA English DT Article ID SYNDROME TYPE-I; CHRONIC MUCOCUTANEOUS CANDIDIASIS; COMMON VARIABLE IMMUNODEFICIENCY; POLYGLANDULAR SYNDROME TYPE-1; B-CELL POPULATION; ADDISONS-DISEASE; REGULATOR GENE; PERIPHERAL-BLOOD; APS-I; AUTOANTIBODIES AB Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare primary immunodeficiency disorder typically caused by homozygous AIRE mutations. It classically presents with chronic mucocutaneous candidiasis and autoimmunity that primarily targets endocrine tissues; hypoparathyroidism and adrenal insufficiency are most common. Developing any two of these classic triad manifestations establishes the diagnosis. Although widely recognized in Europe, where nonendocrine autoimmune manifestations are uncommon, APECED is less defined in patients from the Western Hemisphere. We enrolled 35 consecutive American APECED patients (33 from the US) in a prospective observational natural history study and systematically examined their genetic, clinical, autoantibody, and immunological characteristics. Most patients were compound heterozygous; the most common AIRE mutation was c.967_979del13. All but one patient had anti-IFN-omega autoantibodies, including 4 of 5 patients without biallelic AIRE mutations. Urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis, and Sjogren's-like syndrome, uncommon entities in European APECED cohorts, affected 40%-80% of American cases. Development of a classic diagnostic dyad was delayed at mean 7.38 years. Eighty percent of patients developed a median of 3 non-triad manifestations before a diagnostic dyad. Only 20% of patients had their first two manifestations among the classic triad. Urticarial eruption, intestinal dysfunction, and enamel hypoplasia were prominent among early manifestations. Patients exhibited expanded peripheral CD4(+) T cells and CD21(lo)CD38(lo) B lymphocytes. In summary, American APECED patients develop a diverse syndrome, with dramatic enrichment in organ-specific nonendocrine manifestations starting early in life, compared with European patients. Incorporation of these new manifestations into American diagnostic criteria would accelerate diagnosis by approximately 4 years and potentially prevent life-threatening endocrine complications. C1 [Ferre, Elise M. N.; Rose, Stacey R.; Break, Timothy J.; Swamydas, Muthulekha; Collar, Amanda L.; Pham, Angela; Bondici, Anamaria; Natarajan, Mukil; Yockey, Lynne; Lionakis, Michail S.] NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Rosenzweig, Sergio D.; Romito, Kimberly R.; Niemela, Julie E.; Rampertaap, Shakuntala; Monsale, Joseph; Fleisher, Thomas A.] NIH, Serv Immunol, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Burbelo, Peter D.] Natl Inst Dent & Craniofacial Res, Dent Clin Res Core, Bethesda, MD USA. [Rosen, Lindsey B.; Browne, Sarah K.; Hsu, Amy P.; Yockey, Lynne; Uzel, Gulbu; Holland, Steven M.] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Gu, Wenjuan; Frein, Cathleen] Natl Canc Inst NCI Campus Frederick, Clin Res Directorate, Clin Monitoring Res Program, Leidos Biomed Res Inc, Frederick, MD USA. [Hunsberger, Sally] NIAID, Biostat Res Branch, Div Clin Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kong, Heidi H.; Kleiner, David E.; Quezado, Martha] NCI, Dermatol Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Lee, Chyi-Chia Richard] NCI, Pathol Lab, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Chascsa, David; Simcox, Thomas; Heller, Theo] NIDDK, Translat Hepatol Unit, Liver Dis Branch, Bethesda, MD 20892 USA. [Alevizos, Ilias] Natl Inst Dent & Craniofacial Res, Sjogrens Syndrome & Salivary Gland Dysfunct Unit, NIH, Bethesda, MD USA. [Moutsopoulos, Niki M.] Natl Inst Dent & Craniofacial Res, Oral Immun & Inflammat Unit, NIH, Bethesda, MD USA. [Soldatos, Ariane] NIH, Undiag Dis Program, Common Fund, Off Director, Bldg 10, Bethesda, MD 20892 USA. [Soldatos, Ariane] NHGRI, Bethesda, MD 20892 USA. [Calvo, Katherine R.] NIH, Hematol Sect, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Adjemian, Jennifer] NIAID, Epidemiol Unit, Lab Clin Infect Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Similuk, Morgan N.] NIAID, Immunol Lab, Bldg 10, Bethesda, MD 20892 USA. [Lang, David M.] NIH, Pediat Consult Serv, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Stone, Kelly D.] NIAID, Lab Allerg Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kopp, Jeffrey B.] NIDDK, Kidney Dis Branch, Bethesda, MD 20892 USA. [Bishop, Rachel J.] NEI, Consult Serv Sect, Bethesda, MD 20892 USA. [Olivier, Kenneth N.] NHLBI, Cardiovasc & Pulm Branch, Bldg 10, Bethesda, MD 20892 USA. [Winer, Karen K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Growth & Nutr Branch, NIH, Bethesda, MD USA. [Rose, Stacey R.] Baylor Coll Med, Div Infect Dis, Houston, TX 77030 USA. [Browne, Sarah K.] US FDA, Div Vaccines & Related Prod Applicat, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Lionakis, MS (reprint author), NIAID, Fungal Pathogenesis Unit, LCID, NIH, 9000 Rockville Pike,Bldg 10,Room 11C102, Bethesda, MD 20892 USA. EM lionakism@mail.nih.gov NR 63 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD AUG 18 PY 2016 VL 1 IS 13 DI 10.1172/jci.insight.88782 PG 18 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1NO UT WOS:000387119700010 ER PT J AU Johnson, AD AF Johnson, Andrew D. TI Pairing megakaryopoiesis methylation with PEAR1 SO BLOOD LA English DT Editorial Material ID PLATELET AGGREGABILITY; AGGREGATION; ACTIVATION; VARIANT; GENE C1 [Johnson, Andrew D.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. RP Johnson, AD (reprint author), NHLBI, 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 AUG 18 PY 2016 VL 128 IS 7 BP 890 EP 892 DI 10.1182/blood-2016-06-723940 PG 5 WC Hematology SC Hematology GA DW7ML UT WOS:000383834800006 PM 27539998 ER PT J AU Lama, JR Karuna, ST Grant, SP Swann, EM Ganoza, C Segura, P Montano, SM Lacherre, M De Rosa, SC Buchbinder, S Sanchez, J McElrath, MJ Lemos, MP AF Lama, Javier R. Karuna, Shelly T. Grant, Shannon P. Swann, Edith M. Ganoza, Carmela Segura, Patricia Montano, Silvia M. Lacherre, Martin De Rosa, Stephen C. Buchbinder, Susan Sanchez, Jorge McElrath, M. Juliana Lemos, Maria P. CA HVTN 914 Study Team TI Transient Peripheral Immune Activation follows Elective Sigmoidoscopy or Circumcision in a Cohort Study of MSM at Risk of HIV Infection SO PLOS ONE LA English DT Article ID T-CELL RESPONSES; VIRUS-INFECTION; MEN; SEX; VACCINE; TRIAL; ACQUISITION; PREVENTION; SAFETY; PERU AB Background Rectal and genital sampling in HIV prevention trials permits assessments at the site of HIV entry. Yet the safety and acceptability of circumcision and sigmoidoscopy (and associated abstinence recommendations) are unknown in uncircumcised men who have sex with men (MSM) at high risk of HIV infection. Methods Twenty-nine HIV-seronegative high-risk Peruvian MSM agreed to elective sigmoidoscopy biopsy collections (weeks 2 and 27) and circumcision (week 4) in a 28-week cohort study designed to mimic an HIV vaccine study mucosal collection protocol. We monitored adherence to abstinence recommendations, procedure-related complications, HIV infections, peripheral immune activation, and retention. Results Twenty-three (79.3%) underwent a first sigmoidoscopy, 21 (72.4%) were circumcised, and 16 (55.2%) completed a second sigmoidoscopy during the study period. All who underwent procedures completed the associated follow-up safety visits. Those completing the procedures reported they were well tolerated, and complication rates were similar to those reported in the literature. Immune activation was detected during the healing period (1 week post-sigmoidoscopy, 6 weeks post-circumcision), including increases in CCR5(+)CD4(+)T cells and alpha 4 beta 7(+)CD4(+)T cells. Most participants adhered to post-circumcision abstinence recommendations whereas reduced adherence occurred post-sigmoidoscopy. Conclusion Rectosigmoid mucosal and genital tissue collections were safe in high-risk MSM. Although the clinical implications of the post-procedure increase in peripheral immune activation markers are unknown, they reinforce the need to provide ongoing risk reduction counseling and support for post-procedure abstinence recommendations. Future HIV vaccine studies should also consider the effects of mucosal and tissue collections on peripheral blood endpoints in trial design and analysis. C1 [Lama, Javier R.; Ganoza, Carmela; Segura, Patricia; Lacherre, Martin; Sanchez, Jorge] Asociac Civil Impacta Salud & Educ, Lima, Peru. [Karuna, Shelly T.; Grant, Shannon P.; De Rosa, Stephen C.; McElrath, M. Juliana; Lemos, Maria P.] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA. [Swann, Edith M.] NIAID, Vaccine Clin Res Branch, Div AIDS, US NIH, Bethesda, MD USA. [Montano, Silvia M.] US Naval Med Res Unit 6, Callao, Peru. [De Rosa, Stephen C.; Sanchez, Jorge] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [McElrath, M. Juliana] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [McElrath, M. Juliana] Univ Washington, Dept Med, Seattle, WA USA. [Buchbinder, Susan] San Francisco Dept Hlth, San Francisco, CA USA. RP Lemos, MP (reprint author), Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA. EM mlemos@fredhutch.org FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health [UM1AI068614, UM1AI068618, UM1AI068635, UM1AI069438]; National Institute of Allergy and Infectious Diseases of the U.S. National Institutes of Health FX Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award numbers UM1AI068614, UM1AI068618, UM1AI068635, and UM1AI069438. The content is the responsibility of the authors and does not necessarily represent the official views, policy or position of the U.S. National Institutes of Health, Department of the Navy, Department of Defense, or U.S. Government. Silvia Montano and Edith Swann are employees of the U.S. Government, who contributed to this work as part of their official duties. No copyright protection is available for their work as defined by Title 17 U.S.C. 105 and 101.; Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the U.S. National Institutes of Health. The content is the responsibility of the authors and does not necessarily represent the official views, policy or position of the U.S. National Institutes of Health, the Department of the Navy, the Department of Defense, or the U.S. Government. Silvia Montano and Edith Swann are employees of the U.S. Government who contributed to this work as part of her official duties. No copyright protection is available for their work as defined by Titles 17 U.S.C. 105 and 101. NR 47 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 AUG 18 PY 2016 VL 11 IS 8 AR e0160487 DI 10.1371/journal.pone.0160487 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT6ES UT WOS:000381577000022 PM 27536938 ER PT J AU Sathyanarayana, BK Li, P Lin, JX Leonard, WJ Lee, B AF Sathyanarayana, Bangalore K. Li, Peng Lin, Jian-Xin Leonard, Warren J. Lee, Byungkook TI Molecular Models of STAT5A Tetramers Complexed to DNA Predict Relative GenomeWide Frequencies of the Spacing between the Two Dimer Binding Motifs of the Tetramer Binding Sites SO PLOS ONE LA English DT Article ID TRANSACTIVATION DOMAINS; GENE; TRANSCRIPTION; RECRUITMENT; ACTIVATION; INDUCTION; GROWTH; CELLS AB STAT proteins bind DNA as dimers and tetramers to control cellular development, differentiation, survival, and expansion. The tetramer binding sites are comprised of two dimer-binding sites repeated in tandem. The genome-wide distribution of the spacings between the dimer binding sites shows a distinctive, non-random pattern. Here, we report on estimating the feasibility of building possible molecular models of STAT5A tetramers bound to a DNA double helix with all possible spacings between the dimer binding sites. We found that the calculated feasibility estimates correlated well with the experimentally measured frequency of tetramer-binding sites. This suggests that the feasibility of forming the tetramer complex was a major factor in the evolution of this DNA sequence variation. C1 [Sathyanarayana, Bangalore K.; Lee, Byungkook] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Li, Peng; Lin, Jian-Xin; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Li, Peng; Lin, Jian-Xin; Leonard, Warren J.] NHLBI, Ctr Immunol, NIH, Bethesda, MD 20892 USA. RP Lee, B (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.; Leonard, WJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA.; Leonard, WJ (reprint author), NHLBI, Ctr Immunol, NIH, Bethesda, MD 20892 USA. EM leonardw@nhlbi.nih.gov; BKLee@mail.nih.gov OI Lee, Byungkook/0000-0002-3339-4582 FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research; Division of Intramural Research, National Heart, Lung, and Blood Institute; National Institutes of Health (National Center for Research Resources) [2P41RR001081]; National Institutes of Health (National Institute of General Medical Sciences) [9P41GM103311] FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and the Division of Intramural Research, National Heart, Lung, and Blood Institute. The Chimera software we used was developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from the National Institutes of Health (National Center for Research Resources grant 2P41RR001081, National Institute of General Medical Sciences grant 9P41GM103311). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 18 PY 2016 VL 11 IS 8 AR e0160339 DI 10.1371/journal.pone.0160339 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT6ES UT WOS:000381577000017 PM 27537504 ER PT J AU Shukla, A Yang, YH Madanikia, S Ho, Y Li, MM Sanchez, V Cataisson, C Huang, J Yuspa, SH AF Shukla, Anjali Yang, Yihan Madanikia, Sara Ho, Yan Li, Mangmang Sanchez, Vanesa Cataisson, Christophe Huang, Jing Yuspa, Stuart H. TI Elevating CLIC4 in Multiple Cell Types Reveals a TGF-Dependent Induction of a Dominant Negative Smad7 Splice Variant SO PLOS ONE LA English DT Article ID BETA SUPERFAMILY; SKIN CARCINOGENESIS; TUMOR-SUPPRESSOR; GROWTH; INHIBITION; PROLIFERATION; KERATINOCYTES; NUCLEUS; DISEASE; CANCER AB CLIC4 (Chloride intracellular channel 4) belongs to a family of putative intracellular chloride channel proteins expressed ubiquitously in multiple tissues. CLIC4 is predominantly soluble and traffics between the cytoplasm and nucleus and participates in cell cycle control and differentiation. Transforming growth factor beta (TGF-beta) elevates CLIC4, which enhances TGF-beta signaling through CLIC4 mediated stabilization of phospho-Smad2/3. CLIC4 is essential for TGF-beta induced conversion of fibroblasts to myofibroblasts and expression of matrix proteins, signaling via the p38MAPK pathway. Therefore, regulation of TGF-beta signaling is a major mechanism by which CLIC4 modifies normal growth and differentiation. We now report that elevated CLIC4 alters Smad7 function, a feedback inhibitor of the TGF-beta pathway. Overexpression of CLIC4 in keratinocytes, mouse embryonic fibroblasts and other mouse and human cell types increases the expression of Smad7 Delta, a novel truncated form of Smad7. The alternatively spliced Smad7 Delta variant is missing 94bp in exon 4 of Smad 7 and is conserved between mouse and human cells. The deletion is predicted to lack the TGF-beta signaling inhibitory MH2 domain of Smad7. Treatment with exogenous TGF-beta 1 also enhances expression of Smad7 Delta that is amplified in the presence of CLIC4. While Smad7 expression inhibits TGF-beta signaling, exogenously expressed Smad7 Delta does not inhibit TGF-beta signaling as determined by TGF-beta dependent proliferation, reporter assays and phosphorylation of Smad proteins. Instead, exogenous Smad7 Delta acts as a dominant negative inhibitor of Smad7, thus increasing TGF-beta signaling. This discovery adds another dimension to the myriad ways by which CLIC4 modifies TGF-beta signaling. C1 [Shukla, Anjali; Yang, Yihan; Madanikia, Sara; Ho, Yan; Li, Mangmang; Sanchez, Vanesa; Cataisson, Christophe; Huang, Jing; Yuspa, Stuart H.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. RP Yuspa, SH (reprint author), NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. EM yuspas@mail.nih.gov FU NCI, CCR intramural program [BC005445-30] FX This work was conducted with funding to SHY from the NCI, CCR intramural program under project BC005445-30. NR 36 TC 1 Z9 1 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 AUG 18 PY 2016 VL 11 IS 8 AR e0161410 DI 10.1371/journal.pone.0161410 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT6ES UT WOS:000381577000102 PM 27536941 ER PT J AU Silson, EH Steel, AD Baker, CI AF Silson, Edward H. Steel, Adam D. Baker, Chris I. TI Scene-Selectivity and Retinotopy in Medial Parietal Cortex SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE retinotopy; population receptive fields; scene-selectivity; resting-state functional connectivity; memory ID HUMAN RETROSPLENIAL CORTEX; BOLD-CONTRAST SENSITIVITY; LATERAL OCCIPITAL CORTEX; HUMAN VISUAL-CORTEX; OCCIPITOTEMPORAL CORTEX; PLACE AREA; FMRI; PARAHIPPOCAMPAL; CONNECTIVITY; REGIONS AB Functional imaging studies in human reliably identify a trio of scene-selective regions, one on each of the lateral [occipital place area (OPA)], ventral [parahippocampal place area (PPA)], and medial [retrosplenial complex (RSC)] cortical surfaces. Recently, we demonstrated differential retinotopic biases for the contralateral lower and upper visual fields within OPA and PPA, respectively. Here, using functional magnetic resonance imaging, we combine detailed mapping of both population receptive fields (pRF) and category-selectivity, with independently acquired resting-state functional connectivity analyses, to examine scene and retinotopic processing within medial parietal cortex. We identified a medial scene-selective region, which was contained largely within the posterior and ventral bank of the parieto-occipital sulcus (POS). While this region is typically referred to as RSC, the spatial extent of our scene-selective region typically did not extend into retrosplenial cortex, and thus we adopt the term medial place area (MPA) to refer to this visually defined scene-selective region. Intriguingly MPA co-localized with a region identified solely on the basis of retinotopic sensitivity using pRF analyses. We found that MPA demonstrates a significant contralateral visual field bias, coupled with large pRF sizes. Unlike OPA and PPA. MPA did not show a consistent bias to a single visual quadrant. MPA also co-localized with a region identified by strong differential functional connectivity with PPA and the human face-selective fusiform face area (FFA), commensurate with its functional selectivity. Functional connectivity with OPA was much weaker than with PPA, and similar to that with face-selective occipital face area (OFA), suggesting a closer link with ventral than lateral cortex. Consistent with prior research, we also observed differential functional connectivity in medial parietal cortex for anterior over posterior PPA, as well as a region on the lateral surface, the caudal inferior parietal lobule (cIPL). However, the differential connectivity in medial parietal cortex was found principally anterior of MPA. We suggest that there is posterior anterior gradient within medial parietal cortex, with posterior regions in the POS showing retinotopically based scene-selectivity and more anterior regions showing connectivity that may be more reflective of abstract, navigationally pertinent and possibly mnemonic representations. C1 [Silson, Edward H.; Steel, Adam D.; Baker, Chris I.] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Steel, Adam D.] Univ Oxford, John Radcliffe Hosp, Physiol Neuroimaging Grp, FMRIB Ctr, Oxford, England. RP Silson, EH (reprint author), NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. EM ed.silson@nih.gov OI Steel, Adam/0000-0001-8876-933X FU Intramural Research Program of the National Institutes of Health - National Institute of Mental Health Clinical Study Protocol [ZIAMH002909, 93-M-0170, NCT00001360] FX This work was supported by the Intramural Research Program (ZIAMH002909) of the National Institutes of Health - National Institute of Mental Health Clinical Study Protocol 93-M-0170, NCT00001360. NR 54 TC 3 Z9 3 U1 5 U2 5 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD AUG 18 PY 2016 VL 10 AR 412 DI 10.3389/fnhum.2016.00412 PG 17 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA DT6LR UT WOS:000381596200001 PM 27588001 ER PT J AU Reichert, MC Brown, HE Evans, TA AF Reichert, Marie C. Brown, Haley E. Evans, Timothy A. TI In vivo functional analysis of Drosophila Robo1 immunoglobulin-like domains SO NEURAL DEVELOPMENT LA English DT Article DE Drosophila; Slit; Robo; Axon guidance; Midline crossing; Immunoglobulin-like domain ID COMMISSURAL AXON GUIDANCE; GROWTH CONE GUIDANCE; CNS MIDLINE; ROUNDABOUT RECEPTOR; DISTINCT ROLES; SLIT BINDING; REPULSION; EXPRESSION; NEURONS; SYSTEM AB Background: In animals with bilateral symmetry, midline crossing of axons in the developing central nervous system is regulated by Slit ligands and their neuronal Roundabout (Robo) receptors. Multiple structural domains are present in an evolutionarily conserved arrangement in Robo family proteins, but our understanding of the functional importance of individual domains for midline repulsive signaling is limited. Methods: We have examined the functional importance of each of the five conserved immunoglobulin-like (Ig) domains within the Drosophila Robo1 receptor. We generated a series of Robo1 variants, each lacking one of the five Ig domains (Ig1-5), and tested each for their ability to bind Slit when expressed in cultured Drosophila cells. We used a transgenic approach to express each variant in robo1's normal expression pattern in wild-type and robo1 mutant embryos, and examined the effects of deleting each domain on receptor expression, axonal localization, regulation, and midline repulsive signaling in vivo. Results: We show that individual deletion of Ig domains 2-5 does not interfere with Robo1's ability to bind Slit, while deletion of Ig1 strongly disrupts Slit binding. None of the five Ig domains (Ig1-5) are individually required for proper expression of Robo1 in embryonic neurons, for exclusion from commissural axon segments in wild-type embryos, or for downregulation by Commissureless (Comm), a negative regulator of Slit-Robo repulsion in Drosophila. Each of the Robo1 Ig deletion variants (with the exception of Robo1 Delta Ig1) were able to restore midline crossing in robo1 mutant embryos to nearly the same extent as full-length Robo1, indicating that Ig domains 2-5 are individually dispensable for midline repulsive signaling in vivo. Conclusions: Our findings indicate that four of the five Ig domains within Drosophila Robo1 are dispensable for its role in midline repulsion, despite their strong evolutionary conservation, and highlight a unique requirement for the Slit-binding Ig1 domain in the regulation of midline crossing. C1 [Reichert, Marie C.; Brown, Haley E.; Evans, Timothy A.] Univ Arkansas, Dept Biol Sci, Fayetteville, AR 72701 USA. [Reichert, Marie C.] NHGRI, Intramural Res Training Program, Bethesda, MD 20892 USA. RP Evans, TA (reprint author), Univ Arkansas, Dept Biol Sci, Fayetteville, AR 72701 USA. EM evanst@uark.edu OI Evans, Timothy/0000-0002-2756-8064 FU University of Arkansas FX This work was supported by funds from the University of Arkansas. The funders had no role in the design of the study, collection, analysis, and interpretation of data, decision to publish, or preparation of the manuscript. NR 57 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 1749-8104 J9 NEURAL DEV JI Neural Dev. PD AUG 18 PY 2016 VL 11 AR 15 DI 10.1186/s13064-016-0071-0 PG 11 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA DU9EV UT WOS:000382520000001 PM 27539083 ER PT J AU Sato, K Sato, N Xu, BY Nakamura, Y Nagaya, T Choyke, PL Hasegawa, Y Kobayashi, H AF Sato, Kazuhide Sato, Noriko Xu, Biying Nakamura, Yuko Nagaya, Tadanobu Choyke, Peter L. Hasegawa, Yoshinori Kobayashi, Hisataka TI Spatially selective depletion of tumor-associated regulatory T cells with near-infrared photoimmunotherapy SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID IMMUNE CHECKPOINT BLOCKADE; CANCER-IMMUNOTHERAPY; IN-VIVO; REJECTION; IMMUNOLOGY; METASTASES; MECHANISM; RECEPTOR; THERAPY; GROWTH AB Current immunotherapies for cancer seek to modulate the balance among different immune cell populations, thereby promoting antitumor immune responses. However, because these are systemic therapies, they often cause treatment-limiting autoimmune adverse effects. It would be ideal to manipulate the balance between suppressor and effector cells within the tumor without disturbing homeostasis elsewhere in the body. CD4(+)CD25(+)Foxp3(+) regulatory T cells (T-regs) are well-known immunosuppressor cells that play a key role in tumor immunoevasion and have been the target of systemic immunotherapies. We used CD25-targeted near-infrared photoimmunotherapy (NIR-PIT) to selectively deplete T-regs, thus activating CD8 T and natural killer cells and restoring local antitumor immunity. This not only resulted in regression of the treated tumor but also induced responses in separate untreated tumors of the same cell line derivation. We conclude that CD25-targeted NIR-PIT causes spatially selective depletion of T-regs, thereby providing an alternative approach to cancer immunotherapy. C1 [Sato, Kazuhide; Sato, Noriko; Nakamura, Yuko; Nagaya, Tadanobu; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Sato, Kazuhide; Hasegawa, Yoshinori] Nagoya Univ, Grad Sch Med, Dept Resp Med, Nagoya, Aichi 4668550, Japan. [Xu, Biying] NHLBI, Image Probe Dev Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 43 TC 1 Z9 1 U1 6 U2 6 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD AUG 17 PY 2016 VL 8 IS 352 AR 352ra110 DI 10.1126/scitranslmed.aaf6843 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA DW9WP UT WOS:000384013700004 ER PT J AU Saethang, T Payne, DM Avihingsanon, Y Pisitkun, T AF Saethang, Thammakorn Payne, D. Michael Avihingsanon, Yingyos Pisitkun, Trairak TI A machine learning strategy for predicting localization of post-translational modification sites in protein-protein interacting regions SO BMC BIOINFORMATICS LA English DT Article DE Post-translational modification; Protein-protein interacting region; Machine learning; AAindex ID PAIRWISE CONTACT POTENTIALS; DATA SETS; PHOSPHORYLATION; BINDING; CLASSIFICATION; RESOURCE; GLYCOSYLATION; DATABASE AB Background: One very important functional domain of proteins is the protein-protein interacting region (PPIR), which forms the binding interface between interacting polypeptide chains. Post-translational modifications (PTMs) that occur in the PPIR can either interfere with or facilitate the interaction between proteins. The ability to predict whether sites of protein modifications are inside or outside of PPIRs would be useful in further elucidating the regulatory mechanisms by which modifications of specific proteins regulate their cellular functions. Results: Using two of the comprehensive databases for protein-protein interaction and protein modification site data (PDB and PhosphoSitePlus, respectively), we created new databases that map PTMs to their locations inside or outside of PPIRs. The mapped PTMs represented only 5 % of all known PTMs. Thus, in order to predict localization within or outside of PPIRs for the vast majority of PTMs, a machine learning strategy was used to generate predictive models from these mapped databases. For the three mapped PTM databases which had sufficient numbers of modification sites for generating models (acetylation, phosphorylation, and ubiquitylation), the resulting models yielded high overall predictive performance as judged by a combined performance score (CPS). Among the multiple properties of amino acids that were used in the classification tasks, hydrophobicity was found to contribute substantially to the performance of the final predictive models. Compared to the other classifiers we also evaluated, the SVM provided the best performance overall. Conclusions: These models are the first to predict whether PTMs are located inside or outside of PPIRs, as demonstrated by their high predictive performance. The models and data presented here should be useful in prioritizing both known and newly identified PTMs for further studies to determine the functional relationship between specific PTMs and protein-protein interactions. The implemented R package is available online (http://sysbio.chula.ac.th/PtmPPIR). C1 [Saethang, Thammakorn; Payne, D. Michael; Pisitkun, Trairak] Chulalongkorn Univ, Syst Biol Ctr, Res Affairs, Fac Med, 1873 Rama 4 Rd, Bangkok 10330, Thailand. [Avihingsanon, Yingyos] Chulalongkorn Univ, Div Nephrol, Dept Med, Fac Med, 1873 Rama 4 Rd, Bangkok 10330, Thailand. [Pisitkun, Trairak] NHLBI, Epithelial Syst Biol Lab, NIH, Bethesda, MD 20892 USA. RP Pisitkun, T (reprint author), Chulalongkorn Univ, Syst Biol Ctr, Res Affairs, Fac Med, 1873 Rama 4 Rd, Bangkok 10330, Thailand.; Avihingsanon, Y (reprint author), Chulalongkorn Univ, Div Nephrol, Dept Med, Fac Med, 1873 Rama 4 Rd, Bangkok 10330, Thailand.; Pisitkun, T (reprint author), NHLBI, Epithelial Syst Biol Lab, NIH, Bethesda, MD 20892 USA. EM fmedyah@md.chula.ac.th; pisitkut@nhlbi.nih.gov OI Pisitkun, Trairak/0000-0001-6677-2271 FU Chulalongkorn Academic Advancement into Its 2nd Century Project (CUAASC); Grants for Development of New Faculty Staff Ratchadaphiseksomphot Endowment Fund; Post-Doctoral Scholarship, Chulalongkorn University Ratchadaphiseksomphot Fund FX This work was supported by the Chulalongkorn Academic Advancement into Its 2nd Century Project (CUAASC) (TP), and the Grants for Development of New Faculty Staff Ratchadaphiseksomphot Endowment Fund (TS). TS was also supported by Post-Doctoral Scholarship, Chulalongkorn University Ratchadaphiseksomphot Fund. NR 54 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 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD AUG 17 PY 2016 VL 17 AR 307 DI 10.1186/s12859-016-1165-8 PG 15 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA DV3NR UT WOS:000382829900002 PM 27534850 ER PT J AU Funk, D Coen, K Tamadon, S Hope, BT Shaham, Y Le, AD AF Funk, Douglas Coen, Kathleen Tamadon, Sahar Hope, Bruce T. Shaham, Yavin Le, A. D. TI Role of Central Amygdala Neuronal Ensembles in Incubation of Nicotine Craving SO JOURNAL OF NEUROSCIENCE LA English DT Article DE central amygdala; Daun02; Fos; incubation of craving; nicotine; orbitofrontal cortex ID ADULT MALE RATS; MEDIAL PREFRONTAL CORTEX; TIME-DEPENDENT CHANGES; PROTEIN-KINASE-A; NUCLEUS-ACCUMBENS; DRUG RELAPSE; COCAINE-SEEKING; INDUCED REINSTATEMENT; SMOKING-CESSATION; SIGNALING PATHWAY AB The craving response to smoking-associated cues in humans or to intravenous nicotine-associated cues in adult rats progressively increases or incubates after withdrawal. Here, we further characterized incubation of nicotine craving in the rat model by determining whether this incubation is observed after adolescent-onset nicotine self-administration. We also used the neuronal activity marker Fos and the Daun02 chemogenetic inactivation procedure to identify cue-activated neuronal ensembles that mediate incubation of nicotine craving. Wetrained adolescent and adult male rats to self-administer nicotine (2 h/d for 12 d) and assessed cue-induced nicotine seeking in extinction tests (1 h) after 1, 7, 14, or 28 withdrawal days. In both adult and adolescent rats, nicotine seeking in the relapse tests followed an inverted U-shaped curve, with maximal responding on withdrawal day 14. Independent of the withdrawal day, nicotine seeking in the relapse tests was higher in adult than in adolescent rats. Analysis of Fos expression in different brain areas of adolescent and adult rats on withdrawal days 1 and 14 showed time-dependent increases in the number of Fos-positive neurons in central and basolateral amygdala, orbitofrontal cortex, ventral and dorsal medial prefrontal cortex, and nucleus accumbens core and shell. In adult Fos-lacZ transgenic rats, selective inactivation of nicotine-cue-activated Fos neurons in central amygdala, but not orbitofrontal cortex, decreased "incubated" nicotine seeking on withdrawal day 14. Our results demonstrate that incubation of nicotine craving occurs after adolescent-onset nicotine self-administration and that neuronal ensembles in central amygdala play a critical role in this incubation. C1 [Funk, Douglas; Coen, Kathleen; Tamadon, Sahar; Le, A. D.] Ctr Addict & Mental Hlth, Campbell Family Mental Hlth Res Inst, Neurobiol Alcohol Lab, 33 Russell St, Toronto, ON M5S 2S1, Canada. [Le, A. D.] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON M5S 1A8, Canada. [Le, A. D.] Univ Toronto, Dept Psychiat, Toronto, ON M5S 1A8, Canada. [Hope, Bruce T.; Shaham, Yavin] NIDA, Behav Neurosci Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Funk, D (reprint author), Ctr Addict & Mental Hlth, Campbell Family Mental Hlth Res Inst, Neurobiol Alcohol Lab, 33 Russell St, Toronto, ON M5S 2S1, Canada. EM Douglas.Funk@camh.ca RI Hope, Bruce/A-9223-2010 OI Hope, Bruce/0000-0001-5804-7061 FU National Institute on Drug Abuse-National Institutes of Health [R21DA034394]; National Institute on Drug Abuse-National Institutes of Health (Intramural Research Program grant) FX This work was supported by the National Institute on Drug Abuse-National Institutes of Health (Grant R21DA034394 to A.D.L. and Intramural Research Program grant to Y.S. and B.T.H.). NR 76 TC 1 Z9 1 U1 2 U2 2 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 AUG 17 PY 2016 VL 36 IS 33 BP 8612 EP 8623 DI 10.1523/JNEUROSCI.1505-16.2016 PG 12 WC Neurosciences SC Neurosciences & Neurology GA DU6GW UT WOS:000382313400009 PM 27535909 ER PT J AU Kaufman, DJ Baker, R Milner, LC Devaney, S Hudson, KL AF Kaufman, David J. Baker, Rebecca Milner, Lauren C. Devaney, Stephanie Hudson, Kathy L. TI A Survey of U.S Adults' Opinions about Conduct of a Nationwide Precision Medicine Initiative (R) Cohort Study of Genes and Environment SO PLOS ONE LA English DT Article ID DATABASE; BIOBANK; HEART AB Objectives A survey of a population-based sample of U.S adults was conducted to measure their attitudes about, and inform the design of the Precision Medicine Initiative's planned national cohort study. Methods An online survey was conducted by GfK between May and June of 2015. The influence of different consent models on willingness to share data was examined by randomizing participants to one of eight consent scenarios. Results Of 4,777 people invited to take the survey, 2,706 responded and 2,601 (54% response rate) provided valid responses. Most respondents (79%) supported the proposed study, and 54% said they would definitely or probably participate if asked. Support for and willingness to participate in the study varied little among demographic groups; younger respondents, LGBT respondents, and those with more years of education were significantly more likely to take part if asked. The most important study incentive that the survey asked about was learning about one's own health information. Willingness to share data and samples under broad, study-by-study, menu and dynamic consent models was similar when a statement about transparency was included in the consent scenarios. Respondents were generally interested in taking part in several governance functions of the cohort study. Conclusions A large majority of the U.S. adults who responded to the survey supported a large national cohort study. Levels of support for the study and willingness to participate were both consistent across most demographic groups. The opportunity to learn health information about one's self from the study appears to be a strong motivation to participate. C1 [Kaufman, David J.] NHGRI, Div Genom & Soc, NIH, Rockville, MD 20852 USA. [Baker, Rebecca; Milner, Lauren C.; Devaney, Stephanie; Hudson, Kathy L.] NIH, Off Director, Bldg 10, Bethesda, MD 20892 USA. RP Kaufman, DJ (reprint author), NHGRI, Div Genom & Soc, NIH, Rockville, MD 20852 USA. EM dave.kaufman@nih.gov FU Foundation for the National Institutes of Health FX The authors wish to thank the Foundation for the National Institutes of Health, which funded this survey. The authors would also like to thank Vence Bonham, Laura Rodriguez, Alex Lee and the members of the Consent, Education, Regulation and Consultation Working Group of the eMERGE research consortium for their contributions to the survey and manuscript development.; The Foundation for National Institutes of Health directly paid for GfK to field the survey. The authors themselves received no specific funding for the work. FNIH did not participate in data collection, analysis, decisions to publish or preparation of the manuscript. They were involved in discussions about the logistics of study design but did not influence survey content. NR 25 TC 3 Z9 3 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 AUG 17 PY 2016 VL 11 IS 8 AR e0160461 DI 10.1371/journal.pone.0160461 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT4YN UT WOS:000381487600031 ER PT J AU Frew, PM Parker, K Vo, L Haley, D O'Leary, A Diallo, DD Golin, CE Kuo, I Soto-Torres, L Wang, J Adimora, AA Randall, LA del Rio, C Hodder, S AF Frew, Paula M. Parker, Kimberly Vo, Linda Haley, Danielle O'Leary, Ann Diallo, Dazon Dixon Golin, Carol E. Kuo, Irene Soto-Torres, Lydia Wang, Jing Adimora, Adaora A. Randall, Laura A. del Rio, Carlos Hodder, Sally CA HIV Prevention Trials Network 064 TI Socioecological factors influencing women's HIV risk in the United States: qualitative findings from the women's HIV SeroIncidence study (HPTN 064) SO BMC PUBLIC HEALTH LA English DT Article DE HIV/AIDS; Sexual health; Socioecological model; Women; Minorities; HIV risk reduction ID SEXUALLY-TRANSMITTED INFECTIONS; INTIMATE PARTNER VIOLENCE; AFRICAN-AMERICAN WOMEN; PREVENTION TRIALS NETWORK; NEIGHBORHOOD DISADVANTAGE; DRUG-USERS; PERCEIVED DISCRIMINATION; DEPRESSIVE SYMPTOMS; PHYSICAL HEALTH; SUBSTANCE-ABUSE AB Background: We sought to understand the multilevel syndemic factors that are concurrently contributing to the HIV epidemic among women living in the US. We specifically examined community, network, dyadic, and individual factors to explain HIV vulnerability within a socioecological framework. Methods: We gathered qualitative data (120 interviews and 31 focus groups) from a subset of women ages 18-44 years (N = 2,099) enrolled in the HPTN 064 HIV seroincidence estimation study across 10 US communities. We analyzed data from 4 diverse locations: Atlanta, New York City (the Bronx), Raleigh, and Washington, DC. Data were thematically coded using grounded theory methodology. Intercoder reliability was assessed to evaluate consistency of team-based coding practices. Results: The following themes were identified at 4 levels including 1) exosystem (community): poverty prevalence, discrimination, gender imbalances, community violence, and housing challenges; 2) mesosystem (network): organizational social support and sexual concurrency; 3) microsystem (dyadic): sex exchange, interpersonal social support, intimate partner violence; and 4) individual: HIV/STI awareness, risk taking, and substance use. A strong theme emerged with over 80 % of responses linked to the fundamental role of financial insecurity underlying risktaking behavioral pathways. Conclusions: Multilevel syndemic factors contribute to women's vulnerability to HIV in the US. Financial insecurity is a predominant theme, suggesting the need for tailored programming for women to reduce HIV risk. C1 [Frew, Paula M.; Vo, Linda; Randall, Laura A.; del Rio, Carlos] Emory Univ, Div Infect Dis, Dept Med, Sch Med, 1760 Haygood Rd,Suite 300, Atlanta, GA 30322 USA. [Frew, Paula M.; Haley, Danielle] Emory Rollins Sch Publ Hlth, Dept Behav Sci & Hlth Educ, 1518 Clifton Rd NE, Atlanta, GA 30322 USA. [Frew, Paula M.; del Rio, Carlos] Emory Rollins Sch Publ Hlth, Hubert Dept Global Hlth, 1518 Clifton Rd NE, Atlanta, GA 30329 USA. [Frew, Paula M.; del Rio, Carlos] Emory Univ, Emory Ctr AIDS Res, 1518 Clifton Rd NE,Suite 8050, Atlanta, GA 30322 USA. [Parker, Kimberly] Texas Womans Univ, Dept Hlth Studies, CFO Bldg 1007,POB 425499, Denton, TX 76204 USA. [O'Leary, Ann] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, 1600 Clifton Rd, Atlanta, GA 30333 USA. [Diallo, Dazon Dixon] SisterLove Inc, 3709 Bakers Ferry Rd SW, Atlanta, GA 30331 USA. [Golin, Carol E.; Adimora, Adaora A.] Univ N Carolina, Sch Med, Dept Med, 130 Mason Farm Rd, Chapel Hill, NC 27599 USA. [Kuo, Irene] George Washington Univ, Milken Inst, Sch Publ Hlth, 950 New Hampshire Ave NW,Suite 500, Washington, DC 20052 USA. [Soto-Torres, Lydia] NIAID, Washington, DC USA. [Wang, Jing] Fred Hutchinson Canc Res Ctr, SCHARP, 1124 Columbia St, Seattle, WA 98104 USA. [Hodder, Sally] West Virginia Univ, Sch Med, One Med Ctr Dr,HSC South 2244, Morgantown, WV 26506 USA. RP Frew, PM (reprint author), Emory Univ, Div Infect Dis, Dept Med, Sch Med, 1760 Haygood Rd,Suite 300, Atlanta, GA 30322 USA.; Frew, PM (reprint author), Emory Rollins Sch Publ Hlth, Dept Behav Sci & Hlth Educ, 1518 Clifton Rd NE, Atlanta, GA 30322 USA.; Frew, PM (reprint author), Emory Rollins Sch Publ Hlth, Hubert Dept Global Hlth, 1518 Clifton Rd NE, Atlanta, GA 30329 USA.; Frew, PM (reprint author), Emory Univ, Emory Ctr AIDS Res, 1518 Clifton Rd NE,Suite 8050, Atlanta, GA 30322 USA. EM pfrew@emory.edu RI del Rio, Carlos/B-3763-2012; OI del Rio, Carlos/0000-0002-0153-3517; Frew, Paula/0000-0002-3078-9124 FU National Institute of Allergy and Infectious Diseases, National Institute on Drug Abuse, and National Institute of Mental Health [UM1 AI068619, U01-AI068613, UM1-AI068613]; Centers for Innovative Research to Control AIDS, Mailman School of Public Health, Columbia University [5U1Al069466]; University of North Carolina Clinical Trials Unit [AI069423]; University of North Carolina Clinical Trials Research Center of the Clinical and Translational Science Award [RR 025747]; University of North Carolina Center for AIDS Research [AI050410]; Emory University HIV/AIDS Clinical Trials Unit [5UO1AI069418]; Center for AIDS Research [P30 AI050409]; Clinical and Translational Science Award [UL1 RR025008]; Terry Beirn Community Programs for Clinical Research on AIDS Clinical Trials Unit [5 UM1 AI069503-07]; Johns Hopkins Adult AIDS Clinical Trial Unit [AI069465]; Johns Hopkins Clinical and Translational Science Award [UL1 RR 25005] FX Grant support provided by the National Institute of Allergy and Infectious Diseases, National Institute on Drug Abuse, and National Institute of Mental Health [UM1 AI068619, U01-AI068613, and UM1-AI068613]; Centers for Innovative Research to Control AIDS, Mailman School of Public Health, Columbia University [5U1Al069466]; University of North Carolina Clinical Trials Unit [AI069423]; University of North Carolina Clinical Trials Research Center of the Clinical and Translational Science Award [RR 025747]; University of North Carolina Center for AIDS Research [AI050410]; Emory University HIV/AIDS Clinical Trials Unit [5UO1AI069418], Center for AIDS Research [P30 AI050409], and Clinical and Translational Science Award [UL1 RR025008]; The Terry Beirn Community Programs for Clinical Research on AIDS Clinical Trials Unit [5 UM1 AI069503-07], and; The Johns Hopkins Adult AIDS Clinical Trial Unit [AI069465] and The Johns Hopkins Clinical and Translational Science Award [UL1 RR 25005]. NR 95 TC 1 Z9 1 U1 9 U2 9 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 AUG 17 PY 2016 VL 16 AR 803 DI 10.1186/s12889-016-3364-7 PG 18 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DT5UV UT WOS:000381549400004 PM 27530401 ER PT J AU Maachani, UB Tandle, A Shankavaram, U Kramp, T Camphausen, K AF Maachani, Uday B. Tandle, Anita Shankavaram, Uma Kramp, Tamalee Camphausen, Kevin TI Modulation of miR-21 signaling by MPS1 in human glioblastoma SO ONCOTARGET LA English DT Article DE glioblastoma multiforme; MPS1; MiR21; PDCD4; MSH2; TGF-beta/SMAD signaling ID TUMOR-SUPPRESSOR GENE; BREAST-CANCER CELLS; MITOTIC CHECKPOINT; COLORECTAL-CANCER; MICRORNA MATURATION; DIFFERENTIAL ROLES; PDCD4 EXPRESSION; RENAL FIBROSIS; PROTEIN; KINASE AB Monopolar spindle 1 (MPS1) is an essential spindle assembly checkpoint (SAC) kinase involved in determining spindle integrity. Beyond its mitotic functions, it has been implicated in several other signaling pathways. Our earlier studies have elaborated on role of MPS1 in glioblastoma (GBM) radiosensitization. In this study using reverse phase protein arrays (RPPAs), we assessed MPS1 mediated cell signaling pathways and demonstrated that inhibiting MPS1 could upregulate the expression of the tumor suppressor PDCD4 and MSH2 genes, by down regulating micro RNA-21 (miR-21). In GBMs miR-21 expression is significantly elevated and is associated with chemo and radioresistance. Both MPS1 and miR-21 depletion suppressed GBM cell proliferation, whereas, ectopic expression of miR-21 rescued GBM cell growth from MPS1 inhibition. Further, we demonstrate that MPS1 mediates phosphorylation of SMAD3 but not SMAD2 in GBM cells; A possible mechanism behind miR-21 modulation by MPS1. Collectively, our results shed light onto an important role of MPS1 in TGF-beta/SMAD signaling via miR-21 regulation. We also, show the prognostic effect of miR-21, PDCD4 and MSH2 levels to patient survival across different GBM molecular subtypes. This scenario in which miR-21 is modulated by MPS1 inhibition may be exploited as a potential target for effective GBM therapy. C1 [Maachani, Uday B.; Tandle, Anita; Shankavaram, Uma; Kramp, Tamalee; Camphausen, Kevin] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Camphausen, K (reprint author), NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. EM camphauk@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 54 TC 0 Z9 0 U1 3 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD AUG 16 PY 2016 VL 7 IS 33 BP 52912 EP 52927 DI 10.18632/oncotarget.4143 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY9DG UT WOS:000385433000024 PM 25991676 ER PT J AU Wang, J He, PJ Gaida, M Yang, SH Schetter, AJ Gaedcke, J Ghadimi, BM Ried, T Yfantis, H Lee, D Weiss, JM Stauffer, J Hanna, N Alexander, HR Hussain, SP AF Wang, Jian He, Peijun Gaida, Matthias Yang, Shouhui Schetter, Aaron J. Gaedcke, Jochen Ghadimi, B. Michael Ried, Thomas Yfantis, Harris Lee, Dong Weiss, Jonathan M. Stauffer, Jimmy Hanna, Nader Alexander, H. Richard Hussain, S. Perwez TI Inducible nitric oxide synthase enhances disease aggressiveness in pancreatic cancer SO ONCOTARGET LA English DT Article DE NOS2; NO; PDAC; KPC mouse model ID FORKHEAD TRANSCRIPTION FACTOR; DUCTAL ADENOCARCINOMA; BREAST-CANCER; INFLAMMATION; SURVIVAL; TUMORIGENESIS; INVASION; GROWTH; FOXOS; CELLS AB Pancreatic cancer is one of the most lethal malignancies and is refractory to the available treatments. Pancreatic ductal adenocarcinoma (PDAC) expresses high level of inducible nitric oxide synthase (NOS2), which causes sustained production of nitric oxide (NO). We tested the hypothesis that an aberrantly increased NO-release enhances the development and progression of PDAC. Enhanced NOS2 expression in tumors significantly associated with poor survival in PDAC patients (N = 107) with validation in independent cohorts. We then genetically targeted NOS2 in an autochthonous mouse model of PDAC to examine the effect of NOS2-deficiency on disease progression and survival. Genetic ablation of NOS2 significantly prolonged survival and reduced tumor severity in LSL-Kras(G12D/+); LSL-Trp53(R172H/+); Pdx-1-Cre (KPC) mice. Primary tumor cells isolated from NOS2-deficient KPC (NKPC) mice showed decreased proliferation and invasiveness as compared to those from KPC mice. Furthermore, NKPC tumors showed reduced expression of pERK, a diminished inactivation of Forkhead box transcription factor O (FOXO3), a tumor suppressor, and a decrease in the expression of oncomir-21, when compared with tumors in KPC mice. Taken together, these findings showed that NOS2 is a predictor of prognosis in early stage, resected PDAC patients, and provide proof-of-principle that targeting NOS2 may have potential therapeutic value in this lethal malignancy. C1 [Wang, Jian; He, Peijun; Yang, Shouhui; Hussain, S. Perwez] NCI, Pancreat Canc Unit, Human Carcinogenesis Lab, CCR, Bethesda, MD 20892 USA. [Gaida, Matthias] Univ Heidelberg Hosp, Inst Pathol, Heidelberg, Germany. [Schetter, Aaron J.] US FDA, Silver Spring, MD USA. [Gaedcke, Jochen; Ghadimi, B. Michael] Univ Med, Dept Gen Visceral & Pediat Surg, Gottingen, Germany. [Ried, Thomas] NCI, Genet Branch, CCR, Baltimore Vet Affairs Med Ctr, Baltimore, MD USA. [Yfantis, Harris; Lee, Dong] Baltimore Vet Affairs Med Ctr, Pathol & Lab Med, Baltimore, MD USA. [Weiss, Jonathan M.] NCI, Canc & Inflammat Program, CCR, Frederick, MD 21701 USA. [Stauffer, Jimmy] NCI, Lab Cell & Dev Signaling, Frederick, MD 21701 USA. [Hanna, Nader; Alexander, H. Richard] Univ Maryland, Sch Med, Div Surg Oncol, Baltimore, MD 21201 USA. RP Hussain, SP (reprint author), NCI, Pancreat Canc Unit, Human Carcinogenesis Lab, CCR, Bethesda, MD 20892 USA. EM hussainp@mail.nih.gov FU Intramural Research Program of Center for Cancer Research, National Cancer Institute, NIH FX Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. NR 45 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 AUG 16 PY 2016 VL 7 IS 33 BP 52993 EP 53004 DI 10.18632/oncotarget.10323 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY9DG UT WOS:000385433000029 PM 27367029 ER PT J AU Fu, SW Kirolikar, SP Ginsburg, E Tan, XH Schwartz, A Simmens, SJ Man, YG Pinzone, JJ Teal, C Awate, S Vonderhaar, BK Berg, PE AF Fu, Sidney W. Kirolikar, Saurabh P. Ginsburg, Erika Tan, Xiaohui Schwartz, Arnold Simmens, Samuel J. Man, Yan-gao Pinzone, Joseph J. Teal, Christine Awate, Sanket Vonderhaar, Barbara K. Berg, Patricia E. TI Beta protein 1 homeoprotein induces cell growth and estrogen-independent tumorigenesis by binding to the estrogen receptor in breast cancer SO ONCOTARGET LA English DT Article DE homeobox gene; BP1; estrogen receptor; tamoxifen resistance; tumorigenesis ID GENOME-WIDE ANALYSIS; HOMEOBOX GENE; ER-ALPHA; TAMOXIFEN RESISTANCE; BRCA1 INHIBITION; EXPRESSION; BP1; TUMORS; CARCINOMA; SURVIVAL AB Expression of Beta Protein 1 (BP1), a homeotic transcription factor, increases during breast cancer progression and may be associated with tumor aggressiveness. In our present work, we investigate the influence of BP1 on breast tumor formation and size in vitro and in vivo. Cells overexpressing BP1 showed higher viability when grown in the absence of serum (p < 0.05), greater invasive potential (p < 0.05) and formed larger colonies (p < 0.004) compared with the controls. To determine the influence of BP1 overexpression on tumor characteristics, MCF-7 cells transfected with either empty vector (V1) or overexpressor plasmids (O2 and O4) were injected into the fat pads of athymic nude mice. Tumors grew larger in mice receiving O2 or O4 cells than in mice receiving V1 cells. Moreover, BP1 mRNA expression levels were positively correlated with tumor size in patients (p = 0.01). Interestingly, 20% of mice injected with O2 or O4 cells developed tumors in the absence of estrogen, while no mice receiving V1 cells developed tumors. Several mechanisms of estrogen independent tumor formation related to BP1 were established. These data are consistent with the fact that expression of breast cancer anti-estrogen resistance 1 (BCAR1) was increased in O2 compared to V1 cells (p < 0.01). Importantly, O2 cells exhibited increased proliferation when treated with tamoxifen, while V1 cells showed growth inhibition. Overall, BP1 overexpresssion in MCF-7 breast cancer cells leads to increased cell growth, estrogen-independent tumor formation, and increased proliferation. These findings suggest that BP1 may be an important biomarker and therapeutic target in ER positive breast cancer. C1 [Fu, Sidney W.; Tan, Xiaohui] George Washington Univ, Dept Med, Div Genom Med, Washington, DC 20037 USA. [Kirolikar, Saurabh P.; Awate, Sanket; Berg, Patricia E.] George Washington Univ, Dept Biochem & Mol Med, Washington, DC 20037 USA. [Ginsburg, Erika; Vonderhaar, Barbara K.] NCI, Mammary Biol & Tumorigenesis Lab, NIH, Bethesda, MD 20892 USA. [Schwartz, Arnold] George Washington Univ, Med Ctr, Dept Pathol, Washington, DC 20037 USA. [Simmens, Samuel J.] George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Epidemiol & Biostat, Washington, DC 20037 USA. [Man, Yan-gao] Armed Forces Inst Pathol, Dept Gynecol & Breast Pathol, Washington, DC 20306 USA. [Pinzone, Joseph J.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Teal, Christine] George Washington Univ, Dept Surg, Washington, DC 20037 USA. RP Berg, PE (reprint author), George Washington Univ, Dept Biochem & Mol Med, Washington, DC 20037 USA. EM peb@gwu.edu FU Intramural Research Program of the NIH; Center for Cancer Research; NCI; Elaine H. Snyder Cancer Research Award (SWF); Katherine Birch McCormick Foundation (PEB); [K08 CA102875] FX Portions of this research were supported by grant K08 CA102875 (JJP), by the Intramural Research Program of the NIH, Center for Cancer Research, NCI (E.G. and B.K.V.), the Elaine H. Snyder Cancer Research Award (SWF) and by the Katherine Birch McCormick Foundation (PEB). NR 53 TC 0 Z9 0 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD AUG 16 PY 2016 VL 7 IS 33 BP 53204 EP 53216 DI 10.18632/oncotarget.10633 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY9DG UT WOS:000385433000045 PM 27449292 ER PT J AU Cousin, SF Kaderavek, P Haddou, B Charlier, C Marquardsen, T Tyburn, JM Bovier, PA Engelke, F Maas, W Bodenhausen, G Pelupessy, P Ferrage, F AF Cousin, Samuel F. Kaderavek, Pavel Haddou, Baptiste Charlier, Cyril Marquardsen, Thorsten Tyburn, Jean-Max Bovier, Pierre-Alain Engelke, Frank Maas, Werner Bodenhausen, Geoffrey Pelupessy, Philippe Ferrage, Fabien TI Recovering Invisible Signals by Two-Field NMR Spectroscopy SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE chemical exchange; high-field NMR spectroscopy; kinetics; nuclear magnetic resonance; low-field NMR spectroscopy ID MAGNETIC-RELAXATION DISPERSION; MOLECULAR-WEIGHT PROTEINS; FIELD-CYCLING DEVICE; CONTRAST AGENTS; MOLTEN GLOBULE; RESOLUTION; DYNAMICS; RELAXOMETRY; RESONANCE; NANOSECOND AB Nuclear magnetic resonance (NMR) studies have benefited tremendously from the steady increase in the strength of magnetic fields. Spectacular improvements in both sensitivity and resolution have enabled the investigation of molecular systems of rising complexity. At very high fields, this progress may be jeopardized by line broadening, which is due to chemical exchange or relaxation by chemical shift anisotropy. In this work, we introduce a two-field NMR spectrometer designed for both excitation and observation of nuclear spins in two distinct magnetic fields in a single experiment. NMR spectra of several small molecules as well as a protein were obtained, with two dimensions acquired at vastly different magnetic fields. Resonances of exchanging groups that are broadened beyond recognition at high field can be sharpened to narrow peaks in the low-field dimension. Two-field NMR spectroscopy enables the measurement of chemical shifts at optimal fields and the study of molecular systems that suffer from internal dynamics, and opens new avenues for NMR spectroscopy at very high magnetic fields. C1 [Cousin, Samuel F.; Kaderavek, Pavel; Haddou, Baptiste; Charlier, Cyril; Bodenhausen, Geoffrey; Pelupessy, Philippe; Ferrage, Fabien] PSL Res Univ, Ecole Normale Super, Dept Chem, 24 Rue Lhomond, F-75005 Paris, France. [Cousin, Samuel F.; Kaderavek, Pavel; Haddou, Baptiste; Charlier, Cyril; Bodenhausen, Geoffrey; Pelupessy, Philippe; Ferrage, Fabien] Univ Paris 06, Sorbonne Univ, LBM 4 Pl Jussieu, F-75005 Paris, France. [Cousin, Samuel F.; Kaderavek, Pavel; Charlier, Cyril; Bodenhausen, Geoffrey; Pelupessy, Philippe; Ferrage, Fabien] CNRS, UMR LBM 7203, F-75005 Paris, France. [Haddou, Baptiste] CNRS, UMR Pasteur 8640, F-75005 Paris, France. [Marquardsen, Thorsten; Engelke, Frank] Bruker BioSpin GmbH, Silberstreifen 4, D-76287 Rheinstetten, Germany. [Tyburn, Jean-Max] Bruker BioSpin, 34 Rue Ind BP 10002, F-67166 Wissembourg, France. [Bovier, Pierre-Alain] Bruker BioSpin AG, Ind Str 26, CH-8117 Fallanden, Switzerland. [Maas, Werner] Bruker BioSpin, Billerica, MA 01821 USA. [Charlier, Cyril] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Ferrage, F (reprint author), PSL Res Univ, Ecole Normale Super, Dept Chem, 24 Rue Lhomond, F-75005 Paris, France.; Ferrage, F (reprint author), Univ Paris 06, Sorbonne Univ, LBM 4 Pl Jussieu, F-75005 Paris, France.; Ferrage, F (reprint author), CNRS, UMR LBM 7203, F-75005 Paris, France. EM Fabien.Ferrage@ens.fr RI Kaderavek, Pavel/D-7670-2012 FU European Research Council (ERC) under the European Community Seventh Framework Program [279519 (2F4BIODYN)] FX We thank Kaushik Dutta (New York Structural Biology Center) for the ubiquitin plasmid as well as Lei Bruschweiler-Li and Rafael Bruschweiler (the Ohio State University) for the method for ubiquitin purification. This work was funded by the European Research Council (ERC) under the European Community Seventh Framework Program (FP7/2007-2013), ERC Grant Agreement 279519 (2F4BIODYN). NR 48 TC 1 Z9 1 U1 22 U2 22 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 AUG 16 PY 2016 VL 55 IS 34 BP 9886 EP 9889 DI 10.1002/anie.201602978 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA DW0ZT UT WOS:000383373000009 PM 27417269 ER PT J AU Ahlawat, S Fayad, LM Khan, MS Bredella, MA Harris, GJ Evans, DG Farschtschi, S Jacobs, MA Chhabra, A Salamon, JM Wenzel, R Mautner, VF Dombi, E Cai, WL Plotkin, SR Blakeley, JO AF Ahlawat, Shivani Fayad, Laura M. Khan, Muhammad Shayan Bredella, Miriam A. Harris, Gordon J. Evans, D. Gareth Farschtschi, Said Jacobs, Michael A. Chhabra, Avneesh Salamon, Johannes M. Wenzel, Ralph Mautner, Victor F. Dombi, Eva Cai, Wenli Plotkin, Scott R. Blakeley, Jaishri O. CA Whole Body MRI Comm REiNS TI Current whole-body MRI applications in the neurofibromatoses NF1, NF2, and schwannomatosis SO NEUROLOGY LA English DT Article ID NERVE SHEATH TUMORS; PLEXIFORM NEUROFIBROMAS; INTRAOBSERVER VARIABILITY; DIAGNOSTIC-CRITERIA; METASTATIC-DISEASE; BURDEN; TYPE-1; GROWTH; INTEROBSERVER; FEASIBILITY AB Objectives: The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration Whole-Body MRI (WB-MRI) Working Group reviewed the existing literature on WB-MRI, an emerging technology for assessing disease in patients with neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN), to recommend optimal image acquisition and analysis methods to enable WB-MRI as an endpoint in NF clinical trials. Methods: A systematic process was used to review all published data about WB-MRI in NF syndromes to assess diagnostic accuracy, feasibility and reproducibility, and data about specific techniques for assessment of tumor burden, characterization of neoplasms, and response to therapy. Results: WB-MRI at 1.5T or 3.0T is feasible for image acquisition. Short tau inversion recovery (STIR) sequence is used in all investigations to date, suggesting consensus about the utility of this sequence for detection of WB tumor burden in people with NF. There are insufficient data to support a consensus statement about the optimal imaging planes (axial vs coronal) or 2D vs 3D approaches. Functional imaging, although used in some NF studies, has not been systematically applied or evaluated. There are no comparative studies between regional vs WB-MRI or evaluations of WB-MRI reproducibility. Conclusions: WB-MRI is feasible for identifying tumors using both 1.5T and 3.0T systems. The STIR sequence is a core sequence. Additional investigation is needed to define the optimal approach for volumetric analysis, the reproducibility of WB-MRI in NF, and the diagnostic performance of WB-MRI vs regional MRI. C1 [Ahlawat, Shivani; Fayad, Laura M.; Jacobs, Michael A.] Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD USA. [Jacobs, Michael A.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Blakeley, Jaishri O.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Khan, Muhammad Shayan] Khyber Med Coll, Peshawar, Pakistan. [Bredella, Miriam A.; Harris, Gordon J.; Cai, Wenli] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. Harvard Med Sch, Boston, MA USA. [Evans, D. Gareth] Univ Manchester, Manchester Acad Hlth Sci Ctr, Genom Med, Manchester M13 9PL, Lancs, England. [Farschtschi, Said; Mautner, Victor F.] Univ Med Ctr Hamburg Eppendorf, Dept Neurol, Hamburg, Germany. [Chhabra, Avneesh] Univ Texas Southwestern Med Ctr Dallas, Radiol & Orthoped Surg, Dallas, TX 75390 USA. [Salamon, Johannes M.] Univ Hosp Hamburg Eppendorf, Dept Diagnost & Intervent Radiol, Hamburg, Germany. [Wenzel, Ralph] Radiol Practice Altona, Hamburg, Germany. [Dombi, Eva] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Plotkin, Scott R.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Plotkin, Scott R.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Ahlawat, S (reprint author), Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD USA. EM sahlawa1@jhmi.edu RI North, Kathryn/K-6476-2012; OI North, Kathryn/0000-0003-0841-8009; Evans, Gareth/0000-0002-8482-5784 FU NICHD NIH HHS [U54 HD090255] NR 37 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 16 PY 2016 VL 87 SU 1 BP S31 EP S39 DI 10.1212/WNL.0000000000002929 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DU6MD UT WOS:000382328100006 PM 27527647 ER PT J AU Hanemann, CO Blakeley, JO Nunes, FP Robertson, K Stemmer-Rachamimov, A Mautner, V Kurtz, A Ferguson, M Widemann, BC Evans, DG Ferner, R Carroll, SL Korf, B Wolkenstein, P Knight, P Plotkin, SR AF Hanemann, C. Oliver Blakeley, Jaishri O. Nunes, Fabio P. Robertson, Kent Stemmer-Rachamimov, Anat Mautner, Victor Kurtz, Andreas Ferguson, Michael Widemann, Brigitte C. Evans, D. Gareth Ferner, Rosalie Carroll, Steven L. Korf, Bruce Wolkenstein, Pierre Knight, Pamela Plotkin, Scott R. CA REiNS Int Collaboration TI Current status and recommendations for biomarkers and biobanking in neurofibromatosis SO NEUROLOGY LA English DT Article ID NERVE-SHEATH TUMORS; CLINICAL-TRIALS; TYPE-1; SERUM; MANAGEMENT; EXPRESSION; DIAGNOSIS; CONSENSUS AB Objective: Clinically validated biomarkers for neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis (SWN) have not been identified to date. The biomarker working group's goals are to (1) define biomarker needs in NF1, NF2, and SWN; (2) summarize existing data on biomarkers in NF1, NF2, and SWN; (3) outline recommendations for sample collection and biomarker development; and (4) standardize sample collection and methodology protocols where possible to promote comparison between studies by publishing standard operating procedures (SOPs). Methods: The biomarker group reviewed published data on biomarkers in NF1, NF2, and SWN and on biobanking efforts outside these diseases via literature search, defined the need for biomarkers in NF, and developed recommendations in a series of consensus meetings. Results: We describe existing biomarkers in NF and report consensus recommendations for SOP and a minimal clinical dataset to accompany samples derived from patients with NF1, NF2, and SWN in decentralized biobanks. Conclusions: These recommendations are intended to provide clinicians and researchers with a common set of guidelines to collect and store biospecimens and for establishment of biobanks for NF1, NF2, and SWN. C1 [Hanemann, C. Oliver] Univ Plymouth, Peninsula Sch Med & Dent, Inst Translat & Stratified Med, Plymouth, Devon, England. [Blakeley, Jaishri O.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Nunes, Fabio P.] Indiana Univ, Dept Pediat, Bloomington, IN 47405 USA. [Robertson, Kent; Ferguson, Michael] Indiana Univ, Dept Pediat, Sch Med, Bloomington, IN 47405 USA. [Nunes, Fabio P.] Eli Lilly & Co, Tailored Therapeut, Indianapolis, IN 46285 USA. [Stemmer-Rachamimov, Anat] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Plotkin, Scott R.] Massachusetts Gen Hosp, Neurooncol, Boston, MA 02114 USA. [Mautner, Victor] Uniklin Eppendorf, Neurol Klin, Hamburg, Germany. [Kurtz, Andreas] Charite, Berlin Brandenburg Ctr Regenerat Therapies, Berlin, Germany. [Kurtz, Andreas] Seoul Natl Univ, Coll Vet Med, Seoul, South Korea. [Kurtz, Andreas] Seoul Natl Univ, Res Inst Vet Sci, Seoul, South Korea. [Widemann, Brigitte C.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Evans, D. Gareth] Univ Manchester, Genom Med, Manchester M13 9PL, Lancs, England. [Ferner, Rosalie] Guys & St Thomas NHS Fdn Trust, Dept Neurol, Natl Neurofibromatosis Serv, London, England. [Carroll, Steven L.] Med Univ S Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA. [Korf, Bruce] Univ Alabama Birmingham, Heflin Ctr Genom Sci, Birmingham, AL USA. GHU Henri Mondor, Paris, France. [Knight, Pamela] Childrens Tumor Fdn, New York, NY USA. RP Hanemann, CO (reprint author), Univ Plymouth, Peninsula Sch Med & Dent, Inst Translat & Stratified Med, Plymouth, Devon, England. EM Oliver.Hanemann@plymouth.ac.uk RI North, Kathryn/K-6476-2012; OI North, Kathryn/0000-0003-0841-8009; Hanemann, Clemens Oliver/0000-0002-1951-1025; Evans, Gareth/0000-0002-8482-5784 FU NICHD NIH HHS [U54 HD090255] NR 22 TC 1 Z9 1 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 16 PY 2016 VL 87 SU 1 BP S40 EP S48 DI 10.1212/WNL.0000000000002932 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DU6MD UT WOS:000382328100007 PM 27527649 ER PT J AU Plotkin, SR Davis, SD Robertson, KA Akshintala, S Allen, J Fisher, MJ Blakeley, JO Widemann, BC Ferner, RE Marcus, CL AF Plotkin, Scott R. Davis, Stephanie D. Robertson, Kent A. Akshintala, Srivandana Allen, Julian Fisher, Michael J. Blakeley, Jaishri O. Widemann, Brigitte C. Ferner, Rosalie E. Marcus, Carole L. CA REiNS Int Collaboration TI Sleep and pulmonary outcomes for clinical trials of airway plexiform neurofibromas in NF1 SO NEUROLOGY LA English DT Article ID PHASE-I TRIAL; APNEA SYNDROME; REFERENCE VALUES; RESPIRATORY INDICATIONS; PRACTICE PARAMETERS; CYSTIC-FIBROSIS; CPAP TREATMENT; CHILDREN; POLYSOMNOGRAPHY; SPIROMETRY AB Objective: Plexiform neurofibromas (PNs) are complex, benign nerve sheath tumors that occur in approximately 25%-50% of individuals with neurofibromatosis type 1 (NF1). PNs that cause airway compromise or pulmonary dysfunction are uncommon but clinically important. Because improvement in sleep quality or airway function represents direct clinical benefit, measures of sleep and pulmonary function may be more meaningful than tumor size as endpoints in therapeutic clinical trials targeting airway PN. Methods: The Response Evaluation in Neurofibromatosis and Schwannomatosis functional outcomes group reviewed currently available endpoints for sleep and pulmonary outcomes and developed consensus recommendations for response evaluation in NF clinical trials. Results: For patients with airway PNs, polysomnography, impulse oscillometry, and spirometry should be performed to identify abnormal function that will be targeted by the agent under clinical investigation. The functional group endorsed the use of the apnea hypopnea index (AHI) as the primary sleep endpoint, and pulmonary resistance at 10 Hz (R-10) or forced expiratory volume in 1 or 0.75 seconds (FEV1 or FEV0.75) as primary pulmonary endpoints. The group defined minimum changes in AHI, R-10, and FEV1 or FEV0.75 for response criteria. Secondary sleep outcomes include desaturation and hypercapnia during sleep and arousal index. Secondary pulmonary outcomes include pulmonary resistance and reactance measurements at 5, 10, and 20 Hz; forced vital capacity; peak expiratory flow; and forced expiratory flows. Conclusions: These recommended sleep and pulmonary evaluations are intended to provide researchers with a standardized set of clinically meaningful endpoints for response evaluation in trials of NF1-related airway PNs. C1 [Plotkin, Scott R.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Plotkin, Scott R.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Davis, Stephanie D.] Indiana Univ Sch Med, Riley Childrens Hosp, Sect Pediat Pulmonol Allergy & Sleep Med, Indianapolis, IN 46202 USA. [Robertson, Kent A.] Indiana Univ Sch Med, Riley Childrens Hosp, Stem Cell Transplantat Program, Indianapolis, IN 46202 USA. [Akshintala, Srivandana; Widemann, Brigitte C.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Allen, Julian] Childrens Hosp Philadelphia, Div Pulm Med, Philadelphia, PA 19104 USA. [Fisher, Michael J.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Marcus, Carole L.] Childrens Hosp Philadelphia, Sleep Ctr, Philadelphia, PA 19104 USA. [Fisher, Michael J.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Marcus, Carole L.] Univ Penn, Sleep Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA. [Allen, Julian] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Blakeley, Jaishri O.] Johns Hopkins Med Inst, Dept Neurol, Baltimore, MD 21205 USA. [Ferner, Rosalie E.] Guys & St Thomas NHS Fdn Trust, Dept Neurol, London, England. Kings Coll London, Inst Psychiat, London WC2R 2LS, England. RP Plotkin, SR (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA.; Plotkin, SR (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. EM splotkin@partners.org RI North, Kathryn/K-6476-2012; OI North, Kathryn/0000-0003-0841-8009; Evans, Gareth/0000-0002-8482-5784 FU NICHD NIH HHS [U54 HD090255] NR 42 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 16 PY 2016 VL 87 SU 1 BP S13 EP S20 DI 10.1212/WNL.0000000000002933 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA DU6MD UT WOS:000382328100004 PM 27527645 ER PT J AU Walsh, KS Janusz, J Wolters, PL Martin, S Klein-Tasman, BP Toledo-Tamula, MA Thompson, HL Payne, JM Hardy, KK de Blank, P Semerjian, C Gray, LS Solomon, SE Ullrich, N AF Walsh, Karin S. Janusz, Jennifer Wolters, Pamela L. Martin, Staci Klein-Tasman, Bonita P. Toledo-Tamula, Mary Anne Thompson, Heather L. Payne, Jonathan M. Hardy, Kristina K. de Blank, Peter Semerjian, Claire Gray, Laura Schaffner Solomon, Sondra E. Ullrich, Nicole CA REiNS Int Collaboration TI Neurocognitive outcomes in neurofibromatosis clinical trials Recommendations for the domain of attention SO NEUROLOGY LA English DT Article ID CONSENSUS COGNITIVE BATTERY; DEFICIT/HYPERACTIVITY DISORDER; TYPE-1; CHILDREN; ADHD; DEFICITS; NF1; SPAN; METHYLPHENIDATE; COMPLICATION AB Neurofibromatosis type 1 (NF1) is associated with neurocognitive deficits that can impact everyday functioning of children, adolescents, and adults with this disease. However, there is little agreement regarding measures to use as cognitive endpoints in clinical trials. This article describes the work of the Neurocognitive Committee of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration. The goal of this committee is to identify standardized and specific cognitive assessment tools for use in NF clinical trials. The committee first identified cognitive domains relevant to NF1 and prioritized attention as the first domain of focus given prior and current trends in NF1 cognitive clinical trials. Performance measures and behavioral rating questionnaires of attention were reviewed by the group using established criteria to assess patient characteristics, psychometric properties, and feasibility. The highest rated tests underwent side-by-side comparison. The Digit Span subtest from the Wechsler scales was given the highest ratings of the performance measures due to its good psychometrics, feasibility, utility across a wide age range, and extensive use in previous research. The Conners scales achieved the highest ratings of the behavioral questionnaires for similar reasons. Future articles will focus on other cognitive domains, with the ultimate goal of achieving agreement for cognitive endpoints that can be used across NF clinical trials. C1 [Walsh, Karin S.; Hardy, Kristina K.] George Washington Sch Med, Childrens Natl Hlth Syst, Washington, DC 20052 USA. [Janusz, Jennifer] Univ Colorado, Sch Med, Childrens Hosp Colorado, Aurora, CO USA. [Wolters, Pamela L.; Martin, Staci] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Klein-Tasman, Bonita P.] Univ Wisconsin, Milwaukee, WI 53201 USA. [Toledo-Tamula, Mary Anne] NCI, Clin Res Directorate, Clin Monitoring Res Program, Leidos Biomed Res Inc, Frederick, MD 21701 USA. [Thompson, Heather L.] Calif State Univ Sacramento, Sacramento, CA 95819 USA. [Payne, Jonathan M.] Murdoch Childrens Res Inst, Parkville, Vic, Australia. [de Blank, Peter] Rainbow Babies & Childrens Hosp, 2101 Adelbert Rd, Cleveland, OH 44106 USA. [Semerjian, Claire] Roosevelt Univ, Chicago, IL 60605 USA. [Gray, Laura Schaffner; Ullrich, Nicole] Boston Childrens Hosp, Boston, MA USA. [Solomon, Sondra E.] Univ Vermont, Burlington, VT 05405 USA. RP Walsh, KS (reprint author), George Washington Sch Med, Childrens Natl Hlth Syst, Washington, DC 20052 USA. EM kwalsh@childrensnational.org RI North, Kathryn/K-6476-2012; OI North, Kathryn/0000-0003-0841-8009; Payne, Jonathan/0000-0001-9565-3845; Evans, Gareth/0000-0002-8482-5784 FU NICHD NIH HHS [U54 HD090255] NR 50 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 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 16 PY 2016 VL 87 SU 1 BP S21 EP S30 DI 10.1212/WNL.0000000000002928 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA DU6MD UT WOS:000382328100005 PM 27527646 ER PT J AU Widemann, BC Plotkin, SR AF Widemann, Brigitte C. Plotkin, Scott R. TI Consensus for NF clinical trials Recommendations of the REiNS collaboration (Supplement II) INTRODUCTION SO NEUROLOGY LA English DT Editorial Material ID PROGRESSIVE VESTIBULAR SCHWANNOMAS; INTERNATIONAL COLLABORATION; NEUROFIBROMATOSIS TYPE-2; PHASE-II; OUTCOMES AB The neurofibromatoses (NFs) can result in substantial morbidity in affected patients. In order to accelerate the development of effective therapies for NF-related tumor and nontumor manifestations, the development of standardized meaningful outcome measures for clinical trials is critical. The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration was established with the goal to develop consensus recommendations for outcome measures and endpoints in future NF trials and provided the first set of recommendations in a Neurology (R) supplement in 2013. This second supplement updates on clinical trials that have incorporated the recommended measures and provides new recommendations for (1) standardized and specific cognitive assessment tools for use in NF clinical trials, (2) patient-reported outcome measures including pain and physical functioning, (3) functional outcome measures for airway plexiform neurofibromas, (4) the use of whole-body MRI in NF, and (5) the development of biomarkers in NF and guidelines for collection of biospecimens and establishment of biobanks for neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis. Through engagement of the NF research community, regulatory agencies, NF advocacy groups, industry, and patients with NF, REiNS will provide a framework for comprehensive review of these recommendations, continue development of outcome measures relevant to patients, and compare results of trials, which use identical outcome measures. C1 [Widemann, Brigitte C.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Plotkin, Scott R.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Widemann, BC (reprint author), NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. EM widemanb@mail.nih.gov NR 14 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 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 16 PY 2016 VL 87 SU 1 BP S1 EP S3 DI 10.1212/WNL.0000000000002930 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA DU6MD UT WOS:000382328100001 ER PT J AU Wolters, PL Martin, S Merker, VL Tonsgard, JH Solomon, SE Baldwin, A Bergner, AL Walsh, K Thompson, HL Gardner, KL Hingtgen, CM Schorry, E Dudley, WN Franklin, B AF Wolters, Pamela L. Martin, Staci Merker, Vanessa L. Tonsgard, James H. Solomon, Sondra E. Baldwin, Andrea Bergner, Amanda L. Walsh, Karin Thompson, Heather L. Gardner, Kathy L. Hingtgen, Cynthia M. Schorry, Elizabeth Dudley, William N. Franklin, Barbara CA REiNS Int Collaboration TI Patient-reported outcomes of pain and physical functioning in neurofibromatosis clinical trials SO NEUROLOGY LA English DT Article ID QUALITY-OF-LIFE; PROMISA(R) PEDIATRIC SCALES; INFORMATION-SYSTEM PROMIS; ITEM RESPONSE THEORY; PLEXIFORM NEUROFIBROMAS; INTERFERENCE INDEX; CHILDREN; TYPE-1; HEALTH; VALIDATION AB Objective: Tumors and other disease complications of neurofibromatosis (NF) can cause pain and negatively affect physical functioning. To document the clinical benefit of treatment in NF trials targeting these manifestations, patient-reported outcomes (PROs) assessing pain and physical functioning should be included as study endpoints. Currently, there is no consensus on the selection and use of such measures in the NF population. This article presents the recommendations of the PRO group of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration for assessing the domains of pain and physical functioning for NF clinical trials. Methods: The REiNS PRO group reviewed and rated existing PRO measures assessing pain intensity, pain interference, and physical functioning using their systematic method. Final recommendations are based primarily on 4 main criteria: patient characteristics, item content, psychometric properties, and feasibility for clinical trials. Results: The REiNS PRO group chose the Numeric Rating Scale-11 (>= 8 years) to assess pain intensity, the Pain Interference Index (6-24 years) and the Patient-Reported Outcome Measurement Information System (PROMIS) Pain Interference Scale (>= 18 years) to evaluate pain interference, and the PROMIS Physical Functioning Scale to measure upper extremity function and mobility (>= 5 years) for NF clinical trials. Conclusions: The REiNS Collaboration currently recommends these PRO measures to assess the domains of pain and physical functioning for NF clinical trials; however, further research is needed to evaluate their use in individuals with NF. A final consensus recommendation for the pain interference measure will be disseminated in a future publication based on findings from additional published research. C1 [Wolters, Pamela L.; Martin, Staci; Baldwin, Andrea] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Merker, Vanessa L.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Merker, Vanessa L.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Tonsgard, James H.] Univ Chicago, Pritzker Sch Med, Chicago, IL 60637 USA. [Solomon, Sondra E.] Univ Vermont, Dept Psychol Sci, Burlington, VT 05405 USA. [Bergner, Amanda L.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Bergner, Amanda L.] Johns Hopkins Univ, Dept Genet, Baltimore, MD USA. [Walsh, Karin] Childrens Natl Hlth Syst, Washington, DC USA. [Walsh, Karin] George Washington Sch Med, Washington, DC USA. [Thompson, Heather L.] Calif State Univ Sacramento, Dept Speech Pathol & Audiol, Sacramento, CA 95819 USA. [Gardner, Kathy L.] Vet Adm Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Gardner, Kathy L.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Hingtgen, Cynthia M.] Michigan State Univ, Dept Clin Neurosci, Spectrum Hlth Med Grp, E Lansing, MI 48824 USA. [Hingtgen, Cynthia M.] Michigan State Univ, Coll Human Med, E Lansing, MI 48824 USA. [Schorry, Elizabeth] Cincinnati Childrens Hosp, Div Human Genet, Cincinnati, OH USA. [Dudley, William N.] Univ N Carolina, Sch Hlth & Human Sci, Dept Publ Hlth Educ, Greensboro, NC USA. [Franklin, Barbara] Advocure NF2 Inc, Los Angeles, CA USA. RP Wolters, PL (reprint author), NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. EM woltersp@mail.nih.gov RI North, Kathryn/K-6476-2012; OI North, Kathryn/0000-0003-0841-8009; Merker, Vanessa/0000-0002-4542-5227; Evans, Gareth/0000-0002-8482-5784 FU NICHD NIH HHS [U54 HD090255] NR 44 TC 2 Z9 2 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 AUG 16 PY 2016 VL 87 SU 1 BP S4 EP S12 DI 10.1212/WNL.0000000000002927 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DU6MD UT WOS:000382328100002 PM 27527648 ER PT J AU Rosario, AM Perez-Stable, EJ AF Rosario, Adelaida M. Perez-Stable, Eliseo J. TI Making Neighborhoods Good for Your Health SO CIRCULATION LA English DT Editorial Material DE Editorials; atherosclerosis; cardiovascular diseases; health status disparities; outcome assessment (health care); residence characteristics ID UNITED-STATES; ATHEROSCLEROSIS; ENVIRONMENT; IMPACT; COUNTY C1 [Rosario, Adelaida M.] Natl Inst Minor Hlth & Hlth Dispar, Div Sci Programs, NIH, Bethesda, MD USA. [Perez-Stable, Eliseo J.] Natl Inst Minor Hlth & Hlth Dispar, Off Director, NIH, Bethesda, MD USA. RP Perez-Stable, EJ (reprint author), 6707 Democracy Blvd,Suite 800, Bethesda, MD 20892 USA. EM eliseo.perez-stable@nih.gov NR 14 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 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD AUG 16 PY 2016 VL 134 IS 7 BP 514 EP 516 DI 10.1161/CIRCULATIONAHA.116.024158 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DU5XC UT WOS:000382286000006 PM 27528646 ER PT J AU Simon, R AF Simon, Richard TI Genomic Alteration-Driven Clinical Trial Designs in Oncology SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID PHASE-II TRIALS; LUNG-CANCER; VEMURAFENIB; THERAPY; PARADIGM; MEDICINE AB The established molecular heterogeneity of human cancers necessitates the development of new paradigms to serve as a reliable basis for precision medicine. The assumptions underlying some of the conventional approaches to clinical trial design and analysis are no longer appropriate because of the molecular heterogeneity of tumors of a given primary site. This article reviews some clinical trial designs that have been actively applied in the codevelopment of therapeutics and predictive biomarkers to inform their use in oncology. These include the enrichment design, the basket design, and the umbrella design. Oncology leads most other therapeutic areas in development of personalized or precision medicine. Personalized or precision medicine is practiced daily in oncology on the basis of tumor genomics and may evolve in other therapeutic areas as it has in oncology, rather than according to inherited polymorphisms as so often imagined. Consequently, some of the clinical trial designs described here may serve as a possible blueprint for therapeutic development in fields other than oncology. C1 [Simon, Richard] NCI, Rockville, MD 20892 USA. RP Simon, R (reprint author), NCI, Div Canc Treatment & Diag, Biometr Res Program, 9609 Med Ctr Dr, Rockville, MD 20892 USA. EM rsimon@nih.gov NR 27 TC 1 Z9 1 U1 2 U2 4 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD AUG 16 PY 2016 VL 165 IS 4 BP 270 EP U114 DI 10.7326/M15-2413 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DT1UI UT WOS:000381267200016 PM 27214515 ER PT J AU Chertow, DS Nath, A Suffredini, AF Danner, RL Reich, DS Bishop, RJ Childs, RW Arai, AE Palmore, TN Lane, HC Fauci, AS Davey, RT AF Chertow, Daniel S. Nath, Avindra Suffredini, Anthony F. Danner, Robert L. Reich, Daniel S. Bishop, Rachel J. Childs, Richard W. Arai, Andrew E. Palmore, Tara N. Lane, H. Clifford Fauci, Anthony S. Davey, Richard T. TI Severe Meningoencephalitis in a Case of Ebola Virus Disease: A Case Report SO ANNALS OF INTERNAL MEDICINE LA English DT Letter C1 [Chertow, Daniel S.; Suffredini, Anthony F.; Danner, Robert L.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Nath, Avindra; Reich, Daniel S.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Bishop, Rachel J.] NEI, NIH, Bethesda, MD 20892 USA. [Childs, Richard W.; Arai, Andrew E.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Palmore, Tara N.] NIH, Hosp Epidemiol Serv, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Lane, H. Clifford; Fauci, Anthony S.; Davey, Richard T.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Chertow, DS (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CL999999] NR 6 TC 5 Z9 5 U1 2 U2 2 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 AUG 16 PY 2016 VL 165 IS 4 BP 301 EP 304 DI 10.7326/M15-3066 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA DT1UI UT WOS:000381267200030 PM 27043004 ER PT J AU Crompton, PD Pierce, SK AF Crompton, Peter D. Pierce, Susan K. TI PD-L2 Elbows out PD-L1 to Rescue T Cell Immunity to Malaria SO IMMUNITY LA English DT Editorial Material AB How early interactions between innate and adaptive immune cells influence outcomes of acute infections is incompletely understood. In this issue of Immunity, Karunarathne et al. (2016) show that dendritic cells help CD4(+) T helper 1 cell immunity against malaria through PD-L2' s competition with PD-L1. C1 [Crompton, Peter D.] NIAID, Malaria Infect Biol & Immun Unit, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Pierce, Susan K.] NIAID, Lymphocyte Activat Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Pierce, SK (reprint author), NIAID, Lymphocyte Activat Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM spierce@nih.gov RI Crompton, Peter/N-1130-2016 NR 10 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 AUG 16 PY 2016 VL 45 IS 2 BP 231 EP 233 DI 10.1016/j.immuni.2016.08.001 PG 4 WC Immunology SC Immunology GA DU5QV UT WOS:000382267300004 PM 27533008 ER PT J AU Hess, C Kemper, C AF Hess, Christoph Kemper, Claudia TI Complement-Mediated Regulation of Metabolism and Basic Cellular Processes SO IMMUNITY LA English DT Review ID NLRP3 INFLAMMASOME ACTIVATION; ADIPOSE-TISSUE INFLAMMATION; TOLL-LIKE RECEPTORS; CD4(+) T-CELLS; INSULIN-RESISTANCE; GLYCOLYTIC SWITCH; INDUCED APOPTOSIS; HUMAN MONOCYTES; INDUCED INJURY; GLUCOSE-UPTAKE AB Complement is well appreciated as a critical arm of innate immunity. It is required for the removal of invading pathogens and works by directly destroying them through the activation of innate and adaptive immune cells. However, complement activation and function is not confined to the extracellular space but also occurs within cells. Recent work indicates that complement activation regulates key metabolic pathways and thus can impact fundamental cellular processes, such as survival, proliferation, and autophagy. Newly identified functions of complement include a key role in shaping metabolic reprogramming, which underlies T cell effector differentiation, and a role as a nexus for interactions with other effector systems, in particular the inflammasome and Notch transcription-factor networks. This review focuses on the contributions of complement to basic processes of the cell, in particular the integration of complement with cellular metabolism and the potential implications in infection and other disease settings. C1 [Hess, Christoph] Univ Basel, Dept Biomed, Immunobiol, 20 Hebelstr, CH-4031 Basel, Switzerland. [Kemper, Claudia] Kings Coll London, Guys Hosp, Div Transplant Immunol & Mucosal Biol, Med Res Council,Ctr Transplantat, London SE1 9RT, England. [Kemper, Claudia] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Kemper, Claudia] NHLBI, Ctr Immunol, NIH, Bethesda, MD 20892 USA. RP Hess, C (reprint author), Univ Basel, Dept Biomed, Immunobiol, 20 Hebelstr, CH-4031 Basel, Switzerland.; Kemper, C (reprint author), Kings Coll London, Guys Hosp, Div Transplant Immunol & Mucosal Biol, Med Res Council,Ctr Transplantat, London SE1 9RT, England.; Kemper, C (reprint author), NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA.; Kemper, C (reprint author), NHLBI, Ctr Immunol, NIH, Bethesda, MD 20892 USA. EM chess@uhbs.ch; claudia.kemper@kcl.ac.uk FU MRC Centre grant [MR/J006742/1]; EU-funded Innovative Medicines Initiative BTCURE; Wellcome Trust Investigator Award; King's Bioscience Institute at King's College London; National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust; King's College London; Division of Intramural Research of the National Heart, Lung, and Blood Institute at the NIH; intramural research program of NIAID, NIH; Swiss National Science Foundation [310030_154059, CRSII_160766]; Gebert-Ruf Foundation [GER-058/14]; Swiss Cancer League [KFS-3773-08-2015] FX Work in the Hess and Kemper laboratories is supported by MRC Centre grant MR/J006742/1, an EU-funded Innovative Medicines Initiative BTCURE (C.K.), a Wellcome Trust Investigator Award (C.K.), the King's Bioscience Institute at King's College London (G.A.), the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London, the Division of Intramural Research of the National Heart, Lung, and Blood Institute at the NIH, the intramural research program of NIAID, NIH, the Swiss National Science Foundation (310030_154059 and CRSII_160766) (C.H.), the Gebert-Ruf Foundation (GER-058/14), and the Swiss Cancer League (KFS-3773-08-2015). NR 150 TC 1 Z9 1 U1 16 U2 17 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 AUG 16 PY 2016 VL 45 IS 2 BP 240 EP 254 DI 10.1016/j.immuni.2016.08.003 PG 15 WC Immunology SC Immunology GA DU5QV UT WOS:000382267300008 PM 27533012 ER PT J AU Krishnamurty, AT Thouvenel, CD Portugal, S Keitany, GJ Kim, KS Holder, A Crompton, PD Rawlings, DJ Pepper, M AF Krishnamurty, Akshay T. Thouvenel, Christopher D. Portugal, Silvia Keitany, Gladys J. Kim, Karen S. Holder, Anthony Crompton, Peter D. Rawlings, David J. Pepper, Marion TI Somatically Hypermutated Plasmodium-Specific IgM(+) Memory B Cells Are Rapid, Plastic, Early Responders upon Malaria Rechallenge SO IMMUNITY LA English DT Article ID MEROZOITE SURFACE PROTEIN-1; CD4(+) T-CELLS; PLASMA-CELLS; IMMUNOLOGICAL MEMORY; PARASITE DEVELOPMENT; IMMUNE-RESPONSES; ANTIBODY-LEVELS; IN-VITRO; FALCIPARUM; ANTIGEN AB Humoral immunity consists of pre-existing antibodies expressed by long-lived plasma cells and rapidly reactive memory B cells (MBC). Recent studies of MBC development and function after protein immunization have uncovered significant MBC heterogeneity. To clarify functional roles for distinct MBC subsets during malaria infection, we generated tetramers that identify Plasmodium-specific MBCs in both humans and mice. Long-lived murine Plasmodium-specific MBCs consisted of three populations: somatically hypermutated immunoglobulin M+ (IgM +) and IgG(+) MBC subsets and an unmutated IgD(+) MBC population. Rechallenge experiments revealed that high affinity, somatically hypermutated Plasmodium-specific IgM(+) MBCs proliferated and gave rise to antibody-secreting cells that dominated the early secondary response to parasite rechallenge. IgM (+) MBCs also gave rise to T cell-dependent IgM(+) and IgG(+) B220(+) CD138(+) plasmablasts or T cell-independent B220-CD138(+) IgM(+) plasma cells. Thus, even in competition with IgG(+) MBCs, IgM(+) MBCs are rapid, plastic, early responders to a secondary Plasmodium rechallenge and should be targeted by vaccine strategies. C1 [Krishnamurty, Akshay T.; Keitany, Gladys J.; Kim, Karen S.; Rawlings, David J.; Pepper, Marion] Univ Washington, Dept Immunol, Sch Med, Seattle, WA 98109 USA. [Thouvenel, Christopher D.; Rawlings, David J.] Seattle Childrens Res Inst, Ctr Immun & Immunotherapies, Seattle, WA 98101 USA. [Portugal, Silvia; Crompton, Peter D.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20892 USA. [Holder, Anthony] Francis Crick Inst, Mill Hill Lab, Ridgeway,Mill Hill, London NW7 1AA, England. RP Pepper, M (reprint author), Univ Washington, Dept Immunol, Sch Med, Seattle, WA 98109 USA. EM mpepper@uw.edu RI Holder, Anthony/A-7554-2013; Crompton, Peter/N-1130-2016 OI Holder, Anthony/0000-0002-8490-6058; FU NIH [T32-AI10667701]; [R01AI108626-01A-A87299] FX We thank Dr. J. Langhorne and D. Perez-Mazliah for providing recombinant MSP1 constructs and technical assistance, Dr. J. Rayner for providing P. falciparum AMA1 protein, and Drs. M. Bevan and B. Hondowicz for reviewing the manuscript and providing valuable discussion. We also thank Drs. O. Doumbo and B. Traore and the residents of Kambila, Mali, for helping acquire human PBMC samples. This work was supported by grants to M.P. (NIH R01AI108626-01A-A87299), A.T.K. (NIH T32-AI10667701), D.J.R. (Seattle Children's Research Institute, Center for Immunity and Immunotherapies [CIIT]; the CIIT, Program for Cell and Gene Therapy; and the Benaroya Family Gift Fund) and P.D.C. (NIH, Division of Intramural Research, National Institute of Allergy and Infectious Diseases). NR 57 TC 1 Z9 1 U1 3 U2 5 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 AUG 16 PY 2016 VL 45 IS 2 BP 402 EP 414 DI 10.1016/j.immuni.2016.06.014 PG 13 WC Immunology SC Immunology GA DU5QV UT WOS:000382267300020 PM 27473412 ER PT J AU Rosenberg, HF Druey, KM AF Rosenberg, Helene F. Druey, Kirk M. TI Eosinophils, galectins, and a reason to breathe SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID GLYCAN INTERACTIONS; MURINE MODEL; ASTHMA; INFLAMMATION; HYPERRESPONSIVENESS; MEPOLIZUMAB; PROTEIN; HEALTH; LECTIN; CELLS C1 [Rosenberg, Helene F.] NIH, Inflammat Immunobiol Sect, Lab Allerg Dis, Bethesda, MD 20892 USA. [Druey, Kirk M.] NIH, Mol Signal Transduct Sect, Lab Allerg Dis, Bethesda, MD 20892 USA. RP Rosenberg, HF (reprint author), NIH, Inflammat Immunobiol Sect, Lab Allerg Dis, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov FU NIAID NIH HHS [Z01 AI000746, Z01 AI000939, Z01 AI000941, Z01 AI000943] NR 25 TC 0 Z9 0 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 16 PY 2016 VL 113 IS 33 BP 9139 EP 9141 DI 10.1073/pnas.1610644113 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT3RS UT WOS:000381399200030 PM 27496328 ER PT J AU Nolte-'t Hoen, E Cremer, T Gallo, RC Margolis, LB AF Nolte-'t Hoen, Esther Cremer, Tom Gallo, Robert C. Margolis, Leonid B. TI Extracellular vesicles and viruses: Are they close relatives? SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE extracellular vesicles; exosomes; viruses; defective viruses; infection ID EXOSOMAL TRANSFER; DENDRITIC CELLS; RECIPIENT CELLS; INNATE IMMUNITY; HIV-1; INFECTION; RNA; SECRETION; MICROVESICLES; MECHANISM AB Extracellular vesicles (EVs) released by various cells are small phospholipid membrane-enclosed entities that can carry miRNA. They are now central to research in many fields of biology because they seem to constitute a new system of cell-cell communication. Physical and chemical characteristics of many EVs, as well as their biogenesis pathways, resemble those of retroviruses. Moreover, EVs generated by virus-infected cells can incorporate viral proteins and fragments of viral RNA, being thus indistinguishable from defective (noninfectious) retroviruses. EVs, depending on the proteins and genetic material incorporated in them, play a significant role in viral infection, both facilitating and suppressing it. Deciphering the mechanisms of EV-cell interactions may facilitate the design of EVs that inhibit viral infection and can be used as vehicles for targeted drug delivery. C1 [Nolte-'t Hoen, Esther; Cremer, Tom] Univ Utrecht, Fac Vet Med, Dept Biochem & Cell Biol, NL-3584 CM Utrecht, Netherlands. [Gallo, Robert C.] Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. [Margolis, Leonid B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Intercellular Interact, NIH, Bethesda, MD 20892 USA. RP Gallo, RC (reprint author), Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. EM rgallo@ihv.umaryland.edu FU European Research Council (ERC) under the European Union's Seventh Framework Programme (FP)/ERC grant [337581]; National Institute of Child Health and Human Development/NIH Intramural Program; Gates Foundation; National Institute of Allergy and Infectious Diseases; University of Maryland School of Medicine FX E.N.-t.H. receives funding from the European Research Council (ERC) under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC grant agreement 337581; the work of L.B.M. is funded by the National Institute of Child Health and Human Development/NIH Intramural Program; the work of R.C.G. is funded by the Gates Foundation, the National Institute of Allergy and Infectious Diseases, and the University of Maryland School of Medicine. NR 63 TC 2 Z9 2 U1 14 U2 17 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 AUG 16 PY 2016 VL 113 IS 33 BP 9155 EP 9161 DI 10.1073/pnas.1605146113 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT3RS UT WOS:000381399200034 PM 27432966 ER PT J AU Salie, ZL Kirby, KA Michailidis, E Marchand, B Singh, K Rohan, LC Kodama, EN Mitsuya, H Parniak, MA Sarafianos, SG AF Salie, Zhe Li Kirby, Karen A. Michailidis, Eleftherios Marchand, Bruno Singh, Kamalendra Rohan, Lisa C. Kodama, Eiichi N. Mitsuya, Hiroaki Parniak, Michael A. Sarafianos, Stefan G. TI Structural basis of HIV inhibition by translocation-defective RT inhibitor 4 '-ethynyl-2-fluoro-2 '-deoxyadenosine (EFdA) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE EFdA; HIV-1 reverse transcriptase; inhibitors; NRTIs; X-ray crystallography ID REVERSE-TRANSCRIPTASE INHIBITOR; IMMUNODEFICIENCY-VIRUS TYPE-1; HEPATITIS-B; DRUG-RESISTANCE; NUCLEOSIDE EFDA; POTENT; DNA; SOFOSBUVIR; ENTECAVIR; SOFTWARE AB 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) is the most potent nucleoside analog inhibitor of HIV reverse transcriptase (RT). It retains a 3'-OH yet acts as a chain-terminating agent by diminishing translocation from the pretranslocation nucleotide-binding site (N site) to the posttranslocation primer-binding site (P site). Also, facile misincorporation of EFdA-monophosphate (MP) results in difficult-to-extend mismatched primers. To understand the high potency and unusual inhibition mechanism of EFdA, we solved RT crystal structures (resolutions from 2.4 to 2.9 angstrom) that include inhibition intermediates (i) before inhibitor incorporation (catalytic complex, RT/DNA/EFdA-triphosphate), (ii) after incorporation of EFdA-MP followed by dT-MP (RT/DNA(EFdA-MPP center dot dT-MPN)), or (iii) after incorporation of two EFdA-MPs (RT/DNA(EFdA-MPP center dot EFdA-MPN)); (iv) the latter was also solved with EFdA-MP mismatched at the N site (RT/DNA(EFdA-MPP center dot EFdA-MP*N)). We report that the inhibition mechanism and potency of EFdA stem from interactions of its 4'-ethynyl at a previously unexploited conserved hydrophobic pocket in the polymerase active site. The high resolution of the catalytic complex structure revealed a network of ordered water molecules at the polymerase active site that stabilize enzyme interactions with nucleotide and DNA substrates. Finally, decreased translocation results from favorable interactions of primer-terminating EFdA-MP at the pretranslocation site and unfavorable posttranslocation interactions that lead to observed localized primer distortions. C1 [Salie, Zhe Li; Sarafianos, Stefan G.] Univ Missouri, Dept Biochem, CS Bond Life Sci Ctr, Columbia, MO 65211 USA. [Kirby, Karen A.; Michailidis, Eleftherios; Marchand, Bruno; Singh, Kamalendra; Sarafianos, Stefan G.] Univ Missouri, Sch Med, Dept Mol Microbiol & Immunol, CS Bond Life Sci Ctr, Columbia, MO 65211 USA. [Rohan, Lisa C.] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. [Rohan, Lisa C.] Univ Pittsburgh, Magee Womens Res Inst, Pittsburgh, PA 15213 USA. [Kodama, Eiichi N.] Tohoku Univ, Div Infect Dis, Sendai, Miyagi 9808575, Japan. [Kodama, Eiichi N.] Tohoku Med Megabank Org, Sendai, Miyagi 9808575, Japan. [Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. [Mitsuya, Hiroaki] Kumamoto Univ, Grad Sch Med Sci, Dept Infect Dis, Kumamoto 8608556, Japan. [Mitsuya, Hiroaki] Kumamoto Univ, Grad Sch Med Sci, Dept Hematol, Kumamoto 8608556, Japan. [Mitsuya, Hiroaki] Natl Ctr Global Hlth & Med, Res Inst, Tokyo 1628655, Japan. [Mitsuya, Hiroaki] Natl Ctr Global Hlth & Med, Ctr Clin Sci, Tokyo 1628655, Japan. [Parniak, Michael A.] Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA 15219 USA. RP Sarafianos, SG (reprint author), Univ Missouri, Dept Biochem, CS Bond Life Sci Ctr, Columbia, MO 65211 USA.; Sarafianos, SG (reprint author), Univ Missouri, Sch Med, Dept Mol Microbiol & Immunol, CS Bond Life Sci Ctr, Columbia, MO 65211 USA. EM sarafianoss@missouri.edu RI Kodama, Eiichi /C-4032-2009; OI Kodama, Eiichi /0000-0002-6622-2752; Li, Zhe/0000-0003-2063-1013; Sarafianos, Stefan G/0000-0002-5840-154X; Kirby, Karen A./0000-0003-2468-4796 FU Office of Science, Office of Basic Energy Sciences, of the US Department of Energy (DOE) [DE-AC02-05CH11231]; US DOE [DE-AC02-06CH11357]; National Institutes of Health [AI076119, AI099284, AI100890, AI120860, GM103368, GM118012]; Mizzou Advantage; Trail to a Cure FX We thank Jay Nix of Advanced Light Source beamline 4.2.2 for support. The ALS is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the US Department of Energy (DOE) under Contract DE-AC02-05CH11231. We also acknowledge the Advanced Photon Source. Use of the Advanced Photon Source, an Office of Science User Facility operated for the US DOE Office of Science by Argonne National Laboratory, was supported by the US DOE under Contract DE-AC02-06CH11357. This work was supported in part by grants from the National Institutes of Health (AI076119, AI099284, AI100890, AI120860, GM103368, and GM118012), Mizzou Advantage, and Trail to a Cure. NR 26 TC 1 Z9 1 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 AUG 16 PY 2016 VL 113 IS 33 BP 9274 EP 9279 DI 10.1073/pnas.1605223113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT3RS UT WOS:000381399200054 PM 27489345 ER PT J AU Levine, ME Lu, AT Chen, BH Hernandez, DG Singleton, AB Ferrucci, L Bandinelli, S Salfati, E Manson, JE Quach, A Kusters, CDJ Kuh, D Wong, A Teschendorff, AE Widschwendter, M Ritz, BR Absher, D Assimes, TL Horvath, S AF Levine, Morgan E. Lu, Ake T. Chen, Brian H. Hernandez, Dena G. Singleton, Andrew B. Ferrucci, Luigi Bandinelli, Stefania Salfati, Elias Manson, JoAnn E. Quach, Austin Kusters, Cynthia D. J. Kuh, Diana Wong, Andrew Teschendorff, Andrew E. Widschwendter, Martin Ritz, Beate R. Absher, Devin Assimes, Themistocles L. Horvath, Steve TI Menopause accelerates biological aging SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE menopause; DNA methylation; aging; WHI; epigenetic clock ID BRITISH BIRTH COHORT; DNA METHYLATION AGE; NATURAL MENOPAUSE; EPIGENETIC AGE; PARKINSONS-DISEASE; PREFRONTAL CORTEX; LIFE-SPAN; BLOOD; MORTALITY; EPIDEMIOLOGY AB Although epigenetic processes have been linked to aging and disease in other systems, it is not yet known whether they relate to reproductive aging. Recently, we developed a highly accurate epigenetic biomarker of age (known as the "epigenetic clock"), which is based on DNA methylation levels. Here we carry out an epigenetic clock analysis of blood, saliva, and buccal epithelium using data from four large studies: the Women's Health Initiative (n = 1,864); Invec-chiare nel Chianti (n = 200); Parkinson's disease, Environment, and Genes (n = 256); and the United Kingdom Medical Research Council National Survey of Health and Development (n = 790). We find that increased epigenetic age acceleration in blood is significantly associated with earlier menopause (P = 0.00091), bilateral oophorectomy (P = 0.0018), and a longer time since menopause (P = 0.017). Conversely, epigenetic age acceleration in buccal epithelium and saliva do not relate to age at menopause; however, a higher epigenetic age in saliva is exhibited in women who undergo bilateral oophorectomy (P = 0.0079), while a lower epigenetic age in buccal epithelium was found for women who underwent menopausal hormone therapy (P = 0.00078). Using genetic data, we find evidence of coheritability between age at menopause and epigenetic age acceleration in blood. Using Mendelian randomization analysis, we find that two SNPs that are highly associated with age at menopause exhibit a significant association with epigenetic age acceleration. Overall, our Mendelian randomization approach and other lines of evidence suggest that menopause accelerates epigenetic aging of blood, but mechanistic studies will be needed to dissect cause-and-effect relationships further. C1 [Levine, Morgan E.; Lu, Ake T.; Quach, Austin; Horvath, Steve] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Levine, Morgan E.] Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA 90095 USA. [Chen, Brian H.; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, Intramural Res Program,NIH, Bethesda, MD 20892 USA. [Hernandez, Dena G.; Singleton, Andrew B.] NIA, Lab Neurogenet, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, I-50100 Florence, Italy. [Salfati, Elias; Assimes, Themistocles L.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Manson, JoAnn E.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Kusters, Cynthia D. J.; Ritz, Beate R.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90095 USA. [Kuh, Diana; Wong, Andrew] UCL, Unit Lifelong Hlth & Ageing, Med Res Council, London WC1B 5JU, England. [Teschendorff, Andrew E.; Widschwendter, Martin] UCL, Dept Womens Canc, London WC1 6BT, England. [Teschendorff, Andrew E.] UCL, Inst Canc, London WC1 6BT, England. [Teschendorff, Andrew E.] UCL, Inst Canc, Stat Genom Grp, London WC1E 6DD, England. [Teschendorff, Andrew E.] Chinese Acad Sci, Shanghai Inst Biol, Chinese Acad Sci Max Planck Soc Partner Inst Comp, Key Lab Computat Biol, Shanghai 200031, Peoples R China. [Absher, Devin] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. [Horvath, Steve] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90095 USA. RP Horvath, S (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA.; Horvath, S (reprint author), Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90095 USA. EM shorvath@mednet.ucla.edu RI Assimes, Themistocles/D-9696-2015; Wong, Andrew/M-8899-2016 OI Assimes, Themistocles/0000-0003-2349-0009; Wong, Andrew/0000-0003-2079-4779 FU NIH/NHLBI Grant [60442456 BAA23]; NIH/National Institute on Aging Grant [1U34AG051425-01]; NIH/National Institute of Neurological Disorders and Stroke Grant [T32NS048004]; NHLBI of the NIH, US Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; Eve Appeal; Department of Health National Institute for Health Research Biomedical Research Centres funding scheme; UK Medical Research Council Grant [MC_UU_12019/1]; NIH/National Institute of Environmental Health Sciences Grants [R21-ES024356, R01-ES10544] FX This study was supported by NIH/NHLBI Grant 60442456 BAA23 (to T.L.A., D.A., and S.H.), NIH/National Institute on Aging Grant 1U34AG051425-01 (to S.H.), and NIH/National Institute of Neurological Disorders and Stroke Grant T32NS048004 (to M.E.L.). The WHI program is funded by the NHLBI of the NIH, US Department of Health and Human Services through Contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. Part of this work was funded by the Eve Appeal (https://www.eveappeal.org.uk/) and was done at University College London Hospital/University College London, which received a proportion of its funding from the Department of Health National Institute for Health Research Biomedical Research Centres funding scheme (M.W.). The NSHD is funded by UK Medical Research Council Grant MC_UU_12019/1. The PEG study was funded by NIH/National Institute of Environmental Health Sciences Grants R21-ES024356 (to S.H. and B.R.R.) and R01-ES10544 (to B.R.R.). NR 47 TC 7 Z9 7 U1 11 U2 15 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 AUG 16 PY 2016 VL 113 IS 33 BP 9327 EP 9332 DI 10.1073/pnas.1604558113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT3RS UT WOS:000381399200063 PM 27457926 ER PT J AU Yim, KH Prince, TL Qu, SW Bai, F Jennings, PA Onuchic, JN Theodorakis, EA Neckers, L AF Yim, Kendrick H. Prince, Thomas L. Qu, Shiwei Bai, Fang Jennings, Patricia A. Onuchic, Jose N. Theodorakis, Emmanuel A. Neckers, Leonard TI Gambogic acid identifies an isoform-specific druggable pocket in the middle domain of Hsp90 beta SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE molecular chaperone; heat-shock protein 90; isoform-specific inhibitor; molecular docking; caged xanthone ID SHOCK-PROTEIN 90; POTENT ANTITUMOR-ACTIVITY; CAGED GARCINIA XANTHONES; MOLECULAR CHAPERONE; BINDING-SITE; CANCER-CELLS; DOWN-REGULATION; ATOMIC CHARGES; BREAST-CANCER; TUMOR-GROWTH AB Because of their importance in maintaining protein homeostasis, molecular chaperones, including heat-shock protein 90 (Hsp90), represent attractive drug targets. Although a number of Hsp90 inhibitors are in preclinical/clinical development, none strongly differentiate between constitutively expressed Hsp90 beta and stress-induced Hsp90 alpha, the two cytosolic paralogs of this molecular chaperone. Thus, the importance of inhibiting one or the other paralog in different disease states remains unknown. We show that the natural product, gambogic acid (GBA), binds selectively to a site in the middle domain of Hsp90 beta, identifying GBA as an Hsp90 beta-specific Hsp90 inhibitor. Furthermore, using computational and medicinal chemistry, we identified a GBA analog, referred to as DAP-19, which binds potently and selectively to Hsp90 beta. Because of its unprecedented selectivity for Hsp90 beta among all Hsp90 paralogs, GBA thus provides a new chemical tool to study the unique biological role of this abundantly expressed molecular chaperone in health and disease. C1 [Yim, Kendrick H.; Prince, Thomas L.; Neckers, Leonard] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Qu, Shiwei; Jennings, Patricia A.; Theodorakis, Emmanuel A.] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA. [Bai, Fang; Onuchic, Jose N.] Rice Univ, Ctr Theoret Biol Phys, Houston, TX 77005 USA. [Onuchic, Jose N.] Rice Univ, Dept Phys & Astron, Houston, TX 77005 USA. [Onuchic, Jose N.] Rice Univ, Dept Chem, Houston, TX 77005 USA. [Onuchic, Jose N.] Rice Univ, Dept Biosci, Houston, TX 77005 USA. RP Neckers, L (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM neckersl@mail.nih.gov FU Intramural Research Program, Center for Cancer Research, National Cancer Institute Grant [Z01 SC010074-12]; National Institutes of Health Grants [CA 133002, GM101467]; Cancer Research Coordinating Committee [CRC-15-380737]; National Science Foundation [PHY-1427654, MCB-1214457]; Cancer Prevention and Research Institute of Texas; Welch Foundation Grant [C-1792] FX This work was supported in part by the Intramural Research Program, Center for Cancer Research, National Cancer Institute Grant Z01 SC010074-12 (to L.N.); National Institutes of Health Grants CA 133002 (to E.A.T.) and GM101467 (to P.A.J.); and a grant from the Cancer Research Coordinating Committee (CRC-15-380737) (to E.A.T.). Work at the Center for Theoretical Biological Physics was sponsored by the National Science Foundation (Grants PHY-1427654 and MCB-1214457) and the Cancer Prevention and Research Institute of Texas. F.B. was also supported by Welch Foundation Grant C-1792. NR 66 TC 2 Z9 2 U1 11 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 AUG 16 PY 2016 VL 113 IS 33 BP E4801 EP E4809 DI 10.1073/pnas.1606655113 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT3RS UT WOS:000381399200009 PM 27466407 ER PT J AU Warnick, EP Dupuis, RJ Piro, NA Kassel, WS Nataro, C AF Warnick, Eugene P. Dupuis, Ryan J. Piro, Nicholas A. Kassel, W. Scott Nataro, Chip TI Compounds containing weak, non-covalent interactions to the metal in the backbone of 1,1 '-bis(phosphino)metallocene ligands SO POLYHEDRON LA English DT Article DE Halide abstraction; Chloride-bridged dimer; Weak non-covalent interaction; X-ray crystal structure; Cyclic voltammetry ID SYMMETRICALLY DISUBSTITUTED FERROCENES; X-RAY STRUCTURES; 1,1'-BIS(DIPHENYLPHOSPHINO)FERROCENE DPPF; MOLECULAR-STRUCTURES; CRYSTAL-STRUCTURE; ROOM-TEMPERATURE; COMPLEXES; PALLADIUM; CHEMISTRY; PHOSPHINE AB The reactions of Na[BArF] (BArF = tetrakis(3,5-bis(trifluoromethyl)phenyl)borate) with a series of [Pd(dpEMc)Cl-2] (dpEMc = 1,1'-bis(diphenylphosphino)ruthenocene (dppr), 1,1'-bis(diphenylphosphino)osmocene (dppo) or 1,1'-bis(diphenylarsino)ferrocene (dpaf)) compounds were examined. The reaction of Na[BArF] with [Pd(dppMc)Cl-2] (dppMc = dppr or dppo) resulted in the formation of the corresponding chloride-bridged dimers, [Pd(dppMc)(mu-Cl)](2)(2+), which were structurally characterized. However, these dimers appear to be unstable in CH2Cl2 and partially (Ru) or fully (Os) convert into the corresponding monomers, [Pd(dppMc)Cl](+), which are proposed to have a weak, non-covalent M-Pd (M = Ru or Os) interaction. Similar compounds, [Pd(dppo)PPh3](2+) and [Pt(dppMc)PPh3](2+) (M = Fe (1,1'-bis(diphenylphosphino)ferrocene (dppf)) or Os (dppo)), were also prepared and structurally characterized. These compound also exhibit weak, non-covalent M-Pd/Pt interactions. In addition, the electrochemical properties of these compounds were examined by cyclic voltammetry. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Warnick, Eugene P.; Dupuis, Ryan J.; Nataro, Chip] Dept Chem, Lafayette Coll, Easton, PA 18042 USA. [Piro, Nicholas A.; Kassel, W. Scott] Villanova Univ, Dept Chem, Villanova, PA 19085 USA. [Warnick, Eugene P.] NIH, Bethesda, MD 20892 USA. RP Nataro, C (reprint author), Dept Chem, Lafayette Coll, Easton, PA 18042 USA. EM nataroc@lafayette.edu OI Nataro, Chip/0000-0003-0439-9218 FU Academic Research Committee at Lafayette College FX E.P.W., R.J.D. and C.N. thank Kresge Foundation for the purchase of the JEOL NMR, and the Academic Research Committee at Lafayette College for funding EXCEL scholars. NR 48 TC 0 Z9 0 U1 3 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-5387 J9 POLYHEDRON JI Polyhedron PD AUG 16 PY 2016 VL 114 SI SI BP 156 EP 164 DI 10.1016/j.poly.2015.11.025 PG 9 WC Chemistry, Inorganic & Nuclear; Crystallography SC Chemistry; Crystallography GA DQ9YE UT WOS:000379564400023 ER PT J AU Ma, B Xu, LY Pan, XD Sun, LX Ding, JH Xie, CS Koliatsos, VE Cai, HB AF Ma, Bo Xu, Leyan Pan, Xiaodong Sun, Lixin Ding, Jinhui Xie, Chengsong Koliatsos, Vassilis E. Cai, Huaibin TI LRRK2 modulates microglial activity through regulation of chemokine (C-X3-C) receptor 1-mediated signalling pathways SO HUMAN MOLECULAR GENETICS LA English DT Article ID PARKINSONS-DISEASE; FRACTALKINE RECEPTOR; CULTURED MICROGLIA; ALPHA-SYNUCLEIN; MOUSE MODEL; KINASE; CELLS; ACTIVATION; CX3CL1; PHOSPHORYLATION AB Multiple missense mutations in Leucine-rich repeat kinase 2 (LRRK2) have been linked to Parkinson's disease (PD), the most common degenerative movement disorder. LRRK2 is expressed by both neurons and microglia, the residential immune cells in the brain. Increasing evidence supports a role of LRRK2 in modulating microglial activity, of which Lrrk2-null rodent microglia display less inflammatory response to endotoxin lipopolysaccharide (LPS). The underlying molecular mechanism, however, remains elusive. Chemokine (C-X3-C) receptor 1 (CX3CR1), predominantly expressed by microglia, suppresses microglial inflammation while promotes migration. Using whole-genome microarray screening, we found that Cx3cr1 mRNA levels were substantially higher in microglia derived from Lrrk2 knockout (Lrrk2(-/-)) mice. The total and cell surface levels of CX3CR1 proteins were also remarkably increased. In correlation with the enhanced CX3CR1 expression, Lrrk2-null microglia migrated faster and travelled longer distance toward the source of fractalkine (CX3CL1), an endogenous ligand of CX3CR1. To investigate the impact of CX3CR1 elevation in vivo, we compared LPS-induced inflammation in the striatum of Lrrk2(-/-) knockout mice with Cx3cr1 heterozygous and homozygous knockout background. We found that a complete loss of Cx3cr1 restored the responsiveness of Lrrk2(-/-) microglia to LPS stimulation. In conclusion, our findings reveal a previously unknown regulatory role for LRRK2 in CX3CR1 signalling and suggest that an increase of CX3CR1 activity contributes to the attenuated inflammatory responses in Lrrk2-null microglia. C1 [Ma, Bo; Pan, Xiaodong; Sun, Lixin; Xie, Chengsong; Cai, Huaibin] NIA, Transgen Sect, Neurogenet Lab, NIH, Bldg 35,Room 1A112,MSC 3707,35 Convent Dr, Bethesda, MD 20892 USA. [Xu, Leyan; Koliatsos, Vassilis E.] Johns Hopkins Univ, Sch Med, Dept Pathol, Div Neuropathol, Baltimore, MD 21205 USA. [Ding, Jinhui] NIA, Bioinformat Core, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Ma, Bo] Univ Florida, Coll Med, Dept Anesthesiol, Ctr Translat Res Neurodegenerat Dis, 1275 Ctr Dr,Biomed Sci J448, Gainesville, FL 32610 USA. [Pan, Xiaodong] Fujian Med Univ, Union Hosp, Dept Neurol, 29 Xinquan Rd, Fuzhou 350001, Peoples R China. RP Cai, HB (reprint author), NIA, Transgen Sect, Neurogenet Lab, NIH, Bldg 35,Room 1A112,MSC 3707,35 Convent Dr, Bethesda, MD 20892 USA. EM caih@mail.nih.gov FU intramural research programs of the National Institutes of Health (NIH)-National Institute on Aging [AG000928, AG000944]; National Natural Science Grant of China [81571257] FX This work was supported in part by the intramural research programs of the National Institutes of Health (NIH)-National Institute on Aging (Grants AG000928 and AG000944 to H.C.), and National Natural Science Grant of China (No. 81571257 to XD P.). NR 43 TC 1 Z9 1 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 15 PY 2016 VL 25 IS 16 BP 3515 EP 3523 DI 10.1093/hmg/ddw194 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EJ4IO UT WOS:000393180400011 PM 27378696 ER PT J AU Permuth, JB Pirie, A Chen, YA Lin, HY Reid, BM Chen, ZH Monteiro, A Dennis, J Mendoza-Fandino, G Anton-Culver, H Bandera, EV Bisogna, M Brinton, L Brooks-Wilson, A Carney, ME Chenevix-Trench, G Cook, LS Cramer, DW Cunningham, JM Cybulski, C D'Aloisio, AA Doherty, JA Earp, M Edwards, RP Fridley, BL Gayther, SA Gentry-Maharaj, A Goodman, MT Gronwald, J Hogdall, E Iversen, ES Jakubowska, A Jensen, A Karlan, BY Kelemen, LE Kjaer, SK Kraft, P Le, ND Levine, DA Lissowska, J Lubinski, J Matsuo, K Menon, U Modugno, R Moysich, KB Nakanishi, T Ness, RB Olson, S Orlow, I Pearce, CL Pejovic, T Poole, EM Ramus, SJ Rossing, MA Sandler, DP Shu, XO Song, H Taylor, JA Teo, SH Terry, KL Thompson, PJ Tworoger, SS Webb, PM Wentzensen, N Wilkens, LR Winham, S Woo, YL Wu, AH Yang, H Zheng, W Ziogas, A Phelan, CM Schildkraut, JM Berchuck, A Goode, EL Pharoah, PDP Sellers, TA AF Permuth, Jennifer B. Pirie, Ailith Chen, Y. Ann Lin, Hui-Yi Reid, Brett M. Chen, Zhihua Monteiro, Alvaro Dennis, Joe Mendoza-Fandino, Gustavo Anton-Culver, Hoda Bandera, Elisa V. Bisogna, Maria Brinton, Louise Brooks-Wilson, Angela Carney, Michael E. Chenevix-Trench, Georgia Cook, Linda S. Cramer, Daniel W. Cunningham, Julie M. Cybulski, Cezary D'Aloisio, Aimee A. Doherty, Jennifer Anne Earp, Madalene Edwards, Robert P. Fridley, Brooke L. Gayther, Simon A. Gentry-Maharaj, Aleksandra Goodman, Marc T. Gronwald, Jacek Hogdall, Estrid Iversen, Edwin S. Jakubowska, Anna Jensen, Allan Karlan, Beth Y. Kelemen, Linda E. Kjaer, Suzanne K. Kraft, Peter Le, Nhu D. Levine, Douglas A. Lissowska, Jolanta Lubinski, Jan Matsuo, Keitaro Menon, Usha Modugno, Rosemary Moysich, Kirsten B. Nakanishi, Toru Ness, Roberta B. Olson, Sara Orlow, Irene Pearce, Celeste L. Pejovic, Tanja Poole, Elizabeth M. Ramus, Susan J. Rossing, Mary Anne Sandler, Dale P. Shu, Xiao-Ou Song, Honglin Taylor, Jack A. Teo, Soo-Hwang Terry, Kathryn L. Thompson, Pamela J. Tworoger, Shelley S. Webb, Penelope M. Wentzensen, Nicolas Wilkens, Lynne R. Winham, Stacey Woo, Yin-Ling Wu, Anna H. Yang, Hannah Zheng, Wei Ziogas, Argyrios Phelan, Catherine M. Schildkraut, Joellen M. Berchuck, Andrew Goode, Ellen L. Pharoah, Paul D. P. Sellers, Thomas A. CA AOCS Study Grp Australian Canc Study Ovarian Canc Ovarian Canc Assoc Consortium TI Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; MAXIMUM-LIKELIHOOD TEST; SUSCEPTIBILITY LOCI; GENE-EXPRESSION; BREAST-CANCER; CUSHINGS-SYNDROME; PROSTATE-CANCER; COMPLEX DISEASE; IDENTIFICATION; CARCINOMA AB Rare and low frequency variants are not well covered in most germline genotyping arrays and are understudied in relation to epithelial ovarian cancer (EOC) risk. To address this gap, we used genotyping arrays targeting rarer protein-coding variation in 8,165 EOC cases and 11,619 controls from the international Ovarian Cancer Association Consortium (OCAC). Pooled association analyses were conducted at the variant and gene level for 98,543 variants directly genotyped through two exome genotyping projects. Only common variants that represent or are in strong linkage disequilibrium (LD) with previously-identified signals at established loci reached traditional thresholds for exome-wide significance (P < 5.0 x 10(-7)). One of the most significant signals (P-all histologies = 1.01 x 10(-13);P-serous = 3.54 x 10(-14)) occurred at 3q25.31 for rs62273959, a missense variant mapping to the LEKR1 gene that is in LD (r(2) = 0.90) with a previously identified 'best hit' (rs7651446) mapping to an intron of TIPARP. Suggestive associations (5.0 x 10(-5) > P >= 5.0 x10(-7)) were detected for rare and low-frequency variants at 16 novel loci. Four rare missense variants were identified (ACTBL2 rs73757391 (5q11.2), BTD rs200337373 (3p25.1), KRT13 rs150321809 (17q21.2) and MC2R rs104894658 (18p11.21)), but only MC2R rs104894668 had a large effect size (OR = 9.66). Genes most strongly associated with EOC risk included ACTBL2 (P-AML = 3.23 x 10(-5); PSKAT-o = 9.23 x 10(-4)) and KRT13 (PAML = 1.67 x 10(-4); PSKAT-o = 1.07 x 10(-5)), reaffirming variant-level analysis. In summary, this large study identified several rare and low-frequency variants and genes that may contribute to EOC susceptibility, albeit with possible small effects. Future studies that integrate epidemiology, sequencing, and functional assays are needed to further unravel the unexplained heritability and biology of this disease C1 [Permuth, Jennifer B.; Reid, Brett M.; Monteiro, Alvaro; Mendoza-Fandino, Gustavo; Phelan, Catherine M.; Sellers, Thomas A.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA. [Pirie, Ailith; Dennis, Joe; Pharoah, Paul D. P.] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge, England. [Chen, Y. Ann; Lin, Hui-Yi; Chen, Zhihua] H Lee Moffitt Canc Ctr & Res Inst, Dept Biostat & Bioinformat, Tampa, FL USA. [Chenevix-Trench, Georgia; AOCS Study Grp; Australian Canc Study Ovarian Canc] QIMR Berghofer Med Res Inst, Genet & Computat Biol Dept, Brisbane, Qld, Australia. [Anton-Culver, Hoda] Univ Calif Irvine, UCI Sch Med, Dept Epidemiol, Genet Epidemiol Res Inst, Irvine, CA USA. [Bandera, Elisa V.] Rutgers Canc Inst New Jersey, Canc Prevent & Control Program, New Brunswick, NJ USA. [Bisogna, Maria; Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10021 USA. [Brinton, Louise] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Brooks-Wilson, Angela] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC, Canada. [Brooks-Wilson, Angela] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC, Canada. [Carney, Michael E.] Univ Hawaii, John A Burns Sch Med, Dept Obstet & Gynecol, Honolulu, HI 96822 USA. [Cook, Linda S.] Univ New Mexico, Dept Internal Med, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA. [Cramer, Daniel W.; Terry, Kathryn L.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, 75 Francis St, Boston, MA 02115 USA. [Cunningham, Julie M.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Cybulski, Cezary; Gronwald, Jacek; Jakubowska, Anna; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [D'Aloisio, Aimee A.] Social & Sci Syst Inc, Durham, NC USA. [Doherty, Jennifer Anne] Dartmouth Coll, Geisel Sch Med, Dept Epidemiol, Hanover, NY USA. [Earp, Madalene; Goode, Ellen L.] Mayo Clin, Div Epidemiol, Dept Hlth Sci Res, Rochester, MN USA. [Edwards, Robert P.; Modugno, Rosemary] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Div Gynecol Oncol, Pittsburgh, PA USA. [Edwards, Robert P.; Modugno, Rosemary] Magee Womens Res Inst, Womens Canc Res Program, Ovarian Canc Ctr Excellence, Pittsburgh, PA USA. [Edwards, Robert P.; Modugno, Rosemary] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Fridley, Brooke L.] Univ Kansas, Med Ctr, Dept Biostat, Kansas City, KS 66103 USA. [Gayther, Simon A.; Pearce, Celeste L.; Ramus, Susan J.; Wu, Anna H.] Univ Southern Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Gentry-Maharaj, Aleksandra; Menon, Usha] UCL, Womens Canc Inst Womens Hlth, London, England. [Goodman, Marc T.] Cedars Sinai Med Ctr, Samuel Oshin Comprehens Canc Inst, Canc Prevent & Control, Los Angeles, CA 90048 USA. [Goodman, Marc T.] Cedars Sinai Med Ctr, Dept Biomed Sci, Community & Populat Hlth Res Inst, Los Angeles, CA 90048 USA. [Hogdall, Estrid; Jensen, Allan; Kjaer, Suzanne K.] Danish Canc Soc, Res Ctr, Dept Virus Lifestyle & Genes, Copenhagen, Denmark. [Hogdall, Estrid] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, Copenhagen, Denmark. [Iversen, Edwin S.] Duke Univ, Dept Stat Sci, Durham, NC USA. [Karlan, Beth Y.; Thompson, Pamela J.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA. [Kelemen, Linda E.] Med Univ South Carolina, Coll Med, Dept Publ Hlth Sci, Charleston, SC USA. [Kjaer, Suzanne K.] Univ Copenhagen, Rigshosp, Dept Gynaecol, Copenhagen, Denmark. [Kraft, Peter] Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA. [Le, Nhu D.] BC Canc Agcy, Canc Control Res, Vancouver, BC, Canada. [Lissowska, Jolanta] Maria Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Matsuo, Keitaro] Aichi Canc Ctr, Res Inst, Div Mol Med, Nagoya, Aichi, Japan. [Modugno, Rosemary] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Moysich, Kirsten B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Nakanishi, Toru] Aichi Canc Ctr, Cent Hosp, Dept Gynecol Oncol, Nagoya, Aichi, Japan. [Ness, Roberta B.] Univ Texas Sch Publ Hlth, Houston, TX USA. [Olson, Sara; Orlow, Irene] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Pearce, Celeste L.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Pejovic, Tanja] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. [Pejovic, Tanja] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Harvard Med Sch, Boston, MA USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Rossing, Mary Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, 1124 Columbia St, Seattle, WA 98104 USA. [Rossing, Mary Anne] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Sandler, Dale P.; Taylor, Jack A.] NIEHS, Epidemiol Branch, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Shu, Xiao-Ou] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Song, Honglin; Pharoah, Paul D. P.] Univ Cambridge, Strangeways Res Lab, Dept Oncol, Cambridge, England. [Teo, Soo-Hwang] Canc Res Malaysia, Subang Jaya, Malaysia. [Teo, Soo-Hwang] Univ Malaya, Med Ctr, Kuala Lumpur, Malaysia. [Webb, Penelope M.] QIMR Berghofer Med Res Inst, Populat Hlth Dept, Herston, Qld, Australia. [Wentzensen, Nicolas; Yang, Hannah] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Wilkens, Lynne R.] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96822 USA. [Winham, Stacey] Mayo Clin, Div Biomed Stat & Informat, Dept Hlth Sci Res, Rochester, MN USA. [Woo, Yin-Ling] Univ Malaya, Med Ctr, Dept Obstet & Gynaecol, Kuala Lumpur, Malaysia. [Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. [Ziogas, Argyrios] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Schildkraut, Joellen M.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC USA. [Schildkraut, Joellen M.] Duke Canc Inst, Canc Control & Populat Sci, Durham, NC USA. [Berchuck, Andrew] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. RP Sellers, TA (reprint author), H Lee Moffitt Canc Ctr & Res Inst, 12902 Magnolia Dr, Tampa, FL 33612 USA. RI Gronwald, Jacek/A-4576-2017; Brooks-Wilson, Angela/E-9399-2012; OI Gronwald, Jacek/0000-0002-3643-2871; Brooks-Wilson, Angela/0000-0003-1009-6408; taylor, jack/0000-0001-5303-6398; Sandler, Dale/0000-0002-6776-0018; Matsuo, Keitaro/0000-0003-1761-6314; Winham, Stacey/0000-0002-8492-9102 FU National Institute of Health; Genetic Associations and Mechanisms in Oncology (GAME-ON), a NCI Cancer Post-GWAS Initiative [U19-CA148112]; NHMRC; Medical Research Council studentship; U.S. National Institutes of Health [R01-CA112523, R01-CA87538, R01- CA58598, N01-CN-55424, N01-PC-67001]; DOD [DAMD17-02-1-0669]; NCI [K07-CA080668, R01-CA95023, P50-CA159981]; NIH/National Center for Research Resources/General Clinical Research Center grant [M01-RR000056, R01-CA126841]; Ministry of Health, Labour and Welfare; American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]; L & S Milken Foundation; National Cancer Institute, Bethesda, MD [R01- CA61107]; Danish Cancer Society, Copenhagen, Denmark [94 222 52]; Mermaid I project; National Institutes of Health [R01-CA122443, P30-CA15083, P50-CA136393, R01-CA76016, R01-CA54419, P50-CA105009, P01-CA87696, R01-CA49449]; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; Malaysian Ministry of Higher Education [UM.C/HIR/MOHE/06]; Cancer Research Initiatives Foundation; Department of Defense [DAMD17-02-1-0666, W81XWH- 10-1-02802]; OHSU Foundation; Pomeranian Medical University; National Cancer Institute [NIH-K07 CA095666, R01-CA83918, NIH-K22-CA138563, P30-CA072720]; Cancer Institute of New Jersey; NCI CCSG award [P30- CA008748]; Intramural Research Program of the NCI; Cancer Research UK [C490/A10119 C490/A10124]; UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, SEARCH team; National Institute of Environmental Health Sciences [Z01ES044005]; National Institute for Health [R37-CA070867]; Eve Appeal (The Oak Foundation); National Institute for Health Research University College London Hospitals Biomedical Research Centre; Lon V Smith Foundation [LVS-39420]; California Cancer Research Program [00-01389V-20170, 2II0200]; Biostatistics and Cancer Informatics Core Facilities at the H. Lee Moffitt Cancer Center & Research Institute, an NCI designated Comprehensive Cancer Center [P30-CA076292]; [MOP-86727]; [MSH-87734] FX Funding for this study was supported by the National Institute of Health and the Genetic Associations and Mechanisms in Oncology (GAME-ON), a NCI Cancer Post-GWAS Initiative (U19-CA148112). In addition, we acknowledge the following: AUS: U.S. Army Medical Research and Materiel Command (DAMD17-01-1-0729), National Health & Medical Research Council of Australia, Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania, Cancer Foundation of Western Australia; National Health and Medical Research Council of Australia (199600 and 400281). The Australian Ovarian Cancer Study Management Group (D. Bowtell, G. Chenevix-Trench, A. deFazio, D. Gertig, A. Green, P. Webb) and ACS Investigators (A. Green, P. Parsons, N. Hayward, P. Webb, D. Whiteman) thank all the clinical and scientific collaborators (see http://www.aocstudy.org/) and the women for their contribution. GCT & PW are supported by Fellowships from NHMRC; AP is funded by a Medical Research Council studentship; DOV: U.S. National Institutes of Health R01-CA112523 and R01-CA87538; HAW: U.S. National Institutes of Health (R01- CA58598, N01-CN-55424 and N01-PC-67001); HOP: DOD DAMD17-02-1-0669 and NCI K07-CA080668, R01-CA95023, P50-CA159981; NIH/National Center for Research Resources/General Clinical Research Center grant M01-RR000056; R01-CA126841; JPN: Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare; LAX: American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the L & S Milken Foundation; MAL: Funding for this study was provided by research grant R01- CA61107 from the National Cancer Institute, Bethesda, MD; research grant 94 222 52 from the Danish Cancer Society, Copenhagen, Denmark; and the Mermaid I project.; MAC and MAY: National Institutes of Health (R01-CA122443, P30-CA15083, P50-CA136393), Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; MAS: Malaysian Ministry of Higher Education (UM.C/HIR/MOHE/06) and Cancer Research Initiatives Foundation; NCO: National Institutes of Health (R01-CA76016) and the Department of Defense (DAMD17-02-1-0666); NEC: National Institutes of Health R01-CA54419 and P50-CA105009 and Department of Defense W81XWH- 10-1-02802; NHS: National Institute of Health (P01-CA87696 and R01-CA49449); ORE: OHSU Foundation; POC: Pomeranian Medical University; NJO: National Cancer Institute (NIH-K07 CA095666, R01-CA83918, NIH-K22-CA138563, and P30-CA072720), the Cancer Institute of New Jersey, and NCI CCSG award (P30- CA008748). POL: Intramural Research Program of the NCI; RMH: Cancer Research UK (no grant number is available); OVA: (MOP-86727, MSH-87734; SEA: Cancer Research UK (C490/A10119 C490/A10124); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, SEARCH team, Craig Luccarini, Caroline Baynes, Don Conroy; SIS: National Institute of Environmental Health Sciences, (Z01ES044005); SWH: National Institute for Health (R37-CA070867); UKO: The UKOPS study was funded by The Eve Appeal (The Oak Foundation) and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. We particularly thank I. Jacobs, M. Widschwendter, E. Wozniak, A. Ryan, J. Ford and N.; Balogun for their contribution to the study; UCI: NIH R01-CA058860, NIH R01-CA092044, US Public Health Service PSA-042205, and the Lon V Smith Foundation grant LVS-39420; USC: P01-CA17054, P30-CA14089, R01-CA61132, N01-PC67010, R03-CA113148, R03-CA115195, N01-CN025403, and California Cancer Research Program (00-01389V-20170, 2II0200). This study was also supported in part by the Biostatistics and Cancer Informatics Core Facilities at the H. Lee Moffitt Cancer Center & Research Institute, an NCI designated Comprehensive Cancer Center (P30-CA076292). NR 56 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 15 PY 2016 VL 25 IS 16 BP 3600 EP 3612 DI 10.1093/hmg/ddw196 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA EJ4IO UT WOS:000393180400018 PM 27378695 ER PT J AU Mohile, SG Hurria, A Cohen, HJ Rowland, JH Leach, CR Arora, NK Canin, B Muss, HB Magnuson, A Flannery, M Lowenstein, L Allore, HG Mustian, KM Demark-Wahnefried, W Extermann, M Ferrell, B Inouye, SK Studenski, SA Dale, W AF Mohile, Supriya G. Hurria, Arti Cohen, Harvey J. Rowland, Julia H. Leach, Corinne R. Arora, Neeraj K. Canin, Beverly Muss, Hyman B. Magnuson, Allison Flannery, Marie Lowenstein, Lisa Allore, Heather G. Mustian, Karen M. Demark-Wahnefried, Wendy Extermann, Martine Ferrell, Betty Inouye, Sharon K. Studenski, Stephanie A. Dale, William TI Improving the Quality of Survivorship for Older Adults With Cancer SO CANCER LA English DT Review DE aging; elderly; quality of life; research priorities; survivorship ID COMPREHENSIVE GERIATRIC ASSESSMENT; ELDERLY-PATIENTS; AGING RESEARCH; CHEMOTHERAPY TOXICITY; INTERNATIONAL SOCIETY; ONCOLOGY RESEARCH; CONTROLLED-TRIAL; CLINICAL-TRIALS; CARE; MULTICENTER AB In May 2015, the Cancer and Aging Research Group, in collaboration with the National Cancer Institute and the National Institute on Aging through a U13 grant, convened a conference to identify research priorities to help design and implement intervention studies to improve the quality of life and survivorship of older, frailer adults with cancer. Conference attendees included researchers with multidisciplinary expertise and advocates. It was concluded that future intervention trials for older adults with cancer should: 1) rigorously test interventions to prevent the decline of or improve health status, especially interventions focused on optimizing physical performance, nutritional status, and cognition while undergoing cancer treatment; 2) use standardized care plans based on geriatric assessment findings to guide targeted interventions; and 3) incorporate the principles of geriatrics into survivorship care plans. Also highlighted was the need to integrate the expertise of interdisciplinary team members into geriatric oncology research, improve funding mechanisms to support geriatric oncology research, and disseminate high-impact results to the research and clinical community. In conjunction with the 2 prior U13 meetings, this conference provided the framework for future research to improve the evidence base for the clinical care of older adults with cancer. (C) 2016 American Cancer Society. C1 [Mohile, Supriya G.] Univ Rochester, Dept Med, Rochester, NY 14642 USA. [Hurria, Arti] City Hope Natl Med Ctr, Med Oncol & Expt Therapeut, 1500 E Duarte Rd, Duarte, CA 91010 USA. [Cohen, Harvey J.] Duke Univ, Ctr Study Aging & Human Dev, Durham, NC USA. [Rowland, Julia H.; Leach, Corinne R.] NCI, Off Canc Survivorship, Bethesda, MD 20892 USA. [Arora, Neeraj K.] Patient Ctr Outcomes Res Inst, Washington, DC USA. [Canin, Beverly] SCOREboard Advocacy Grp, Rochester, NY USA. [Muss, Hyman B.] Univ N Carolina, Breast Canc, Geriatr Oncol Program, Sch Med, Chapel Hill, NC USA. [Magnuson, Allison] Univ Rochester, Div Med Oncol, 601 Elmwood Ave, Rochester, NY 14642 USA. [Flannery, Marie; Mustian, Karen M.] Univ Rochester, Dept Surg, 601 Elmwood Ave, Rochester, NY 14642 USA. [Lowenstein, Lisa] Univ Texas MD Anderson Canc Ctr, Dept Hlth Serv Res, Houston, TX 77030 USA. [Allore, Heather G.] Yale Univ, Dept Med & Publ Hlth Serv, New Haven, CT USA. [Demark-Wahnefried, Wendy] Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. [Extermann, Martine] H Lee Moffitt Canc Ctr & Res Inst, Senior Adult Oncol Program, Tampa, FL USA. [Ferrell, Betty] City Hope Natl Med Ctr, Dept Nursing, 1500 E Duarte Rd, Duarte, CA 91010 USA. [Inouye, Sharon K.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Hebrew SeniorLife, Inst Aging Res, Boston, MA USA. [Studenski, Stephanie A.] NIA, Bethesda, MD 20892 USA. [Dale, William] Univ Chicago, Dept Med, Div Geriatr, 5841 S Maryland Ave, Chicago, IL 60637 USA. RP Mohile, SG (reprint author), Univ Rochester, Med Ctr, Dept Med, 601 Elmwood Ave,Box 704, Rochester, NY 14642 USA. EM Supriya_mohile@urmc.rochester.edu OI Allore, Heather/0000-0001-7685-8175 FU National Institute on Aging [U13 AG038151]; American Cancer Society; Patient-Centered Outcomes Research Institute [4634]; James Wilmot Cancer Institute; Alliance for Clinical Trials in Oncology (National Cancer Institute of the National Institutes of Health) [U10CA18082, 1UG1CA189823]; National Cancer Institute [UG1 CA189961] FX Funded by grant U13 AG038151 from the National Institute on Aging. The current study also was funded by the American Cancer Society and a Patient-Centered Outcomes Research Institute Program contract (4634). The work received support from the James Wilmot Cancer Institute, the Alliance for Clinical Trials in Oncology (National Cancer Institute of the National Institutes of Health under awards U10CA18082 and 1UG1CA189823), and grant UG1 CA189961 from the National Cancer Institute. This work was made possible by the generous donors to the James Wilmot Cancer Institute geriatric oncology philanthropy fund. All statements in this report, including its findings and conclusions, are solely those of the authors; do not necessarily represent the official views of the funding agencies; and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute, its Board of Governors, or Methodology Committee. NR 47 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD AUG 15 PY 2016 VL 122 IS 16 BP 2459 EP 2468 DI 10.1002/cncr.30053 PG 10 WC Oncology SC Oncology GA DW4MG UT WOS:000383616600005 PM 27172129 ER PT J AU Siskind, RL Andrasik, M Karuna, ST Broder, GB Collins, C Liu, A Lucas, JP Harper, GW Renzullo, PO AF Siskind, Rona L. Andrasik, Michele Karuna, Shelly T. Broder, Gail B. Collins, Clare Liu, Albert Lucas, Jonathan Paul Harper, Gary W. Renzullo, Philip O. TI Engaging Transgender People in NIH-Funded HIV/AIDS Clinical Trials Research SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE transgender; HIV; AIDS; clinical trials; research; NIH ID PARTICIPANTS; HVTN AB In 2009, the National Institutes of Health recognized the need to expand knowledge of lesbian, gay, bisexual, and transgender (LGBT) health and commissioned the Institute of Medicine to report on the health of these populations in the United States. The resulting Institute of Medicine publication called for more knowledge of the health of LGBT populations, as well as improved methodologies to reach them, more LGBT-focused research, and enhanced training programs and cultural competency of physicians and researchers. Several of the National Institutes of Health-funded HIV/AIDS clinical trials networks, including the Adolescent Medicine Trials Network for HIV/AIDS Interventions, HIV Prevention Trials Network, HIV Vaccine Trials Network, and Microbicide Trials Network, have focused attention on engaging transgender (TG) individuals in research. They have identified issues that transcend the nature of research (ie, treatment or prevention, adult or adolescent) and have adopted various approaches to effectively engage the TG community. Each network has recognized the importance of developing partner-ships to build trust with and seek input from TG individuals on research plans and policies. They have established standing advisory groups and convened consultations for this purpose. To ensure that trial data are reflective of the participants they are seeking to enroll, they have reviewed and revised data collection forms to incorporate the 2-step method of collecting sex at birth and gender identity as 2 independent variables, and some have also revised research protocol templates and policies for concept development to ensure that they are appropriate for the inclusion of TG participants. The networks have also initiated trainings to enhance cultural sensitivity and developed a range of materials and resources for network and clinical research site staff. They continue to identify TG-specific research needs in an effort to be more responsive to and improve the health of TG individuals, particularly related to HIV/AIDS. C1 [Siskind, Rona L.; Renzullo, Philip O.] NIAID, Div Aids, NIH, 5601 Fishers Lane,Room 8D28A, Bethesda, MD 20852 USA. [Andrasik, Michele; Karuna, Shelly T.; Broder, Gail B.] Fred Hutchinson Canc Res Ctr, HIV Vaccine Trials Network, 1124 Columbia St, Seattle, WA 98104 USA. [Collins, Clare] Microbicide Trials Network, Pittsburgh, PA USA. [Liu, Albert] San Francisco Dept Publ Hlth, Bridge HIV, San Francisco, CA USA. [Lucas, Jonathan Paul] FHI360, HIV Prevent Trials Network, Durham, NC USA. [Harper, Gary W.] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. RP Siskind, RL (reprint author), NIAID, Div Aids, NIH, 5601 Fishers Lane,Room 8D28A, Bethesda, MD 20852 USA. EM rsiskind@niaid.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute on Drug Abuse (NIDA); National Institute of Mental Health (NIMH) [U01HD040533, U01HD040474]; National Institute of Allergy and Infectious Diseases (NIAID); NIMH; NIDA [UM1AI068619, UM1AI068617, UM1AI068613]; NIAID [UM1AI68614, UM1AI68618, UM1AI68635]; NICHD; NIMH [UM1AI068633, UM1AI068615, UM1AI106707] FX Overall support for the Adolescent Medicine Trials Network for HIV/AIDS Interventions is funded by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) with supplemental funding from the National Institute on Drug Abuse (NIDA) and the National Institute of Mental Health (NIMH) (U01HD040533 and U01HD040474); support for the HIV Prevention Trials Network is provided by the National Institute of Allergy and Infectious Diseases (NIAID), NIMH, and NIDA (UM1AI068619, UM1AI068617, and UM1AI068613); support for the HIV Vaccine Trials Network is provided by NIAID (UM1AI68614, UM1AI68618, and UM1AI68635); support for the Microbicides Trials Network (MTN) is provided by NIAID with co-funding from NICHD and the NIMH (UM1AI068633, UM1AI068615, and UM1AI106707). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIAID, NICHD, NIDA, NIMH, or the National Institutes of Health. NR 14 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 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 15 PY 2016 VL 72 SU 3 BP S243 EP S247 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DY6YM UT WOS:000385275700007 PM 27429190 ER PT J AU Naradikian, MS Myles, A Beiting, DP Roberts, KJ Dawson, L Herati, RS Bengsch, B Linderman, SL Stelekati, E Spolski, R Wherry, EJ Hunter, C Hensley, SE Leonard, WJ Cancro, MP AF Naradikian, Martin S. Myles, Arpita Beiting, Daniel P. Roberts, Kenneth J. Dawson, Lucas Herati, Ramin Sedaghat Bengsch, Bertram Linderman, Susanne L. Stelekati, Erietta Spolski, Rosanne Wherry, E. John Hunter, Christopher Hensley, Scott E. Leonard, Warren J. Cancro, Michael P. TI Cutting Edge: IL-4, IL-21, and IFN-gamma Interact To Govern T-bet and CD11c Expression in TLR-Activated B Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FOLLICULAR HELPER-CELLS; AUTOANTIBODY PRODUCTION; TRANSCRIPTION FACTOR; AGED MICE; MEMORY; EXPANSION; RESPONSES; RECEPTOR; INFECTION; ANTIGEN AB T-bet and CD11c expression in B cells is linked with IgG(2c) isotype switching, virus-specific immune responses, and humoral autoimmunity. However, the activation requisites and regulatory cues governing T-bet and CD11c expression in B cells remain poorly defined. In this article, we reveal a relationship among TLR engagement, IL-4, IL-21, and IFN-gamma that regulates T-bet expression in B cells. We find that IL-21 or IFN-gamma directly promote T-bet expression in the context of TLR engagement. Further, IL-4 antagonizes T-bet induction. Finally, IL-21, but not IFN-gamma, promotes CD11c expression independent of T-bet. Using influenza virus and Heligmosomoides polygyrus infections, we show that these interactions function in vivo to determine whether T-bet(+) and CD11c(+) B cells are formed. These findings suggest that T-bet(+) B cells seen in health and disease share the common initiating features of TLR-driven activation within this circumscribed cytokine milieu. C1 [Naradikian, Martin S.; Myles, Arpita; Roberts, Kenneth J.; Cancro, Michael P.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Naradikian, Martin S.; Myles, Arpita; Beiting, Daniel P.; Dawson, Lucas; Herati, Ramin Sedaghat; Bengsch, Bertram; Linderman, Susanne L.; Stelekati, Erietta; Wherry, E. John; Hunter, Christopher; Hensley, Scott E.; Cancro, Michael P.] Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA. [Beiting, Daniel P.; Dawson, Lucas; Hunter, Christopher] Univ Penn, Sch Vet Med, Philadelphia, PA 19104 USA. [Herati, Ramin Sedaghat] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Bengsch, Bertram; Linderman, Susanne L.; Stelekati, Erietta; Wherry, E. John; Hensley, Scott E.] Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Linderman, Susanne L.; Hensley, Scott E.] Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA. [Spolski, Rosanne; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. [Spolski, Rosanne; Leonard, Warren J.] NHLBI, Ctr Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Cancro, MP (reprint author), Univ Penn, Perelman Sch Med, 284 John Morgan Bldg,3620 Hamilton Walk, Philadelphia, PA 19104 USA. EM cancro@mail.med.upenn.edu FU NCI NIH HHS [T32 CA009171]; NIA NIH HHS [R01 AG030227]; NIAID NIH HHS [R01 AI118691, K08 AI114852, R01 AI108686, R01 AI113047, T32 AI055428] NR 31 TC 2 Z9 2 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 AUG 15 PY 2016 VL 197 IS 4 BP 1023 EP 1028 DI 10.4049/jimmunol.1600522 PG 6 WC Immunology SC Immunology GA DY3NB UT WOS:000384999100003 PM 27430719 ER PT J AU Su, P Chen, S Zheng, YH Zhou, HY Yan, CH Yu, F Zhang, YG He, L Zhang, Y Wang, YM Wu, L Wu, XA Yu, BK Ma, LY Yang, ZR Wang, JH Zhao, GX Zhu, JF Wu, ZY Sun, B AF Su, Pan Chen, Sheng Zheng, Yu Han Zhou, Hai Yan Yan, Cheng Hua Yu, Fang Zhang, Ya Guang He, Lan Zhang, Yuan Wang, Yanming Wu, Lei Wu, Xiaoai Yu, Bingke Ma, Li Yan Yang, Zhiru Wang, Jianhua Zhao, Guixian Zhu, Jinfang Wu, Zhi-Ying Sun, Bing TI Novel Function of Extracellular Matrix Protein 1 in Suppressing Th17 Cell Development in Experimental Autoimmune Encephalomyelitis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID REGULATORY T-CELLS; GROWTH-FACTOR-BETA; TGF-BETA; MULTIPLE-SCLEROSIS; DENDRITIC CELLS; HUMAN SKIN; DIFFERENTIATION; ACTIVATION; EXPRESSION; RESPONSES AB Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS characterized by demyelination and axonal damage. Experimental autoimmune encephalomyelitis (EAE) is a well-established animal model for human MS. Although Th17 cells are important for disease induction, Th2 cells are inhibitory in this process. In this article, we report the effect of a Th2 cell product, extracellular matrix protein 1 (ECM1), on the differentiation of Th17 cells and the development of EAE. Our results demonstrated that ECM1 administration from day 1 to day 7 following the EAE induction could ameliorate the Th17 cell responses and EAE development in vivo. Further study of the mechanism revealed that ECM1 could interact with alpha v integrin on dendritic cells and block the alpha v integrin-mediated activation of latent TGF-beta, resulting in an inhibition of Th17 cell differentiation at an early stage of EAE induction. Furthermore, overexpression of ECM1 in vivo significantly inhibited the Th17 cell response and EAE induction in ECM1 transgenic mice. Overall, our work has identified a novel function of ECM1 in inhibiting Th17 cell differentiation in the EAE model, suggesting that ECM1 may have the potential to be used in clinical applications for understanding the pathogenesis of MS and its diagnosis. C1 [Su, Pan; Zheng, Yu Han; Zhou, Hai Yan; Yan, Cheng Hua; Zhang, Ya Guang; He, Lan; Zhang, Yuan; Wang, Yanming; Ma, Li Yan; Sun, Bing] Chinese Acad Sci, State Key Lab Cell Biol, CAS Ctr Excellence Mol Cell Sci, Inst Biochem & Cell Biol,Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China. [Chen, Sheng; Wu, Lei; Wu, Zhi-Ying] Zhejiang Univ, Sch Med, Dept Neurol, Hangzhou 310058, Zhejiang, Peoples R China. [Chen, Sheng; Wu, Lei; Wu, Zhi-Ying] Zhejiang Univ, Sch Med, Res Ctr Neurol, Affiliated Hosp 2, Hangzhou 310058, Zhejiang, Peoples R China. [Chen, Sheng; Wu, Lei; Wu, Zhi-Ying] Zhejiang Univ, Sch Med, Collaborat Innovat Ctr Brain Sci, Hangzhou 310058, Zhejiang, Peoples R China. [Chen, Sheng] Fujian Med Univ, Affiliated Hosp 1, Dept Neurol, Fuzhou 350004, Peoples R China. [Chen, Sheng] Fujian Med Univ, Affiliated Hosp 1, Inst Neurol, Fuzhou 350004, Peoples R China. [Yu, Fang] NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Wu, Xiaoai; Yu, Bingke; Yang, Zhiru] Novo Nordisk Res Ctr, Beijing 100000, Peoples R China. [Wang, Jianhua] Chinese Acad Sci, Inst Pasteur Shanghai, Key Lab Mol Virol & Immunol, Shanghai 200031, Peoples R China. [Zhao, Guixian] Fudan Univ, Dept Neurol, Shanghai Med Coll, Huashan Hosp, Shanghai 200032, Peoples R China. [Zhao, Guixian] Fudan Univ, Inst Neurol, Shanghai Med Coll, Huashan Hosp, Shanghai 200032, Peoples R China. RP Sun, B (reprint author), Chinese Acad Sci, State Key Lab Cell Biol, CAS Ctr Excellence Mol Cell Sci, Inst Biochem & Cell Biol,Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China.; Zhu, JF; Wu, ZY; Sun, B (reprint author), Chinese Acad Sci, Inst Biochem & Cell Biol, Shanghai Inst Biol Sci, 320 Yue Yang Rd, Shanghai 200031, Peoples R China. EM jfZhu@niaid.nih.gov; zhiyingwu@zju.edu.cn; bsun@sibs.ac.cn RI Zhu, Jinfang/B-7574-2012 FU Intramural NIH HHS [ZIA AI001169-04] NR 50 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 AUG 15 PY 2016 VL 197 IS 4 BP 1054 EP 1064 DI 10.4049/jimmunol.1502457 PG 11 WC Immunology SC Immunology GA DY3NB UT WOS:000384999100007 PM 27316685 ER PT J AU Cao, X Lu, Y Zhang, XY Kovalovsky, D AF Cao, Xin Lu, Ying Zhang, Xianyu Kovalovsky, Damian TI Zbtb1 Safeguards Genome Integrity and Prevents p53-Mediated Apoptosis in Proliferating Lymphoid Progenitors SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD8(+) T-CELLS; ZINC-FINGER; PLZF CONTROLS; CHK1; REPLICATION; PHOSPHORYLATION; LINEAGE; REPAIR; BCL-2; ATR AB Expression of the transcription factor Zbtb1 is required for normal lymphoid development. We report in the present study that Zbtb1 maintains genome integrity in immune progenitors, without which cells undergo increased DNA damage and p53-mediated apoptosis during replication and differentiation. Increased DNA damage in Zbtb1-mutant (ScanT) progenitors was due to increased sensitivity to replication stress, which was a consequence of inefficient activation of the S-phase checkpoint response. Increased p53-mediated apoptosis affected not only lymphoid but also myeloid development in competitive bone marrow chimeras, and prevention of apoptosis by transgenic Bcl2 expression and p53 deficiency rescued lymphoid as well as myeloid development from Zbtb1-mutant progenitors. Interestingly, however, protection from apoptosis rescued only the early stages of T cell development, and thymocytes remained arrested at the double-negative 3 developmental stage, indicating a strict requirement of Zbtb1 at later T cell developmental stages. Collectively, these results indicate that Zbtb1 prevents DNA damage in replicating immune progenitors, allowing the generation of B cells, T cells, and myeloid cells. C1 [Cao, Xin] Northwest Univ Nationalities, Coll Life Sci & Engn, Lanzhou 730030, Peoples R China. [Cao, Xin; Lu, Ying; Zhang, Xianyu; Kovalovsky, Damian] NCI, Expt Immunol Branch, NIH, 9000 Rockville Pike,Bldg 10-4B17, Bethesda, MD 20892 USA. RP Kovalovsky, D (reprint author), NCI, Expt Immunol Branch, NIH, 9000 Rockville Pike,Bldg 10-4B17, Bethesda, MD 20892 USA. EM kovalovskyd@mail.nih.gov FU Intramural NIH HHS [ZIA BC011429-02, ZIA BC011429-01, Z99 CA999999, ZIA BC011429-03, ZIA BC011429-04]; NCI NIH HHS [ZIA BC011429] NR 36 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 AUG 15 PY 2016 VL 197 IS 4 BP 1199 EP 1211 DI 10.4049/jimmunol.1600013 PG 13 WC Immunology SC Immunology GA DY3NB UT WOS:000384999100020 PM 27402700 ER PT J AU Seedhom, MO Hickman, HD Wei, JJ David, A Yewdell, JW AF Seedhom, Mina O. Hickman, Heather D. Wei, Jiajie David, Alexandre Yewdell, Jonathan W. TI Protein Translation Activity: A New Measure of Host Immune Cell Activation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD8(+) T-CELLS; MEMORY PHENOTYPE; LYMPH-NODES; ANTIGEN; STIMULATION; INNATE AB We describe the in vivo ribopuromycylation (RPM) method, which uses a puromycin-specific Ab to fluorescently label ribosome-bound puromycylated nascent chains, enabling measurement of translational activity via immunohistochemistry or flow cytometry. Tissue staining provides a unique view of virus-induced activation of adaptive, innate, and stromal immune cells. RPM flow precisely quantitates virus-induced activation of lymphocytes and innate immune cells, and it provides a unique measure of immune cell deactivation and quiescence. Using RPM we find that high endothelial cells in draining lymph nodes rapidly increase translation in the first day of vaccinia virus infection. We also find a population of constitutively activated splenic T cells in naive mice and further that most bone marrow T cells activate 3 d after vaccinia virus infection. Bone marrow T cell activation is nonspecific, IL-12-dependent, and induces innate memory T cell phenotypic markers. Thus, RPM measures translational activity to uniquely identify cell populations that participate in the immune response to pathogens, other foreign substances, and autoantigens. C1 [Seedhom, Mina O.; Hickman, Heather D.; Wei, Jiajie; David, Alexandre; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [David, Alexandre] Inst Genom Fonct, Montpellier, France. RP Yewdell, JW (reprint author), NIAID, NIH, 33 North Dr,Room 2E13C-1,Bldg 33, Bethesda, MD 20892 USA. EM jyewdell@niaid.nih.gov FU Intramural NIH HHS [ZIA AI000814-16] NR 22 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 AUG 15 PY 2016 VL 197 IS 4 BP 1498 EP 1506 DI 10.4049/jimmunol.1600088 PG 9 WC Immunology SC Immunology GA DY3NB UT WOS:000384999100048 PM 27385780 ER PT J AU Doritchamou, JYA Herrera, R Aebig, JA Morrison, R Nguyen, V Reiter, K Shimp, RL MacDonald, NJ Narum, DL Fried, M Duffy, PE AF Doritchamou, Justin Yai Alamou Herrera, Raul Aebig, Joan A. Morrison, Robert Vu Nguyen Reiter, Karine Shimp, Richard L. MacDonald, Nicholas J. Narum, David L. Fried, Michal Duffy, Patrick E. TI VAR2CSA Domain-Specific Analysis of Naturally Acquired Functional Antibodies to Plasmodium falciparum Placental Malaria SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE malaria; pregnancy; multigravidae; VAR2CSA; DBL domains; functional antibody; vaccine ID CHONDROITIN-SULFATE-A; ADHESION-INHIBITORY ANTIBODIES; APICAL MEMBRANE ANTIGEN-1; VARIANT SURFACE-ANTIGENS; INFECTED ERYTHROCYTES; PREGNANT-WOMEN; BLOCKING ANTIBODIES; PARASITE ADHESION; VACCINE CANDIDATE; MATERNAL MALARIA AB Background. Placental malaria is caused by Plasmodium falciparum infected erythrocytes (IEs) that surface-express VAR2CSA and bind chondroitin sulfate A. The inflammatory response to placenta-sequestered parasites is associated with poor pregnancy outcomes, and protection may be mediated in part by VAR2CSA antibodies that block placental IE adhesion. Methods. In this study, we used a new approach to assess VAR2CSA domains for functional epitopes recognized by naturally acquired antibodies. Antigen-specific immunoglobulin (Ig) G targeting Duffy binding like (DBL) domains from different alleles were sequentially purified from plasma pooled from multigravid women and then characterized using enzyme-linked immunosorbent assay, flow cytometry, and antiadhesion assays. Results. Different DBL domain-specific IgGs could react to homologous as well as heterologous antigens and parasites, suggesting that conserved epitopes are shared between allelic variants. Homologous blocking of IE binding was observed with ID1-DBL2-ID2a-, DBL4-, and DBL5-specific IgG (range, 42%-75%), whereas partial cross-inhibition activity was observed with purified IgG specific to ID1-DBL2-ID2a and DBL4 antigens. Plasma retained broadly neutralizing activity after complete depletion of these VAR2CSA specificities. Conclusions. Broadly neutralizing antibodies of multigravidae are not depleted on VAR2CSA recombinant antigens, and hence development of VAR2CSA vaccines based on a single construct and variant might induce antibodies with limited broadly neutralizing activity. C1 [Doritchamou, Justin Yai Alamou; Herrera, Raul; Aebig, Joan A.; Morrison, Robert; Vu Nguyen; Reiter, Karine; Shimp, Richard L.; MacDonald, Nicholas J.; Narum, David L.; Fried, Michal; Duffy, Patrick E.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Twinbrook 1,Rm 1111,5640 Fishers Ln, Rockville, MD 20852 USA. [Morrison, Robert] Seattle Biomed Res Inst, MOMS Project, 4 Nickerson St, Seattle, WA 98109 USA. RP Duffy, PE (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, NIH, Twinbrook 1,Rm 1111,5640 Fishers Ln, Rockville, MD 20852 USA. EM patrick.duffy@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 49 TC 1 Z9 1 U1 1 U2 1 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 AUG 15 PY 2016 VL 214 IS 4 BP 577 EP 586 DI 10.1093/infdis/jiw197 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DY1JB UT WOS:000384849600010 PM 27190180 ER PT J AU Powers, JH Howard, K Saretsky, T Clifford, S Hoffmann, S Llorens, L Talbot, G AF Powers, John H., III Howard, Kellee Saretsky, Todd Clifford, Sarah Hoffmann, Steve Llorens, Lily Talbot, George TI Patient-Reported Outcome Assessments as Endpoints in Studies in Infectious Diseases SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE infectious diseases; clinical trials; patient-reported outcomes; endpoints; clinical practice ID CONTROLLED SERIES; CYSTIC-FIBROSIS; CLINICAL-TRIALS; SYMPTOMS; FOUNDATION; QUESTIONNAIRE; SULFANILAMIDE; RELIABILITY; ERYSIPELAS; PNEUMONIA AB The goal of administering medical interventions is to help patients live longer or live better. In keeping with this goal, there has been increasing interest in taking the "voice" of the patient into account during the development process, specifically in the evaluation of treatment benefits of medical interventions, and use of patient-centered outcome data to justify reimbursement. Patient-reported outcomes (PROs) are outcome assessments (OAs) used to define endpoints that can provide direct evidence of treatment benefit on how patients feel or function. When PROs are appropriately developed, they can increase the efficiency and clinical relevance of clinical trials. Several PROs have been developed for OA in specific infectious diseases indications, and more are under development. PROs also hold promise for use in evaluating adherence, adverse effects, satisfaction with care, and routine clinical practice. C1 [Powers, John H., III] George Washington Univ, Sch Med, Washington, DC 20052 USA. [Howard, Kellee; Saretsky, Todd; Clifford, Sarah] ICON PLC, San Francisco, CA USA. [Hoffmann, Steve] Fdn Natl Inst Hlth, Bethesda, MD USA. [Llorens, Lily] Llorens Consulting, Bay Village, OH USA. [Talbot, George] Talbot Advisors LLC, Anna Maria, FL USA. RP Powers, JH (reprint author), 15915 Emory Lane, Rockville, MD 20853 USA. EM jpowers3@aol.com FU Clinical Trials Transformation Initiative FX This article appears as part of the supplement "Facilitating Antibacterial Drug Development in a Time of Great Need," sponsored by the Clinical Trials Transformation Initiative. NR 44 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 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2016 VL 63 SU 2 BP S52 EP S56 DI 10.1093/cid/ciw317 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DV8QX UT WOS:000383202700007 PM 27481954 ER PT J AU Chen, HM Larson, DR AF Chen, Huimin Larson, Daniel R. TI What have single-molecule studies taught us about gene expression? SO GENES & DEVELOPMENT LA English DT Review DE fluorescence; single molecule; splicing; transcription ID RNA-POLYMERASE-II; PRE-MESSENGER-RNA; TRANSCRIPTION FACTOR-BINDING; START-SITE SELECTION; EMBRYONIC STEM-CELLS; U4/U6.U5 TRI-SNRNP; REAL-TIME ANALYSIS; ESCHERICHIA-COLI; MAMMALIAN-CELLS; IN-VIVO AB The production of a single mRNA is the result of many sequential steps, from docking of transcription factors to polymerase initiation, elongation, splicing, and, finally, termination. Much of our knowledge about the fundamentals of RNA synthesis and processing come from ensemble in vitro biochemical measurements. Single-molecule approaches are very much in this same reductionist tradition but offer exquisite sensitivity in space and time along with the ability to observe heterogeneous behavior and actually manipulate macromolecules. These techniques can also be applied in vivo, allowing one to address questions in living cells that were previously restricted to reconstituted systems. In this review, we examine the unique insights that single-molecule techniques have yielded on the mechanisms of gene expression. C1 [Chen, Huimin; Larson, Daniel R.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Larson, DR (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM dan.larson@nih.gov RI Larson, Daniel/B-9829-2008 OI Larson, Daniel/0000-0001-9253-3055 FU Intramural Research Program of the National Cancer Institute FX We acknowledge Maxime Dahan, Timothee Lionnet, Aaron Hoskins, Tineke Lenstra, and Murali Palangat for critical comments on the manuscript. In addition, both anonymous referees provided advice that greatly improved the final review. This work was supported by the Intramural Research Program of the National Cancer Institute. NR 153 TC 1 Z9 1 U1 14 U2 14 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD AUG 15 PY 2016 VL 30 IS 16 BP 1796 EP 1810 DI 10.1101/gad.281725.116 PG 15 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA DW6CJ UT WOS:000383733700003 PM 27601529 ER PT J AU Patterson, TF Thompson, GR Denning, DW Fishman, JA Hadley, S Herbrecht, R Kontoyiannis, DP Marr, KA Morrison, VA Nguyen, MH Segal, BH Steinbach, WJ Stevens, DA Walsh, TJ Wingard, JR Young, JAH Bennett, JE AF Patterson, Thomas F. Thompson, George R., III Denning, David W. Fishman, Jay A. Hadley, Susan Herbrecht, Raoul Kontoyiannis, Dimitrios P. Marr, Kieren A. Morrison, Vicki A. Nguyen, M. Hong Segal, Brahm H. Steinbach, William J. Stevens, David A. Walsh, Thomas J. Wingard, John R. Young, Jo-Anne H. Bennett, John E. TI Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE aspergillosis; invasive aspergillosis; allergic aspergillosis; chronic aspergillosis; fungal diagnostics; azoles; echniocandins; amphotericin AB It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances. C1 [Patterson, Thomas F.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Patterson, Thomas F.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Thompson, George R., III] Univ Calif Davis, Davis, CA 95616 USA. [Denning, David W.] Univ Manchester, Univ South Manchester Hosp, Natl Aspergillosis Ctr, Manchester M13 9PL, Lancs, England. [Fishman, Jay A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fishman, Jay A.] Harvard Med Sch, Boston, MA USA. [Hadley, Susan] Tufts Med Ctr, Boston, MA USA. [Herbrecht, Raoul] Univ Strasbourg, Strasbourg, France. [Kontoyiannis, Dimitrios P.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Marr, Kieren A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Marr, Kieren A.] Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Morrison, Vicki A.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Morrison, Vicki A.; Young, Jo-Anne H.] Univ Minnesota, Minneapolis, MN USA. [Nguyen, M. Hong] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Segal, Brahm H.] SUNY Buffalo, Jacobs Sch Med & Biomed Sci, Buffalo, NY USA. [Segal, Brahm H.] Roswell Pk Canc Inst, New York, NY USA. [Steinbach, William J.] Duke Univ, Med Ctr, Durham, NC USA. [Stevens, David A.] Calif Inst Med Res, San Jose, CA 95128 USA. [Walsh, Thomas J.] New York Presbyterian Hosp, Weill Cornell Med Ctr, New York, NY USA. [Wingard, John R.] Univ Florida, Gainesville, FL USA. [Bennett, John E.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Patterson, TF (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Div Infect Dis, San Antonio Ctr Med Mycol, 7703 Floyd Curl Dr,MSC 7881, San Antonio, TX 78229 USA. EM patterson@uthscsa.edu FU IDSA FX Support for this guideline was provided by the IDSA. NR 1 TC 9 Z9 9 U1 6 U2 6 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 AUG 15 PY 2016 VL 63 IS 4 BP 433 EP 442 DI 10.1093/cid/ciw444 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DV8QU UT WOS:000383202400002 PM 27481947 ER PT J AU Xie, YDL Chen, RY Sereti, I Zerbe, CS Holland, SM Browne, SK AF Xie, Yingda L. Chen, Ray Y. Sereti, Irini Zerbe, Christa S. Holland, Steven M. Browne, Sarah K. TI Neutralizing Anti-Interferon-Gamma Autoantibody Levels May Not Correlate With Clinical Course of Disease Reply SO CLINICAL INFECTIOUS DISEASES LA English DT Letter C1 [Xie, Yingda L.; Chen, Ray Y.; Zerbe, Christa S.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Sereti, Irini] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Browne, Sarah K.] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA. RP Holland, SM (reprint author), CRC B3-4141 MSC 1684, Bethesda, MD 20892 USA. EM smh@nih.gov NR 5 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 AUG 15 PY 2016 VL 63 IS 4 BP 573 EP 574 DI 10.1093/cid/ciw352 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DV8QU UT WOS:000383202400026 PM 27225244 ER PT J AU Patterson, TF Thompson, GR Denning, DW Fishman, JA Hadley, S Herbrecht, R Kontoyiannis, DP Marr, KA Morrison, VA Nguyen, MH Segal, BH Steinbach, WJ Stevens, DA Walsh, TJ Wingard, JR Young, JAH Bennett, JE AF Patterson, Thomas F. Thompson, George R., III Denning, David W. Fishman, Jay A. Hadley, Susan Herbrecht, Raoul Kontoyiannis, Dimitrios P. Marr, Kieren A. Morrison, Vicki A. Nguyen, M. Hong Segal, Brahm H. Steinbach, William J. Stevens, David A. Walsh, Thomas J. Wingard, John R. Young, Jo-Anne H. Bennett, John E. TI Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE aspergillosis; invasive aspergillosis; allergic aspergillosis; chronic aspergillosis; fungal diagnostics; azoles; echniocandins; amphotericin ID INVASIVE FUNGAL-INFECTIONS; CELL TRANSPLANT RECIPIENTS; LIPOSOMAL AMPHOTERICIN-B; CHRONIC PULMONARY ASPERGILLOSIS; ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS; CENTRAL-NERVOUS-SYSTEM; BRONCHOALVEOLAR LAVAGE FLUID; CHRONIC GRANULOMATOUS-DISEASE; RANDOMIZED CONTROLLED-TRIAL; SOLID-ORGAN TRANSPLANT AB It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances. C1 [Patterson, Thomas F.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Patterson, Thomas F.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Thompson, George R., III] Univ Calif Davis, Davis, CA 95616 USA. [Denning, David W.] Univ Manchester, Univ South Manchester Hosp, Natl Aspergillosis Ctr, Manchester M13 9PL, Lancs, England. [Fishman, Jay A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fishman, Jay A.] Harvard Med Sch, Boston, MA USA. [Hadley, Susan] Tufts Med Ctr, Boston, MA USA. [Herbrecht, Raoul] Univ Strasbourg, Strasbourg, France. [Kontoyiannis, Dimitrios P.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Marr, Kieren A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Marr, Kieren A.] Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Morrison, Vicki A.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Morrison, Vicki A.; Young, Jo-Anne H.] Univ Minnesota, Minneapolis, MN USA. [Nguyen, M. Hong] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Segal, Brahm H.] SUNY Buffalo, Jacobs Sch Med & Biomed Sci, Buffalo, NY USA. [Segal, Brahm H.] Roswell Pk Canc Inst, New York, NY USA. [Steinbach, William J.] Duke Univ, Med Ctr, Durham, NC USA. [Stevens, David A.] Calif Inst Med Res, San Jose, CA 95128 USA. [Walsh, Thomas J.] New York Presbyterian Hosp, Weill Cornell Med Ctr, New York, NY USA. [Wingard, John R.] Univ Florida, Gainesville, FL USA. [Bennett, John E.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Patterson, TF (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Div Infect Dis, San Antonio Ctr Med Mycol, 7703 Floyd Curl Dr,MSC 7881, San Antonio, TX 78229 USA. EM patterson@uthscsa.edu OI Herbrecht, Raoul/0000-0002-9381-4876 FU IDSA FX Support for this guideline was provided by the IDSA. NR 657 TC 27 Z9 27 U1 10 U2 11 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 AUG 15 PY 2016 VL 63 IS 4 BP E1 EP E60 DI 10.1093/cid/ciw326 PG 60 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DV8QU UT WOS:000383202400001 PM 27365388 ER PT J AU Eitan, E Petralia, RS Wang, YX Indig, FE Mattson, MP Yao, PJ AF Eitan, Erez Petralia, Ronald S. Wang, Ya-Xian Indig, Fred E. Mattson, Mark P. Yao, Pamela J. TI Probing extracellular Sonic hedgehog in neurons SO BIOLOGY OPEN LA English DT Article DE Sonic hedgehog; Hippocampal neurons; Extracellular vesicle; Filopodia ID HIPPOCAMPAL-NEURONS; CAENORHABDITIS-ELEGANS; NMDA RECEPTORS; BRAIN; PROLIFERATION; CYCLOPAMINE; INHIBITION; CEREBELLUM; ASTROCYTES; EXPRESSION AB The bioactivity of Sonic hedgehog (Shh) depends on specific lipid modifications; a palmitate at its N-terminus and a cholesterol at its C-terminus. This dual-lipid modification makes Shh molecules lipophilic, which prevents them from diffusing freely in extracellular space. Multiple lines of evidence indicate that Shh proteins are carried by various forms of extracellular vesicles (EVs). It also has been shown, for instance, that in some tissues Shh proteins are transported to neighboring cells directly via filopodia. We have previously reported that Shh proteins are expressed in hippocampal neurons. In this study we show that, in the hippocampus and cerebellum of postnatal day (P)2 rats, Shh is mostly found near or on the membrane surface of small neurites or filopodia. We also examined cultured hippocampal neurons where we observed noticeable and widespread Shh-immunolabeled vesicles located outside neurons. Through immunoelectron microscopy and biochemical analysis, we find Shh-containing EVs with a wide range of sizes. Unlike robust Shh activity in EVs isolated from cells overexpressing an N-terminal Shh fragment construct, we did not detect measurable Shh activity in EVs purified from the medium of cultured hippocampal neurons. These results suggest the complexity of the transcellular Shh signaling mechanisms in neurons. C1 [Eitan, Erez; Mattson, Mark P.; Yao, Pamela J.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Petralia, Ronald S.; Wang, Ya-Xian] NIDCD, Adv Imaging Core, NIH, Bethesda, MD 20892 USA. [Indig, Fred E.] NIA, Adv Imaging Core, Clin Invest Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Yao, PJ (reprint author), NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. EM yaopa@grc.nia.nih.gov FU Intramural Research Programs of National Institute on Aging - National Institutes of Health; National Institute on Deafness and Other Communication Disorders - National Institutes of Health FX This study was supported by the Intramural Research Programs of National Institute on Aging - National Institutes of Health and National Institute on Deafness and Other Communication Disorders - National Institutes of Health. NR 50 TC 2 Z9 2 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 2046-6390 J9 BIOL OPEN JI Biol. Open PD AUG 15 PY 2016 VL 5 IS 8 BP 1086 EP 1092 DI 10.1242/bio.019422 PG 7 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DU6DQ UT WOS:000382304400009 PM 27387534 ER PT J AU Bellad, RM Bang, A Carlo, WA McClure, EM Meleth, S Goco, N Goudar, SS Derman, RJ Hibberd, PL Patel, A Esamai, F Bucher, S Gisore, P Wright, LL AF Bellad, Roopa M. Bang, Akash Carlo, Waldemar A. McClure, Elizabeth M. Meleth, Sreelatha Goco, Norman Goudar, Shivaprasad S. Derman, Richard J. Hibberd, Patricia L. Patel, Archana Esamai, Fabian Bucher, Sherri Gisore, Peter Wright, Linda L. CA HBB Study Grp TI A pre-post study of a multi-country scale up of resuscitation training of facility birth attendants: does Helping Babies Breathe training save lives? SO BMC PREGNANCY AND CHILDBIRTH LA English DT Article ID MIDDLE-INCOME COUNTRIES; MORTALITY; ETHIOPIA; WOMEN AB Background: Whether facility-based implementation of Helping Babies Breathe (HBB) reduces neonatal mortality at a population level in low and middle income countries (LMIC) has not been studied. Therefore, we evaluated HBB implementation in this context where our study team has ongoing prospective outcome data on all pregnancies regardless of place of delivery. Methods: We compared outcomes of birth cohorts in three sites in India and Kenya pre-post implementation of a facility-based intervention, using a prospective, population-based registry in 52 geographic clusters. Our hypothesis was that HBB implementation would result in a 20 % decrease in the perinatal mortality rate (PMR) among births >= 1500 g. Results: We enrolled 70,704 births during two 12-month study periods. Births within each site did not differ pre-post intervention, except for an increased proportion of <2500 g newborns and deliveries by caesarean section in the post period. There were no significant differences in PMR among all registry births; however, a post-hoc analysis stratified by birthweight documented improvement in <2500 g mortality in Belgaum in both registry and in HBB-trained facility births. No improvement in <2500 g mortality measures was noted in Nagpur or Kenya and there was no improvement in normal birth weight survival. Conclusions: Rapid scale up of HBB training of facility birth attendants in three diverse sites in India and Kenya was not associated with consistent improvements in mortality among all neonates >= 1500 g; however, differential improvements in <2500 g survival in Belgaum suggest the need for careful implementation of HBB training with attention to the target population, data collection, and ongoing quality monitoring activities. C1 [Bellad, Roopa M.; Goudar, Shivaprasad S.] KLE Univ Jawaharlal Nehru Med Coll, Belgaum, Karnataka, India. [Bang, Akash] Mahatma Gandhi Inst Med Sci, Sevagram, Maharashtra, India. [Carlo, Waldemar A.] Univ Alabama Birmingham, Birmingham, AL USA. [McClure, Elizabeth M.; Meleth, Sreelatha; Goco, Norman] RTI Int, Durham, NC USA. [Derman, Richard J.] Christiana Care Hlth Syst, Dept Obstet & Gynecol, Newark, DE USA. [Hibberd, Patricia L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Patel, Archana] Lata Med Res Fdn, Nagpur, Maharashtra, India. [Patel, Archana] Indira Gandhi Govt Med Coll, Nagpur, Maharashtra, India. [Esamai, Fabian; Gisore, Peter] Moi Univ Sch Med, Dept Child Hlth & Paediat, Eldoret, Kenya. [Bucher, Sherri] Indiana Univ, Sch Med, Indianapolis, IN USA. [Wright, Linda L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Wright, Linda L.] 5800 Nicholson Lane,1206, Rockville, MD 20852 USA. RP Wright, LL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA.; Wright, LL (reprint author), 5800 Nicholson Lane,1206, Rockville, MD 20852 USA. EM lindawright.md@gmail.com OI Somannavar, Manjunath/0000-0002-8871-5072 FU Norad; Laerdal Foundation; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) FX The study was funded by grants from Norad, Laerdal Foundation and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). NICHD staff had input into the study design, data interpretation and writing of the report. RTI staff had access to all the study data. The corresponding author wrote the first draft of the manuscript and had final responsibility for the decision to submit for publication. NR 17 TC 1 Z9 1 U1 6 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2393 J9 BMC PREGNANCY CHILDB JI BMC Pregnancy Childbirth PD AUG 15 PY 2016 VL 16 AR 222 DI 10.1186/s12884-016-0997-6 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DT4UL UT WOS:000381476500001 PM 27527831 ER PT J AU Gerfen, CR Sawchenko, PE AF Gerfen, Charles R. Sawchenko, Paul E. TI An anterograde neuroanatomical tracing method that shows the detailed morphology of neurons, their axons and terminals: Immunohistochemical localization of an axonally transported plant lectin, Phaseolus vulgaris-leucoagglutinin (PHA-L) SO BRAIN RESEARCH LA English DT Review DE Neuroanatomy; Axonal tract tracing ID CENTRAL-NERVOUS-SYSTEM; NEUROENDOCRINE STRESS-RESPONSE; SUPRAOPTIC NUCLEI; NEURAL CIRCUITS; ORGANIZATION; HYPOTHALAMUS; INHIBITION; INPUTS; BRAIN; RAT AB A new neuroanatomical method for tracing connections in the central nervous system based on the anterograde axonal transport of the kidney bean lectin, Phaseolus vulgaris-leucoagglutinin (PHA-L) is described. The method, for which a detailed protocol is presented, offers several advantages over present techniques. First, when the lectin is delivered iontophoretically, PHA-L injection sites as small as 50200 mu m in diameter can be produced, and are clearly demarcated since the neurons within the labeled zone are completely filled. Second, many morphological features of such filled neurons are clearly demonstrated including their cell bodies, axons, dendritic arbors and even dendritic spines. Third, there is some evidence to suggest that only the neurons at the injection site that are filled transport demonstrable amounts of the tracer, raising the possibility that the effective injection site can be defined quite precisely. Fourth, even with the most restricted injections, the morphology of the labeled axons and axon terminals is clearly demonstrated; this includes boutons en passant, fine collateral branches, and various terminal specialization, all of which can be visualized as well as in the best rapid Golgi preparations. Fifth, when introduced iontophoretically, PHA-L appears to be transported preferentially in the anterograde direction; only rarely is it transported retrogradely. Sixth, PHA-L does not appear to be taken up and transported effectively by fibers of passage. Seventh, there is no discernible degradation of the transported PHA-L with survival times of up to 17 days. Finally, since the transported marker can be demonstrated with either peroxidase or fluorescent antibody techniques, it may be used in conjunction with other neuroanatomical methods. For example, double anterograde labeling experiments can be done using the autoradiographic method along with immunoperoxidase localization of PHA-L, and the retrogradely transported fluorescent dyes can be visualized in the same tissue sections as PHA-L localized with immunofluorescence techniques. 1984. This article is part of a Special Issue entitled SI:50th Anniversary Issue. Published by Elsevier B.V. C1 [Gerfen, Charles R.] NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. [Sawchenko, Paul E.] Salk Inst Biol Studies, Lab Neuronal Struct & Funct, La Jolla, CA USA. RP Gerfen, CR (reprint author), NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. EM gerfenc@mail.nih.gov NR 19 TC 1 Z9 1 U1 3 U2 3 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 AUG 15 PY 2016 VL 1645 SI SI BP 42 EP 45 DI 10.1016/j.brainres.2015.12.040 PG 4 WC Neurosciences SC Neurosciences & Neurology GA DT5QJ UT WOS:000381537400014 PM 26790346 ER PT J AU Madlala, P Singh, R An, P Werner, L Mlisana, K Karim, SSA Winkler, CA Ndung'u, T AF Madlala, Paradise Singh, Ravesh An, Ping Werner, Lise Mlisana, Koleka Karim, Salim S. Abdool Winkler, Cheryl A. Ndung'u, Thumbi TI Association of Polymorphisms in the Regulatory Region of the Cyclophilin a Gene (PPIA) with Gene Expression and HIV/AIDS Disease Progression SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE SNP; CypA; PPIA; HIV-1; mRNA expression ID HIV-1 INFECTION; SUSCEPTIBILITY; DETERMINANTS; VIRIONS AB Background:Human cyclophilin A (CypA) encoded by peptidyl prolyl isomerase A gene (PPIA), enhances HIV-1 replication by aiding capsid uncoating. The association of genetic variation in the PPIA regulatory region with susceptibility to HIV-1 infection, disease progression, and gene expression among black South Africans at risk for infection or infected with HIV-1 is unknown.Methods:We genotyped 539 participants from 2 longitudinal study cohorts of black South Africans at high risk for infection or infected with HIV-1 for PPIA regulatory single nucleotide polymorphisms by polymerase chain reaction-restriction fragment length polymorphism.Results:Minor allele (G) of SNP rs6850 (rs6850 G) significantly associated with higher viral loads (mean 4.85 versus 4.46 log copies/mL, P = 0.0006) and lower CD4(+) T-cell counts (mean 506 versus 557 cells/L, P = 0.0256) during the acute phase of infection in the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 002 cohort. Consistently, rs6850 G significantly associated with higher viral loads (mean 4.49 versus 4.01 log copies/mL, P < 0.0001) and lower CD4(+) T-cell counts (mean 442 versus 494 cells/L, P = 0.0002) during the early chronic phase of infection in the CAPRISA 002 cohort; rs6850 G further associated significantly with rapid CD4(+) T-cell decline in the CAPRISA 002 cohort (P = 0.0481) and Sinikithemba chronic infection cohort (P = 0.0156). Interestingly, rs6850 G significantly associated with elevated CypA mRNA levels in HIV-1-positive individuals (P = 0.0061).Conclusions:These data suggest that rs6850 G enhances HIV-1 replication through upregulation of CypA expression following HIV-1 infection. The data support ongoing efforts to develop anti-HIV-1 drugs that block interaction of HIV-1 and cellular proteins. C1 [Madlala, Paradise; Singh, Ravesh; Ndung'u, Thumbi] Univ KwaZulu Natal, Nelson R Mandela Sch Med, HIV Pathogenesis Programme, Durban, South Africa. [Werner, Lise; Mlisana, Koleka; Karim, Salim S. Abdool] Univ KwaZulu Natal, Ctr AIDS Programme Res South Africa CAPRISA, Nelson R Mandela Sch Med, Durban, South Africa. [An, Ping; Winkler, Cheryl A.] NCI, Basic Res Lab, Ctr Canc Res, Leidos Biomed Res Inc,Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Ndung'u, Thumbi] Univ KwaZulu Natal, KwaZulu Natal Res Inst TB & HIV, Nelson R Mandela Sch Med, Durban, South Africa. RP Ndung'u, T (reprint author), Univ KwaZulu Natal, HIV Pathogenesis Programme, Doris Duke Med Res Inst, Nelson R Mandela Sch Med, Level 1,Room 117, ZA-4013 Durban, South Africa. EM ndungu@ukzn.ac.za OI Abdool Karim, Salim/0000-0002-4986-2133 FU seventh framework programme (FP7) of the European Commission (THINC) [HEALTH-F3-2008-201032]; South African Department of Science and Technology/National Research Foundation Research Chairs Initiative; Victor Daitz Foundation; Howard Hughes Medical Institute International Early Career Scientist award; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX Supported by the seventh framework programme (FP7) of the European Commission (THINC, HEALTH-F3-2008-201032). Additional funding was provided by the South African Department of Science and Technology/National Research Foundation Research Chairs Initiative and the Victor Daitz Foundation. Part of the work was funded by the Howard Hughes Medical Institute International Early Career Scientist award to TN. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. This Research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 22 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 15 PY 2016 VL 72 IS 5 BP 465 EP 473 DI 10.1097/QAI.0000000000001028 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DT3KC UT WOS:000381378700002 PM 27088296 ER PT J AU Smith, SJ Pauly, GT Akram, A Melody, K Ambrose, Z Schneider, JP Hughes, SH AF Smith, Steven J. Pauly, Gary T. Akram, Aamir Melody, Kevin Ambrose, Zandrea Schneider, Joel P. Hughes, Stephen H. TI Rilpivirine and Doravirine Have Complementary Efficacies Against NNRTI-Resistant HIV-1 Mutants SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV-1; antiviral activity; susceptibility; potency; resistance; non-nucleoside reverse transcriptase inhibitor ID REVERSE-TRANSCRIPTASE INHIBITORS; NONNUCLEOSIDE INHIBITORS; POSITIONAL ADAPTABILITY; HIV-1-INFECTED PATIENTS; DOUBLE-BLIND; WILD-TYPE; DRUG; MECHANISM; PHASE-3; TMC278 AB Background:Rilpivirine (RPV) is the latest non-nucleoside reverse transcriptase inhibitor (NNRTI) to be approved by Food and Drug Administration to combat HIV-1 infections. NNRTIs inhibit the chemical step in viral DNA synthesis by binding to an allosteric site located about 10 angstrom from the polymerase active site of reverse transcriptase (RT). Although NNRTIs potently inhibit the replication of wild-type HIV-1, the binding site is not conserved, and mutations arise in the binding pocket. Doravirine (DOR) is a new NNRTI in phase III clinical trials.Methods:Using a single round HIV-1 infection assay, we tested RPV and DOR against a broad panel of NNRTI-resistant mutants to determine their respective activities. We also used molecular modeling to determine if the susceptibility profile of each compound was related to how they bind RT.Results:Several mutants displayed decreased susceptibility to DOR. However, with the exception of E138K, our data suggest that the mutations that reduce the potency of DOR and RPV are non-overlapping. Thus, these 2 NNRTIs have the potential to be used together in combination therapy. We also show that the location at which DOR and RPV bind with the NNRTI binding pocket of RT correlates with the differences in their respective susceptibility to the panel of NNRTI-resistance mutations.Conclusions:This shows that (1) DOR is susceptible to a number of well-known NNRTI resistance mutations and (2) an understanding of the mutational susceptibilities and binding interactions of NNRTIs with RT could be used to develop pairs of compounds with non-overlapping mutational susceptibilities. C1 [Smith, Steven J.; Akram, Aamir; Hughes, Stephen H.] NCI, HIV Dynam & Replicat Program, NIH, POB B 1050 Boyles St,539-130, Frederick, MD 21702 USA. [Pauly, Gary T.; Schneider, Joel P.] NCI, Biol Chem Lab, NIH, Frederick, MD 21701 USA. [Melody, Kevin; Ambrose, Zandrea] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Infect Dis & Microbiol, Pittsburgh, PA 15261 USA. [Ambrose, Zandrea] Univ Pittsburgh, Sch Med, Dept Med, Div Infect Dis, Pittsburgh, PA 15213 USA. RP Hughes, SH (reprint author), NCI, HIV Dynam & Replicat Program, NIH, POB B 1050 Boyles St,539-130, Frederick, MD 21702 USA. EM hughesst@mail.nih.gov FU Intramural Research Programs of the National Cancer Institute; Intramural AIDS Targeted Antiviral Program (IATAP); NIH [R01 AI080290, T32 AI065380] FX Supported by the Intramural Research Programs of the National Cancer Institute and the Intramural AIDS Targeted Antiviral Program (IATAP) and NIH grants R01 AI080290 (Z.A.) and T32 AI065380 (K.M.). NR 27 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 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 15 PY 2016 VL 72 IS 5 BP 485 EP 491 DI 10.1097/QAI.0000000000001031 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DT3KC UT WOS:000381378700004 PM 27124362 ER PT J AU Huang, B Wang, Q Deng, CS Wang, JH Yang, T Huang, SG Su, XZ Liu, YJ Pan, LH Li, GM Li, D Zhang, HY Bacar, A Abdallah, KS Attoumane, R Mliva, AMSA Zheng, SQ Xu, Q Lu, FL Guan, YZ Song, JP AF Huang, Bo Wang, Qi Deng, Changsheng Wang, Jianhua Yang, Tao Huang, Shiguang Su, Xin-zhuan Liu, Yajun Pan, Longhua Li, Guoming Li, Di Zhang, Hongying Bacar, Afane Abdallah, Kamal Said Attoumane, Rachad Mliva, Ahamada M. S. A. Zheng, Shaoqin Xu, Qin Lu, Fangli Guan, Yezhi Song, Jianping TI Prevalence of crt and mdr-1 mutations in Plasmodium falciparum isolates from Grande Comore island after withdrawal of chloroquine SO MALARIA JOURNAL LA English DT Article DE Comoros; Plasmodium falciparum; Chloroquine resistance; pfcrt; pfmdr-1 ID GENE HAPLOTYPE SVMNT; DRUG-RESISTANCE; ARTEMETHER-LUMEFANTRINE; MOLECULAR MARKER; TRANSPORTER GENE; TREATMENT POLICY; COPY NUMBER; IN-VIVO; MALARIA; PFCRT AB Background: In Comoros, the widespread of chloroquine (CQ)-resistant Plasmodium falciparum populations was a major obstacle to malaria control, which led to the official withdrawal of CQ in 2004. Continuous monitoring of CQ-resistant markers of the P. falciparum CQ resistant transporter (pfcrt) and the P. falciparum multiple drug resistance 1 (pfmdr-1) is necessary inder to obtain first-hand information on CQ susceptibility of parasite populations in the field. The objective of this study is to assess the prevalence and evolution of CQ-resistance in the P. falciparum populations on the Comoros' Grande Comore island after withdrawal of CQ. Methods: A total of 207 P. falciparum clinical isolates were collected from the island, including 118 samples from 2006 to 2007 and 89 samples from 2013 to 2014. Nucleotide substitutions in the pfcrt and pfmdr-1 genes linked to CQ response in parasite isolates were assessed using nested PCR and DNA sequencing. Results: From the pfcrt gene segment sequenced, we detected C72S, M74I, N75E, and K76T substitutions in the parasite isolates collected from both 2006-2007 to 2013-2014 periods. Significant decline of pfcrt resistant alleles at C72S (42.6 to 6.9 %), M74I (39.1 to 14.9 %), N75E (63.5 to 18.3 %), and K76T (72.2 to 19.5 %) from 2006-2007 to 2013-2014 were observed, and the frequency of pfcrt wild type allele was significantly increased from 19.1 % in 2006-2007 to 75.8 % in 2013-2014. Sequence analysis of pfmdr-1 also detected point mutations at codons N86Y, Y184F, and D1246Y, but not S1034C and N1042D, in the isolates collected from both examined periods. An increasing trend in the prevalence of the pfmdr-1 wild type allele (NYD, 4.3 % in 2006-2007; and 28.7 % in 2013-2014), and a decreasing trend for pfmdr-1 N86Y mutation (87.0 % in 2006-2007; and 40.2 % in 2013-2014) were observed in our samples. Conclusions: The present data indicate that the prevalence and patterns of mutant pfcrt and pfmdr-1 dramatically decreased in the Grande Comore isolates from 2006 to 2014, suggesting that the CQ-sensitive P. falciparum strains have returned after the withdrawal of CQ. The data also suggests that the parasites with wild type pfcrt/pfdmr-1 genes may have growth and/or transmission advantages over the mutant parasites. The information obtained from this study will be useful for developing and updating anti-malarial treatment policy in Grande Comore island. C1 [Huang, Bo; Wang, Qi; Deng, Changsheng; Wang, Jianhua; Yang, Tao; Zhang, Hongying; Zheng, Shaoqin; Guan, Yezhi; Song, Jianping] Guangzhou Univ Chinese Med, Sci & Technol Pk, Guangzhou 510006, Guangdong, Peoples R China. [Huang, Shiguang] Jinan Univ, Sch Med, Guangzhou 510632, Guangdong, Peoples R China. [Su, Xin-zhuan] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Su, Xin-zhuan] Xiamen Univ, Sch Life Sci, State Key Lab Cellular Stress Biol, Xiamen 361005, Fujian, Peoples R China. [Liu, Yajun] Guangzhou Univ Chinese Med, Affiliated Hosp 1, Guangzhou 510006, Guangdong, Peoples R China. [Pan, Longhua; Li, Guoming; Li, Di] Guangdong Newsouth Artepharm Co Ltd, Guangzhou 510405, Guangdong, Peoples R China. [Bacar, Afane; Abdallah, Kamal Said; Attoumane, Rachad] Natl Malaria Control Programme, BP 500 Moroni, Moroni, Comoros. [Mliva, Ahamada M. S. A.] Minist Hlth Comoros, BP 500 Moroni, Moroni, Comoros. [Xu, Qin] Guangzhou Univ Chinese Med, Res Inst Trop Med, Guangzhou 510006, Guangdong, Peoples R China. [Lu, Fangli] Sun Yat Sen Univ, Zhongshan Sch Med, Dept Parasitol, Guangzhou 510080, Guangdong, Peoples R China. RP Guan, YZ; Song, JP (reprint author), Guangzhou Univ Chinese Med, Sci & Technol Pk, Guangzhou 510006, Guangdong, Peoples R China. EM gyz111@hotmail.com; songjpgz@sina.com OI Su, Xinzhuan/0000-0003-3246-3248 FU Natural Science Foundation of China [81273643]; Guangdong Provincial Science and Technology Program [2014B050502013]; China Postdoctoral Science Foundation [2015M570699, 2016T90773]; Guangdong Provincial Science Foundation [2015A030310107]; Guangdong Provincial Medicine Science Foundation [A2016315]; Foundation of Traditional Chinese Medicine Bureau of Guangdong Province [20141074]; Science and Technology Program of Guangzhou [2014J4500037]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported in part by grants from Natural Science Foundation of China [Grant Number 81273643] and Guangdong Provincial Science and Technology Program [Grant Number 2014B050502013] to JS, China Postdoctoral Science Foundation [Grant Number 2015M570699 and 2016T90773], Guangdong Provincial Science Foundation [Grant Number 2015A030310107], and Guangdong Provincial Medicine Science Foundation [Grant Number A2016315] to BH, Foundation of Traditional Chinese Medicine Bureau of Guangdong Province [Grant Number 20141074] to QW, Science and Technology Program of Guangzhou [2014J4500037] to YG, and by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (XzS). The funds had no role in the study design, data collection and analysis, decision to publish, or the preparation of the manuscript. NR 52 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 1475-2875 J9 MALARIA J JI Malar. J. PD AUG 15 PY 2016 VL 15 AR 414 DI 10.1186/s12936-016-1474-4 PG 9 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DT3CQ UT WOS:000381358500004 PM 27527604 ER PT J AU Wu, SP Pfeiffer, RM Ahn, IE Mailankody, S Sonneveld, P van Duin, M Munshi, NC Walker, BA Morgan, G Landgren, O AF Wu, S. Peter Pfeiffer, Ruth M. Ahn, Inhye E. Mailankody, Sham Sonneveld, Pieter van Duin, Mark Munshi, Nikhil C. Walker, Brian A. Morgan, Gareth Landgren, Ola TI Impact of Genes Highly Correlated with MMSET Myeloma on the Survival of Non-MMSET Myeloma Patients SO CLINICAL CANCER RESEARCH LA English DT Article ID RISK MULTIPLE-MYELOMA; BREAST-CANCER RISK; T(4/14) MYELOMA; CELL-CYCLE; C-MYC; PLASMA-CELLS; EXPRESSION; PREDICTION; TRANSLOCATION; TRANSCRIPTS AB Purpose: The poor prognosis of multiple myeloma with t(4;14) is driven by the fusion of genes encoding multiple myeloma SET domain (MMSET) and immunoglobulin heavy chain. Specific genes affected by MMSET and their clinical implications in non-MMSET myeloma remain undetermined. Experimental Design: We obtained gene expression profiles of 1,032 newly diagnosed myeloma patients enrolled in Total Therapy 2, Total Therapy 3, Myeloma IX, and HOVON65-GMMGHD4 trials and 156 patients from Multiple Myeloma Resource Collection. Probes that correlated most with MMSET myeloma were selected on the basis of a multivariable linear regression and Bonferroni correction and refined on the basis of the strength of association with survival in non-MMSET patients. Results: Ten MMSET-like probes were associated with poor survival in non-MMSET myeloma. Non-MMSET myeloma patients in the highest quartile of the 10-gene signature (MMSET-like myeloma) had 5-year overall survival similar to that of MMSET myeloma [highest quartile vs. lowest quartile HR = 2.0; 95% confidence interval (CI), 1.5-2.8 in MMSET-like myeloma; HR = 2.3; 95% CI, 1.6-3.3 in MMSET myeloma]. Analyses of MMSET-like gene signature suggested the involvement of p53 and MYC pathways. Conclusions: MMSET-like gene signature captures a subset of high-risk myeloma patients underrepresented by conventional risk stratification platforms and defines a distinct biologic subtype. (C) 2016 AACR. C1 [Wu, S. Peter; Ahn, Inhye E.] NCI, Multiple Myeloma Sect, NIH, Bethesda, MD 20892 USA. [Pfeiffer, Ruth M.] NCI, Dept Canc Epidemiol & Genet, Biostat Branch, NIH, Rockville, MD USA. [Mailankody, Sham; Landgren, Ola] Mem Sloan Kettering Canc Ctr, Myeloma Serv, New York, NY 10021 USA. [Sonneveld, Pieter; van Duin, Mark] Erasmus Univ, Med Ctr, Dept Hematol, Rotterdam, Netherlands. [Munshi, Nikhil C.] Harvard Med Sch, Lebow Inst Myeloma Therapeut, Boston, MA USA. [Munshi, Nikhil C.] Harvard Med Sch, Jerome Lipper Multiple Myeloma Ctr, Dana Farber Canc Inst, Boston, MA USA. [Walker, Brian A.] Inst Canc Res, Sect Haematooncol, London, England. [Morgan, Gareth] Univ Arkansas Med Sci, Myeloma Inst Res & Therapy, Little Rock, AR 72205 USA. RP Landgren, O (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10065 USA. EM landgrec@mskcc.org OI Walker, Brian/0000-0002-8615-6254 FU NIH; NIH Medical Research Scholars Program FX This work was supported by the intramural research program of the NIH. Research support for S.P. Wu 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 Leona M. and Harry B. Helmsley Charitable Trust, and the Howard Hughes Medical Institute, as well as other private donors. For a complete list, please visit the Foundation website at http://www.fnih.org/work/programs-development/medical-research-scholars- program. NR 35 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2016 VL 22 IS 16 BP 4039 EP 4044 DI 10.1158/1078-0432.CCR-15-2366 PG 6 WC Oncology SC Oncology GA DU5QH UT WOS:000382265900009 PM 26847058 ER PT J AU Osgood, CL Maloney, N Kidd, CG Kitchen-Goosen, S Segars, L Gebregiorgis, M Woldemichael, GM He, M Sankar, S Lessnick, SL Kang, M Smith, M Turner, L Madaj, ZB Winn, ME Nunez, LE Gonzalez-Sabin, J Helman, LJ Moris, F Grohar, PJ AF Osgood, Christy L. Maloney, Nichole Kidd, Christopher G. Kitchen-Goosen, Susan Segars, Laura Gebregiorgis, Meti Woldemichael, Girma M. He, Min Sankar, Savita Lessnick, Stephen L. Kang, Min Smith, Malcolm Turner, Lisa Madaj, Zachary B. Winn, Mary E. Nunez, Luz-Elena Gonzalez-Sabin, Javier Helman, Lee J. Moris, Francisco Grohar, Patrick J. TI Identification of Mithramycin Analogues with Improved Targeting of the EWS-FLI1 Transcription Factor SO CLINICAL CANCER RESEARCH LA English DT Article ID CHILDRENS ONCOLOGY GROUP; LOCALIZED EWING SARCOMA; IN-VIVO; COMBINATORIAL BIOSYNTHESIS; ONCOGENIC TRANSCRIPTION; NEUROECTODERMAL TUMOR; ANTITUMOR-ACTIVITY; GENE-EXPRESSION; GROWTH; EWS/FLI AB Purpose: The goal of this study was to identify second-generation mithramycin analogues that better target the EWS-FLI1 transcription factor for Ewing sarcoma. We previously established mithramycin as an EWS-FLI1 inhibitor, but the compound's toxicity prevented its use at effective concentrations in patients. Experimental Design: We screened a panel of mithralogs to establish their ability to inhibit EWS-FLI1 in Ewing sarcoma. We compared the IC50 with the MTD established in mice to determine the relationship between efficacy and toxicity. We confirmed the suppression of EWS-FLI1 at the promoter, mRNA, gene signature, and protein levels. We established an improved therapeutic window by using time-lapse microscopy to model the effects on cellular proliferation in Ewing sarcoma cells relative to HepG2 control cells. Finally, we established an improved therapeutic window using a xenograft model of Ewing sarcoma. Results: EC-8105 was found to be the most potent analogue and was able to suppress EWS-FLI1 activity at concentrations nontoxic to other cell types. EC-8042 was substantially less toxic than mithramycin in multiple species but maintained suppression of EWS-FLI1 at similar concentrations. Both compounds markedly suppressed Ewing sarcoma xenograft growth and inhibited EWS-FLI1 in vivo. Conclusions: These results provide a basis for the continued development of EC-8042 and EC-8105 as EWS-FLI1 inhibitors for the clinic. (C) 2016 AACR. C1 [Osgood, Christy L.; Maloney, Nichole; Kidd, Christopher G.; Segars, Laura; Grohar, Patrick J.] Vanderbilt Univ, Sch Med, Div Pediat Hematol Oncol, Nashville, TN 37212 USA. [Kitchen-Goosen, Susan; Turner, Lisa; Madaj, Zachary B.; Winn, Mary E.; Grohar, Patrick J.] Van Andel Res Inst, 333 Bostwick Ave NE, Grand Rapids, MI 49503 USA. [Segars, Laura; Gebregiorgis, Meti; Smith, Malcolm; Helman, Lee J.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Woldemichael, Girma M.] Frederick Natl Lab Canc Res, Basic Sci Program, Leidos Biomed Res Lab Inc, Mol Targets Lab, Frederick, MD USA. [He, Min; Smith, Malcolm] NCI, Dev Therapeut Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Sankar, Savita] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO USA. [Lessnick, Stephen L.] Ohio State Univ, Nationwide Childrens Hosp, Div Pediat Hematol Oncol BMT, Ctr Childhood Canc & Blood Disorders, Columbus, OH 43210 USA. [Kang, Min] Texas Tech Univ, Hlth Sci Ctr, Sch Med, Lubbock, TX 79430 USA. [Nunez, Luz-Elena; Gonzalez-Sabin, Javier; Moris, Francisco] EntreChem SL, Oviedo, Spain. [Grohar, Patrick J.] Helen De Vos Childrens Hosp, Grand Rapids, MI USA. [Grohar, Patrick J.] Michigan State Univ, Sch Med, Dept Pediat, E Lansing, MI 48824 USA. RP Grohar, PJ (reprint author), Van Andel Res Inst, 333 Bostwick Ave NE, Grand Rapids, MI 49503 USA. EM patrick.grohar@vai.org FU Hyundai Hope on Wheels Program; T32 training grant; Vanderbilt Clinical Oncology Research Career Development K12; Vanderbilt University Department of Pediatrics; Lily's Garden Foundation; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E] FX The majority of the funding for this work was from the Hyundai Hope on Wheels Program (to P.J. Grohar, C.G. Kidd, and N. Maloney). Funding was also provided by the T32 training grant conducting research in pediatric oncology (Principal Investigator, D. Friedman) as well as the Vanderbilt Clinical Oncology Research Career Development K12 both for C.L. Osgood (Principal Investigator, D. Friedman). Additional internal funds were provided by the Vanderbilt University Department of Pediatrics (to P.J. Grohar, C.L. Osgood, and N. Maloney). Immunofluorescent assay development was supported by the Alex's Lemonade Stand Reach Award (to P.J. Grohar). Additional funding was provided by the Lily's Garden Foundation (to P.J. Grohar and L. Segars). EntreChem thanks Mariam Hermosilla and Patricia Oro for superior technical assistance. This project has also been funded in part with federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health under contract HHSN261200800001E (to G.M. Woldemichael). NR 49 TC 3 Z9 3 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2016 VL 22 IS 16 BP 4105 EP 4118 DI 10.1158/1078-0432.CCR-15-2624 PG 14 WC Oncology SC Oncology GA DU5QH UT WOS:000382265900016 PM 26979396 ER PT J AU Dellibovi-Ragheb, T Altan-Bonnet, N AF Dellibovi-Ragheb, Teegan Altan-Bonnet, Nihal TI Cloud storage for endosomes SO EMBO JOURNAL LA English DT Editorial Material AB Coordinated regulation of vesicle trafficking is critical for the proper functioning of a cell. The bulk of cellular transport vesicles are sequestered in a "perinuclear cloud", with only a small fraction released to the cell periphery. Jongsma et al (2016) found that the ER-associated E3 ubiquitin ligase RNF26 is responsible for establishing and maintaining the architecture of the perinuclear cloud and that this spatiotemporal positioning is critical for effective regulation of the endocytic and exocytic systems. C1 [Dellibovi-Ragheb, Teegan; Altan-Bonnet, Nihal] NHLBI, Lab Host Pathogen Dynam, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Altan-Bonnet, N (reprint author), NHLBI, Lab Host Pathogen Dynam, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM nihal.altan-bonnet@nih.gov NR 7 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD AUG 15 PY 2016 VL 35 IS 16 BP 1724 EP 1725 DI 10.15252/embj.201695080 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DU6II UT WOS:000382317500002 PM 27378788 ER PT J AU Kehrl, JH AF Kehrl, John H. TI The impact of RGS and other G-protein regulatory proteins on G alpha(i)-mediated signaling in immunity SO BIOCHEMICAL PHARMACOLOGY LA English DT Review DE G-protein; RGS proteins; Chemokine receptors; Sphingosine 1-phosphate; Cell trafficking ID G-ALPHA-I; HETEROTRIMERIC G-PROTEINS; RECEPTOR-INDEPENDENT ACTIVATORS; T-LYMPHOCYTE MIGRATION; ELEGANS NERVOUS-SYSTEM; G-BETA-GAMMA; NEUTROPHIL CHEMOTAXIS; PERTUSSIS-TOXIN; COUPLED RECEPTORS; CELL-DIVISION AB Leukocyte chemoattractant receptors are members of the G-protein coupled receptor (GPCR) family. Signaling downstream of these receptors directs the localization, positioning and homeostatic trafficking of leukocytes; as well as their recruitment to, and their retention at, inflammatory sites. Ligand induced changes in the molecular conformation of chemoattractant receptors results in the engagement of heterotrimeric G-proteins, which promotes alpha subunits to undergo GTP/GDP exchange. This results in the functional release of B gamma subunits from the heterotrimers, thereby activating downstream effector molecules, which initiate leukocyte polarization, gradient sensing, and directional migration. Pertussis toxin ADP ribosylates G alpha(i) subunits and prevents chemoattractant receptors from triggering G alpha(i) nucleotide exchange. The use of pertussis toxin revealed the essential importance of G alpha(i) subunit nucleotide exchange for chemoattractant receptor signaling. More recent studies have identified a range of regulatory mechanisms that target these receptors and their associated heterotrimeric G-proteins, thereby helping to control the magnitude, kinetics, and duration of signaling. A failure in these regulatory pathways can lead to impaired receptor signaling and immunopathology. The analysis of mice with targeted deletions of G alpha(i) isoforms as well as some of these G-protein regulatory proteins is providing insights into their roles in chemoattractant receptor signaling. Published by Elsevier Inc. C1 [Kehrl, John H.] NIAID, Immunoregulat Lab, NIH, Bldg 10,Room 11B08,10 Ctr Dr MSC 1876, Bethesda, MD 20892 USA. RP Kehrl, JH (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Room 11B08,10 Ctr Dr MSC 1876, Bethesda, MD 20892 USA. EM jkehrl@niaid.nih.gov FU intramural program of the National Institutes of Allergy and Infectious Diseases FX The author would like to thank the members of his laboratory that contributed to some of the studies described in this review and thank Dr. Anthony Fauci for his long standing support. The intramural program of the National Institutes of Allergy and Infectious Diseases supported some of the research described in this review. NR 154 TC 1 Z9 1 U1 7 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 EI 1873-2968 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD AUG 15 PY 2016 VL 114 SI SI BP 40 EP 52 DI 10.1016/j.bcp.2016.04.005 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DT1KK UT WOS:000381241000005 PM 27071343 ER PT J AU Kersey, RK Brodigan, TM Fukushige, T Krause, MW AF Kersey, Rossio K. Brodigan, Thomas M. Fukushige, Tetsunari Krause, Michael W. TI Regulation of UNC-130/FOXD-mediated mesodermal patterning in C-elegans SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Forkhead; FOXD; UNC-130; UNC-129; Embryogenesis; Transcriptional regulation ID FORKHEAD TRANSCRIPTION FACTORS; CAENORHABDITIS-ELEGANS; DNA-BINDING; GENETIC INTERFERENCE; MUSCLE DEVELOPMENT; FEEDBACK LOOP; BOX PROTEINS; TGF-BETA; EXPRESSION; GENOME AB Spatial polarity cues in animals are used repeatedly during development for many processes, including cell fate determination, cell migration, and axon guidance. In Caenorhabditis elegans, the body wall muscle extends the length of the animal in four distinct quadrants and generates an UNC-129/TGF-beta-related signal that is much higher in the dorsal two muscle quadrants compared to their ventral counterparts. This pattern of unc-129 expression requires the activity of the proposed transcriptional repressor UNC-130/FOXD whose body wall muscle activity is restricted to the ventral two body wall muscle quadrants. To understand how these dorsal-ventral differences in UNC-130 activity are established and maintained, we have analyzed the regulation of unc-130 expression and the distribution of UNC-130 protein. We have identified widespread, cis-acting elements in the unc-130 promoter that function to positively regulate ventral body wall muscle expression and negatively regulate dorsal body wall muscle expression. We have defined the temporal distribution of UNC-130 protein in body wall muscle cells during embryogenesis, demonstrated that this pattern is required to establish the dorsal-ventral polarity of UNC-129/TGF-beta, and shown that UNC-130 is not required post-embryonically to maintain the asymmetry of body wall muscle unc-129 expression. Finally, we have tested the impact of the depletion of a variety of transcription factors, repressors, and signaling molecules to identify additional regulators of body wall muscle UNC-130 polarity. Our results confirm and extend earlier studies to clarify the mechanisms by which UNC-130 is controlled and affects the pattern of unc-129 expression in body wall muscle. These results further our understanding of the transcriptional logic behind the generation of polarity cues involving this poorly understood subclass of Forkhead factors. Published by Elsevier Inc. C1 [Kersey, Rossio K.; Brodigan, Thomas M.; Fukushige, Tetsunari; Krause, Michael W.] NIDDK, Mol Biol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Krause, MW (reprint author), NIDDK, Mol Biol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM michaelkr@niddk.nih.gov OI Krause, Michael/0000-0001-6127-3940 FU NIH Office of Research Infrastructure Programs [P40 OD010440]; Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX Our thanks to Lyn Noordam for help with the text and figures, Andy Golden, Harold Smith, and Jim McGhee for plasmids, Harald Hutter for strains, Piali Sengupta and Michel Labouesse for antibodies, Jun "Kelly" Liu for reagents and comments on the manuscript, Ward Odenwald for help with EvoPrinter-based identifications of conserved promoter sequences, and WormBase as a resource. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). This work was supported by the Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). NR 51 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 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD AUG 15 PY 2016 VL 416 IS 2 BP 300 EP 311 DI 10.1016/j.ydbio.2016.06.029 PG 12 WC Developmental Biology SC Developmental Biology GA DT9QE UT WOS:000381836600005 PM 27341757 ER PT J AU Peer, CJ Strope, JD Beedie, S Ley, AM Holly, A Calis, K Farkas, R Parepally, J Men, A Fadiran, EO Scott, P Jenkins, M Theodore, WH Sissung, TM AF Peer, Cody J. Strope, Jonathan D. Beedie, Shaunna Ley, Ariel M. Holly, Alesia Calis, Karim Farkas, Ronald Parepally, Jagan Men, Angela Fadiran, Emmanuel O. Scott, Pamela Jenkins, Marjorie Theodore, William H. Sissung, Tristan M. TI Alcohol and Aldehyde Dehydrogenases Contribute to Sex-Related Differences in Clearance of Zolpidem in Rats SO FRONTIERS IN PHARMACOLOGY LA English DT Article DE zolpidem; drug metabolism; pharmacokinetics; testosterone ID ETHANOL-METABOLISM; HUMAN LIVER; PHARMACOKINETICS; EXPRESSION; MECHANISM; GENDER; BRAIN; MUCOSA; ADULTS; AGE AB Objectives: The recommended zolpidem starting dose was lowered in females (5 mg vs. 10 mg) since side effects were more frequent and severe than those of males; the mechanism underlying sex differences in pharmacokinetics (PK) is unknown. We hypothesized that such differences were caused by known sex-related variability in alcohol dehydrogenase (ADH) expression. Methods: Male, female, and castrated male rats were administered 2.6 mg/kg zolpidem, +/- disulfiram (ADH/ALDH pathway inhibitor) to compare PK changes induced by sex and gonadal hormones. PK analyses were conducted in rat plasma and rat brain. Key findings: Sex differences in PK were evident: females had a higher C-MAX (112.4 vs. 68.1 ug/L) and AUG (537.8 vs. 231.8 h*ug/L) than uncastrated males. Castration induced an earlier T-MAX (0.25 vs. 1 h), greater C-MAX (109.1 vs. 68.1 ug/L), and a corresponding AUG increase (339.7 vs. 231.8 h*ug/L). Administration of disulfiram caused more drastic C-MAX and T-MAX changes in male vs. female rats that mirrored the effects of castration on first-pass metabolism, suggesting that the observed PK differences may be caused by ADH/ALDH expression. Brain concentrations paralleled plasma concentrations. Conclusion: These findings indicate that sex differences in zolpidem PK are influenced by variation in the expression of ADH/ALDH due to gonadal androgens. C1 [Peer, Cody J.; Sissung, Tristan M.] NCI, Clin Pharmacol Program, NIH, Bethesda, MD 20892 USA. [Strope, Jonathan D.; Beedie, Shaunna; Ley, Ariel M.; Holly, Alesia] NCI, Mol Pharmacol Program, NIH, Bethesda, MD 20892 USA. [Calis, Karim] Food & Drug Adm, Ctr Drug Evaluat & Res, Off Med Policy, Silver Spring, MD USA. [Farkas, Ronald] Food & Drug Adm, Ctr Drug Evaluat & Res, Div Neurol Prod, Off New Drugs, Silver Spring, MD USA. [Parepally, Jagan; Men, Angela] Food & Drug Adm, Ctr Drug Evaluat & Res, Off Translat Sci, Off Clin Pharmacol, Silver Spring, MD USA. [Fadiran, Emmanuel O.; Scott, Pamela; Jenkins, Marjorie] Food & Drug Adm, Off Commissioner, Off Womens Hlth, Silver Spring, MD USA. [Theodore, William H.] NINDS, Clin Epilepsy Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Sissung, TM (reprint author), NCI, Clin Pharmacol Program, NIH, Bethesda, MD 20892 USA. EM sissungt@mail.nih.gov FU National Cancer Institute (National Institutes of Health); Intramural Research Program of the NIH, National Cancer Institute; Office of Women's Health, Food, and Drug Administration; Food Drug Administration FX This project has been funded in whole or in part with federal funds from the National Cancer Institute (National Institutes of Health) and the Food Drug Administration. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, and the Office of Women's Health, Food, and Drug Administration. NR 44 TC 1 Z9 1 U1 3 U2 6 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1663-9812 J9 FRONT PHARMACOL JI Front. Pharmacol. PD AUG 15 PY 2016 VL 7 AR 260 DI 10.3380/fphar.2016.00260 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DT2ZU UT WOS:000381351100001 PM 27574509 ER PT J AU Lau, MWL Ferre-D'Amare, AR AF Lau, Matthew W. L. Ferre-D'Amare, Adrian R. TI In vitro evolution of coenzyme-independent variants from the glmS ribozyme structural scaffold SO METHODS LA English DT Article DE SELEX; Catalytic RNA; Divalent cation; Riboswitch; Mercury-thiol affinity chromatography ID SMALL MOLECULES; INTERVENING SEQUENCE; GENE-EXPRESSION; RNA; TETRAHYMENA; RIBOSWITCH; COFACTOR; BINDING; GLUCOSAMINE-6-PHOSPHATE; TRANSCRIPTION AB Uniquely among known natural ribozymes that cleave RNA sequence-specifically, the glmS ribozyme-riboswitch employs a small molecule, glucosamine-6-phosphate (GlcN6P) as a catalytic cofactor. In vitro selection was employed to search for coenzyme-independent variants of this ribozyme. In addition to shedding light on the catalytic mechanism of the ribozyme, such variants could resemble the evolutionary ancestors of the modern, GlcN6P-regulated ribozyme-riboswitch. A mutant pool was constructed such that the secondary structure elements, which define the triply-pseudoknotted global fold of the ribozyme, was preserved. A stringent selection scheme that relies on thiol-mercury affinity chromatography for separating active and inactive sequences ultimately yielded a triple mutant with a cleavage rate exceeding 3 min(-1) that only requires divalent cations for activity. Mutational analysis demonstrated that a point reversion of the variant toward the wild-type sequence was sufficient to partially restore GlcN6P-dependence, suggesting that coenzyme dependence can be readily be acquired by RNA5 that adopt the glmS ribozyme fold. The methods employed to perform this selection experiment are described in detail in this review. Published by Elsevier Inc. C1 [Lau, Matthew W. L.; Ferre-D'Amare, Adrian R.] NHLBI, 50 South Dr,MSC 8012, Bethesda, MD 20892 USA. RP Ferre-D'Amare, AR (reprint author), NHLBI, 50 South Dr,MSC 8012, Bethesda, MD 20892 USA. EM adrian.ferre@nih.gov FU Intramural Program of the National Heart, Lung and Blood Institute, NIH FX We thank S. Bachas, N. Baird, M. Chen, J. Hogg, C. Jones, J. Posakony, R. Trachman, K. Warner, and J. Zhang for discussions. M.W.L. was a Croucher Foundation Postdoctoral Fellow. This work was supported in part by the Intramural Program of the National Heart, Lung and Blood Institute, NIH. NR 41 TC 2 Z9 2 U1 5 U2 5 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 AUG 15 PY 2016 VL 106 BP 76 EP 81 DI 10.1016/j.ymeth.2016.04.027 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DT9PZ UT WOS:000381836100011 PM 27130889 ER PT J AU Hoinka, J Przytycka, T AF Hoinka, Jan Przytycka, Teresa TI AptaPLEX - A dedicated, multithreaded demultiplexer for HT-SELEX data SO METHODS LA English DT Article DE Aptamers; HT-SELEX; Demultiplexing; Quality control AB Aptamers, short and synthetic RNA/DNA molecules binding distinct targets with high affinity and specificity, are identified via Systematic Evolution of Ligands by Exponential Enrichment (SELEX), an in vitro procedure that, starting from a pool of random ssDNA/RNA sequences, selects sequences by amplifying target-affine species through a series of selection cycles. This versatile protocol has recently been combined with high throughput sequencing, allowing arbitrary stages of the selection to be sequenced and analyzed in silico. As a prerequisite, these data require extensive preprocessing by means of quality controls, error correction and demultiplexing, all while taking into account the specific design of aptamers. Existing solutions addressing this task are currently present only as integrated components in larger pipelines, limiting their applicability in independent software solutions. Here we present AptaPLEX, a standalone and platform independent demultiplexer specifically designed for HT-SELEX data. Given the multiplexed data from one or multiple HT-SELEX experiments, AptaPLEX extracts and restores aptamers into the original selection cycles by identifying the barcode and primer regions in each read. AptaPLEX is capable of fuzzy matching for both the barcode and primers, and automatically corrects mismatches between forward and reverse reads for paired-end data. Our software provides a rich set of additional features and can easily be integrated into existing analysis automation pipelines on multiple platforms ranging from desktop machines to cloud based solutions. (C) 2016 Published by Elsevier Inc. C1 [Hoinka, Jan; Przytycka, Teresa] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Hoinka, J (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM jan.hoinka@nih.gov FU Intramural Research Program of the NIH, National Library of Medicine FX This work was supported by the Intramural Research Program of the NIH, National Library of Medicine. NR 18 TC 2 Z9 2 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 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD AUG 15 PY 2016 VL 106 BP 82 EP 85 DI 10.1016/j.ymeth.2016.04.011 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DT9PZ UT WOS:000381836100012 PM 27080809 ER PT J AU Billeskov, R Tan, EV Cang, M Abalos, RM Burgos, J Pedersen, BV Christensen, D Agger, EM Andersen, P AF Billeskov, Rolf Tan, Esterlina V. Cang, Marjorie Abalos, Rodolfo M. Burgos, Jasmin Pedersen, Bo Vestergaard Christensen, Dennis Agger, Else Marie Andersen, Peter TI Testing the H56 Vaccine Delivered in 4 Different Adjuvants as a BCG-Booster in a Non-Human Primate Model of Tuberculosis SO PLOS ONE LA English DT Article ID BACILLUS-CALMETTE-GUERIN; T-CELL RESPONSES; MYCOBACTERIUM-TUBERCULOSIS; PROTECTIVE IMMUNITY; CYNOMOLGUS MACAQUES; INTERFERON-GAMMA; RHESUS MACAQUES; INFECTION; MEMORY; FREQUENCY AB The search for new and improved tuberculosis (TB) vaccines has focused on IFN-gamma both for selecting antigens and for evaluating vaccine delivery strategies. The essential role of IFN-gamma in endogenous host protection is well established, but it is still uncertain whether this also holds true for vaccine protection. Here we evaluate the H56 fusion protein vaccine as a BCG booster in a non-human primate (NHP) model of TB that closely recapitulates human TB pathogenesis. To date, only a handful of novel adjuvants have been tested in the NHP model of TB, and therefore we administered H56 in 3 novel cationic liposome adjuvants of increasing immunogenicity (CAF01, CAF04, CAF05) and compared them to H56 in the IC31 (R) adjuvant previously reported to promote protection in this model. The individual clinical parameters monitored during infection (weight, ESR, X-ray) all correlated with survival, and boosting BCG with H56 in all adjuvants resulted in better survival rates compared to BCG alone. The adjuvants promoted IFN-gamma responses of increasing intensity as measured by ELISPOT in the peripheral blood, but the level of vaccine-specific IFN-gamma production did not correlate with or predict disease outcome. This study's main outcome underscores the importance of the choice of adjuvant for TB subunit vaccines, and secondly it highlights the need for better correlates of protection in preclinical models of TB. C1 [Billeskov, Rolf; Christensen, Dennis; Agger, Else Marie; Andersen, Peter] Statens Serum Inst, Dept Infect Dis Immunol, Copenhagen, Denmark. [Billeskov, Rolf] NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Tan, Esterlina V.; Cang, Marjorie; Abalos, Rodolfo M.; Burgos, Jasmin] Leonard Wood Mem LWM Ctr Leprosy Res, Cebu, Philippines. [Pedersen, Bo Vestergaard] Statens Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark. RP Billeskov, R; Andersen, P (reprint author), Statens Serum Inst, Dept Infect Dis Immunol, Copenhagen, Denmark.; Billeskov, R (reprint author), NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM rob@ssi.dk; pa@ssi.dk OI Christensen, Dennis/0000-0003-2382-8639; Billeskov, Rolf/0000-0003-4533-7304 FU European Commission [FP7-HEALTH-2011.1.4-4-280873]; National Institutes of Health [AI 105422] FX The parts of this work that was performed at the SSI was funded by the European Commission [contract number FP7-HEALTH-2011.1.4-4-280873 (ADITEC)], and National Institutes of Health [grant number AI 105422]. The funders had no role in design of studies or preparation of the manuscript. NR 43 TC 1 Z9 1 U1 5 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 15 PY 2016 VL 11 IS 8 AR e0161217 DI 10.1371/journal.pone.0161217 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT4SL UT WOS:000381471100043 PM 27525651 ER PT J AU Desai, A Krynitsky, J Pohida, TJ Zhao, HY Schuck, P AF Desai, Abhiksha Krynitsky, Jonathan Pohida, Thomas J. Zhao, Huaying Schuck, Peter TI 3D-Printing for Analytical Ultracentrifugation SO PLOS ONE LA English DT Article ID VELOCITY ANALYTICAL ULTRACENTRIFUGATION; SEDIMENTATION EQUILIBRIUM; PROTEIN INTERACTIONS; QUANTITATION; PRECISION; ACCURACY; DENSITY; SIZE AB Analytical ultracentrifugation (AUC) is a classical technique of physical biochemistry providing information on size, shape, and interactions of macromolecules from the analysis of their migration in centrifugal fields while free in solution. A key mechanical element in AUC is the centerpiece, a component of the sample cell assembly that is mounted between the optical windows to allow imaging and to seal the sample solution column against high vacuum while exposed to gravitational forces in excess of 300,000 g. For sedimentation velocity it needs to be precisely sector-shaped to allow unimpeded radial macromolecular migration. During the history of AUC a great variety of centerpiece designs have been developed for different types of experiments. Here, we report that centerpieces can now be readily fabricated by 3D printing at low cost, from a variety of materials, and with customized designs. The new centerpieces can exhibit sufficient mechanical stability to withstand the gravitational forces at the highest rotor speeds and be sufficiently precise for sedimentation equilibrium and sedimentation velocity experiments. Sedimentation velocity experiments with bovine serum albumin as a reference molecule in 3D printed centerpieces with standard double-sector design result in sedimentation boundaries virtually indistinguishable from those in commercial double-sector epoxy centerpieces, with sedimentation coefficients well within the range of published values. The statistical error of the measurement is slightly above that obtained with commercial epoxy, but still below 1%. Facilitated by modern open-source design and fabrication paradigms, we believe 3D printed centerpieces and AUC accessories can spawn a variety of improvements in AUC experimental design, efficiency and resource allocation. C1 [Desai, Abhiksha; Zhao, Huaying; Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. [Krynitsky, Jonathan; Pohida, Thomas J.] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Schuck, P (reprint author), Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. EM schuckp@mail.nih.gov FU Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, United States [ZIA EB000051-09 LCIM] FX This work was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, United States (ZIA EB000051-09 LCIM to PS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 0 Z9 0 U1 12 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 15 PY 2016 VL 11 IS 8 AR e0155201 DI 10.1371/journal.pone.0155201 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT4SL UT WOS:000381471100001 PM 27525659 ER PT J AU Ofori, E Zhu, XY Etukala, JR Peprah, K Jordan, KR Adkins, AA Bricker, BA Kang, HJ Huang, XP Roth, BL Ablordeppey, SY AF Ofori, Edward Zhu, Xue Y. Etukala, Jagan R. Peprah, Kwakye Jordan, Kamanski R. Adkins, Adia A. Bricker, Barbara A. Kang, Hye J. Huang, Xi-Ping Roth, Bryan L. Ablordeppey, Seth Y. TI Design and synthesis of dual 5-HT1A and 5-HT7 receptor ligands SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Dual receptor ligands; Multi-receptor targeting; CNS ligands; Serotonin receptors; 5-HT1A receptor and 5-HT7 receptor ligands ID ATYPICAL ANTIPSYCHOTIC-DRUG; SEROTONIN RECEPTORS; ROBUST PHARMACOLOGY; NEGATIVE SYMPTOMS; PARTIAL AGONIST; DOPAMINE D-3; ARIPIPRAZOLE; CARIPRAZINE; SCHIZOPHRENIA; ANTAGONIST AB 5-HT1A and 5-HT7 receptors have been at the center of discussions recently due in part to their major role in the etiology of major central nervous system diseases such as depression, sleep disorders, and schizophrenia. As part of our search to identify dual targeting ligands for these receptors, we have carried out a systematic modification of a selective 5HT(7) receptor ligand culminating in the identification of several dual 5-HT1A and 5-HT7 receptor ligands. Compound 16, a butyrophenone derivative of tetrahydroisoquinoline (THIQ), was identified as the most potent agent with low nanomolar binding affinities to both receptors. Interestingly, compound 16 also displayed moderate affinity to other clinically relevant dopamine receptors. Thus, it is anticipated that compound 16 may serve as a lead for further exploitation in our quest to identify new ligands with the potential to treat diseases of CNS origin. Published by Elsevier Ltd. C1 [Ofori, Edward; Zhu, Xue Y.; Etukala, Jagan R.; Peprah, Kwakye; Jordan, Kamanski R.; Adkins, Adia A.; Bricker, Barbara A.; Ablordeppey, Seth Y.] Florida A&M Univ, Coll Pharm & Pharmaceut Sci, Div Basic Pharmaceut Sci, Tallahassee, FL 32307 USA. [Kang, Hye J.; Huang, Xi-Ping; Roth, Bryan L.] Univ North Carolina Chapel Hill, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Kang, Hye J.; Huang, Xi-Ping; Roth, Bryan L.] Univ North Carolina Chapel Hill, Sch Med, NIMH PDSP, Chapel Hill, NC 27599 USA. [Roth, Bryan L.] Univ North Carolina Chapel Hill, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. RP Ablordeppey, SY (reprint author), Florida A&M Univ, Coll Pharm & Pharmaceut Sci, Div Basic Pharmaceut Sci, Tallahassee, FL 32307 USA. FU NIH/NIGMS SCORE grant [2SC1GM116724]; RCMI grant from NIMHD [G12 RR 03020]; Pharmaceutical Research Center NIH/NCRR [1C06-RR12512-01]; National Institute of Mental Health's Psychoactive Drug Screening Program [HHSN-271-2013-00017-C]; Title III Grant FX This work would not have been possible without the continuing financial support of the NIH/NIGMS SCORE grant number 2SC1GM116724, RCMI grant number G12 RR 03020 from NIMHD and a Title III Grant to Florida A&M University. The work was also supported in part by the Pharmaceutical Research Center NIH/NCRR 1C06-RR12512-01 Grant. Ki determinations and receptor binding profiles were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract # HHSN-271-2013-00017-C (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA. Funding sources acknowledged had no involvement in the study design, data collection and interpretation, or article preparation and submission of this manuscript. NR 42 TC 1 Z9 1 U1 5 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD AUG 15 PY 2016 VL 24 IS 16 BP 3464 EP 3471 DI 10.1016/j.bmc.2016.05.053 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DS2AF UT WOS:000380515700015 PM 27312422 ER PT J AU Etukala, JR Zhu, XY Eyunni, SVK Onyameh, EK Ofori, E Bricker, BA Kang, HJ Huang, P Roth, BL Ablordeppey, SY AF Etukala, Jagan R. Zhu, Xue Y. Eyunni, Suresh V. K. Onyameh, Edem K. Ofori, Edward Bricker, Barbara A. Kang, Hye J. Huang, Ping Roth, Bryan L. Ablordeppey, Seth Y. TI Development of CNS multi-receptor ligands: Modification of known D-2 pharmacophores SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Multi-receptor targeting; Dopamine receptor ligands; Antipsychotic; Pharmacophore; CNS receptor ID REVERSES MK-801-INDUCED IMPAIRMENT; INDUCED DOPAMINE RELEASE; SIGMA(2) BINDING-SITE; ANTIPSYCHOTIC AGENT; PREFRONTAL CORTEX; BIPOLAR DEPRESSION; WEIGHT-GAIN; HALOPERIDOL; DRUG; LURASIDONE AB Several known D-2 pharmacophores have been explored as templates for identifying ligands with multiple binding affinities at dopamine and serotonin receptors considered as clinically relevant receptors in the treatment of neuropsychiatric diseases. This approach has resulted in the identification of ligands that target multiple CNS receptors while avoiding others associated with deleterious effects. In particular, compounds 11, 15 and 22 may have potential for further development as antipsychotic agents as they favorably interact with the clinically relevant receptors including D2R, 5-HT1AR, and 5-HT7R. We have also identified the pair of compounds 11 and 10 as high affinity D2R ligands with and without SERT binding affinities, respectively. These differential binding profiles endow the pair with the potential for evaluating SERT contributions to antipsychotic drug activity in animal behavioral models. In addition, compound 11 has no significant affinity for 5-HT2CR and binds only moderately to the H1R, suggesting it may not induce weight gain or sedation when used clinically. Taken together, compound 11 displays an interesting pharmacological profile that necessitates the evaluation of its functional and in vivo effects in animal models which are currently ongoing. Published by Elsevier Ltd. C1 [Etukala, Jagan R.; Zhu, Xue Y.; Eyunni, Suresh V. K.; Onyameh, Edem K.; Ofori, Edward; Bricker, Barbara A.; Ablordeppey, Seth Y.] Florida A&M Univ, Coll Pharm & Pharmaceut Sci, Div Basic Pharmaceut Sci, Tallahassee, FL 32307 USA. [Kang, Hye J.; Huang, Ping; Roth, Bryan L.] Univ North Carolina Chapel Hill, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Kang, Hye J.; Huang, Ping; Roth, Bryan L.] Univ North Carolina Chapel Hill, Sch Med, NIMH PDSP, Chapel Hill, NC 27599 USA. [Roth, Bryan L.] Univ North Carolina Chapel Hill, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. RP Ablordeppey, SY (reprint author), Florida A&M Univ, Coll Pharm & Pharmaceut Sci, Div Basic Pharmaceut Sci, Tallahassee, FL 32307 USA. EM seth.ablordeppey@famu.edu FU NIH/NIGMS SCORE grant [2SC1GM116724]; NIMHD RCMI grant [G12 RR03020]; Title III Grant; Pharmaceutical Research Center NIH/NCRR [1C06RR12512]; National Institute of Mental Health's Psychoactive Drug Screening Program [HHSN-271-2013-00017-C] FX This work would not have been possible without the continuing financial support of the NIH/NIGMS SCORE grant number 2SC1GM116724, NIMHD RCMI grant number G12 RR03020 and a Title III Grant to Florida A&M University. The work was also supported in part by the Pharmaceutical Research Center NIH/NCRR grant number 1C06RR12512. Ki determinations and receptor binding profiles were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract #HHSN-271-2013-00017-C (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA. Funding sources acknowledged had no involvement in the study design, data collection and interpretation, or article preparation and submission of this manuscript. NR 49 TC 0 Z9 0 U1 6 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD AUG 15 PY 2016 VL 24 IS 16 BP 3671 EP 3679 DI 10.1016/j.bmc.2016.06.011 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA DS2AF UT WOS:000380515700038 PM 27364609 ER PT J AU Kosa, P Ghazali, D Tanigawa, M Barbour, C Cortese, I Kelley, W Snyder, B Ohayon, J Fenton, K Lehky, T Wu, TX Greenwood, M Nair, G Bielekova, B AF Kosa, Peter Ghazali, Danish Tanigawa, Makoto Barbour, Chris Cortese, Irene Kelley, William Snyder, Blake Ohayon, Joan Fenton, Kaylan Lehky, Tanya Wu, Tianxia Greenwood, Mark Nair, Govind Bielekova, Bibiana TI Development of a sensitive Outcome for economical Drug screening for Progressive Multiple sclerosis Treatment SO FRONTIERS IN NEUROLOGY LA English DT Article DE multiple sclerosis; clinical trial; outcome measure; composite scale; progressive MS; disability scale; quantitative MRI ID MAGNETIZATION-TRANSFER RATIO; CLINICAL-TRIALS; DIFFUSION MRI; DOUBLE-BLIND; MATTER; BRAIN; NEUROPROTECTION; DISABILITY; ROBUST; MSFC AB Therapeutic advance in progressive multiple sclerosis (MS) has been very slow. Based on the transformative role magnetic resonance imaging (MRI) contrast-enhancing lesions had on drug development for relapsing-remitting MS, we consider the lack of sensitive outcomes to be the greatest barrier for developing new treatments for progressive MS. The purpose of this study was to compare 58 prospectively acquired candidate outcomes in the real-world situation of progressive MS trials to select and validate the best-performing outcome. The 1-year pre-treatment period of adaptively designed IPPoMS (ClinicalTrials. gov #NCT00950248) and RIVITaLISe (ClinicalTrials. gov #NCT01212094) Phase II trials served to determine the primary outcome for the subsequent blinded treatment phase by comparing 8 clinical, 1 electrophysiological, 1 optical coherence tomography, 7 MRI volumetric, 9 quantitative T1 MRI, and 32 diffusion tensor imaging MRI outcomes. Fifteen outcomes demonstrated significant progression over 1 year (Delta) in the predetermined analysis and seven out of these were validated in two independent cohorts. Validated MRI outcomes had limited correlations with clinical scales, relatively poor signal-to-noise ratios (SNR) and recorded overlapping values between healthy subjects and MS patients with moderate-severe disability. Clinical measures correlated better, even though each reflects a somewhat different disability domain. Therefore, using machine-learning techniques, we developed a combinatorial weight-adjusted disability score (CombiWISE) that integrates four clinical scales: expanded disability status scale (EDSS), Scripps neurological rating scale, 25 foot walk and 9 hole peg test. CombiWISE outperformed all clinical scales (Delta = 9.10%; p = 0.0003) and all MRI outcomes. CombiWISE recorded no overlapping values between healthy subjects and disabled MS patients, had high SNR, and predicted changes in EDSS in a longitudinal assessment of 98 progressive MS patients and in a cross-sectional cohort of 303 untreated subjects. One point change in EDSS corresponds on average to 7.50 point change in CombiWISE with a standard error of 0.10. The novel validated clinical outcome, CombiWISE, outperforms the current broadly utilized MRI brain atrophy outcome and more than doubles sensitivity in detecting clinical deterioration in progressive MS in comparison to the scale traditionally used for regulatory approval, EDSS. C1 [Kosa, Peter; Ghazali, Danish; Tanigawa, Makoto; Barbour, Chris; Kelley, William; Snyder, Blake; Bielekova, Bibiana] NINDS, Neuroimmunol Dis Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Barbour, Chris; Greenwood, Mark] Montana State Univ, Dept Math Sci, Bozeman, MT 59717 USA. [Cortese, Irene; Ohayon, Joan; Fenton, Kaylan; Nair, Govind] NINDS, Neuroimmunol Clin, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Lehky, Tanya] NINDS, EMG Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Wu, Tianxia] NINDS, Clin Trials Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Bielekova, B (reprint author), NINDS, Neuroimmunol Dis Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM bibi.bielekova@nih.gov FU Intramural Research Program of National Institute of Neurological Disorders and Stroke, National Institutes of Health [NS003055-08, NS003056-08] FX Intramural Research Program of National Institute of Neurological Disorders and Stroke, National Institutes of Health (NS003055-08, NS003056-08). NR 40 TC 2 Z9 2 U1 6 U2 6 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2295 J9 FRONT NEUROL JI Front. Neurol. PD AUG 15 PY 2016 VL 7 AR 131 DI 10.3389/fneur.2016.00131 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DT3HD UT WOS:000381370700001 PM 27574516 ER PT J AU Bai, RL Hamel, E AF Bai, Ruoli Hamel, Ernest TI (-)-Rhazinilam and the diphenylpyridazinone NSC 613241: Two compounds inducing the formation of morphologically similar tubulin spirals but binding apparently to two distinct sites on tubulin SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE Diphenylpyridazinone derivatives; NSC 613241; (-)-Rhazinilam; Tubulin polymer of aberrant morphology; Inhibition of tubulin assembly; Glutaraldehyde-fixed microtubules ID MICROTUBULE-ASSOCIATED PROTEINS; AMINO-ACID-SEQUENCE; ANTIMITOTIC AGENTS; STRUCTURAL BASIS; PORCINE BRAIN; BETA-TUBULIN; TAXOID SITE; VINBLASTINE; LAULIMALIDE; RHAZINILAM AB The most potent microtubule assembly inhibitor of newer diphenylpyridazinone derivatives examined was NSC 613241. Because NSC 613241 and (-)-rhazinilam also induce the formation of similar 2-filament spirals, these aberrant reactions were compared. Spiral formation with both compounds was enhanced by GTP and inhibited by GDP and by 15 other inhibitors of microtubule assembly. Similarly, microtubule assembly induced by paclitaxel or laulimalide is enhanced by GTP and inhibited by GDP and assembly inhibitors, but neither [H-3]NSC 613241 nor [H-3](-)-rhazinilam bound to microtubules or inhibited the binding of [H-3]paclitaxel or [H-3]peloruside A to microtubules. Differences in the pitch of aberrant polymers were found: NSC 613241-induced and (-)-rhazinilam-induced spirals had average repeats of 85 and 79-80 nm, respectively. We found no binding of [H-3]NSC 613241 or [H-3](-)-rhazinilam to alpha beta-tubulin dimer, but both compounds were incorporated into the polymers they induced in substoichiometric reactions, with as little as 0.1-0.2 mol compound/mal of tubulin, and no cross-inhibition by NSC 613241 or (-)-rhazinilam into spirals occurred. Under reaction conditions where neither compound induced spiral formation, both compounds together synergistically induced substantial spiral formation. We conclude that (-)-rhazinilam and NSC 613241 bind to different sites on tubulin that differ from binding sites for other antitubulin agents. Published by Elsevier Inc. C1 [Bai, Ruoli; Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. RP Hamel, E (reprint author), Frederick Natl Lab Canc Res, Bldg 322,Room 102, Frederick, MD 21702 USA. EM hamele@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 43 TC 1 Z9 1 U1 2 U2 3 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 AUG 15 PY 2016 VL 604 BP 63 EP 73 DI 10.1016/j.abb.2016.06.008 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DS2PY UT WOS:000380627200008 PM 27311615 ER PT J AU Li, SS Sun, YF Huang, CY Follmann, DA Krause, R AF Li, Shanshan Sun, Yifei Huang, Chiung-Yu Follmann, Dean A. Krause, Richard TI Recurrent event data analysis with intermittently observed time-varying covariates SO STATISTICS IN MEDICINE LA English DT Article DE estimating equations; kernel smoothing; partial likelihood; recurrent events; survival analysis ID SEMIPARAMETRIC ANALYSIS; SURVIVAL ANALYSIS; REGRESSION-MODEL; CASE SERIES AB Although recurrent event data analysis is a rapidly evolving area of research, rigorous studies on estimation of the effects of intermittently observed time-varying covariates on the risk of recurrent events have been lacking. Existing methods for analyzing recurrent event data usually require that the covariate processes are observed throughout the entire follow-up period. However, covariates are often observed periodically rather than continuously. We propose a novel semiparametric estimator for the regression parameters in the popular proportional rate model. The proposed estimator is based on an estimated score function where we kernel smooth the mean covariate process. We show that the proposed semiparametric estimator is asymptotically unbiased, normally distributed, and derives the asymptotic variance. Simulation studies are conducted to compare the performance of the proposed estimator and the simple methods carrying forward the last covariates. The different methods are applied to an observational study designed to assess the effect of group A streptococcus on pharyngitis among school children in India. Copyright (c) 2016 John Wiley & Sons, Ltd. C1 [Li, Shanshan] Indiana Univ Fairbanks, Sch Publ Hlth, Dept Biostat, Indianapolis, IN 46202 USA. [Sun, Yifei; Huang, Chiung-Yu] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Huang, Chiung-Yu] Johns Hopkins Univ, Div Biostat & Bioinformat, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA. [Follmann, Dean A.; Krause, Richard] NIAID, Natl Inst Hlth, Bethesda, MD 20817 USA. RP Huang, CY (reprint author), Johns Hopkins Univ, Div Biostat & Bioinformat, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA. EM cyhuang@jhu.edu FU National Cancer Institute [R01CA193888] FX The authors are grateful to the editor, associate editor, and referees for their comments that helped improve this paper. This research was supported by the National Cancer Institute grant R01CA193888. NR 30 TC 0 Z9 0 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD AUG 15 PY 2016 VL 35 IS 18 BP 3049 EP 3065 DI 10.1002/sim.6901 PG 17 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA DR6PZ UT WOS:000380025100002 PM 26887664 ER PT J AU Begre, L Rohner, E Mbulaiteye, SM Egger, M Bohlius, J AF Begre, Lorin Rohner, Eliane Mbulaiteye, Sam M. Egger, Matthias Bohlius, Julia TI Is human herpesvirus 8 infection more common in men than in women? Systematic review and meta-analysis SO INTERNATIONAL JOURNAL OF CANCER LA English DT Review DE human herpesvirus 8; Kaposi sarcoma; seroprevalence; gender; meta-analysis ID SARCOMA-ASSOCIATED HERPESVIRUS; SEXUALLY-TRANSMITTED-DISEASES; MOTHER-TO-CHILD; KAPOSIS-SARCOMA; RISK-FACTORS; GENERAL-POPULATION; ENDEMIC POPULATION; UNITED-STATES; TRANSMISSION; SEROPREVALENCE AB All forms of Kaposi sarcoma (KS) are more common in men than in women. It is unknown if this is due to a higher prevalence of human herpesvirus 8 (HHV-8), the underlying cause of KS, in men compared to women. We did a systematic review and meta-analysis to examine the association between HHV-8 seropositivity and gender in the general population. Studies in selected populations like for example, blood donors, hospital patients and men who have sex with men were excluded. We searched Medline and Embase from January 1994 to February 2015. We included observational studies that recruited participants from the general population and reported HHV-8 seroprevalence for men and women or boys and girls. We used random-effects meta-analysis to pool odds ratios (OR) of the association between HHV-8 and gender. We used meta-regression to identify effect modifiers, including age, geographical region and type of HHV-8 antibody test. We included 22 studies, with 36,175 participants. Men from sub-Saharan Africa (SSA) [OR 1.21, 95% confidence interval (CI) 1.09-1.34], but not men from elsewhere (OR 0.94, 95% CI 0.83-1.06), were more likely to be HHV-8 seropositive than women (p value for interaction = 0.010). There was no difference in HHV-8 seroprevalence between boys and girls from SSA (OR 0.90, 95% CI 0.72-1.13). The type of HHV-8 assay did not affect the overall results. A higher HHV-8 seroprevalence in men than women in SSA may partially explain why men have a higher KS risk in this region. C1 [Begre, Lorin; Rohner, Eliane; Egger, Matthias; Bohlius, Julia] Univ Bern, ISPM, Finkenhubelweg 11, CH-3012 Bern, Switzerland. [Mbulaiteye, Sam M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Egger, Matthias] Univ Cape Town, Sch Publ Hlth & Family Med, Ctr Infect Dis Epidemiol & Res, ZA-7925 Cape Town, South Africa. RP Bohlius, J (reprint author), Univ Bern, ISPM, Finkenhubelweg 11, CH-3012 Bern, Switzerland. EM julia.bohlius@ispm.unibe.ch OI Rohner, Eliane/0000-0002-0554-2875 FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health [U01AI069924]; National Cancer Institute [5U01A1069924-05]; Swiss National Science Foundation [Ambizione-PROSPER PZ00P3_160407] FX Grant sponsor: National Institute of Allergy and Infectious Diseases of the National Institutes of Health; Grant number: U01AI069924 to M.E.; Grant sponsor: National Cancer Institute; Grant number: 5U01A1069924-05 to M.E.; Grant sponsor: Swiss National Science Foundation; Grant number: Ambizione-PROSPER PZ00P3_160407 to J.B. NR 41 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD AUG 15 PY 2016 VL 139 IS 4 BP 776 EP 783 DI 10.1002/ijc.30129 PG 8 WC Oncology SC Oncology GA DP3TM UT WOS:000378418300013 PM 27062038 ER PT J AU Hare, DJ Raven, EP Roberts, BR Bogeski, M Portbury, SD McLean, CA Masters, CL Connor, JR Bush, AI Crouch, PJ Doble, PA AF Hare, Dominic J. Raven, Erika P. Roberts, Blaine R. Bogeski, Mirjana Portbury, Stuart D. McLean, Catriona A. Masters, Colin L. Connor, James R. Bush, Ashley I. Crouch, Peter J. Doble, Philip A. TI Laser ablation-inductively coupled plasma-mass spectrometry imaging of white and gray matter iron distribution in Alzheimer's disease frontal cortex SO NEUROIMAGE LA English DT Article ID NON-HAEMIN IRON; LA-ICP-MS; BRAIN IRON; IN-VIVO; SUBSTANTIA-NIGRA; MRI CONTRAST; PARKINSONS-DISEASE; TRANSITION-METALS; CEREBRAL-CORTEX; TISSUE AB Iron deposition in the brain is a feature of normal aging, though in several neurodegenerative disorders, including Alzheimer's disease, the rate of iron accumulation is more advanced than in age-matched controls. Using laser ablation-inductively coupled plasma-mass spectrometry imaging we present here a pilot study that quantitatively assessed the iron content of white and gray matter in paraffin-embedded sections from the frontal cortex of Alzheimer's and control subjects. Using the phosphorus image as a confirmed proxy for the white/gray matter boundary, we found that increased intrusion of iron into gray matter occurs in the Alzheimer's brain compared to controls, which may be indicative of either a loss of iron homeostasis in this vulnerable brain region, or provide evidence of increased inflammatory processes as a response to chronic neurodegeneration. We also observed a trend of increasing iron within the white matter of the frontal cortex, potentially indicative of disrupted iron metabolism preceding loss of myelin integrity. Considering the known potential toxicity of excessive iron in the brain, our results provide supporting evidence for the continuous development of novel magnetic resonance imaging approaches for assessing white and gray matter iron accumulation in Alzheimer's disease. Crown Copyright (C) 2016 Published by Elsevier Inc. All rights reserved. C1 [Hare, Dominic J.; Doble, Philip A.] Univ Technol Sydney, Elemental Bioimaging Facil, Sydney, NSW 2007, Australia. [Hare, Dominic J.; Roberts, Blaine R.; Bogeski, Mirjana; Portbury, Stuart D.; Masters, Colin L.; Bush, Ashley I.] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Melbourne, Vic 3010, Australia. [Raven, Erika P.] Georgetown Univ, Ctr Funct & Mol Imaging, Med Ctr, Washington, DC 20057 USA. [Raven, Erika P.] NINDS, Adv Magnet Resonance Imaging Sect, Lab Funct & Mol Imaging, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [McLean, Catriona A.] Alfred Hosp, Dept Anat Pathol, Melbourne, Vic, Australia. [McLean, Catriona A.] Monash Univ, Dept Med, Cent Clin Sch, Clayton, Vic 3800, Australia. [Connor, James R.] Penn State Hershey Med Ctr, Dept Neural & Behav Sci, Hershey, PA USA. [Connor, James R.] Penn State Hershey Med Ctr, Dept Neurosurg, Hershey, PA USA. [Crouch, Peter J.] Univ Melbourne, Dept Pathol, Sch Biomed Sci, Melbourne, Vic 3010, Australia. RP Hare, DJ; Doble, PA (reprint author), Univ Technol Sydney, POB 123, Sydney, NSW 2007, Australia. EM dominic.hare@uts.edu.au; philip.doble@uts.edu.au FU Australian Research Council Linkage Project [LP120200081, LP140100095]; ESI Ltd.; Agilent Technologies; National Science Foundation Graduate Research Fellowship [DGE-1444316]; National Health and Medical Research Council [1005651, 1061550]; Victorian Government's Operational Infrastructure Support Program; Victorian Brain Bank Network FX The authors would like to thank Dr. Ian Birchall and Dr. Jeff Duyn for their helpful advice, and Ms. Fairlie Hilton of the Victorian Brain Bank Network for her assistance with case notes. D.J.H. and P.A.D. are supported by funds from Australian Research Council Linkage Project (LP120200081) in conjunction with ESI Ltd. and Agilent Technologies. D.J.H. and B.R.R. are additionally supported through Australian Research Council Linkage Project (LP140100095) with Agilent Technologies. E.P.R. is supported by the National Science Foundation Graduate Research Fellowship under Grant No. DGE-1444316. P.J.C. is supported by funds from the National Health and Medical Research Council (1005651 and 1061550). We gratefully acknowledge the support of the Victorian Government's Operational Infrastructure Support Program and the Victorian Brain Bank Network. NR 74 TC 1 Z9 1 U1 20 U2 46 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 AUG 15 PY 2016 VL 137 BP 124 EP 131 DI 10.1016/j.neuroimage.2016.05.057 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DO8QO UT WOS:000378048700013 PM 27233149 ER PT J AU Zavala, B Tan, HL Ashkan, K Foltynie, T Limousin, P Zrinzo, L Zaghloul, K Brown, P AF Zavala, Baltazar Tan, Huiling Ashkan, Keyoumars Foltynie, Thomas Limousin, Patricia Zrinzo, Ludvic Zaghloul, Kareem Brown, Peter TI Human subthalamic nucleus-medial frontal cortex theta phase coherence is involved in conflict and error related cortical monitoring SO NEUROIMAGE LA English DT Article DE Conflict; Subthalamic nucleus; Theta; Coherence; Errors ID ANTERIOR CINGULATE CORTEX; DEEP BRAIN-STIMULATION; PARKINSONS-DISEASE; COGNITIVE CONTROL; DECISION-MAKING; RESPONSE CONFLICT; TASK-DIFFICULTY; DYNAMICS; OSCILLATIONS; RESOLUTION AB The medial prefrontal cortex (mPFC) is thought to control the shift from automatic to controlled action selection when conflict is present or when mistakes have been recently committed. Growing evidence suggests that this process involves frequency specific communication in the theta (4-8 Hz) band between the mPFC and the subthalamic nucleus (STN), which is the main target of deep brain stimulation (DBS) for Parkinson's disease. Key in this hypothesis is the finding that DBS can lead to impulsivity by disrupting the correlation between higher mPFC oscillations and slower reaction times during conflict. In order to test whether theta band coherence between the mPFC and the STN underlies adjustments to conflict and to errors, we simultaneously recorded mPFC and STN electrophysiological activity while DBS patients performed an arrowed flanker task. These recordings revealed higher theta phase coherence between the two sites during the high conflict trials relative to the low conflict trials. These differences were observed soon after conflicting arrows were displayed, but before a response was executed. Furthermore, trials that occurred after an error was committed showed higher phase coherence relative to trials that followed a correct trial, suggesting that mPFC-STN connectivity may also play a role in error related adjustments in behavior. Interestingly, the phase coherence we observed occurred before increases in theta power, implying that the theta phase and power may influence behavior at separate times during cortical monitoring. Finally, we showed that pre-stimulus differences in STN theta power were related to the reaction time on a given trial, which may help adjust behavior based on the probability of observing conflict during a task. (C) 2016 The Authors. Published by Elsevier Inc. C1 [Zavala, Baltazar; Tan, Huiling; Brown, Peter] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Neurol, Oxford OX3 9DU, England. [Zavala, Baltazar; Zaghloul, Kareem] NIH, Surg Neurol Branch, 10 Ctr Dr,3D20, Bethesda, MD 20814 USA. [Tan, Huiling; Brown, Peter] Univ Oxford, Med Res Council, Brain Network Dynam Unit, Mansfield Rd, Oxford OX1 3TH, England. [Ashkan, Keyoumars] Kings Coll Hosp London, Dept Neurosurg, Kings Coll, London SE5 9RS, England. [Foltynie, Thomas; Limousin, Patricia; Zrinzo, Ludvic] UCL Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London WC1 3BG, England. RP Zavala, B (reprint author), Natl Inst Neurol Dis & Stroke, Surg Neurol Branch, Bldg 10,Room 3D20,10 Ctr Dr, Bethesda, MD 20892 USA. EM zarzavala@gmail.com OI Zavala, Baltazar/0000-0002-7284-7994; Brown, Peter/0000-0002-5201-3044; Tan, Huiling /0000-0001-8038-3029 FU National Institutes of Health Oxford-Cambridge fellowship; Department of Health National Institute for Health Research UCL Biomedical Research Center; Monument Trust; Parkinson's Appeal for Deep Brain Stimulation; Medical Research Council; Department of Health National Institute for Health Research Oxford Biomedical Research Centre FX B.Z. is supported by the National Institutes of Health Oxford-Cambridge fellowship. T.F. and L.Z. are funded by the Department of Health National Institute for Health Research UCL Biomedical Research Center, The Monument Trust, and Parkinson's Appeal for Deep Brain Stimulation. P.B. and H.T. are funded by the Medical Research Council, and P.B. is further funded by the Department of Health National Institute for Health Research Oxford Biomedical Research Centre. NR 50 TC 2 Z9 2 U1 10 U2 15 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 AUG 15 PY 2016 VL 137 BP 178 EP 187 DI 10.1016/j.neuroimage.2016.05.031 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DO8QO UT WOS:000378048700018 PM 27181763 ER PT J AU Scuteri, A Morrell, CH Orru, M AlGhatrif, M Saba, PS Terracciano, A Ferreli, LAP Loi, F Marongiu, M Pilia, MG Delitala, A Tarasov, KV Schlessinger, D Ganau, A Cucca, F Lakatta, EG AF Scuteri, Angelo Morrell, Christopher H. Orru, Marco AlGhatrif, Majid Saba, Pier Sergio Terracciano, Antonio Ferreli, Liana Anna Pina Loi, Francesco Marongiu, Michele Pilia, Maria Grazia Delitala, Alessandro Tarasov, Kirill V. Schlessinger, David Ganau, Antonello Cucca, Francesco Lakatta, Edward G. TI Gender specific profiles of white coat and masked hypertension impacts on arterial structure and function in the SardiNIA study SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Arterial stiffness; Pulse wave velocity; Carotid thickness; Arterial aging; Masked hypertension; White coat hypertension; 24 hour blood pressure monitoring ID PULSE-WAVE VELOCITY; AMBULATORY BLOOD-PRESSURE; LONG-TERM RISK; SUSTAINED HYPERTENSION; COGNITIVE IMPAIRMENT; METABOLIC SYNDROME; ORGAN DAMAGE; METAANALYSIS; STIFFNESS; STROKE AB Background: There is no definite consensus on the CV burden associated to Masked hypertension (MH) or White Coat Hypertension (WCH) - conditions that can be detected by out-of-office blood pressure measurements (24 hour Ambulatory Blood Pressure Monitoring, 24 h ABPM). Methods: We investigated the association of WCH and MH with arterial aging, indexed by a range of parameters of large artery structure and function in 2962 subjects, taking no antihypertensive medications, who are participating in a large community-based population of both men and women over a broad age range (14-102 years). Results: The overall prevalence of WCH was 9.5% and was 5.0% for MH, with 54.9% of subjects classified as true normotensive and 30.6% as true hypertensive. Both WCH and MH were associated with a stiffer aorta, a less distensible and thicker common carotid artery, and greater central BP than true normotensive subjects. Notably, the profile of arterial alterations in WCH and MH did not significantly differ from what was observed in true hypertensive subjects. The arterial changes accompanying WCH and MH differed in men and women, with women showing a greater tendency towards concentric remodeling, greater parietal wall stress, and PWV than men. Conclusion: Both WCH, and MH are associated with early arterial aging, and therefore, neither can be regarded as innocent conditions. Future studies are required to establish whether measurement of arterial aging parameters in subjects with WCH or MH will identify subjects at higher risk of CV events and cognitive impairment, who may require more clinical attention and pharmacological intervention. (C) 2016 Published by Elsevier Ireland Ltd. C1 [Morrell, Christopher H.; AlGhatrif, Majid; Tarasov, Kirill V.; Schlessinger, David; Lakatta, Edward G.] NIA, NIH, Baltimore, MD 21224 USA. [Orru, Marco; Ferreli, Liana Anna Pina; Loi, Francesco; Marongiu, Michele; Pilia, Maria Grazia; Delitala, Alessandro; Cucca, Francesco] Cittadella Univ Monserrato, Ist Ric Genet & Biomed, CNR, Cagliari, Italy. [Saba, Pier Sergio; Ganau, Antonello] Univ Sassari, I-07100 Sassari, Italy. [Terracciano, Antonio] Florida State Univ, Coll Med, Tallahassee, FL 32306 USA. [Morrell, Christopher H.] Loyola Univ Maryland, Baltimore, MD USA. [Orru, Marco] Presidio Osped A Businco, Unita Operat Complessa Cardiol, Cagliari, Italy. RP Scuteri, A (reprint author), Policlin Tor Vergata, Hypertens Ctr, Hypertens & Nephrol Unit, Rome, Italy. EM angeloelefante@interfree.it RI Delitala, Alessandro/L-3194-2016 OI Delitala, Alessandro/0000-0003-1729-8969 FU NIA [NO1-AG-1-2109]; Intramural Research Program of the NIH, U.S. National Institute on Aging FX The SardiNIA team was supported by Contract NO1-AG-1-2109 from the NIA. This research was supported in part by the Intramural Research Program of the NIH, U.S. National Institute on Aging. NR 31 TC 2 Z9 2 U1 1 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD AUG 15 PY 2016 VL 217 BP 92 EP 98 DI 10.1016/j.ijcard.2016.04.172 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DO5OO UT WOS:000377832700014 PM 27179214 ER PT J AU Metcalf, CJE Farrar, J Cutts, FT Basta, NE Graham, AL Lessler, J Ferguson, NM Burke, DS Grenfell, BT AF Metcalf, C. Jessica E. Farrar, Jeremy Cutts, Felicity T. Basta, Nicole E. Graham, Andrea L. Lessler, Justin Ferguson, Neil M. Burke, Donald S. Grenfell, Bryan T. TI Use of serological surveys to generate key insights into the changing global landscape of infectious disease SO LANCET LA English DT Editorial Material ID INFLUENZA; TRANSMISSION; DYNAMICS; ANTIBODY; MODEL C1 [Metcalf, C. Jessica E.; Graham, Andrea L.; Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Metcalf, C. Jessica E.; Basta, Nicole E.; Graham, Andrea L.; Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Farrar, Jeremy] Wellcome Trust Res Labs, Gibbs Bldg, London, England. [Cutts, Felicity T.] London Sch Hyg & Trop Med, London, England. [Basta, Nicole E.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Lessler, Justin] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Ferguson, Neil M.] Imperial Coll London, Dept Med, Sch Publ Hlth, London, England. [Burke, Donald S.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. RP Metcalf, CJE (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. EM cmetcalf@princeton.edu RI Graham, Andrea/A-8808-2010; OI Graham, Andrea/0000-0002-6580-2755; Lessler, Justin/0000-0002-9741-8109; /0000-0002-5704-8094 FU Medical Research Council [, MR/K010174/1]; NICHD NIH HHS [P2C HD047879]; NIH HHS [DP5 OD009162] NR 14 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD AUG 13 PY 2016 VL 388 IS 10045 BP 728 EP 730 DI 10.1016/S0140-6736(16)30164-7 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DT1UX UT WOS:000381268700033 PM 27059886 ER PT J AU Verma, A Verma, SS Pendergrass, SA Crawford, DC Crosslin, DR Kuivaniemi, H Bush, WS Bradford, Y Kullo, I Bielinski, SJ Li, RL Denny, JC Peissig, P Hebbring, S De Andrade, M Ritchie, MD Tromp, G AF Verma, Anurag Verma, Shefali S. Pendergrass, Sarah A. Crawford, Dana C. Crosslin, David R. Kuivaniemi, Helena Bush, William S. Bradford, Yuki Kullo, Iftikhar Bielinski, Suzette J. Li, Rongling Denny, Joshua C. Peissig, Peggy Hebbring, Scott De Andrade, Mariza Ritchie, Marylyn D. Tromp, Gerard TI eMERGE Phenome-Wide Association Study (PheWAS) identifies clinical associations and pleiotropy for stop-gain variants SO BMC MEDICAL GENOMICS LA English DT Article; Proceedings Paper CT 5th Translational Bioinformatics Conference (TBC) CY NOV 07-09, 2015 CL Tokyo, JAPAN ID ELECTRONIC MEDICAL-RECORDS; GENETIC-VARIANTS; GENOME; SUSCEPTIBILITY; POLYMORPHISMS; DISEASE; HYPOTHYROIDISM; ANNOTATION; CHALLENGES; DISPERSION AB Background: We explored premature stop-gain variants to test the hypothesis that variants, which are likely to have a consequence on protein structure and function, will reveal important insights with respect to the phenotypes associated with them. We performed a phenome-wide association study (PheWAS) exploring the association between a selected list of functional stop-gain genetic variants (variation resulting in truncated proteins or in nonsense-mediated decay) and an extensive group of diagnoses to identify novel associations and uncover potential pleiotropy. Results: In this study, we selected 25 stop-gain variants: 5 stop-gain variants with previously reported phenotypic associations, and a set of 20 putative stop-gain variants identified using dbSNP. For the PheWAS, we used data from the electronic MEdical Records and GEnomics (eMERGE) Network across 9 sites with a total of 41,057 unrelated patients. We divided all these samples into two datasets by equal proportion of eMERGE site, sex, race, and genotyping platform. We calculated single effect associations between these 25 stop-gain variants and ICD-9 defined case-control diagnoses. We also performed stratified analyses for samples of European and African ancestry. Associations were adjusted for sex, site, genotyping platform and the first three principal components to account for global ancestry. We identified previously known associations, such as variants in LPL associated with hyperglyceridemia indicating that our approach was robust. We also found a total of three significant associations with p < 0.01 in both datasets, with the most significant replicating result being LPL SNP rs328 and ICD-9 code 272. 1 "Disorder of Lipoid metabolism" (p(discovery) = 2.59x10-6, p(replicating) = 2.7x10-4). The other two significant replicated associations identified by this study are: variant rs1137617 in KCNH2 gene associated with ICD-9 code category 244 "Acquired Hypothyroidism" (p(discovery) = 5.31x103, p(replicating) = 1.15x10-3) and variant rs12060879 in DPT gene associated with ICD-9 code category 996 "Complications peculiar to certain specified procedures" (p(discovery) = 8. 65x103, p(replicating) = 4.16x10-3). Conclusion: In conclusion, this PheWAS revealed novel associations of stop-gained variants with interesting phenotypes (ICD-9 codes) along with pleiotropic effects. C1 [Verma, Anurag; Verma, Shefali S.; Bradford, Yuki; Ritchie, Marylyn D.] Penn State Univ, Ctr Syst Genom, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Verma, Anurag; Verma, Shefali S.; Pendergrass, Sarah A.; Ritchie, Marylyn D.] Geisinger Hlth Syst, Biomed & Translat Informat, Danville, PA USA. [Kuivaniemi, Helena; Tromp, Gerard] Univ Stellenbosch, Fac Med & Hlth Sci, Dept Biomed Sci, Div Mol Biol & Human Genet, ZA-7505 Tygerberg, South Africa. [Crawford, Dana C.; Bush, William S.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Crosslin, David R.] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Denny, Joshua C.] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. [Peissig, Peggy; Hebbring, Scott] Marshfield Clin Fdn Med Res & Educ, Marshfield, WI USA. [De Andrade, Mariza] Mayo Clin, Rochester, MN USA. [Li, Rongling] NHGRI, Bethesda, MD 20892 USA. RP Verma, A; Verma, SS (reprint author), Penn State Univ, Ctr Syst Genom, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. EM anurag.verma@psu.edu; szs14@psu.edu OI Kuivaniemi, Helena/0000-0001-5753-8766 FU NCATS NIH HHS [UL1 TR000427]; NHGRI NIH HHS [U01 HG006388, U01 HG004424, U01 HG004438, U01 HG006375, U01 HG006378, U01 HG006379, U01 HG006380, U01 HG006382, U01 HG006385, U01 HG006389, U01 HG006828, U01 HG006830, U01 HG008657, U01 HG008684, U01 HG008701] NR 52 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1755-8794 J9 BMC MED GENOMICS JI BMC Med. Genomics PD AUG 12 PY 2016 VL 9 SU 1 AR 32 DI 10.1186/s12920-016-0191-8 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA DT2OH UT WOS:000381319300005 PM 27535653 ER PT J AU Goodman, PJ Tangen, CM Darke, AK Arnold, KB Hartline, J Yee, M Anderson, K Caban-Holt, A Christen, WG Cassano, PA Lance, P Klein, EA Crowley, JJ Minasian, LM Meyskens, FL AF Goodman, Phyllis J. Tangen, Catherine M. Darke, Amy K. Arnold, Kathryn B. Hartline, JoAnn Yee, Monica Anderson, Karen Caban-Holt, Allison Christen, William G. Cassano, Patricia A. Lance, Peter Klein, Eric A. Crowley, John J. Minasian, Lori M. Meyskens, Frank L. TI Opportunities and challenges in incorporating ancillary studies into a cancer prevention randomized clinical trial SO TRIALS LA English DT Article DE Prostate cancer; Ancillary studies; Randomized controlled trial; Study implementation ID VITAMIN-E; ALZHEIMERS-DISEASE; PROSTATE-CANCER; SELENIUM; SELECT; DEMENTIA; RISK AB Background: The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was a randomized, double-blind, placebo-controlled, prostate cancer prevention study funded by the National Cancer Institute and conducted by SWOG (Southwest Oncology Group). A total of 35,533 men were assigned randomly to one of four treatment groups (vitamin E + placebo, selenium + placebo, vitamin E + selenium, placebo + placebo). At the time of the trial's development, NIH had invested substantial resources in evaluating the potential benefits of these antioxidants. To capitalize on the knowledge gained from following a large cohort of healthy, aging males on the effects of selenium and/or vitamin E, ancillary studies with other disease endpoints were solicited. Methods: Four ancillary studies were added. Each drew from the same population but had independent objectives and an endpoint other than prostate cancer. These studies fell into two categories: those prospectively enrolling and following participants (studies of Alzheimer's disease and respiratory function) and those requiring a retrospective medical record review after a reported event (cataracts/age-related macular degeneration and colorectal screening). An examination of the challenges and opportunities of adding ancillary studies is provided. The impact of the ancillary studies on adherence to SELECT was evaluated using a Cox proportional hazards model. Results: While the addition of ancillary studies appears to have improved participant adherence to the primary trial, this did not come without added complexity. Activation of the ancillary studies happened after the SELECT randomizations had begun resulting in accrual problems to some of the studies. Study site participation in the ancillary trials varied greatly and depended on the interest of the study site principal investigator. Procedures for each were integrated into the primary trial and all monitoring was done by the SELECT Data and Safety Monitoring Committee. The impact of the early closure of the primary trial was different for each of the ancillary trials. Conclusions: The ancillary studies allowed study sites to broaden the research opportunities for their participants. Their implementation was efficient because of the established infrastructure of the primary trial. Implementation of these ancillary trials took substantial planning and coordination but enriched the overall primary trial. C1 [Goodman, Phyllis J.; Tangen, Catherine M.; Darke, Amy K.; Arnold, Kathryn B.] Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, 1100 Fairview Ave N,M3-C102, Seattle, WA 98109 USA. [Hartline, JoAnn; Yee, Monica; Anderson, Karen; Crowley, John J.] SWOG Stat Ctr, Canc Res & Biostat, Seattle, WA USA. [Caban-Holt, Allison] Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA. [Christen, William G.] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. [Cassano, Patricia A.] Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. [Lance, Peter] Univ Arizona, Arizona Canc Ctr, Phoenix, AZ USA. [Klein, Eric A.] Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44106 USA. [Minasian, Lori M.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Meyskens, Frank L.] Univ Calif Irvine, Orange, CA 92668 USA. RP Goodman, PJ (reprint author), Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, 1100 Fairview Ave N,M3-C102, Seattle, WA 98109 USA. EM pgoodman@fredhutch.org FU Public Health Service - National Cancer Institute, National Institutes of Health, Department of Health and Human Services [CA37429, UM1 CA182883]; National Center for Complementary and Alternative Medicine (National Institutes of Health); NIA [R01 AG19241]; NEI [EY014418]; NHLBI [RO1HL071022]; NCI [R01CA124862] FX This work was supported in part by Public Health Service Cooperative Agreement grant CA37429 and UM1 CA182883 awarded by the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, and in part by the National Center for Complementary and Alternative Medicine (National Institutes of Health). It was also supported in part by NIA R01 AG19241 (PREADVISE), NEI EY014418 (SEE), NHLBI (RO1HL071022) (RAS) and NCI R01CA124862 (ACP). Study agents and packaging were provided by Perrigo Company (Allegan, MI, USA), Sabinsa Corporation (Piscataway, NJ, USA), Tishcon Corporation (Westbury, NY, USA) and DSM Nutritional Products Inc. (Parsipanny, NJ, USA). NR 12 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 1745-6215 J9 TRIALS JI Trials PD AUG 12 PY 2016 VL 17 AR 400 DI 10.1186/s13063-016-1524-9 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DT2ZE UT WOS:000381349500001 PM 27519183 ER PT J AU Bucher, S Konana, O Liechty, E Garces, A Gisore, P Marete, I Tenge, C Shipala, E Wright, L Esamai, F AF Bucher, Sherri Konana, Olive Liechty, Edward Garces, Ana Gisore, Peter Marete, Irene Tenge, Constance Shipala, Evelyn Wright, Linda Esamai, Fabian TI Self-reported practices among traditional birth attendants surveyed in western Kenya: a descriptive study SO BMC PREGNANCY AND CHILDBIRTH LA English DT Article DE Traditional birth attendant; Maternal-newborn health; Delivery practices; Africa; Kenya; Health policy ID NEWBORN HEALTH REGISTRY; HELPING BABIES BREATHE; PREVENT POSTPARTUM HEMORRHAGE; RESOURCE-LIMITED SETTINGS; IN-HOME BIRTHS; MATERNAL HEALTH; GLOBAL-NETWORK; NEONATAL-MORTALITY; INCOME COUNTRIES; CONTROLLED-TRIAL AB Background: The high rate of home deliveries conducted by unskilled birth attendants in resource-limited settings is an important global health issue because it is believed to be a significant contributing factor to maternal and newborn mortality. Given the large number of deliveries that are managed by unskilled or traditional birth attendants outside of health facilities, and the fact that there is on-going discussion regarding the role of traditional birth attendants in the maternal newborn health (MNH) service continuum, we sought to ascertain the practices of traditional birth attendants in our catchment area. The findings of this descriptive study might help inform conversations regarding the roles that traditional birth attendants can play in maternal-newborn health care. Methods: A structured questionnaire was used in a survey that included one hundred unskilled birth attendants in western Kenya. Descriptive statistics were employed. Results: Inappropriate or outdated practices were reported in relation to some obstetric complications and newborn care. Encouraging results were reported with regard to positive relationships that traditional birth attendants have with their local health facilities. Furthermore, high rates of referral to health facilities was reported for many common obstetric emergencies and similar rates for reporting of pregnancy outcomes to village elders and chiefs. Conclusions: Potentially harmful or outdated practices with regard to maternal and newborn care among traditional birth attendants in western Kenya were revealed by this study. There were high rates of traditional birth attendant referrals of pregnant mothers with obstetric complications to health facilities. Policy makers may consider re-educating and re-defining the roles and responsibilities of traditional birth attendants in maternal and neonatal health care based on the findings of this survey. C1 [Bucher, Sherri; Konana, Olive; Liechty, Edward] Indiana Univ Sch Med, Sect Neonatal Perinatal Med, Dept Pediat, 699 Riley Hosp Dr,RR208, Indianapolis, IN 46202 USA. [Garces, Ana] INSALUD, Guatemala City, Guatemala. [Gisore, Peter; Marete, Irene; Tenge, Constance; Esamai, Fabian] Moi Univ, Sch Med, Dept Paediat & Child Hlth, Eldoret, Kenya. [Shipala, Evelyn] Moi Teaching & Referral Hosp, Eldoret, Kenya. [Wright, Linda] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Ctr Res Mothers & Children, Bethesda, MD USA. RP Bucher, S (reprint author), Indiana Univ Sch Med, Sect Neonatal Perinatal Med, Dept Pediat, 699 Riley Hosp Dr,RR208, Indianapolis, IN 46202 USA. EM shbucher@iu.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health [U01 HD058326, U01 HD040657, U01 HD040636]; Bill & Melinda Gates Foundation FX This study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under Award Numbers U01 HD058326 (Kenya), U01 HD040657 (Guatemala), and U01 HD040636 (RTI). This study was supported in part by a grant from the Bill & Melinda Gates Foundation. The investigators were solely responsible for the study design, data collection, analysis, interpretation of the data, and writing of the manuscript, without influence from the funding agencies. NR 55 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 1471-2393 J9 BMC PREGNANCY CHILDB JI BMC Pregnancy Childbirth PD AUG 12 PY 2016 VL 16 AR 219 DI 10.1186/s12884-016-1007-8 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DT4UK UT WOS:000381476400002 PM 27514379 ER PT J AU Toombes, GES Swartz, KJ AF Toombes, Gilman E. S. Swartz, Kenton J. TI Twists and turns in gating ion channels with voltage The EAG potassium channel may use an alternative voltage-dependent gating mechanism SO SCIENCE LA English DT Editorial Material ID CRYSTAL-STRUCTURE; DOMAINS C1 [Toombes, Gilman E. S.; Swartz, Kenton J.] NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Swartz, KJ (reprint author), NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. EM kenton.swartz@nih.gov NR 15 TC 0 Z9 0 U1 5 U2 8 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD AUG 12 PY 2016 VL 353 IS 6300 BP 646 EP 647 DI 10.1126/science.aah4194 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT5ZC UT WOS:000381561200018 PM 27516583 ER PT J AU Hoenen, T Groseth, A Safronetz, D Wollenberg, K Feldmann, H AF Hoenen, Thomas Groseth, Allison Safronetz, David Wollenberg, Kurt Feldmann, Heinz TI Response to Comment on "Mutation rate and genotype variation of Ebola virus from Mali case sequences" SO SCIENCE LA English DT Editorial Material ID SIERRA-LEONE; OUTBREAK; TRANSMISSION; MACAQUES; DISEASE; STRAIN AB Rambaut et al. show that the erratum to our report on Ebola virus Makona evolution not only corrected sample dates modified by others in GenBank but also corrected an additional transcriptional error in our original analysis. We agree with their observation that both factors contributed to our revised evolutionary rate estimate but continue to stand by our revised estimate and conclusions. C1 [Hoenen, Thomas; Groseth, Allison; Safronetz, David; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Wollenberg, Kurt] NIAID, Bioinformat & Computat Biosci Branch, NIH, Bethesda, MD USA. RP Feldmann, H (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. EM feldmannh@niaid.nih.gov OI Hoenen, Thomas/0000-0002-5829-6305 FU Intramural NIH HHS NR 13 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD AUG 12 PY 2016 VL 353 IS 6300 DI 10.1126/science.aaf4561 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT5ZC UT WOS:000381561200030 PM 27516593 ER PT J AU Enose-Akahata, Y Caruso, B Haner, B Charlip, E Nair, G Massoud, R Billioux, BJ Ohayon, J Switzer, WM Jacobson, S AF Enose-Akahata, Yoshimi Caruso, Breanna Haner, Benjamin Charlip, Emily Nair, Govind Massoud, Raya Billioux, Bridgette J. Ohayon, Joan Switzer, William M. Jacobson, Steven TI Development of neurologic diseases in a patient with primate T lymphotropic virus type 1 (PTLV-1) SO RETROVIROLOGY LA English DT Article DE HTLV; PTLV; STLV; HAM/TSP ID TROPICAL SPASTIC PARAPARESIS; I-ASSOCIATED MYELOPATHY; HTLV-I; NONHUMAN-PRIMATES; PERIPHERAL-BLOOD; MOLECULAR EPIDEMIOLOGY; CEREBROSPINAL-FLUID; HAM/TSP PATIENTS; CENTRAL-AFRICA; COTE-DIVOIRE AB Background: Virus transmission from various wild and domestic animals contributes to an increased risk of emerging infectious diseases in human populations. HTLV-1 is a human retrovirus associated with acute T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 originated from ancient zoonotic transmission from nonhuman primates, although cases of zoonotic infections continue to occur. Similar to HTLV-1, the simian counterpart, STLV-1, causes chronic infection and leukemia and lymphoma in naturally infected monkeys, and combined are called primate T-lymphotropic viruses (PTLV-1). However, other clinical syndromes typically seen in humans such as a chronic progressive myelopathy have not been observed in nonhuman primates. Little is known about the development of neurologic and inflammatory diseases in human populations infected with STLV-1-like viruses following nonhuman primate exposure. Results: We performed detailed laboratory analyses on an HTLV-1 seropositive patient with typical HAM/TSP who was born in Liberia and now resides in the United States. Using a novel droplet digital PCR for the detection of the HTLV-1 tax gene, the proviral load in PBMC and cerebrospinal fluid cells was 12.98 and 51.68 %, respectively; however, we observed a distinct difference in fluorescence amplitude of the positive droplet population suggesting possible mutations in proviral DNA. A complete PTLV-1 proviral genome was amplified from the patient's PBMC DNA using an overlapping PCR strategy. Phylogenetic analysis of the envelope and LTR sequences showed the virus was highly related to PTLV-1 from sooty mangabey monkeys (smm) and humans exposed via nonhuman primates in West Africa. Conclusions: These results demonstrate the patient is infected with a simian variant of PTLV-1, suggesting for the first time that PTLV-1smm infection in humans may be associated with a chronic progressive neurologic disease. C1 [Enose-Akahata, Yoshimi; Caruso, Breanna; Haner, Benjamin; Charlip, Emily; Massoud, Raya; Billioux, Bridgette J.; Ohayon, Joan; Jacobson, Steven] NINDS, Viral Immunol Sect, Neuroimmunol Branch, NIH, 9000 Rockville Pike,Bldg 10 Room 5C-103, Bethesda, MD 20892 USA. [Nair, Govind] NINDS, Translat Neuroradiol Unit, Neuroimmunol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Switzer, William M.] Ctr Dis Control & Prevent, Branch Lab, Div HIV AIDS, Natl Ctr HIV Hepatitis STD & TB Prevent, Atlanta, GA 30329 USA. RP Jacobson, S (reprint author), NINDS, Viral Immunol Sect, Neuroimmunol Branch, NIH, 9000 Rockville Pike,Bldg 10 Room 5C-103, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov FU Intramural Research Program of the NINDS, NIH FX This research was supported by the Intramural Research Program of the NINDS, NIH. NR 45 TC 1 Z9 1 U1 1 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 AUG 12 PY 2016 VL 13 AR 56 DI 10.1186/s12977-016-0290-9 PG 13 WC Virology SC Virology GA DT1RX UT WOS:000381260900001 PM 27519553 ER PT J AU Eveland, M Brokamp, GA Lue, CH Harbison, ST Leips, J De Luca, M AF Eveland, Matthew Brokamp, Gabrielle A. Lue, Chia-Hua Harbison, Susan T. Leips, Jeff De Luca, Maria TI Knockdown expression of Syndecan in the fat body impacts nutrient metabolism and the organismal response to environmental stresses in Drosophila melanogaster SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Fat body; Syndecans; Metabolism; Survival; AKT; ERK1/2 ID EXTENDS LIFE-SPAN; ENERGY-METABOLISM; GENE-EXPRESSION; CROSS-TALK; OBESITY; LOCALIZATION; TOLERANCE; PATHWAYS; BEHAVIOR; WEIGHT AB The heparan sulfate proteoglycan syndecans are transmembrane proteins involved in multiple physiological processes, including cell-matrix adhesion and inflammation. Recent evidence from model systems and humans suggest that syndecans have a role in energy balance and nutrient metabolism regulation. However, much remains to be learned about the mechanisms through which syndecans influence these phenotypes. Previously, we reported that Drosophila melanogaster Syndecan (Sdc) mutants had reduced metabolic activity compared to controls. Here, we knocked down endogenous Sdc expression in the fat body (the functional equivalent of mammalian adipose tissue and liver) to investigate whether the effects on metabolism originate from this tissue. We found that knocking down Sdc in the fat body leads to flies with higher levels of glycogen and fat and that survive longer during starvation, likely due to their extra energy reserves and an increase in gluconeogenesis. However, compared to control flies, they are also more sensitive to environmental stresses (e.g. bacterial infection and cold) and have reduced metabolic activity under normal feeding conditions. Under the same conditions, fat-body Sdc reduction enhances expression of genes involved in glyceroneogenesis and gluconeogenesis and induces a drastic decrease in phosphorylation levels of AI CT and extracellular signal regulated kinase 1/2 (ERK1/2). Altogether, these findings strongly suggest that Drosophila fat body Sdc is involved in a mechanism that shifts resources to different physiological functions according to nutritional status. (C) 2016 Elsevier Inc. All rights reserved. C1 [Eveland, Matthew; Brokamp, Gabrielle A.; De Luca, Maria] Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. [Lue, Chia-Hua; Leips, Jeff] Univ Maryland Baltimore Cty, Dept Biol Sci, Baltimore, MD 21228 USA. [Harbison, Susan T.] NHLBI, Lab Syst Genet, Bldg 10, Bethesda, MD 20892 USA. [Eveland, Matthew] Columbia Univ, Dept Biochem & Mol Biophys, Med Ctr, New York, NY 10032 USA. RP De Luca, M (reprint author), Univ Alabama Birmingham, Webb 451-1530 3rd Ave S, Birmingham, AL 35294 USA. EM mdeluca2@uab.edu RI Harbison, Susan/P-2577-2016 OI Harbison, Susan/0000-0001-7233-0947 FU National Institutes of Health [R01 DK084219]; UAB Diabetes Research Center Pilot & Feasibility Program [P30 DK079626] FX We are grateful to Michael Crowley and David K. Crossman at the UAB Heflin Center for Genomic Sciences for performing RNA sequencing analysis. This work was supported by the National Institutes of Health (R01 DK084219) and UAB Diabetes Research Center Pilot & Feasibility Program (P30 DK079626) grants to MD. NR 31 TC 1 Z9 1 U1 5 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 12 PY 2016 VL 477 IS 1 BP 103 EP 108 DI 10.1016/j.bbrc.2016.06.027 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DS0OQ UT WOS:000380297000016 PM 27289019 ER PT J AU Yeo, S Hodgkinson, CA Zhou, ZF Jung, J Leung, M Yuan, QP Goldman, D AF Yeo, Seungeun Hodgkinson, Colin A. Zhou, Zhifeng Jung, Jeesun Leung, Ming Yuan, Qiaoping Goldman, David TI The abundance of cis-acting loci leading to differential allele expression in F1 mice and their relationship to loci harboring genes affecting complex traits SO BMC GENOMICS LA English DT Article DE RNA-Seq; Differential allelic expression; cis-acting loci; Quantitative trait loci ID INBRED MOUSE STRAINS; IMPRINTED GENES; MONOALLELIC EXPRESSION; VOLUNTARY CONSUMPTION; RNA-SEQ; MICE; IDENTIFICATION; BRAIN; PHENOTYPES; ETHANOL AB Background: Genome-wide surveys have detected cis-acting quantitative trait loci altering levels of RNA transcripts (RNA-eQTLs) by associating SNV alleles to transcript levels. However, the sensitivity and specificity of detection of cis- expression quantitative trait loci (eQTLs) by genetic approaches, reliant as it is on measurements of transcript levels in recombinant inbred strains or offspring from arranged crosses, is unknown, as is their relationship to QTL's for complex phenotypes. Results: We used transcriptome-wide differential allele expression (DAE) to detect cis-eQTLs in forebrain and kidney from reciprocal crosses between three mouse inbred strains, 129S1/SvlmJ, DBA/2J, and CAST/EiJ and C57BL/6 J. Two of these crosses were previously characterized for cis-eQTLs and QTLs for various complex phenotypes by genetic analysis of recombinant inbred (RI) strains. 5.4 %, 1.9 % and 1.5 % of genes assayed in forebrain of B6/129SF1, B6/DBAF1, and B6/CASTF1 mice, respectively, showed differential allelic expression, indicative of cis-acting alleles at these genes. Moreover, the majority of DAE QTLs were observed to be tissue-specific with only a small fraction showing cis-effects in both tissues. Comparing DAE QTLs in F1 mice to cis-eQTLs previously mapped in RI strains we observed that many of the cis-eQTLs were not confirmed by DAE. Additionally several novel DAE-QTLs not identified as cis-eQTLs were identified suggesting that there are differences in sensitivity and specificity for QTL detection between the two methodologies. Strain specific DAE QTLs in B6/DBAF1 mice were located in excess at candidate genes for alcohol use disorders, seizures, and angiogenesis previously implicated by genetic linkage in C57BL/6J x DBA/2JF2 mice or BXD RI strains. Conclusions: Via a survey for differential allele expression in F1 mice, a substantial proportion of genes were found to have alleles altering expression in cis-acting fashion. Comparing forebrain and kidney, many or most of these alleles were tissue-specific in action. The identification of strain specific DAE QTLs, can assist in assessment of candidate genes located within the large intervals associated with trait QTLs. C1 [Yeo, Seungeun; Hodgkinson, Colin A.; Zhou, Zhifeng; Leung, Ming; Yuan, Qiaoping; Goldman, David] NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20852 USA. [Jung, Jeesun] NIAAA, Lab Epidemiol & Biometry, NIH, Bethesda, MD 20852 USA. RP Goldman, D (reprint author), NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20852 USA. EM davidgoldman@mail.nih.gov FU National Institutes of Health [AA000301] FX Financial support was provided by the National Institutes of Health (AA000301) NR 51 TC 1 Z9 1 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD AUG 11 PY 2016 VL 17 AR 620 DI 10.1186/s12864-016-2922-9 PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DX0JP UT WOS:000384047900012 PM 27515598 ER PT J AU Wolfe, GI Kaminski, HJ Aban, IB Minisman, G Kuo, HC Marx, A Strobel, P Mazia, C Oger, J Cea, JG Heckmann, JM Evoli, A Nix, W Ciafaloni, E Antonini, G Witoonpanich, R King, JO Beydoun, SR Chalk, CH Barboi, AC Amato, AA Shaibani, AI Katirji, B Lecky, BRF Buckley, C Vincent, A Dias-Tosta, E Yoshikawa, H Waddington-Cruz, M Pulley, MT Rivner, MH Kostera-Pruszczyk, A Pascuzzi, RM Jackson, CE Ramos, GSG Verschuuren, JJGM Massey, JM Kissel, JT Werneck, LC Benatar, M Barohn, RJ Tandan, R Mozaffar, T Conwit, R Odenkirchen, J Sonett, JR Jaretzki, A Newsom-Davis, J Cutter, GR AF Wolfe, G. I. Kaminski, H. J. Aban, I. B. Minisman, G. Kuo, H-C Marx, A. Strobel, P. Mazia, C. Oger, J. Cea, J. G. Heckmann, J. M. Evoli, A. Nix, W. Ciafaloni, E. Antonini, G. Witoonpanich, R. King, J. O. Beydoun, S. R. Chalk, C. H. Barboi, A. C. Amato, A. A. Shaibani, A. I. Katirji, B. Lecky, B. R. F. Buckley, C. Vincent, A. Dias-Tosta, E. Yoshikawa, H. Waddington-Cruz, M. Pulley, M. T. Rivner, M. H. Kostera-Pruszczyk, A. Pascuzzi, R. M. Jackson, C. E. Ramos, G. S. Garcia Verschuuren, J. J. G. M. Massey, J. M. Kissel, J. T. Werneck, L. C. Benatar, M. Barohn, R. J. Tandan, R. Mozaffar, T. Conwit, R. Odenkirchen, J. Sonett, J. R. Jaretzki, A., III Newsom-Davis, J. Cutter, G. R. CA MGTX Study Grp TI Randomized Trial of Thymectomy in Myasthenia Gravis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID EXTENDED THYMECTOMY; THORACOSCOPIC THYMECTOMY; MYCOPHENOLATE-MOFETIL; FOLLOW-UP; PREDNISONE; STANDARDS; SCORE AB BACKGROUND Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone. METHODS We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period. RESULTS A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P < 0.001); patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (44 mg vs. 60 mg, P < 0.001). Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P < 0.001) or were hospitalized for exacerbations (9% vs. 37%, P < 0.001). The number of patients with treatment-associated complications did not differ significantly between groups (P = 0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P < 0.001) and lower distress levels related to symptoms (P = 0.003). CONCLUSIONS Thymectomy improved clinical outcomes over a 3-year period in patients with nonthymomatous myasthenia gravis. (Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX ClinicalTrials.gov number, NCT00294658.) C1 [Wolfe, G. I.] Univ Buffalo, Jacobs Sch Med & Biomed Sci, Dept Neurol, 100 High St, Buffalo, NY 14203 USA. [Ciafaloni, E.] Univ Rochester, Med Ctr, Dept Neurol, Rochester, NY 14627 USA. [Sonett, J. R.; Jaretzki, A., III] Columbia Univ, Sect Gen Thorac Surg, Med Ctr, New York, NY USA. [Kaminski, H. J.] George Washington Univ, Dept Neurol, Sch Med & Hlth Sci, Washington, DC USA. [Aban, I. B.; Minisman, G.; Kuo, H-C; Cutter, G. R.] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Marx, A.] Heidelberg Univ, Inst Pathol, Univ Med Ctr Mannheim, Mannheim, Germany. [Strobel, P.] Univ Gottingen, Inst Pathol, Gottingen, Germany. [Nix, W.] Johannes Gutenberg Univ Mainz, Dept Neurol, Mainz, Germany. [Mazia, C.] Univ Buenos Aires, Dept Neurol, Buenos Aires, DF, Argentina. [Oger, J.] Univ British Columbia, Div Neurol, Vancouver, BC, Canada. [Chalk, C. H.] McGill Univ, Dept Neurol, Montreal, PQ, Canada. [Cea, J. G.] Univ Chile, Dept Neurol, Santiago, Chile. [Heckmann, J. M.] Univ Cape Town, Div Neurol, Dept Med, Cape Town, South Africa. [Evoli, A.] Catholic Univ, Dept Neurol, Rome, Italy. [Antonini, G.] Sapienza Univ Rome, Dept Neurosci Mental Hlth & Sensory Organs, Rome, Italy. [Witoonpanich, R.] Mahidol Univ, Div Neurol, Ramathibodi Hosp, Bangkok, Thailand. [King, J. O.] Univ Melbourne, Dept Neurol, Melbourne, Vic, Australia. [Beydoun, S. R.] Univ Southern Calif, Dept Neurol, Los Angeles, CA USA. [Mozaffar, T.] Univ Calif Irvine, Dept Neurol, Med Ctr, Orange, CA 92668 USA. [Barboi, A. C.] Med Coll Wisconsin, Dept Neurol, Milwaukee, WI 53226 USA. [Amato, A. A.] Harvard Med Sch, Dept Neurol, Boston, MA USA. [Shaibani, A. I.] Nerve & Muscle Ctr Texas, Houston, TX USA. [Jackson, C. E.] Univ Texas Hlth Sci Ctr San Antonio, Dept Neurol, San Antonio, TX 78229 USA. [Katirji, B.] Case Western Reserve Univ, Dept Neurol, Cleveland, OH 44106 USA. [Kissel, J. T.] Ohio State Univ, Dept Neurol, Wexner Med Ctr, Columbus, OH 43210 USA. [Lecky, B. R. F.] Walton Ctr Neurol & Neurosurg, Liverpool, Merseyside, England. [Buckley, C.; Vincent, A.; Newsom-Davis, J.] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford, England. [Dias-Tosta, E.] Univ Brasilia, Neurol Unit, Brasilia, DF, Brazil. [Waddington-Cruz, M.] Fed Univ, Dept Neurol, Rio De Janeiro, Brazil. [Werneck, L. C.] Univ Fed Parana, Dept Neurol, Curitiba, Parana, Brazil. [Yoshikawa, H.] Kanazawa Univ, Dept Neurol, Kanazawa, Ishikawa, Japan. [Pulley, M. T.] Univ Florida, Dept Neurol, Jacksonville, FL USA. [Benatar, M.] Univ Miami, Dept Neurol, Miami, FL USA. [Rivner, M. H.] Georgia Regents Univ, Dept Neurol, Augusta, GA USA. [Kostera-Pruszczyk, A.] Med Univ Warsaw, Dept Neurol, Warsaw, Poland. [Pascuzzi, R. M.] Indiana Sch Med, Dept Neurol, Indianapolis, IN USA. [Ramos, G. S. Garcia] Inst Nacl Nutr, Dept Neurol & Psychiat, Tlalpan, Mexico. [Verschuuren, J. J. G. M.] Leiden Univ Med Ctr, Dept Neurol, Leiden, Netherlands. [Massey, J. M.] Duke Univ, Med Ctr, Dept Neurol, Durham, NC USA. [Barohn, R. J.] Univ Kansas, Med Ctr, Dept Neurol, Kansas City, KS 66103 USA. [Tandan, R.] Univ Vermont, Coll Med, Dept Neurol Sci, Burlington, VT USA. [Conwit, R.; Odenkirchen, J.] NINDS, Div Extramural Res, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Wolfe, GI (reprint author), Univ Buffalo, Jacobs Sch Med & Biomed Sci, Dept Neurol, 100 High St, Buffalo, NY 14203 USA. EM gilwolfe@buffalo.edu OI Heckmann, Jeannine/0000-0002-8999-718X; Venuta, Federico/0000-0001-9296-877X FU National Institute of Neurological Disorders and Stroke FX Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX ClinicalTrials.gov number, NCT00294658. NR 32 TC 19 Z9 19 U1 7 U2 7 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 11 PY 2016 VL 375 IS 6 BP 511 EP 522 DI 10.1056/NEJMoa1602489 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DU4OT UT WOS:000382193100004 PM 27509100 ER PT J AU Silva, NCS Vale, VF Franco, PF Gontijo, NF Valenzuela, JG Pereira, MH Sant'Anna, MRV Rodrigues, DS Lima, WS Fux, B Araujo, RN AF Silva, Naylene C. S. Vale, Vladimir F. Franco, Paula F. Gontijo, Nelder F. Valenzuela, Jesus G. Pereira, Marcos H. Sant'Anna, Mauricio R. V. Rodrigues, Daniel S. Lima, Walter S. Fux, Blima Araujo, Ricardo N. TI Saliva of Rhipicephalus (Boophilus) microplus (Acari: Ixodidae) inhibits classical and alternative complement pathways SO PARASITES & VECTORS LA English DT Article DE Rhipicephalus (Boophilus) microplus; Saliva; Complement inhibition; Classical pathway; Alternative pathway ID MANNOSE-BINDING LECTIN; IXODES-DAMMINI; ANTICOMPLEMENT PROTEINS; C3 CONVERTASE; TICK; CALRETICULIN; SYSTEM; CATTLE; ACTIVATION; MECHANISM AB Background: Rhipicephalus (Boophilus) microplus is the main ectoparasite affecting livestock worldwide. For a successful parasitism, ticks need to evade several immune responses of their hosts, including the activation of the complement system. In spite of the importance of R. microplus, previous work only identified one salivary molecule that blocks the complement system. The current study describes complement inhibitory activities induced by R. microplus salivary components and mechanisms elicited by putative salivary proteins on both classical and alternative complement pathways. Results: We found that R. microplus saliva from fully-and partially engorged females was able to inhibit both pathways. Saliva acts strongly at the initial steps of both complement activation pathways. In the classical pathway, the saliva blocked C4 cleavage, and hence, deposition of C4b on the activation surface, suggesting that the inhibition occurs at some point between C1q and C4. In the alternative pathway, saliva acts by binding to initial components of the cascade (C3b and properdin) thereby preventing the C3 convertase formation and reducing C3b production and deposition as well as cleavage of factor B. Saliva has no effect on formation or decay of the C6 to C8 components of the membrane attack complex. Conclusion: The saliva of R. microplus is able to inhibit the early steps of classical and alternative pathways of the complement system. Saliva acts by blocking C4 cleavage and deposition of C4b on the classical pathway activation surface and, in the alternative pathway, saliva bind to initial components of the cascade (C3b and properdin) thereby preventing the C3 convertase formation and the production and deposition of additional C3b. C1 [Silva, Naylene C. S.; Vale, Vladimir F.; Franco, Paula F.; Gontijo, Nelder F.; Pereira, Marcos H.; Sant'Anna, Mauricio R. V.; Lima, Walter S.; Araujo, Ricardo N.] Univ Fed Minas Gerais, Dept Parasitol, Lab Fisiol Insetos Hematofagos, Belo Horizonte, MG, Brazil. [Vale, Vladimir F.] Fiocruz MS, Inst Oswaldo Cruz, Lab Simulideos & Oncocercose, Rio De Janeiro, RJ, Brazil. [Gontijo, Nelder F.; Pereira, Marcos H.] Inst Nacl Ciencia & Tecnol Entomol Mol, BR-21941591 Rio De Janeiro, Brazil. [Valenzuela, Jesus G.] NIAID, Vector Mol Biol Sect, LMVR, NIH, Rockville, MD USA. [Rodrigues, Daniel S.] Empresa Pesquisa Agr Minas Gerais, Rodovia MG 424 Km 64,Caixa Postal 295, BR-35701970 Prudente De Morais, MG, Brazil. [Fux, Blima] Univ Fed Espirito Santo, Dept Patol, Vitoria, MG, Brazil. RP Araujo, RN (reprint author), Univ Fed Minas Gerais, Dept Parasitol, Lab Fisiol Insetos Hematofagos, Belo Horizonte, MG, Brazil. EM rnaraujo@icb.ufmg.br FU Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG); Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq); INCT- Entomologia Molecular FX The work was supported by Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) and INCT- Entomologia Molecular. NR 55 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 1756-3305 J9 PARASITE VECTOR JI Parasites Vectors PD AUG 11 PY 2016 VL 9 AR 445 DI 10.1186/s13071-016-1726-8 PG 14 WC Parasitology SC Parasitology GA DW7NJ UT WOS:000383837500001 PM 27515662 ER PT J AU Horvath, S Gurven, M Levine, ME Trumble, BC Kaplan, H Allayee, H Ritz, BR Chen, B Lu, AT Rickabaugh, TM Jamieson, BD Sun, D Li, SX Chen, W Quintana-Murci, L Fagny, M Kobor, MS Tsao, PS Reiner, AP Edlefsen, KL Absher, D Assimes, TL AF Horvath, Steve Gurven, Michael Levine, Morgan E. Trumble, Benjamin C. Kaplan, Hillard Allayee, Hooman Ritz, Beate R. Chen, Brian Lu, Ake T. Rickabaugh, Tammy M. Jamieson, Beth D. Sun, Dianjianyi Li, Shengxu Chen, Wei Quintana-Murci, Lluis Fagny, Maud Kobor, Michael S. Tsao, Philip S. Reiner, Alexander P. Edlefsen, Kerstin L. Absher, Devin Assimes, Themistocles L. TI An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease SO GENOME BIOLOGY LA English DT Article DE DNA methylation; Epigenetic clock; Race; Gender; Aging; Coronary heart disease; Hispanic paradox; Black/white mortality cross-over ID DNA METHYLATION AGE; HUMAN BRAIN; ALZHEIMERS-DISEASE; TELOMERE LENGTH; PARKINSONS-DISEASE; AFRICAN-AMERICANS; UNITED-STATES; HUMAN TISSUES; ALL-CAUSE; T-CELLS AB Background: Epigenetic biomarkers of aging (the "epigenetic clock") have the potential to address puzzling findings surrounding mortality rates and incidence of cardio-metabolic disease such as: (1) women consistently exhibiting lower mortality than men despite having higher levels of morbidity; (2) racial/ethnic groups having different mortality rates even after adjusting for socioeconomic differences; (3) the black/white mortality cross-over effect in late adulthood; and (4) Hispanics in the United States having a longer life expectancy than Caucasians despite having a higher burden of traditional cardio-metabolic risk factors. Results: We analyzed blood, saliva, and brain samples from seven different racial/ethnic groups. We assessed the intrinsic epigenetic age acceleration of blood (independent of blood cell counts) and the extrinsic epigenetic aging rates of blood (dependent on blood cell counts and tracks the age of the immune system). In blood, Hispanics and Tsimane Amerindians have lower intrinsic but higher extrinsic epigenetic aging rates than Caucasians. African-Americans have lower extrinsic epigenetic aging rates than Caucasians and Hispanics but no differences were found for the intrinsic measure. Men have higher epigenetic aging rates than women in blood, saliva, and brain tissue. Conclusions: Epigenetic aging rates are significantly associated with sex, race/ethnicity, and to a lesser extent with CHD risk factors, but not with incident CHD outcomes. These results may help elucidate lower than expected mortality rates observed in Hispanics, older African-Americans, and women. C1 [Horvath, Steve; Levine, Morgan E.; Lu, Ake T.] Univ Calif Los Angeles, David Geffen Sch Med, Human Genet, Los Angeles, CA 90095 USA. [Horvath, Steve] Univ Calif Los Angeles, Sch Publ Hlth, Biostat, Los Angeles, CA 90095 USA. [Gurven, Michael; Trumble, Benjamin C.] Univ Calif Santa Barbara, Dept Anthropol, Santa Barbara, CA 93106 USA. [Kaplan, Hillard] Univ New Mexico, Dept Anthropol, Albuquerque, NM 87131 USA. [Allayee, Hooman] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. [Allayee, Hooman] Univ Southern Calif, Keck Sch Med, Inst Med Genet, Los Angeles, CA 90089 USA. [Ritz, Beate R.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90095 USA. [Chen, Brian] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Rickabaugh, Tammy M.; Jamieson, Beth D.] Univ Calif Los Angeles, AIDS Inst, Dept Med, Div Hematol Oncol, Los Angeles, CA USA. [Sun, Dianjianyi; Li, Shengxu; Chen, Wei] Tulane Univ, Dept Epidemiol, New Orleans, LA 70112 USA. [Quintana-Murci, Lluis] CNRS, Inst Pasteur, URA3012, URA3012,Unit Human Evolutionary Genet, F-75015 Paris, France. [Fagny, Maud] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Fagny, Maud] Dana Farber Canc Inst, Dept Computat Biol & Biostat, Boston, MA 02115 USA. [Kobor, Michael S.] Univ British Columbia, Ctr Mol Med & Therapeut, Child & Family Res Inst, Vancouver, BC V5Z 4H4, Canada. [Kobor, Michael S.] Univ British Columbia, Dept Med Genet, Vancouver, BC V5Z 4H4, Canada. [Tsao, Philip S.; Assimes, Themistocles L.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Tsao, Philip S.] VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Reiner, Alexander P.] Univ Washington, Fred Hutchinson Canc Res Ctr, Dept Epidemiol, Seattle, WA 98109 USA. [Edlefsen, Kerstin L.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Absher, Devin] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. RP Horvath, S (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Human Genet, Los Angeles, CA 90095 USA.; Horvath, S (reprint author), Univ Calif Los Angeles, Sch Publ Hlth, Biostat, Los Angeles, CA 90095 USA. EM shorvath@mednet.ucla.edu RI Assimes, Themistocles/D-9696-2015; OI Assimes, Themistocles/0000-0003-2349-0009; Horvath, Steve/0000-0002-4110-3589; Fagny, Maud/0000-0002-7740-2521 FU NIH/NHLBI [60442456 BAA23]; National Institutes of Health NIH/NIA [1U34AG051425-01]; National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; NIEHS [RO1ES10544, R21 ES024356]; NIH/NIA [R01AG024119, R56AG02411]; [P30AG10161]; [R01AG17917]; [RF1AG15819]; [R01AG36042] FX This study was supported by NIH/NHLBI 60442456 BAA23 (Assimes, Absher, Horvath), National Institutes of Health NIH/NIA 1U34AG051425-01 (Horvath). The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. The PEG data were supported by NIEHS RO1ES10544 (Ritz) and NIEHS R21 ES024356 (Horvath, Ritz). Gurven and Trumble were funded by NIH/NIA R01AG024119 and R56AG02411. The Religious Order study and Rush Memory and Aging Project (brain dataset 6) were funded by P30AG10161, R01AG17917, RF1AG15819, and R01AG36042. NR 89 TC 4 Z9 4 U1 18 U2 27 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 AUG 11 PY 2016 VL 17 AR 171 DI 10.1186/s13059-016-1030-0 PG 22 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DT8EH UT WOS:000381721400001 PM 27511193 ER PT J AU Boritz, EA Darko, S Swaszek, L Wolf, G Wells, D Wu, XL Henry, AR Laboune, F Hu, JF Ambrozak, D Hughes, MS Hoh, R Casazza, JP Vostal, A Bunis, D Nganou-Makamdop, K Lee, JS Migueles, SA Koup, RA Connors, M Moir, S Schacker, T Maldarelli, F Hughes, SH Deeks, SG Douek, DC AF Boritz, Eli A. Darko, Samuel Swaszek, Luke Wolf, Gideon Wells, David Wu, Xiaolin Henry, Amy R. Laboune, Farida Hu, Jianfei Ambrozak, David Hughes, Marybeth S. Hoh, Rebecca Casazza, Joseph P. Vostal, Alexander Bunis, Daniel Nganou-Makamdop, Krystelle Lee, James S. Migueles, Stephen A. Koup, Richard A. Connors, Mark Moir, Susan Schacker, Timothy Maldarelli, Frank Hughes, Stephen H. Deeks, Steven G. Douek, Daniel C. TI Multiple Origins of Virus Persistence during Natural Control of HIV Infection SO CELL LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; CD4(+) T-CELLS; ELITE SUPPRESSORS; LATENT RESERVOIR; IN-VIVO; REPLICATION; PROLIFERATION; TYPE-1; LYMPHOCYTES; ACTIVATION AB Targeted HIV cure strategies require definition of the mechanisms that maintain the virus. Here, we tracked HIV replication and the persistence of infected CD4 T cells in individuals with natural virologic control by sequencing viruses, T cell receptor genes, HIV integration sites, and cellular transcriptomes. Our results revealed three mechanisms of HIV persistence operating within distinct anatomic and functional compartments. In lymph node, we detected viruses with genetic and transcriptional attributes of active replication in both T follicular helper (T-FH) cells and non-T-FH memory cells. In blood, we detected inducible proviruses of archival origin among highly differentiated, clonally expanded cells. Linking the lymph node and blood was a small population of circulating cells harboring inducible proviruses of recent origin. Thus, HIV replication in lymphoid tissue, clonal expansion of infected cells, and recirculation of recently infected cells act together to maintain the virus in HIV controllers despite effective antiviral immunity. C1 [Boritz, Eli A.; Darko, Samuel; Swaszek, Luke; Wolf, Gideon; Henry, Amy R.; Laboune, Farida; Hu, Jianfei; Bunis, Daniel; Nganou-Makamdop, Krystelle; Lee, James S.; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Wells, David; Wu, Xiaolin] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Ambrozak, David; Casazza, Joseph P.; Koup, Richard A.] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Hughes, Marybeth S.] NCI, Thorac & Gastrointestinal Oncol Branch, NIH, Bethesda, MD 20892 USA. [Hoh, Rebecca; Deeks, Steven G.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94110 USA. [Migueles, Stephen A.; Connors, Mark; Moir, Susan] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Maldarelli, Frank; Hughes, Stephen H.] NCI, HIV Dynam & Replicat Program, NIH, Frederick, MD 21702 USA. [Schacker, Timothy] Univ Minnesota, Dept Med, Program HIV Med, Minneapolis, MN 55455 USA. RP Douek, DC (reprint author), NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. EM ddouek@mail.nih.gov OI Jianfei, Hu/0000-0001-8458-6683 FU NIH Intramural Research Program; NIAID Division of AIDS; NIH Office of AIDS Research; AIDS Vaccine Discovery grant from the Bill and Melinda Gates Foundation [OPP1032325]; Delaney AIDS Research Enterprise [AI096109]; NIAID [AI069994]; UCSF/Gladstone Institute of Virology & Immunology CFAR [P30 AI027763]; NCI FX We thank the study participants for their involvement in the study. We thank S. Kosakovsky-Pond for help with phylogenetic analysis and C. Petrovas for helpful discussions. D.C.D. and E.A.B. are funded by the NIH Intramural Research Program. D.C.D. is also funded by the NIAID Division of AIDS and the NIH Office of AIDS Research. Additional funding came from AIDS Vaccine Discovery grant OPP1032325 from the Bill and Melinda Gates Foundation (to R.A.K.), the Delaney AIDS Research Enterprise (AI096109 to S.G.D.), NIAID K24 (AI069994 to S.G.D.), the UCSF/Gladstone Institute of Virology & Immunology CFAR (P30 AI027763 to S.G.D.), and federal funds from the NCI (to F.M. and S.H.H.). NR 40 TC 9 Z9 9 U1 11 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD AUG 11 PY 2016 VL 166 IS 4 BP 1004 EP 1015 DI 10.1016/j.cell.2016.06.039 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DU5NO UT WOS:000382258700021 PM 27453467 ER PT J AU Zhao, HY Fernandez, E Dowd, KA Speer, SD Platt, DJ Gorman, MJ Govero, J Nelson, CA Pierson, TC Diamond, MS Fremont, DH AF Zhao, Haiyan Fernandez, Estefania Dowd, Kimberly A. Speer, Scott D. Platt, Derek J. Gorman, Matthew J. Govero, Jennifer Nelson, Christopher A. Pierson, Theodore C. Diamond, Michael S. Fremont, Daved H. TI Structural Basis of Zika Virus-Specific Antibody Protection SO CELL LA English DT Article ID WEST-NILE-VIRUS; CROSS-REACTIVE ANTIBODIES; TICK-BORNE ENCEPHALITIS; DENGUE VIRUS; MONOCLONAL-ANTIBODY; ENVELOPE PROTEIN; DOMAIN-III; FUSION-LOOP; NEUTRALIZATION; INFECTION AB Zika virus (ZIKV) infection during pregnancy has emerged as a global public health problem because of its ability to cause severe congenital disease. Here, we developed six mouse monoclonal antibodies (mAbs) against ZIKV including four (ZV-48, ZV-54, ZV-64, and ZV-67) that were ZIKV specific and neutralized infection of African, Asian, and American strains to varying degrees. X-ray crystallographic and competition binding analyses of Fab fragments and scFvs defined three spatially distinct epitopes in DIII of the envelope protein corresponding to the lateral ridge (ZV-54 and ZV-67), C-C' loop (ZV-48 and ZV-64), and ABDE sheet (ZV-2) regions. In vivo passive transfer studies revealed protective activity of DIII-lateral ridge specific neutralizing mAbs in a mouse model of ZIKV infection. Our results suggest that DIII is targeted by multiple type-specific antibodies with distinct neutralizing activity, which provides a path for developing prophylactic antibodies for use in pregnancy or designing epitope-specific vaccines against ZIKV. C1 [Zhao, Haiyan; Gorman, Matthew J.; Nelson, Christopher A.; Diamond, Michael S.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Fernandez, Estefania; Platt, Derek J.; Govero, Jennifer; Diamond, Michael S.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Diamond, Michael S.; Fremont, Daved H.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Fremont, Daved H.] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. [Nelson, Christopher A.; Diamond, Michael S.; Fremont, Daved H.] Washington Univ, Sch Med, Ctr Human Immunol & Immunotherapy Programs, St Louis, MO 63110 USA. [Dowd, Kimberly A.; Speer, Scott D.; Pierson, Theodore C.] NIAID, Viral Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. RP Diamond, MS (reprint author), Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA.; Diamond, MS (reprint author), Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA.; Diamond, MS; Fremont, DH (reprint author), Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA.; Fremont, DH (reprint author), Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA.; Diamond, MS; Fremont, DH (reprint author), Washington Univ, Sch Med, Ctr Human Immunol & Immunotherapy Programs, St Louis, MO 63110 USA. EM diamond@borcim.wustl.edu; fremont@wustl.edu FU NIH [R01 AI073755, R01 AI104972, T32 AI007163]; NIAID [HHSN272201400018C, HHSN272201200026C]; NIH Research Education Program [R25 HG006687]; NIAID FX This work was supported by NIH grants R01 AI073755 (to M.S.D. and D.H.F) and R01 AI104972 (to M.S.D.), and NIAID contracts HHSN272201400018C (to D.H.F. and M.S.D) and HHSN272201200026C (CSGID; to D.H.F.). E.F. and D.J.P. were supported by an NIH Pre-doctoral training grant award (T32 AI007163) and the NIH Research Education Program (R25 HG006687), respectively. K.A.D., S.D.S., and T.C.P. were funded by the intramural program of NIAID. We acknowledge Jay Nix (MBC 4.2.2 beamline at ALS Berkeley) for aid in remote data collection. M.S.D. consults for Inbios, Visterra, Sanofi, and Takeda Pharmaceuticals, is on the Scientific Advisory Boards of Moderna and OraGene, and has received research grants from Moderna, Sanofi, and Visterra. NR 53 TC 22 Z9 24 U1 23 U2 28 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD AUG 11 PY 2016 VL 166 IS 4 BP 1016 EP 1027 DI 10.1016/j.cell.2016.07.020 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DU5NO UT WOS:000382258700022 PM 27475895 ER PT J AU Lee, SM Wu, CK Plieskatt, J McAdams, DH Miura, K Ockenhouse, C King, CR AF Lee, Shwu-Maan Wu, Chia-Kuei Plieskatt, Jordan McAdams, David H. Miura, Kazutoyo Ockenhouse, Chris King, C. Richter TI Assessment of Pfs25 expressed from multiple soluble expression platforms for use as transmission-blocking vaccine candidates SO MALARIA JOURNAL LA English DT Article DE Malaria; Pfs25; Plasmodium falciparum; Transmission blocking vaccine; Baculovirus; Pichia; Glycosylation; Recombinant protein ID PLASMODIUM-FALCIPARUM; PICHIA-PASTORIS; LINKED GLYCOSYLATION; MALARIA VACCINES; SEXUAL STAGE; PROTEIN; ANTIBODIES; PEPTIDES; SEQUENCE; CRYSTALLIZATION AB Background: Transmission-blocking vaccines (TBVs) have become a focus of strategies to control and eventually eliminate malaria as they target the entry of sexual stage into the Anopheles stephensi mosquito thereby preventing transmission, an essential component of the parasite life cycle. Such vaccines are envisioned as complements to vaccines that target human infection, such as RTS, S as well as drug treatment, and vector control strategies. A number of conserved proteins, including Pfs25, have been identified as promising TBV targets in research or early stage development. Pfs25 is a 25 kDa protein of Plasmodium falciparum expressed on the surface of zygotes and ookinetes. Its complex tertiary structure, including numerous cysteines, has led to difficulties in the expression of a recombinant protein that is homogeneous, with proper conformation, and free of glycosylation, a phenomenon not found in native parasite machinery. Methods: While the expression and purification of Pfs25 in various systems, has been previously independently reported, here a parallel analysis of Pfs25 is presented to inform on the biochemical features of Pfs25 and their impact on functionality. Three scalable expression systems were used to express, purify, and evaluate Pfs25 both in vitro and in vivo, including the ability of each protein to produce functional antibodies through the standard membrane feeding assay. Results: Through numerous attempts, soluble, monomeric Pfs25 derived from Escherichia coli was not achieved, while Pichia pastoris presented Pfs25 as an inhomogeneous product with glycosylation. In comparison, baculovirus produced a pure, monomeric protein free of glycosylation. The glycosylation present for Pichia produced Pfs25, showed no notable decrease in the ability to elicit transmission reducing antibodies in functional evaluation, while a reduced and alkylated Pfs25 (derived from plant and used as a control) was found to have significantly decreased transmission reducing activity, emphasizing the importance of ensuring correct disulfide stabilized conformation during vaccine design and production. Conclusions: In this study, the biochemical features of Pfs25, produced from different expression systems, are described along with their impact on the ability of the protein to elicit functional antibodies. Pfs25 expressed using baculovirus and Pichia showed promise as candidates for vaccine development. C1 [Lee, Shwu-Maan; Wu, Chia-Kuei; Plieskatt, Jordan; Ockenhouse, Chris; King, C. Richter] PATH Malaria Vaccine Initiat MVI, 455 Massachusetts Ave NW,Suite 1000, Washington, DC 20001 USA. [McAdams, David H.] PATH, 2201 Westlake Ave,Suite 200, Seattle, WA 98121 USA. [Miura, Kazutoyo] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Lee, SM (reprint author), PATH Malaria Vaccine Initiat MVI, 455 Massachusetts Ave NW,Suite 1000, Washington, DC 20001 USA. EM smlee@path.org OI Lee, Shwu-Maan/0000-0003-0819-0569 FU Bill & Melinda Gates Foundation FX The work presented here was funded in whole or part by a grant from the Bill & Melinda Gates Foundation. The views expressed herein are solely those of the authors and do not necessarily reflect the views of the Foundation. NR 35 TC 2 Z9 2 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD AUG 11 PY 2016 VL 15 AR 405 DI 10.1186/s12936-016-1464-6 PG 12 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DT3CI UT WOS:000381357700004 PM 27515826 ER PT J AU Bennett, WD Ivins, S Alexis, NE Wu, JH Bromberg, PA Brar, SS Travlos, G London, SJ AF Bennett, William D. Ivins, Sally Alexis, Neil E. Wu, Jihong Bromberg, Philip A. Brar, Sukhdev S. Travlos, Gregory London, Stephanie J. TI Effect of Obesity on Acute Ozone-Induced Changes in Airway Function, Reactivity, and Inflammation in Adult Females SO PLOS ONE LA English DT Article ID BRONCHIAL RESPONSIVENESS; PULMONARY-FUNCTION; HUMAN-LUNG; RESPONSES; ASTHMA; MICE; METHACHOLINE; DECREMENTS; MECHANISMS; CHALLENGE AB We previously observed greater ozone-induced lung function decrements in obese than non-obese women. Animal models suggest that obesity enhances ozone-induced airway reactivity and inflammation. In a controlled exposure study, we compared the acute effect of randomized 0.4ppm ozone and air exposures (2 h with intermittent light exercise) in obese (N= 20) (30 < BMI < 40Kg/m2) vs. non- obese (N= 20) (BMI < 25Kg/m2) non- smoking 18-35 year old women. We measured spirometry and bronchial reactivity to inhaled methacholine (3h post-exposure). Inflammation and obesity markers were assessed in the blood (pre, 4h post, and 20h post exposures) and induced-sputum (4h post-exposures and on 24h preexposure training day, no exercise): measures of C reactive protein (CRP) (blood only), leptin (blood only), adiponectin, interleukins IL-6, IL-1b, and IL-8, and tumor necrosis factor alpha, and sputum cell differential cell counts. The pre-topost-exposure decrease in forced vital capacity after ozone (adjusted for the change after air exposure) was significantly greater in the obese group (12.5+/-7.5vs.8.0+/-5.8%,p < 0.05). Post ozone exposure, 6 obese and 6 non-obese subjects responded to methacholine at <= 10mg/ml ( the maximum dose); the degree of hyperresponsiveness was similar for the two groups. Both BMI groups showed similar and significant ozone-induced increases in sputum neutrophils. Plasma IL-6 was increased by exercise (4 hr post air exposure vs. pre) only in the obese but returned to pre-air exposure levels at 20hr post-exposure. Plasma IL-6 was significantly increased at 4hr post ozone exposure in both groups and returned to pre-exposure levels by 20h postexposure. These results confirm our previous findings of greater post-ozone spirometric decrements in obese young women. However, acute ozone-induced airway reactivity to methacholine and airway inflammation did not differ by obesity at the exposure and exercise levels used. C1 [Bennett, William D.; Ivins, Sally; Alexis, Neil E.; Wu, Jihong; Bromberg, Philip A.] Univ N Carolina, Ctr Environm Med Asthma & Lung Biol, Chapel Hill, NC 27599 USA. [Brar, Sukhdev S.; Travlos, Gregory; London, Stephanie J.] NIEHS, Div Intramural Res, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. RP Bennett, WD (reprint author), Univ N Carolina, Ctr Environm Med Asthma & Lung Biol, Chapel Hill, NC 27599 USA. EM William_Bennett@med.unc.edu OI London, Stephanie/0000-0003-4911-5290 FU National Institutes of Health, National Institute of Environmental Health Sciences, USEPA [CR 83578501, CR 83346301] FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences, USEPA cooperative agreement #CR 83578501, USEPA cooperative agreement #CR 83346301. NR 30 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 AUG 11 PY 2016 VL 11 IS 8 AR e0160030 DI 10.1371/journal.pone.0160030 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT3KY UT WOS:000381381100023 PM 27513854 ER PT J AU La Porta, J Matus-Nicodemos, R Valentin-Acevedo, A Covey, LR AF La Porta, James Matus-Nicodemos, Rodrigo Valentin-Acevedo, Anibal Covey, Lori R. TI The RNA-Binding Protein, Polypyrimidine Tract-Binding Protein 1 (PTBP1) Is a Key Regulator of CD4 T Cell Activation SO PLOS ONE LA English DT Article ID KINASE MESSENGER-RNA; GENE-EXPRESSION; CYCLIN D1; LIGAND EXPRESSION; POSTTRANSCRIPTIONAL REGULATION; LYMPHOCYTE DEVELOPMENT; GLUCOSE-METABOLISM; DEPENDENT MANNER; IN-VIVO; B-CELLS AB We have previously shown that the RNA binding protein, polypyrimidine tract-binding protein (PTBP1) plays a critical role in regulating the expression of CD40L in activated CD4 T cells. This is achieved mechanistically through message stabilization at late times of activation as well as by altered distribution of CD40L mRNA within distinct cellular compartments. PTBP1 has been implicated in many different processes, however whether PTBP1 plays a broader role in CD4 T cell activation is not known. To examine this question, experiments were designed to introduce shRNA into primary human CD4 T cells to achieve decreased, but not complete ablation of PTBP1 expression. Analyses of shPTB-expressing CD4 T cells revealed multiple processes including cell proliferation, activation-induced cell death and expression of activation markers and cytokines that were regulated in part by PTBP1 expression. Although there was an overall decrease in the steady-state level of several activation genes, only IL-2 and CD40L appeared to be regulated by PTBP1 at the level of RNA decay suggesting that PTBP1 is critical at different regulatory steps of expression that is gene-specific. Importantly, even though the IL-2 protein levels were reduced in cells with lowered PTBP1, the steady-state level of IL-2 mRNA was significantly higher in these cells suggesting a block at the translational level. Evaluation of T cell activation in shPTBexpressing T cells revealed that PTBP1 was linked primarily to the activation of the PLC.1/ ERK1/2 and the NF-.B pathways. Overall, our results reveal the importance of this critical RNA binding protein in multiple steps of T cell activation. C1 [La Porta, James; Matus-Nicodemos, Rodrigo; Valentin-Acevedo, Anibal; Covey, Lori R.] Rutgers State Univ, Dept Cell Biol & Neurosci, New Brunswick, NJ 08903 USA. [Matus-Nicodemos, Rodrigo] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD USA. [Valentin-Acevedo, Anibal] Univ Puerto Rico, Dept Nat Sci, Aguadilla, PR USA. RP Covey, LR (reprint author), Rutgers State Univ, Dept Cell Biol & Neurosci, New Brunswick, NJ 08903 USA. EM covey@biology.rutgers.edu FU National Institutes of Health/National Institute of Allergy and Infectious Disease [R03 AI107811-01, PO1 AI-57596] FX This work was funded in part by R03 AI107811-01 and PO1 AI-57596 (project #2) (National Institutes of Health/National Institute of Allergy and Infectious Disease)(https://www.niaid.nih.gov) to LRC. NR 76 TC 1 Z9 1 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 11 PY 2016 VL 11 IS 8 AR e0158708 DI 10.1371/journal.pone.0158708 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT3KY UT WOS:000381381100011 PM 27513449 ER PT J AU Louis, JM Baber, JL Ghirlando, R Aniana, A Bax, A Roche, J AF Louis, John M. Baber, James L. Ghirlando, Rodolfo Aniana, Annie Bax, Ad Roche, Julien TI Insights into the Conformation of the Membrane Proximal Regions Critical to the Trimerization of the HIV-1 gp41 Ectodomain Bound to Dodecyl Phosphocholine Micelles SO PLOS ONE LA English DT Article ID FUSION-ACTIVE CONFORMATION; ENVELOPE GLYCOPROTEIN; NEUTRALIZING ANTIBODY; PROTEIN GP41; SEDIMENTATION-VELOCITY; ATOMIC-STRUCTURE; MEDIATED FUSION; EXTERNAL REGION; VIRAL MEMBRANE; INTERMEDIATE AB The transitioning of the ectodomain of gp41 from a pre-hairpin to a six-helix bundle conformation is a crucial aspect of virus-cell fusion. To gain insight into the intermediary steps of the fusion process we have studied the pH and dodecyl phosphocholine (DPC) micelle dependent trimer association of gp41 by systematic deletion analysis of an optimized construct termed 17-172 (residues 528 to 683 of Env) that spans the fusion peptide proximal region (FPPR) to the membrane proximal external region (MPER) of gp41, by sedimentation velocity and double electron-electron resonance (DEER) EPR spectroscopy. Trimerization at pH 7 requires the presence of both the FPPR and MPER regions. However, at pH 4, the protein completely dissociates to monomers. DEER measurements reveal a partial fraying of the C-terminal MPER residues in the 17-172 trimer while the other regions, including the FPPR, remain compact. In accordance, truncating nine C-terminal MPER residues (675-683) in the 17-172 construct does not shift the trimer-monomer equilibrium significantly. Thus, in the context of the gp41 ectodomain spanning residues 17-172, trimerization is clearly dependent on FPPR and MPER regions even when the terminal residues of MPER unravel. The antibody Z13e1, which spans both the 2F5 and 4E10 epitopes in MPER, binds to 17-172 with a K-d of 1 +/- 0.12 mu M. Accordingly, individual antibodies 2F5 and 4E10 also recognize the 17-172 trimer/DPC complex. We propose that binding of the C-terminal residues of MPER to the surface of the DPC micelles models a correct positioning of the trimeric transmembrane domain anchored in the viral membrane. C1 [Louis, John M.; Baber, James L.; Aniana, Annie; Bax, Ad; Roche, Julien] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Roche, Julien] Iowa State Univ, Roy J Carver Dept Biochem Biophys & Mol Biol, Ames, IA USA. RP Louis, JM; Roche, J (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA.; Roche, J (reprint author), Iowa State Univ, Roy J Carver Dept Biochem Biophys & Mol Biol, Ames, IA USA. EM johnl@niddk.nih.gov; julien.roche@nih.gov FU Intramural Research Program of the NIDDK; National Institutes of Health; NIH FX This research was supported by the Intramural Research Program of the NIDDK, National Institutes of Health and the Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH. NR 55 TC 0 Z9 0 U1 11 U2 13 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 AUG 11 PY 2016 VL 11 IS 8 AR e0160597 DI 10.1371/journal.pone.0160597 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT3KY UT WOS:000381381100047 PM 27513582 ER PT J AU Cobos, AJ Nelson, CG Jehn, M Viboud, C Chowell, G AF Cobos, April J. Nelson, Clinton G. Jehn, Megan Viboud, Cecile Chowell, Gerardo TI Mortality and transmissibility patterns of the 1957 influenza pandemic in Maricopa County, Arizona SO BMC INFECTIOUS DISEASES LA English DT Article DE 1957 influenza; H2N2 virus; Asian influenza; Mathematical epidemiology; Mortality rates; Transmissibility; Reproduction number; Maricopa County; Arizona ID EXCESS MORTALITY; REPRODUCTION NUMBER; EPIDEMIC INFLUENZA; WAVE; REGIONS AB Background: While prior studies have quantified the mortality burden of the 1957 H2N2 influenza pandemic at broad geographic regions in the United States, little is known about the pandemic impact at a local level. Here we focus on analyzing the transmissibility and mortality burden of this pandemic in Arizona, a setting where the dry climate was promoted as reducing respiratory illness transmission yet tuberculosis prevalence was high. Methods: Using archival death certificates from 1954 to 1961, we quantified the age-specific seasonal patterns, excess-mortality rates, and transmissibility patterns of the 1957 H2N2 pandemic in Maricopa County, Arizona. By applying cyclical Serfling linear regression models to weekly mortality rates, the excess-mortality rates due to respiratory and all-causes were estimated for each age group during the pandemic period. The reproduction number was quantified from weekly data using a simple growth rate method and assumed generation intervals of 3 and 4 days. Local newspaper articles published during 1957-1958 were also examined. Results: Excess-mortality rates varied between waves, age groups, and causes of death, but overall remained low. From October 1959-June 1960, the most severe wave of the pandemic, the absolute excess-mortality rate based on respiratory deaths per 10,000 population was 16.59 in the elderly (>= 65 years). All other age groups exhibit very low excess-mortality and the typical U-shaped age-pattern was absent. However, the standardized mortality ratio was greatest (4.06) among children and young adolescents (5-14 years) from October 1957-March 1958, based on mortality rates of respiratory deaths. Transmissibility was greatest during the same 1957-1958 period, when the mean reproduction number was estimated at 1.08-1.11, assuming 3- or 4-day generation intervals with exponential or fixed distributions. Conclusions: Maricopa County exhibited very low mortality impact associated with the 1957 influenza pandemic. Understanding the relatively low excess-mortality rates and transmissibility in Maricopa County during this historic pandemic may help public health officials prepare for and mitigate future outbreaks of influenza. C1 [Cobos, April J.; Nelson, Clinton G.; Jehn, Megan; Chowell, Gerardo] Arizona State Univ, Sch Human Evolut & Social Change, Tempe, AZ 85281 USA. [Cobos, April J.; Nelson, Clinton G.] Arizona State Univ, Sch Life Sci, Tempe, AZ USA. [Cobos, April J.] Arizona State Univ, Barrett Honors Coll, Tempe, AZ USA. [Viboud, Cecile; Chowell, Gerardo] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Chowell, Gerardo] Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA. RP Chowell, G (reprint author), Arizona State Univ, Sch Human Evolut & Social Change, Tempe, AZ 85281 USA.; Chowell, G (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM gchowell@gsu.edu FU Multinational Influenza Seasonal Mortality Study (MISMS) FX We would like to thank the undergraduate students who assisted in collecting the raw data. April Cobos would like to thank Melinda Jenner for advice on mathematical modeling tools. This work was partially supported by the Multinational Influenza Seasonal Mortality Study (MISMS), an on-going international collaborative effort to understand influenza epidemiological and evolutionary patterns, led by the Fogarty International Center, National Institutes of Health (http://www.origem.info/misms/index.php). NR 44 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 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD AUG 11 PY 2016 VL 16 AR 405 DI 10.1186/s12879-016-1716-7 PG 14 WC Infectious Diseases SC Infectious Diseases GA DT2YP UT WOS:000381348000006 PM 27516082 ER PT J AU Stavreva, DA Varticovski, L Levkova, L George, AA Davis, L Pegoraro, G Blazer, V Iwanowicz, L Hager, GL AF Stavreva, Diana A. Varticovski, Lyuba Levkova, Ludmila George, Anuja A. Davis, Luke Pegoraro, Gianluca Blazer, Vicki Iwanowicz, Luke Hager, Gordon L. TI Novel cell-based assay for detection of thyroid receptor beta-interacting environmental contaminants SO TOXICOLOGY LA English DT Article DE EDCs; TR beta; High-throughput cell assay; BPA; TBBPA ID ENDOCRINE-DISRUPTING CHEMICALS; GREEN FLUORESCENT PROTEIN; REPORTER GENE ASSAY; IN-VITRO; HORMONE DISRUPTION; REPRODUCTIVE HEALTH; NUCLEAR RECEPTORS; LIVING CELLS; BISPHENOL-A; TRANSLOCATION AB Even though the presence of endocrine disrupting chemicals (EDCs) with thyroid hormone (TH)-like activities in the environment is a major health concern, the methods for their efficient detection and monitoring are still limited. Here we describe a novel cell assay, based on the translocation of a green fluorescent protein (GFP) tagged chimeric molecule of glucocorticoid receptor (GR) and the thyroid receptor beta (TR beta) from the cytoplasm to the nucleus in the presence of TR ligands. Unlike the constitutively nuclear TR beta, this GFP-GR-TR beta chimera is cytoplasmic in the absence of hormone while translocating to the nucleus in a time- and concentration-dependent manner upon stimulation with triiodothyronine (T3) and thyroid hormone analogue, TRIAC, while the reverse triiodothyronine (3,3',5'-triiodothyronine, or rT3) was inactive. Moreover, GFP-GR-TR beta chimera does not show any cross reactivity with the GR-activating hormones, thus providing a clean system for the screening of TR beta interacting EDCs. Using this assay, we demonstrated that Bisphenol A (BPA) and 3,3',5,5'-Tetrabromobisphenol (TBBPA) induced GFP-GR-TR beta translocation at micro molar concentrations. We screened over 100 concentrated water samples from different geographic locations in the United States and detected a low, but reproducible contamination in 53% of the samples. This system provides a novel high throughput approach for screening for endocrine disrupting chemicals (EDCs) interacting with TR beta. Published by Elsevier Ireland Ltd. C1 [Stavreva, Diana A.; Varticovski, Lyuba; George, Anuja A.; Davis, Luke; Pegoraro, Gianluca; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bldg 41,B602,41 Lib Dr, Bethesda, MD 20892 USA. [Levkova, Ludmila] Univ Utah, Dept Phys & Astron, Phys & Astron, Salt Lake City, UT USA. [Blazer, Vicki; Iwanowicz, Luke] US Geol Survey, Leetown Sci Ctr, Natl Fish Hlth Res Lab, 11649 Leetown Rd, Kearneysville, WV 25430 USA. [George, Anuja A.] Rutgers Robert Wood Johnson Med Sch, Dept Pharmacol, 675 Hoes Lane, Piscataway, NJ 08854 USA. [Davis, Luke] Tulane Univ, 6823 St Charles Ave, New Orleans, LA 70118 USA. RP Stavreva, DA; Hager, GL (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bldg 41,B602,41 Lib Dr, Bethesda, MD 20892 USA. EM stavrevd@mail.nih.gov; hagerg@exchange.nih.gov RI George, Anuja/C-5963-2017; OI George, Anuja/0000-0003-2643-6307; Iwanowicz, Luke/0000-0002-1197-6178 FU Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NCI High Throughput Facility FX This study has been funded in whole or in part with Federal funds from the Intramural Research Program of the NIH, Center for Cancer Research, 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. The use of trade, firm, or product names is for descriptive purposes only and does not imply endorsement by the U.S. Government. We acknowledge the support of the NCI High Throughput Facility. We also acknowledge the assistance of Tatiana Karpova, LRBGE Fluorescence Imaging Facility. NR 46 TC 0 Z9 0 U1 4 U2 4 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 AUG 10 PY 2016 VL 368 BP 69 EP 79 DI 10.1016/j.tox.2016.08.012 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA EB2NO UT WOS:000387199300008 PM 27528272 ER PT J AU Shenai, S Ronacher, K Malherbe, S Stanley, K Kriel, M Winter, J Peppard, T Barry, CE Wang, J Dodd, LE Via, LE Barry, CE Walzl, G Alland, D AF Shenai, Shubhada Ronacher, Katharina Malherbe, Stefanus Stanley, Kim Kriel, Magdalena Winter, Jill Peppard, Thomas Barry, Charles E. Wang, Jing Dodd, Lori E. Via, Laura E. Barry, Clifton E., III Walzl, Gerhard Alland, David TI Bacterial Loads Measured by the Xpert MTB/RIF Assay as Markers of Culture Conversion and Bacteriological Cure in Pulmonary TB SO PLOS ONE LA English DT Article ID TUBERCULOSIS TREATMENT; MYCOBACTERIUM-TUBERCULOSIS; RIFAMPIN RESISTANCE; TREATMENT RESPONSE; CLINICAL-TRIALS; TIME; BIOMARKERS; RELAPSE; LIQUID; RISK AB Introduction Biomarkers are needed to monitor tuberculosis (TB) treatment and predict treatment outcomes. We evaluated the Xpert MTB/RIF (Xpert) assay as a biomarker for TB treatment during and at the end of the 24 weeks therapy. Methods Sputum from 108 HIV-negative, culture-positive pulmonary TB patients was analyzed using Xpert at time points before and during anti-TB therapy. Results were compared against culture. Direct Xpert cycle-threshold (Ct), a change in the Ct (delta Ct), or a novel "percent closing of baseline Ct deficit" (percent closing) were evaluated as classifiers of same-day and end-of-treatment culture and therapeutic outcomes. Results Xpert was positive in 29/95 (30.5%) of subjects at week 24; and positive one year after treatment in 8/64 (12.5%) successfully-treated patients who remained free of tuberculosis. We identified a relationship between initial bacterial load measured by baseline Xpert Ct and time to culture conversion (hazard ratio 1.06, p = 0.0023), and to the likelihood of being among the 8 treatment failures at week 24 (AUC = 72.8%). Xpert Ct was even more strongly associated with culture conversion on the day the test was performed with AUCs 96.7%, 99.2%, 86.0% and 90.2%, at Day 7, Week 4, 8 and 24, respectively. Compared to baseline Ct measures alone, a combined measure of baseline Ct plus either Delta Ct or percent closing improved the classification of treatment failure status to a 75% sensitivity and 88.9% specificity. Conclusions Genome loads measured by Xpert provide a potentially-useful biomarker for classifying same day culture status and predicting response to therapy. C1 [Shenai, Shubhada; Alland, David] Rutgers Biomed & Hlth Sci, Rutgers New Jersey Med Sch, Div Infect Dis, 185 South Orange Ave, Newark, NJ 07103 USA. [Ronacher, Katharina; Malherbe, Stefanus; Stanley, Kim; Kriel, Magdalena; Walzl, Gerhard] Univ Stellenbosch, Fac Med & Hlth Sci, DST NRF Ctr Excellence Biomed TB Res, Cape Town, South Africa. [Ronacher, Katharina; Malherbe, Stefanus; Stanley, Kim; Kriel, Magdalena; Walzl, Gerhard] Univ Stellenbosch, Fac Med & Hlth Sci, MRC Ctr TB Res, Div Mol Biol & Human Genet,Dept Biomed Sci, Cape Town, South Africa. [Winter, Jill] Catalysis Fdn Hlth, Emeryville, CA 94608 USA. [Peppard, Thomas] Certara LP, Greater Detroit Area, Detroit, MI 48226 USA. [Barry, Charles E.] Brown Univ, Providence, RI 02912 USA. [Wang, Jing] Leidos Biomed Res Inc, Clin Monitoring Res Program, Clin Res Directorate, NCI Campus Frederick, Frederick, MD USA. [Dodd, Lori E.] NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [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, Fac Hlth Sci, Inst Infect Dis & Mol Med, ZA-7701 Rondebosch, South Africa. [Via, Laura E.; Barry, Clifton E., III] Univ Cape Town, Fac Hlth Sci, Dept Clin Lab Sci, ZA-7701 Rondebosch, South Africa. RP Alland, D (reprint author), Rutgers Biomed & Hlth Sci, Rutgers New Jersey Med Sch, Div Infect Dis, 185 South Orange Ave, Newark, NJ 07103 USA. EM allandda@njms.rutgers.edu RI Ronacher, Katharina/N-9603-2016 OI Ronacher, Katharina/0000-0002-6371-1462 FU Catalysis Foundation for Health; Intramural Research Program of the NIAID, National Institutes of Health; Intramural Research program of the NIAID, NIH [OPP51919]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported the Catalysis Foundation for Health and by the Intramural Research Program of the NIAID, National Institutes of Health (CEB), by the Intramural Research program of the NIAID, NIH (CEB) Grant No - OPP51919, and with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We thank all patients for participation in this study and the clinic and Laboratory staff from the Stellenbosch University, Cape Town, South Africa for technical assistance. This work was supported by the Catalysis Foundation for Health and by the Intramural Research Program of the NIAID, National Institutes of Health (CEB), by the Intramural Research program of the NIAID, NIH (CEB) Grant No-OPP51919, and with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 1 Z9 1 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 AUG 10 PY 2016 VL 11 IS 8 AR e0160062 DI 10.1371/journal.pone.0160062 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT3KR UT WOS:000381380400020 PM 27508390 ER PT J AU Shin, SY Kim, S Wilbur, WJ Kwon, D AF Shin, Soo-Yong Kim, Sun Wilbur, W. John Kwon, Dongseop TI BioC viewer: a web-based tool for displaying and merging annotations in BioC SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article AB BioC is an XML-based format designed to provide interoperability for text mining tools and manual curation results. A challenge of BioC as a standard format is to align annotations from multiple systems. Ideally, this should not be a major problem if users follow guidelines given by BioC key files. Nevertheless, the misalignment between text and annotations happens quite often because different systems tend to use different software development environments, e.g. ASCII vs. Unicode. We first implemented the BioC Viewer to assist BioGRID curators as a part of the BioCreative V BioC track (Collaborative Biocurator Assistant Task). For the BioC track, the BioC Viewer helped curate protein-protein interaction and genetic interaction pairs appearing in full-text articles. Here, we describe the BioC Viewer itself as well as improvements made to the BioC Viewer since the BioCreative V Workshop to address the misalignment issue of BioC annotations. While uploading BioC files, a BioC merge process is offered when there are files from the same full-text article. If there is a mismatch between an annotated offset and text, the BioC Viewer adjusts the offset to correctly align with the text. The BioC Viewer has a user-friendly interface, where most operations can be performed within a few mouse clicks. The feedback from BioGRID curators has been positive for the web interface, particularly for its usability and learnability. C1 [Shin, Soo-Yong] Asan Med Ctr, Dept Biomed Informat, Seoul 05505, South Korea. [Kim, Sun; Wilbur, W. John] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Kwon, Dongseop] Myongji Univ, Deptartment Comp Engn, Yongin 17058, Gyeonggi Do, South Korea. RP Kwon, D (reprint author), Myongji Univ, Deptartment Comp Engn, Yongin 17058, Gyeonggi Do, South Korea. EM dongseop@mju.ac.kr FU Myongji University; Genome Program for Fostering New Post-Genome Industry of National Research Foundation (NRF) - Korean government (MSIP) [NRF-2014M3C9A3064706]; Asan Institute for Life Sciences [2013-7205]; Intramural Research Program of National Institutes of Health, National Library of Medicine FX The 2007 Research Fund of Myongji University to D.K.; The Genome Program for Fostering New Post-Genome Industry of the National Research Foundation (NRF) funded by the Korean government (MSIP) (NRF-2014M3C9A3064706) to D.K.; The grant (2013-7205) from the Asan Institute for Life Sciences to S.Y.S.; Intramural Research Program of the National Institutes of Health, National Library of Medicine to S.K. and W.J.W. NR 15 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD AUG 10 PY 2016 AR baw106 DI 10.1093/database/baw106 PG 7 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA DT5KI UT WOS:000381521700001 ER PT J AU Schmidt, MK Hogervorst, F van Hien, R Cornelissen, S Broeks, A Adank, MA Meijers, H Waisfisz, Q Hollestelle, A Schutte, M van den Ouweland, A Hooning, M Andrulis, IL Anton-Culver, H Antonenkova, NN Antoniou, AC Arndt, V Bermisheva, M Bogdanova, NV Bolla, MK Brauch, H Brenner, H Bruning, T Burwinkel, B Chang-Claude, J Chenevix-Trench, G Couch, FJ Cox, A Cross, SS Czene, K Dunning, AM Fasching, PA Figueroa, J Fletcher, O Flyger, H Galle, E Garcia-Closas, M Giles, GG Haeberle, L Hall, P Hillemanns, P Hopper, JL Jakubowska, A John, EM Jones, M Khusnutdinova, E Knight, JA Kosma, VM Kristensen, V Lee, A Lindblom, A Lubinski, J Mannermaa, A Margolin, S Meindl, A Milne, RL Muranen, TA Newcomb, PA Offit, K Park-Simon, TW Peto, J Pharoah, PDP Robson, M Rudolph, A Sawyer, EJ Schmutzler, RK Seynaeve, C Soens, J Southey, MC Spurdle, AB Surowy, H Swerdlow, A Tollenaar, RAEM Tomlinson, I Trentham-Dietz, A Vachon, C Wang, Q Whittemore, AS Ziogas, A van der Kolk, L Nevanlinna, H Dork, T Bojesen, S Easton, DF AF Schmidt, Marjanka K. Hogervorst, Frans van Hien, Richard Cornelissen, Sten Broeks, Annegien Adank, Muriel A. Meijers, Hanne Waisfisz, Quinten Hollestelle, Antoinette Schutte, Mieke van den Ouweland, Ans Hooning, Maartje Andrulis, Irene L. Anton-Culver, Hoda Antonenkova, Natalia N. Antoniou, Antonis C. Arndt, Volker Bermisheva, Marina Bogdanova, Natalia V. Bolla, Manjeet K. Brauch, Hiltrud Brenner, Hermann Bruning, Thomas Burwinkel, Barbara Chang-Claude, Jenny Chenevix-Trench, Georgia Couch, Fergus J. Cox, Angela Cross, Simon S. Czene, Kamila Dunning, Alison M. Fasching, Peter A. Figueroa, Jonine Fletcher, Olivia Flyger, Henrik Galle, Eva Garcia-Closas, Montserrat Giles, Graham G. Haeberle, Lothar Hall, Per Hillemanns, Peter Hopper, John L. Jakubowska, Anna John, Esther M. Jones, Michael Khusnutdinova, Elza Knight, Julia A. Kosma, Veli-Matti Kristensen, Vessela Lee, Andrew Lindblom, Annika Lubinski, Jan Mannermaa, Arto Margolin, Sara Meindl, Alfons Milne, Roger L. Muranen, Taru A. Newcomb, Polly A. Offit, Kenneth Park-Simon, Tjoung-Won Peto, Julian Pharoah, Paul D. P. Robson, Mark Rudolph, Anja Sawyer, Elinor J. Schmutzler, Rita K. Seynaeve, Caroline Soens, Julie Southey, Melissa C. Spurdle, Amanda B. Surowy, Harald Swerdlow, Anthony Tollenaar, Rob A. E. M. Tomlinson, Ian Trentham-Dietz, Amy Vachon, Celine Wang, Qin Whittemore, Alice S. Ziogas, Argyrios van der Kolk, Lizet Nevanlinna, Heli Doerk, Thilo Bojesen, Stig Easton, Douglas F. TI Age- and Tumor Subtype Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID WOMEN; MUTATION; 1100DELC; CHEK2; SUSCEPTIBILITY; PREDICTION; CHK2; KINASES; SURGERY; BRCA1 AB Purpose CHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtype and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC. Patients and Methods CHEK71100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK71100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies. Results Proportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 x 10(-20)). The OR was higher for estrogen receptor (ER) positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 x 10(-21)]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 x 10(-4)). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom. Conclusion These CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into guidelines for intensified screening and follow-up. J Clin Oncol 34:2750-2760. (C) 2016 by American Society of Clinical Oncology C1 [Schmidt, Marjanka K.; Hogervorst, Frans; van Hien, Richard; Cornelissen, Sten; Broeks, Annegien; van der Kolk, Lizet] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Adank, Muriel A.; Meijers, Hanne; Waisfisz, Quinten] Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands. [Hollestelle, Antoinette; Schutte, Mieke; Hooning, Maartje; Seynaeve, Caroline] Erasmus MC, Inst Canc, Rotterdam, Netherlands. [van den Ouweland, Ans] Erasmus MC, Rotterdam, Netherlands. [Tollenaar, Rob A. E. M.] Leiden Univ, Med Ctr, Leiden, Netherlands. [Andrulis, Irene L.; Knight, Julia A.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, New York, NY USA. [Andrulis, Irene L.; Knight, Julia A.] Univ Toronto, Toronto, ON, Canada. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Irvine, CA USA. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [John, Esther M.; Whittemore, Alice S.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Antonenkova, Natalia N.] NN Alexandrov Res Inst Oncol & Med Radiol, Minsk, Byelarus. [Antoniou, Antonis C.; Bolla, Manjeet K.; Dunning, Alison M.; Lee, Andrew; Pharoah, Paul D. P.; Wang, Qin; Easton, Douglas F.] Univ Cambridge, Cambridge CB2 1TN, England. [Cox, Angela; Cross, Simon S.] Univ Sheffield, Sheffield, S Yorkshire, England. [Fletcher, Olivia; Jones, Michael; Swerdlow, Anthony] Kings Coll London, Inst Canc Res, London WC2R 2LS, England. [Peto, Julian] Kings Coll London, London Sch Hyg & Trop Med, London WC2R 2LS, England. [Sawyer, Elinor J.] Kings Coll London, London WC2R 2LS, England. [Figueroa, Jonine] Univ Edinburgh, Sch Med, Edinburgh, Midlothian, Scotland. [Tomlinson, Ian] Univ Oxford, Oxford, England. [Arndt, Volker; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Chang-Claude, Jenny; Rudolph, Anja; Surowy, Harald] German Canc Res Ctr, Heidelberg, Germany. [Burwinkel, Barbara; Surowy, Harald] Heidelberg Univ, Bergheimer Str 58, D-69115 Heidelberg, Germany. [Bogdanova, Natalia V.; Hillemanns, Peter; Park-Simon, Tjoung-Won; Doerk, Thilo] Hannover Med Sch, Hannover, Germany. [Brauch, Hiltrud] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, Tubingen, Germany. [Bruning, Thomas] Inst Ruhr Univ Bochum, German Social Accid Insurance, Bochum, Germany. [Chang-Claude, Jenny] Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany. Friedrich Alexander Univ Erlangen Nuremberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Erlangen, Germany. [Meindl, Alfons] Tech Univ Munich, Munich, Germany. [Schmutzler, Rita K.] Univ Hosp Cologne, Cologne, Germany. [Schmutzler, Rita K.] Univ Cologne, Cologne, Germany. [Bermisheva, Marina] Russian Acad Sci, Ufa Sci Ctr, Moscow, Russia. [Khusnutdinova, Elza] Bashkir State Univ, Ufa, Russia. [Chenevix-Trench, Georgia; Spurdle, Amanda B.] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. [Giles, Graham G.; Milne, Roger L.] Canc Council Victoria, Melbourne, Vic, Australia. [Giles, Graham G.; Hopper, John L.; Milne, Roger L.; Southey, Melissa C.] Univ Melbourne, Melbourne, Vic, Australia. [Couch, Fergus J.; Vachon, Celine] Mayo Clin, Rochester, MN USA. [Czene, Kamila; Hall, Per; Lindblom, Annika; Margolin, Sara] Karolinska Inst, Stockholm, Sweden. [Figueroa, Jonine; Garcia-Closas, Montserrat] NCI, Rockville, MD USA. [Flyger, Henrik; Bojesen, Stig] Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Herlev, Denmark. [Bojesen, Stig] Univ Copenhagen, Copenhagen, Denmark. [Galle, Eva] Univ Leuven, Leuven, Belgium. [Galle, Eva] Vesalius Res Ctr, Leuven, Belgium. [Soens, Julie] Univ Hosp Gasthuisberg, Leuven, Belgium. [Jakubowska, Anna; Lubinski, Jan] Pomeranian Med Univ, Szczecin, Poland. [Kosma, Veli-Matti; Mannermaa, Arto] Univ Eastern Finland, Joensuu, Finland. [Kosma, Veli-Matti; Mannermaa, Arto] Kuopio Univ Hosp, Kuopio, Finland. [Muranen, Taru A.; Nevanlinna, Heli] Univ Helsinki, Helsinki, Finland. [Kristensen, Vessela] Radiumhosp, Oslo Univ Hosp, Oslo, Norway. [Kristensen, Vessela] Univ Oslo, Oslo, Norway. [Newcomb, Polly A.; Trentham-Dietz, Amy] Univ Wisconsin, Madison, WI USA. [Newcomb, Polly A.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Offit, Kenneth; Robson, Mark] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. RP Schmidt, MK (reprint author), Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Mol Pathol, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands.; Schmidt, MK (reprint author), Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Psychosocial Res & Epidemiol, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. EM mk.schmidt@nki.nl RI Knight, Julia/A-6843-2012; Bruning, Thomas/G-8120-2015; Dork, Thilo/J-8620-2012; Khusnutdinova, Elza/A-4810-2013; Brenner, Hermann/B-4627-2017; OI Bruning, Thomas/0000-0001-9560-5464; Brenner, Hermann/0000-0002-6129-1572; Muranen, Taru/0000-0002-5895-1808; Dunning, Alison Margaret/0000-0001-6651-7166 FU Cancer Research UK [10118, 10119, 10124, 11174]; NCI NIH HHS [P50 CA116201, K07 CA092044, R01 CA047147, R01 CA047305, R01 CA058860, R01 CA069664, R01 CA116167, R01 CA176785, R01 CA192393, U01 CA058860, U01 CA116167, UM1 CA164920] NR 28 TC 4 Z9 4 U1 8 U2 10 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 AUG 10 PY 2016 VL 34 IS 23 BP 2750 EP + DI 10.1200/JCO.2016.66.5844 PG 25 WC Oncology SC Oncology GA DU8MF UT WOS:000382467000012 PM 27269948 ER PT J AU Lopatina, N McDannald, MA Styer, CV Peterson, JF Sadacca, BF Cheer, JF Schoenbaum, G AF Lopatina, Nina McDannald, Michael A. Styer, Clay V. Peterson, Jacob F. Sadacca, Brian F. Cheer, Joseph F. Schoenbaum, Geoffrey TI Medial Orbitofrontal Neurons Preferentially Signal Cues Predicting Changes in Reward during Unblocking SO JOURNAL OF NEUROSCIENCE LA English DT Article DE orbitofrontal; Pavlovian; rat; single unit ID VENTROMEDIAL PREFRONTAL CORTEX; DECISION-MAKING; ECONOMIC VALUE; REINFORCER DEVALUATION; BASOLATERAL AMYGDALA; GOAL VALUES; REPRESENTATION; BRAIN AB The orbitofrontal cortex (OFC) has been broadly implicated in the ability to use the current value of expected outcomes to guide behavior. Although value correlates have been prominently reported in lateral OFC, they are more often associated with more medial areas. Further, recent studies in primates have suggested a dissociation in which the lateral OFC is involved in credit assignment and representation of reward identity and more medial areas are critical to representing value. Previously, we used unblocking to test more specifically what information about outcomes is represented by OFC neurons in rats; consistent with the proposed dichotomy between the lateral and medial OFC, we found relatively little linear value coding in the lateral OFC (Lopatina et al., 2015). Here we have repeated this experiment, recording in the medial OFC, to test whether such value signals might be found there. Neurons were recorded in an unblocking task as rats learned about cues that signaled either more, less, or the same amount of reward. We found that medial OFC neurons acquired responses to these cues; however, these responses did not signal different reward values across cues. Surprisingly, we found that cells developed responses to cues predicting a change, particularly a decrease, in reward value. This is consistent with a special role for medial OFC in representing current value to support devaluation/revaluation sensitive changes in behavior. C1 [Lopatina, Nina; Styer, Clay V.; Peterson, Jacob F.; Sadacca, Brian F.; Schoenbaum, Geoffrey] Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD 21224 USA. [McDannald, Michael A.] Boston Coll, Dept Psychol, Chestnut Hill, MA 02467 USA. [Lopatina, Nina] Univ Maryland, Sch Med, Program Neurosci, Baltimore, MD 21201 USA. [Cheer, Joseph F.; Schoenbaum, Geoffrey] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Schoenbaum, Geoffrey] Johns Hopkins Univ, Dept Neurosci, Baltimore, MD 21205 USA. RP Schoenbaum, G (reprint author), Behav Neurophysiol Res Sect, Cellular Neurobiol Res Branch, 251 Bayview Blvd,Suite 200,Bldg BRC,Room 06A705, Baltimore, MD 21224 USA. EM geoffrey.schoenbaum@nih.gov OI Sadacca, Brian/0000-0003-1425-6077 FU Intramural Research Program at the National Institute on Drug Abuse FX This work was supported by the Intramural Research Program at the National Institute on Drug Abuse. The opinions expressed in this article are the authors' own and do not reflect the view of the National Institutes of Health/Department of Health and Human Services. NR 26 TC 0 Z9 0 U1 5 U2 5 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 AUG 10 PY 2016 VL 36 IS 32 BP 8416 EP 8424 DI 10.1523/JNEUROSCI.1101-16.2016 PG 9 WC Neurosciences SC Neurosciences & Neurology GA DU6GQ UT WOS:000382312700012 PM 27511013 ER PT J AU Tran, TM Jones, MB Ongoiba, A Bijker, EM Schats, R Venepally, P Skinner, J Doumbo, S Quinten, E Visser, LG Whalen, E Presnell, S O'Connell, EM Kayentao, K Doumbo, OK Chaussabel, D Lorenzi, H Nutman, TB Ottenhoff, THM Haks, MC Traore, B Kirkness, EF Sauerwein, RW Crompton, PD AF Tran, Tuan M. Jones, Marcus B. Ongoiba, Aissata Bijker, Else M. Schats, Remko Venepally, Pratap Skinner, Jeff Doumbo, Safiatou Quinten, Edwin Visser, Leo G. Whalen, Elizabeth Presnell, Scott O'Connell, Elise M. Kayentao, Kassoum Doumbo, Ogobara K. Chaussabel, Damien Lorenzi, Hernan Nutman, Thomas B. Ottenhoff, Tom H. M. Haks, Marielle C. Traore, Boubacar Kirkness, Ewen F. Sauerwein, Robert W. Crompton, Peter D. TI Transcriptomic evidence for modulation of host inflammatory responses during febrile Plasmodium falciparum malaria SO SCIENTIFIC REPORTS LA English DT Article ID DIFFERENTIAL EXPRESSION ANALYSIS; ACQUIRED-IMMUNITY; GENE-EXPRESSION; PERIPHERAL-BLOOD; PROTECTION; INFECTION; CHILDREN; COHORT AB Identifying molecular predictors and mechanisms of malaria disease is important for understanding how Plasmodium falciparum malaria is controlled. Transcriptomic studies in humans have so far been limited to retrospective analysis of blood samples from clinical cases. In this prospective, proof-of-principle study, we compared whole-blood RNA-seq profiles at pre- and post-infection time points from Malian adults who were either asymptomatic (n = 5) or febrile (n = 3) during their first seasonal PCR-positive P. falciparum infection with those from malaria-naive Dutch adults after a single controlled human malaria infection (n = 5). Our data show a graded activation of pathways downstream of pro-inflammatory cytokines, with the highest activation in malaria-naive Dutch individuals and significantly reduced activation in malaria-experienced Malians. Newly febrile and asymptomatic infections in Malians were statistically indistinguishable except for genes activated by pro-inflammatory cytokines. The combined data provide a molecular basis for the development of a pyrogenic threshold as individuals acquire immunity to clinical malaria. C1 [Tran, Tuan M.; Skinner, Jeff; Crompton, Peter D.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Tran, Tuan M.] Indiana Univ Sch Med, Dept Med, Div Infect Dis, Indianapolis, IN 46202 USA. [Jones, Marcus B.; Venepally, Pratap; Kirkness, Ewen F.] J Craig Venter Inst, Genom Med Grp, Rockville, MD USA. [Ongoiba, Aissata; Doumbo, Safiatou; Kayentao, Kassoum; Doumbo, Ogobara K.; Traore, Boubacar] Univ Sci Tech & Technol Bamako, Mali Int Ctr Excellence Res, Bamako, Mali. [Bijker, Else M.; Sauerwein, Robert W.] Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, Nijmegen, Netherlands. [Schats, Remko; Quinten, Edwin; Visser, Leo G.; Ottenhoff, Tom H. M.; Haks, Marielle C.] Leiden Univ, Med Ctr, Dept Infect Dis, Leiden, Netherlands. [Whalen, Elizabeth; Presnell, Scott; Chaussabel, Damien] Benaroya Res Inst, Syst Immunol Div, Seattle, WA USA. [O'Connell, Elise M.; Nutman, Thomas B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD USA. [Chaussabel, Damien] Sidra Med & Res Ctr, Doha, Qatar. [Lorenzi, Hernan] J Craig Venter Inst, Infect Dis Grp, Bethesda, MD USA. RP Tran, TM (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA.; Tran, TM (reprint author), Indiana Univ Sch Med, Dept Med, Div Infect Dis, Indianapolis, IN 46202 USA. EM tuantran@iu.edu RI Crompton, Peter/N-1130-2016; OI Chaussabel, Damien/0000-0002-6131-7242; Skinner, Jeff/0000-0001-5697-0442 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200900007C]; Division of Intramural Research; Netherlands Organization for Health Research and Development (ZonMw) [m95110086]; Dioraphte Foundation [12010100] FX We thank the residents of Kalifabougou, Mali and the Dutch volunteers for participating in this study. This project was supported with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services under contract number HHSN272200900007C and the Division of Intramural Research. The CHMI trial was supported by The Netherlands Organization for Health Research and Development (ZonMw) (projectm95110086) and the Dioraphte Foundation (project 12010100). NR 41 TC 0 Z9 0 U1 0 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 AUG 10 PY 2016 VL 6 AR 31291 DI 10.1038/srep31291 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS9VP UT WOS:000381131900002 PM 27506615 ER PT J AU Gill, KP Hung, SSC Sharov, A Lo, CY Needham, K Lidgerwood, GE Jackson, S Crombie, DE Nayagam, BA Cook, AL Hewitt, AW Pebay, A Wong, RCB AF Gill, Katherine P. Hung, Sandy S. C. Sharov, Alexei Lo, Camden Y. Needham, Karina Lidgerwood, Grace E. Jackson, Stacey Crombie, Duncan E. Nayagam, Bryony A. Cook, Anthony L. Hewitt, Alex W. Pebay, Alice Wong, Raymond C. B. TI Enriched retinal ganglion cells derived from human embryonic stem cells SO Scientific Reports LA English DT Article ID HEREDITARY OPTIC NEUROPATHY; HUMAN MULLER GLIA; IN-VITRO; GENE-EXPRESSION; MACULAR DEGENERATION; NEURAL PROGENITORS; HUMAN BLASTOCYSTS; BRN-3 FAMILY; HUMAN ESCS; GENERATION AB Optic neuropathies are characterised by a loss of retinal ganglion cells (RGCs) that lead to vision impairment. Development of cell therapy requires a better understanding of the signals that direct stem cells into RGCs. Human embryonic stem cells (hESCs) represent an unlimited cellular source for generation of human RGCs in vitro. In this study, we present a 45-day protocol that utilises magnetic activated cell sorting to generate enriched population of RGCs via stepwise retinal differentiation using hESCs. We performed an extensive characterization of these stem cell-derived RGCs by examining the gene and protein expressions of a panel of neural/RGC markers. Furthermore, whole transcriptome analysis demonstrated similarity of the hESC-derived RGCs to human adult RGCs. The enriched hESC-RGCs possess long axons, functional electrophysiological profiles and axonal transport of mitochondria, suggestive of maturity. In summary, this RGC differentiation protocol can generate an enriched population of functional RGCs from hESCs, allowing future studies on disease modeling of optic neuropathies and development of cell therapies. C1 [Gill, Katherine P.; Hung, Sandy S. C.; Lidgerwood, Grace E.; Jackson, Stacey; Crombie, Duncan E.; Hewitt, Alex W.; Pebay, Alice; Wong, Raymond C. B.] Univ Melbourne, Ctr Eye Res Australia, Royal Victorian Eye & Ear Hosp, Melbourne, Vic 3010, Australia. [Gill, Katherine P.; Hung, Sandy S. C.; Lidgerwood, Grace E.; Jackson, Stacey; Crombie, Duncan E.; Hewitt, Alex W.; Pebay, Alice; Wong, Raymond C. B.] Univ Melbourne, Dept Surg, Ophthalmol, Melbourne, Vic 3010, Australia. [Sharov, Alexei] NIA, NIH, Bethesda, MD 20892 USA. [Lo, Camden Y.] Monash Univ, Monash Micro Imaging, Clayton, Vic 3800, Australia. [Needham, Karina] Univ Melbourne, Dept Otolaryngol, Melbourne, Vic 3010, Australia. [Needham, Karina] Univ Melbourne, Dept Surg, Melbourne, Vic 3010, Australia. [Needham, Karina] Royal Victorian Eye & Ear Hosp, East Melbourne, Vic, Australia. [Nayagam, Bryony A.] Univ Melbourne, Dept Audiol & Speech Pathol, Melbourne, Vic 3010, Australia. [Nayagam, Bryony A.] Univ Melbourne, Dept Ophthalmol, Melbourne, Vic 3010, Australia. [Cook, Anthony L.] Univ Tasmania, Wicking Dementia Res & Educ Ctr, Hobart, Tas 7001, Australia. [Hewitt, Alex W.] Univ Tasmania, Menzies Inst Med Res, Sch Med, Hobart, Tas 7001, Australia. RP Pebay, A; Wong, RCB (reprint author), Univ Melbourne, Ctr Eye Res Australia, Royal Victorian Eye & Ear Hosp, Melbourne, Vic 3010, Australia.; Pebay, A; Wong, RCB (reprint author), Univ Melbourne, Dept Surg, Ophthalmol, Melbourne, Vic 3010, Australia. EM apebay@unimelb.edu.au; wongcb@unimelb.edu.au OI Cook, Anthony/0000-0003-1770-7910 FU National Health and Medical Research Council [1084256]; Bright Focus Foundation; University of Melbourne; Retina Australia; Ophthalmic Research Institute of Australia; National Stem Cell Foundation of Australia; Clifford Craig Medical Research Trust [133]; NHMRC Career Development Fellowship [1004164]; NHMRC Early Career Fellowship; NHMRC-CSL Gustav Nossal postgraduate research scholarship; Australian Research Council Future Fellowship [FT140100047]; Cranbourne Foundation Fellowship; Australian Postgraduate Award; Garnett Passe and Rodney Williams Memorial Foundation Research Fellowship; Senior Wagstaff Fellowship in Otolaryngology; Intramural Research Program of the National Institute on Aging FX This work was supported by grants from the National Health and Medical Research Council (RCBW, 1084256), Bright Focus Foundation (AWH, AP), the University of Melbourne (RCBW, AP), Retina Australia (RCBW, SSCH, AWH, AP) the Ophthalmic Research Institute of Australia (RCBW, SSCH, AWH, AP), National Stem Cell Foundation of Australia (AP), Clifford Craig Medical Research Trust (#133, ALC, AWH, AP), a NHMRC Career Development Fellowship (AP, 1004164), a NHMRC Early Career Fellowship (AWH), a NHMRC-CSL Gustav Nossal postgraduate research scholarship (DEC), an Australian Research Council Future Fellowship (AP, FT140100047), a Cranbourne Foundation Fellowship (RCBW), an Australian Postgraduate Award (KPG), a Garnett Passe and Rodney Williams Memorial Foundation Research Fellowship (BAN), a Senior Wagstaff Fellowship in Otolaryngology (KN), Intramural Research Program of the National Institute on Aging (AS) and operational infrastructure support from the Victorian Government. NR 67 TC 0 Z9 0 U1 4 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 AUG 10 PY 2016 VL 6 AR 30552 DI 10.1038/srep30552 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS9RL UT WOS:000381120900001 PM 27506453 ER PT J AU Nagmetova, G Yagofarova, A Berdimuratova, K Kurmanbayev, A AF Nagmetova, Gulden Yagofarova, Almira Berdimuratova, Kalysh Kurmanbayev, Askar TI Evaluating the performance of electrogenic strains of bacteria in microbial fuel cells SO JOURNAL OF BIOTECHNOLOGY LA English DT Meeting Abstract CT European Biotechnology Conference CY MAY 05-07, 2016 CL LATVIA C1 [Nagmetova, Gulden] LN Gumilyov Eurasian Natl Univ, Fac Nat Sci, Astana, Kazakhstan. [Yagofarova, Almira; Berdimuratova, Kalysh; Kurmanbayev, Askar] Natl Biotechnol Ctr, Lab Ecol Biotechnol, Astana, Kazakhstan. EM solnce30-04@mail.ru NR 0 TC 0 Z9 0 U1 6 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1656 EI 1873-4863 J9 J BIOTECHNOL JI J. Biotechnol. PD AUG 10 PY 2016 VL 231 SU S BP S74 EP S74 DI 10.1016/j.jbiotec.2016.05.270 PG 1 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DR9TZ UT WOS:000380240300231 ER PT J AU Duplat-Bermudez, L Ruiz-Medrano, R Landsman, D Marino-Ramirez, L Xoconostle-Cazares, B AF Duplat-Bermudez, L. Ruiz-Medrano, R. Landsman, D. Marino-Ramirez, L. Xoconostle-Cazares, B. TI Transcriptomic analysis of Arabidopsis overexpressing flowering locus T driven by a meristem-specific promoter that induces early flowering SO GENE LA English DT Article DE Arabidopsis; Flowering locus T; RNA-seq analysis; Plant development; Transgenic plants ID LARGE GENE LISTS; RNA-SEQ; FLORAL INDUCTION; FT PROTEIN; PHYSIOLOGICAL ANALYSIS; EXPRESSION ANALYSIS; PATHWAY INTEGRATOR; LIGHT QUALITY; SEASONAL CUES; THALIANA AB Here we analyzed in leaves the effect of FT overexpression driven by meristem-specific KNAT1 gene homolog of Arabidopsis thaliana (Lincoln et al., 1994; Long et al., 1996) on the transcriptomic response during plant development. Our results demonstrated that meristematic FT overexpression generates a phenotype with an early flowering independent of photoperiod when compared with wild type (WT) plants. Arabidopsis FT-overexpressor lines (AtFTOE) did not show significant differences compared with WT lines neither in leaf number nor in rosette diameter up to day 21, when AtFTOE flowered. After this period AtFTOE plants started flower production and no new rosette leaves were produced. Additionally, WT plants continued on vegetative stage up to day 40, producing 12-14 rosette leaves before flowering. Transcriptomic analysis of rosette leaves studied by sequencing lllumina RNA-seq allowed us to determine the differential expression in mature leaf rosette of 3652 genes, being 626 of them up-regulated and 3026 down-regulated. Overexpressed genes related with flowering showed up-regulated transcription factors such as MADS-box that are known as flowering markers in meristem and which overexpression has been related with meristem identity preservation and the transition from vegetative to floral stage. Genes related with sugar transport have shown a higher demand of monosaccharides derived from the hydrolysis of sucrose to glucose and probably fructose, which can also be influenced by reproductive stage of AtFTOE plants. (C) 2016 Elsevier B.V. All rights reserved. C1 [Duplat-Bermudez, L.; Ruiz-Medrano, R.; Xoconostle-Cazares, B.] Inst Politecn Nacl, Ctr Invest & Estudios Avanzados, Dept Biotecnol & Bioingn, Av IPN 2508 San Pedro Zacatenco, Mexico City 07360, DF, Mexico. [Landsman, D.; Marino-Ramirez, L.] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. RP Xoconostle-Cazares, B (reprint author), Inst Politecn Nacl, Ctr Invest & Estudios Avanzados, Av IPN 2508 San Pedro Zacatenco, Mexico City 07360, DF, Mexico. EM bxoconos@cinvestav.mx OI Marino-Ramirez, Leonardo/0000-0002-5716-8512; Landsman, David/0000-0002-9819-6675 FU CINVESTAV-IPN; CONACyT [156162, 105985, 388937]; SENASICA-SAGARPA grant; Intramural Research Program of the NIH, NLM, NCBI FX This work was supported by departmental funds from CINVESTAV-IPN, by CONACyT grant nos. 156162 to RR-M and 105985 to BX-C, and a SENASICA-SAGARPA grant to BX-C and RR-M. LD-B was supported by a doctoral fellowship from CONACyT no 388937. This research was partially supported by the Intramural Research Program of the NIH, NLM, NCBI. We are grateful to the members of the laboratory of Plant Biotechnology for critical comments to this manuscript. NR 79 TC 0 Z9 0 U1 14 U2 51 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 EI 1879-0038 J9 GENE JI Gene PD AUG 10 PY 2016 VL 587 IS 2 BP 120 EP 131 DI 10.1016/j.gene.2016.04.060 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA DO5MQ UT WOS:000377827600002 PM 27154816 ER PT J AU Bhattacharyya, T Jha, S Wang, HY Kastner, DL Remmers, EF AF Bhattacharyya, Timothy Jha, Smita Wang, Hongying Kastner, Daniel L. Remmers, Elaine F. TI Hypophosphatasia and the risk of atypical femur fractures: a case-control study SO BMC MUSCULOSKELETAL DISORDERS LA English DT Article ID BISPHOSPHONATE USE; FEMORAL FRACTURES; DIAPHYSEAL FRACTURES; STRESS; SHAFT AB Background: Case reports have linked adult hypophosphatasia as a possible cause of atypical femur fractures (AFF) associated with bisphosphonate use. Adult hypophosphatasia is an asymptomatic genetic condition which results in low alkaline phosphatase and elevated pyridoxal phosphate. We conducted a case- control study to assess the role of hypophosphatasia and atypical femur fracture. Methods: We recruited 13 control patients who took long term bisphosphonates without complication and 10 patients who sustained atypical femur fractures (mean bisphosphonate use, 9 years both cohorts). Patients underwent clinical exam and measurement of alkaline phosphatase and pyridoxal phosphate (PLP) levels. In addition, DNA was extracted and the ALPL gene was sequenced in both cohorts. Results: Low alkaline phosphatase levels (< 55 U/L) were seen in 5/10 AFF patients and 5/13 control patients. Two control patients demonstrated low alkaline phosphatase levels and elevated PLP. The alkaline phosphatase (ALPL) gene exons and intron splice sites were sequenced in the atypical femur fracture and control cohorts and no coding mutations were identified in any subjects. Atypical femur fracture patients demonstrated more varus hip alignment (p < 0.048) with no significant difference in mechanical axis. Conclusions: We found no evidence of hypophosphatasia as a risk factor for atypical femur fractures. Laboratory findings of mildly low alkaline phosphatase activity were equally common in atypical and control cohorts and may be due to long term bisphosphonate use. C1 [Bhattacharyya, Timothy] NIAMSD, NIH, 10 Ctr Dr,Mail Code 1468, Bethesda, MD 20892 USA. [Jha, Smita] Natl Inst Child Hlth & Human Dev NICHD, NIH, Bethesda, MD USA. [Wang, Hongying; Kastner, Daniel L.; Remmers, Elaine F.] NHGRI, Inflammatory Dis Sect, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Bhattacharyya, T (reprint author), NIAMSD, NIH, 10 Ctr Dr,Mail Code 1468, Bethesda, MD 20892 USA. EM timothy.bhattacharyya@nih.gov FU Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Human Genome Research Institute FX The study was funded by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Human Genome Research Institute. The funding bodies had no role in the collection of data or review of the manuscript. NR 18 TC 1 Z9 1 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2474 J9 BMC MUSCULOSKEL DIS JI BMC Musculoskelet. Disord. PD AUG 9 PY 2016 VL 17 AR 332 DI 10.1186/s12891-016-1191-8 PG 4 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA EM0OC UT WOS:000395016600001 PM 27507156 ER PT J AU Nakamura, Y Harada, T Nagaya, T Sato, K Okuyama, S Choyke, PL Kobayashi, H AF Nakamura, Yuko Harada, Toshiko Nagaya, Tadanobu Sato, Kazuhide Okuyama, Shuhei Choyke, Peter L. Kobayashi, Hisataka TI Dynamic fluorescent imaging with the activatable probe, gamma-glutamyl hydroxymethyl rhodamine green in the detection of peritoneal cancer metastases: Overcoming the problem of dilution when using a sprayable optical probe SO ONCOTARGET LA English DT Article DE kinetic map; green emitting probe; autofluorescence; gamma-glutamyltranspeptidase; peritoneal cancer metastases ID KILLER-REPORTER ADENOVIRUS; IN-VIVO; GUIDED SURGERY; MOLECULAR PROBES; DRUG-RESISTANCE; LIVE MOUSE; TUMORS; TRANSFERASE; EXPRESSION; CELLS AB Optical fluorescence-guided imaging is increasingly used to guide surgery and endoscopic procedures. Activatable probes are particularly useful because of high target-to-background ratios that increase sensitivity for tiny cancer foci. However, green fluorescent activatable probes suffer from interference from autofluorescence found in biological tissue. The purpose of this study was to determine if dynamic imaging can be used to differentiate specific fluorescence arising from an activated probe in a tumor from autofluorescence in background tissues especially when low concentrations of the dye are applied. Serial fluorescence imaging was performed using various concentrations of gamma-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG) which was sprayed on the peritoneal surface with tiny implants of SHIN3-DsRed ovarian cancer tumors. Temporal differences in signal between specific green fluorescence in cancer foci and non-specific autofluorescence in background tissue were measured at 5, 10, 20 and 30 min after application of gGlu-HMRG and were processed into three kinetic maps reflecting maximum fluorescence signal (MF), wash-in rate (WIR), and area under the curve (AUC), respectively. Using concentrations up to 10 mu M of gGlu-HMRG, the fluorescence intensity of cancer foci was significantly higher than that of small intestine but only at 30 min. However, on kinetic maps derived from dynamic fluorescence imaging, the signal of cancer foci was significantly higher than that of small intestine after only 5 min even at concentrations as low as 2.5 mu M of gGlu-HMRG (p < 0.01). At lower concentrations, kinetic maps derived from dynamic fluorescence imaging were superior to unprocessed images for cancer detection. C1 [Nakamura, Yuko; Harada, Toshiko; Nagaya, Tadanobu; Sato, Kazuhide; Okuyama, Shuhei; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov FU Intramural Research Program of the National Institute of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institute of Health, National Cancer Institute, Center for Cancer Research. NR 42 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 AUG 9 PY 2016 VL 7 IS 32 BP 51124 EP 51137 DI 10.18632/oncotarget.9898 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY9CC UT WOS:000385429100030 PM 27286461 ER PT J AU Earl, LA Subramaniam, S AF Earl, Lesley A. Subramaniam, Sriram TI Cryo-EM of viruses and vaccine design SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID HUMAN RHINOVIRUS C; CRYOELECTRON MICROSCOPY; ELECTRON CRYOMICROSCOPY; CHILDREN; PROTEIN C1 [Earl, Lesley A.; Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. RP Subramaniam, S (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ss1@nih.gov NR 20 TC 1 Z9 1 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 AUG 9 PY 2016 VL 113 IS 32 BP 8903 EP 8905 DI 10.1073/pnas.1609721113 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT2EJ UT WOS:000381293300036 PM 27482113 ER PT J AU Aksoyoglu, MA Podgornik, R Bezrukov, SM Gurnev, PA Muthukumar, M Parsegian, VA AF Aksoyoglu, M. Alphan Podgornik, Rudolf Bezrukov, Sergey M. Gurnev, Philip A. Muthukumar, Murugappan Parsegian, V. Adrian TI Size-dependent forced PEG partitioning into channels: VDAC, OmpC, and alpha-hemolysin SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE beta-barrel pores; nanopore-based sensing; polymer confinement; polymer transport; macromolecular crowding ID MOLECULE MASS-SPECTROMETRY; ACCESS RESISTANCE; FLEXIBLE POLYMERS; PROTEIN STABILITY; ION-CHANNEL; PORE; NANOPORE; CONDUCTIVITY; CONDUCTANCE; MEMBRANE AB Nonideal polymer mixtures of PEGs of different molecular weights partition differently into nanosize protein channels. Here, we assess the validity of the recently proposed theoretical approach of forced partitioning for three structurally different beta-barrel channels: voltage-dependent anion channel from outer mitochondrial membrane VDAC, bacterial porin OmpC (outer membrane protein C), and bacterial channel-forming toxin alpha-hemolysin. Our interpretation is based on the idea that relatively less-penetrating polymers push the more easily penetrating ones into nanosize channels in excess of their bath concentration. Comparison of the theory with experiments is excellent for VDAC. Polymer partitioning data for the other two channels are consistent with theory if additional assumptions regarding the energy penalty of pore penetration are included. The obtained results demonstrate that the general concept of "polymers pushing polymers" is helpful in understanding and quantification of concrete examples of size-dependent forced partitioning of polymers into protein nanopores. C1 [Aksoyoglu, M. Alphan; Podgornik, Rudolf; Gurnev, Philip A.; Parsegian, V. Adrian] Univ Massachusetts, Dept Phys, Amherst, MA 01003 USA. [Podgornik, Rudolf] Univ Ljubljana, Dept Phys, Fac Math & Phys, Ljubljana 1000, Slovenia. [Podgornik, Rudolf] J Stefan Inst, Dept Theoret Phys, Ljubljana 1000, Slovenia. [Bezrukov, Sergey M.; Gurnev, Philip A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Transport, NIH, Bethesda, MD 20892 USA. [Muthukumar, Murugappan] Univ Massachusetts, Dept Polymer Sci & Engn, Amherst, MA 01003 USA. RP Podgornik, R (reprint author), Univ Massachusetts, Dept Phys, Amherst, MA 01003 USA.; Podgornik, R (reprint author), Univ Ljubljana, Dept Phys, Fac Math & Phys, Ljubljana 1000, Slovenia.; Podgornik, R (reprint author), J Stefan Inst, Dept Theoret Phys, Ljubljana 1000, Slovenia.; Bezrukov, SM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Transport, NIH, Bethesda, MD 20892 USA. EM rudolf.podgornik@ijs.si; bezrukos@mail.nih.gov FU US Department of Energy, Office of Basic Energy Sciences, Division of Materials Sciences and Engineering Award [DE-SC0008176]; Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Science Foundation EAGER Award [1249199]; National Science Foundation [DMR-1504265]; Air Force Office of Scientific Research Grant [FA9550-14-1-0164]; NIH [R01HG002776-11] FX This work was supported by US Department of Energy, Office of Basic Energy Sciences, Division of Materials Sciences and Engineering Award DE-SC0008176 (to M.A.A., V.A.P., and R.P.); the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development (S.M.B. and P.A.G.); National Science Foundation EAGER Award 1249199 (to P.A.G.); and National Science Foundation Grant DMR-1504265, Air Force Office of Scientific Research Grant FA9550-14-1-0164, and NIH Grant R01HG002776-11 (all to M.M.). NR 40 TC 2 Z9 2 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 AUG 9 PY 2016 VL 113 IS 32 BP 9003 EP 9008 DI 10.1073/pnas.1602716113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT2EJ UT WOS:000381293300053 PM 27466408 ER PT J AU Won, S Incontro, S Nicoll, RA Roche, KW AF Won, Sehoon Incontro, Salvatore Nicoll, Roger A. Roche, Katherine W. TI PSD-95 stabilizes NMDA receptors by inducing the degradation of STEP61 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE PSD-95; NMDA receptor; STEP; ubiquitination ID PROTEIN-TYROSINE-PHOSPHATASE; D-ASPARTATE RECEPTOR; LONG-TERM POTENTIATION; DISEASE MOUSE MODEL; ALZHEIMERS-DISEASE; MOLECULAR CHARACTERIZATION; GLUTAMATE RECEPTORS; SYNAPTIC PLASTICITY; C-TERMINUS; SUBUNIT AB Phosphorylation regulates surface and synaptic expression of NMDA receptors (NMDARs). Both the tyrosine kinase Fyn and the tyrosine phosphatase striatal-enriched protein tyrosine phosphatase (STEP) are known to target the NMDA receptor subunit GluN2B on tyrosine 1472, which is a critical residue that mediates NMDAR endocytosis. STEP reduces the surface expression of NMDARs by promoting dephosphorylation of GluN2B Y1472, whereas the synaptic scaffolding protein postsynaptic density protein 95 (PSD-95) stabilizes the surface expression of NMDARs. However, nothing is known about a potential functional interaction between STEP and PSD-95. We now report that STEP61 binds to PSD-95 but not to other PSD-95 family members. We find that PSD-95 expression destabilizes STEP61 via ubiquitination and degradation by the proteasome. Using subcellular fractionation, we detect low amounts of STEP61 in the PSD fraction. However, STEP61 expression in the PSD is increased upon knockdown of PSD-95 or in vivo as detected in PSD-95-KO mice, demonstrating that PSD-95 excludes STEP61 from the PSD. Importantly, only extrasynaptic NMDAR expression and currents were increased upon STEP knockdown, as is consistent with low STEP61 localization in the PSD. Our findings support a dual role for PSD-95 in stabilizing synaptic NMDARs by binding directly to GluN2B but also by promoting synaptic exclusion and degradation of the negative regulator STEP61. C1 [Won, Sehoon; Roche, Katherine W.] NINDS, Receptor Biol Sect, NIH, Bethesda, MD 20892 USA. [Incontro, Salvatore; Nicoll, Roger A.] Univ Calif San Francisco, Dept Mol & Cellular Pharmacol, San Francisco, CA 94158 USA. [Nicoll, Roger A.] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94158 USA. RP Roche, KW (reprint author), NINDS, Receptor Biol Sect, NIH, Bethesda, MD 20892 USA.; Nicoll, RA (reprint author), Univ Calif San Francisco, Dept Mol & Cellular Pharmacol, San Francisco, CA 94158 USA.; Nicoll, RA (reprint author), Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94158 USA. EM rochek@ninds.nih.gov; nicoll@cmp.ucsf.edu OI Roche, Katherine/0000-0001-7282-6539 FU NINDS Intramural Research Program; National Institute of Mental Health Grant [MH-38256] FX We thank John D. Badger II for technical assistance and the National Institute of Neurological Disorders and Stroke (NINDS) imaging facility for their assistance. This research was supported by the NINDS Intramural Research Program (S.W. and K.W.R.) and by National Institute of Mental Health Grant MH-38256 (S.I. and R.A.N.). NR 53 TC 1 Z9 1 U1 5 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 9 PY 2016 VL 113 IS 32 BP E4736 EP E4744 DI 10.1073/pnas.1609702113 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT2EJ UT WOS:000381293300022 PM 27457929 ER PT J AU Maurer, CW LaFaver, K Ameli, R Epstein, SA Hallett, M Horovitz, SG AF Maurer, Carine W. LaFaver, Kathrin Ameli, Rezvan Epstein, Steven A. Hallett, Mark Horovitz, Silvina G. TI Impaired self-agency in functional movement disorders A resting-state fMRI study SO NEUROLOGY LA English DT Article ID CONVERSION DISORDER; CONNECTIVITY; EXPERIENCE; SENSE; FLUCTUATIONS; DEPRESSION; NEUROLOGY; STRATEGY; CORTEX; TREMOR AB Objective: To investigate the neural mechanisms underlying impaired self-agency in patients with functional movement disorders using resting-state functional MRI (fMRI). Methods: We obtained resting-state fMRI on 35 patients with clinically definite functional movement disorders and 35 age-and sex-matched healthy controls. Between-group differences in functional connectivity from the right temporo-parietal junction (TPJ), a region previously demonstrated to play a critical role in self-agency by comparing internal predictions of movement with actual external events, were assessed using t tests. All participants were screened for psychiatric diagnoses using a structured clinical interview and completed the Beck Depression Inventory and Childhood Trauma Questionnaire. Results: Compared to the healthy controls, patients with functional movement disorders showed decreased functional connectivity between the right TPJ and the right sensorimotor cortex, cerebellar vermis, bilateral supplementary motor area, and right insula. These findings were independent of depression, anxiety, and childhood trauma scores included in our assessment as covariates. Conclusions: The decreased functional connectivity between the right TPJ and bilateral sensorimotor regions observed in patients with functional movement disorders supports a model whereby impaired motor feed-forward together with altered sensory feedback from sensorimotor regions and areas of sensorimotor integration to the right TPJ contributes to patients' impaired sense of self-agency. C1 [Maurer, Carine W.; LaFaver, Kathrin; Hallett, Mark; Horovitz, Silvina G.] Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, Med Neurol Branch, Bethesda, MD 20824 USA. [Ameli, Rezvan] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. [LaFaver, Kathrin] Univ Louisville, Dept Neurol, Louisville, KY 40292 USA. [Epstein, Steven A.] Georgetown Univ, Dept Psychiat, Washington, DC USA. RP Maurer, CW (reprint author), Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, Med Neurol Branch, Bethesda, MD 20824 USA. EM carine.maurer@nih.gov FU National Institute of Neurological Disorders and Stroke Intramural Research Program FX Supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program. NR 35 TC 2 Z9 2 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 9 PY 2016 VL 87 IS 6 BP 564 EP 570 DI 10.1212/WNL.0000000000002940 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA DU6LT UT WOS:000382327000009 PM 27385746 ER PT J AU Chen, KY Cypess, AM Laughlin, MR Haft, CR Hu, HH Bredella, MA Enerback, S Kinahan, PE Lichtenbelt, WV Lin, FI Sunderland, JJ Virtanen, KA Wahl, RL AF Chen, Kong Y. Cypess, Aaron M. Laughlin, Maren R. Haft, Carol R. Hu, Houchun Harry Bredella, Miriam A. Enerback, Sven Kinahan, Paul E. Lichtenbelt, Wouter van Marken Lin, Frank I. Sunderland, John J. Virtanen, Kirsi A. Wahl, Richard L. TI Brown Adipose Reporting Criteria in Imaging STudies (BARCIST 1.0): Recommendations for Standardized FDG-PET/CT Experiments in Humans SO CELL METABOLISM LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; TYPE-2 DIABETES-MELLITUS; ADULT HUMANS; F-18-FDG PET/CT; ENERGY-EXPENDITURE; OXIDATIVE-METABOLISM; INSULIN SENSITIVITY; COMPUTED-TOMOGRAPHY; TISSUE ACTIVITY; COLD-EXPOSURE AB Human brown adipose tissue (BAT) presence, metabolic activity, and estimated mass are typically measured by imaging [18F]fluorodeoxyglucose (FDG) uptake in response to cold exposure in regions of the body expected to contain BAT, using positron emission tomography combined with X-ray computed tomography (FDG-PET/CT). Efforts to describe the epidemiology and biology of human BAT are hampered by diverse experimental practices, making it difficult to directly compare results among laboratories. An expert panel was assembled by the National Institute of Diabetes and Digestive and Kidney Diseases on November 4, 2014 to discuss minimal requirements for conducting FDG-PET/CT experiments of human BAT, data analysis, and publication of results. This resulted in Brown Adipose Reporting Criteria in Imaging STudies (BARCIST 1.0). Since there are no fully validated best practices at this time, panel recommendations are meant to enhance comparability across experiments, but not to constrain experimental design or the questions that can be asked. C1 [Chen, Kong Y.; Cypess, Aaron M.; Laughlin, Maren R.; Haft, Carol R.] NIDDK, NIH, Bethesda, MD 20892 USA. [Hu, Houchun Harry] Phoenix Childrens Hosp, Phoenix, AZ 85016 USA. [Bredella, Miriam A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bredella, Miriam A.] Harvard Med Sch, Boston, MA 02114 USA. [Enerback, Sven] Univ Gothenburg, S-40530 Gothenburg, Sweden. [Kinahan, Paul E.] Univ Washington, Seattle, WA 98105 USA. [Lichtenbelt, Wouter van Marken] Maastricht Univ, NL-6211 LK Maastricht, Netherlands. [Lin, Frank I.] NCI, NIH, Bethesda, MD 20892 USA. [Sunderland, John J.] Univ Iowa, Iowa City, IA 52242 USA. [Virtanen, Kirsi A.] Turku Univ Hosp, Turku 20500, Finland. [Virtanen, Kirsi A.] Univ Turku, SF-20500 Turku, Finland. [Wahl, Richard L.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO 63110 USA. RP Chen, KY; Cypess, AM; Laughlin, MR (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. EM kong.chen@nih.gov; aaron.cypess@nih.gov; maren.laughlin@nih.gov OI Chen, Kong/0000-0002-0306-1904 FU Intramural Research Program of the NIH; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Cancer Institute (NCI) FX This research was supported in part by the Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the National Cancer Institute (NCI). NR 74 TC 4 Z9 4 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD AUG 9 PY 2016 VL 24 IS 2 BP 210 EP 222 DI 10.1016/j.cmet.2016.07.014 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA DT3PH UT WOS:000381392800010 PM 27508870 ER PT J AU Cox, PJ Kirk, T Ashmore, T Willerton, K Evans, R Smith, A Murray, AJ Stubbs, B West, J McLure, SW King, MT Dodd, MS Holloway, C Neubauer, S Drawer, S Veech, RL Griffin, JL Clarke, K AF Cox, Pete J. Kirk, Tom Ashmore, Tom Willerton, Kristof Evans, Rhys Smith, Alan Murray, Andrew J. Stubbs, Brianna West, James McLure, Stewart W. King, M. Todd Dodd, Michael S. Holloway, Cameron Neubauer, Stefan Drawer, Scott Veech, Richard L. Griffin, Julian L. Clarke, Kieran TI Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes SO CELL METABOLISM LA English DT Article ID HUMAN METABOLIC RESPONSE; HUMAN SKELETAL-MUSCLE; FATTY-ACID CYCLE; KETONE-BODIES; PROLONGED EXERCISE; CALORIC RESTRICTION; INSULIN-RESISTANCE; OXIDATION RATES; KETOGENIC DIET; NICOTINIC-ACID AB Ketosis, the metabolic response to energy crisis, is a mechanism to sustain life by altering oxidative fuel selection. Often overlooked for its metabolic potential, ketosis is poorly understood outside of starvation or diabetic crisis. Thus, we studied the biochemical advantages of ketosis in humans using a ketone ester-based form of nutrition without the unwanted milieu of endogenous ketone body production by caloric or carbohydrate restriction. In five separate studies of 39 high-performance athletes, we show how this unique metabolic state improves physical endurance by altering fuel competition for oxidative respiration. Ketosis decreased muscle glycolysis and plasma lactate concentrations, while providing an alternative substrate for oxidative phosphorylation. Ketosis increased intramuscular triacylglycerol oxidation during exercise, even in the presence of normal muscle glycogen, co-ingested carbohydrate and elevated insulin. These findings may hold clues to greater human potential and a better understanding of fuel metabolism in health and disease. C1 [Cox, Pete J.; Kirk, Tom; Willerton, Kristof; Evans, Rhys; Stubbs, Brianna; McLure, Stewart W.; Dodd, Michael S.; Holloway, Cameron; Clarke, Kieran] Univ Oxford, Dept Physiol Anat & Genet, S Parks Rd, Oxford OX1 3PT, England. [Cox, Pete J.; Holloway, Cameron; Neubauer, Stefan] Univ Oxford, Dept Cardiovasc Med, Oxford OX3 9DU, England. [Ashmore, Tom; West, James; Griffin, Julian L.] Univ Cambridge, Dept Biochem, Oxford CB1 9NL, England. [Ashmore, Tom; West, James; Griffin, Julian L.] Univ Cambridge, Cambridge Syst Biol Ctr, Oxford CB1 9NL, England. [Ashmore, Tom; West, James; Griffin, Julian L.] MRC Human Nutr Res, Oxford CB1 9NL, England. [Smith, Alan; Drawer, Scott] UK Sport, 40 Bernard St, London WC1N 1ST, England. [Murray, Andrew J.] Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3EG, England. [King, M. Todd; Veech, Richard L.] NIAAA, Lab Metab Control, NIH, Rockville, MD 20852 USA. RP Cox, PJ (reprint author), Univ Oxford, Dept Physiol Anat & Genet, S Parks Rd, Oxford OX1 3PT, England.; Cox, PJ (reprint author), Univ Oxford, Dept Cardiovasc Med, Oxford OX3 9DU, England. EM petejcox456@gmail.com FU Defence Advanced Research Projects Agency (DARPA); UK Sport FX The authors thank Dr. R. Stillion, Dr. O. Faull, E. Carter, Dr. N Boehlke, and Y Green for their excellent assistance with these studies. The authors thank the Defence Advanced Research Projects Agency (DARPA) and UK Sport for funding this work. NR 47 TC 8 Z9 8 U1 41 U2 51 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD AUG 9 PY 2016 VL 24 IS 2 BP 256 EP 268 DI 10.1016/j.cmet.2016.07.010 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA DT3PH UT WOS:000381392800014 PM 27475046 ER PT J AU Moon, HY Becke, A Berron, D Becker, B Sah, N Benoni, G Janke, E Lubejko, ST Greig, NH Mattison, JA Duzel, E van Praag, H AF Moon, Hyo Youl Becke, Andreas Berron, David Becker, Benjamin Sah, Nirnath Benoni, Galit Janke, Emma Lubejko, Susan T. Greig, Nigel H. Mattison, Julie A. Duzel, Emrah van Praag, Henriette TI Running-Induced Systemic Cathepsin B Secretion Is Associated with Memory Function SO CELL METABOLISM LA English DT Article ID HIPPOCAMPAL NEUROGENESIS; PHYSICAL-EXERCISE; ALZHEIMER-DISEASE; SKELETAL-MUSCLE; IMPROVE MEMORY; ANNEXIN A2; BRAIN; MICE; NEURONS; CELLS AB Peripheral processes that mediate beneficial effects of exercise on the brain remain sparsely explored. Here, we show that a muscle secretory factor, cathepsin B (CTSB) protein, is important for the cognitive and neurogenic benefits of running. Proteomic analysis revealed elevated levels of CTSB in conditioned medium derived from skeletal muscle cell cultures treated with AMP-kinase agonist AICAR. Consistently, running increased CTSB levels in mouse gastrocnemius muscle and plasma. Furthermore, recombinant CTSB application enhanced expression of brain-derived neurotrophic factor (BDNF) and doublecortin (DCX) in adult hippocampal progenitor cells through a mechanism dependent on the multifunctional protein P11. In vivo, in CTSB knockout (KO) mice, running did not enhance adult hippocampal neurogenesis and spatial memory function. Interestingly, in Rhesus monkeys and humans, treadmill exercise elevated CTSB in plasma. In humans, changes in CTSB levels correlated with fitness and hippocampus-dependent memory function. Our findings suggest CTSB as a mediator of effects of exercise on cognition. C1 [Moon, Hyo Youl; Becker, Benjamin; Sah, Nirnath; Benoni, Galit; Janke, Emma; Lubejko, Susan T.; van Praag, Henriette] NIA, Neuroplast & Behav Unit, Lab Neurosci, Baltimore, MD 21224 USA. [Becke, Andreas; Berron, David; Duzel, Emrah] Univ Magdeburg, Inst Cognit Neurol & Dementia Res, Leipziger Str 44, D-39120 Magdeburg, Germany. [Duzel, Emrah] German Ctr Neurodegenerat Dis DZNE, Leipziger Str 44, D-39120 Magdeburg, Germany. [Greig, Nigel H.] NIA, Drug Design & Dev Sect, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Mattison, Julie A.] NIA, Nonhuman Primate Core, Translat Gerontol Branch, Baltimore, MD 21224 USA. RP van Praag, H (reprint author), NIA, Neuroplast & Behav Unit, Lab Neurosci, Baltimore, MD 21224 USA. EM vanpraag17@gmail.com RI van Praag, Henriette/F-3939-2015 OI van Praag, Henriette/0000-0002-5727-434X FU BMBF (EnergI Project); National Institute on Aging, Intramural Research Program; Korean Visiting Scientist Training Award [HI13C1149]; Deutsche Forschungs Gemeinschaft [SFB 779 TP A7] FX This work was supported in part by the BMBF (EnergI Project), the National Institute on Aging, Intramural Research Program, the Korean Visiting Scientist Training Award (HI13C1149 to H.Y.M.), and the Deutsche Forschungs Gemeinschaft (SFB 779 TP A7). We thank Drs. Young Ah Goo and Hyung Won Choi for proteomic analysis, Yang An for statistical advice, Linda R. Kitabayashi for image preparation, and Bryan Christie Design for illustration. NR 41 TC 4 Z9 4 U1 14 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD AUG 9 PY 2016 VL 24 IS 2 BP 332 EP 340 DI 10.1016/j.cmet.2016.05.025 PG 9 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA DT3PH UT WOS:000381392800020 PM 27345423 ER PT J AU Dowd, KA DeMaso, CR Pelc, RS Speer, SD Smith, ARY Goo, L Platt, DJ Mascola, JR Graham, BS Mulligan, MJ Diamond, MS Ledgerwood, JE Pierson, TC AF Dowd, Kimberly A. DeMaso, Christina R. Pelc, Rebecca S. Speer, Scott D. Smith, Alexander R. Y. Goo, Leslie Platt, Derek J. Mascola, John R. Graham, Barney S. Mulligan, Mark J. Diamond, Michael S. Ledgerwood, Julie E. Pierson, Theodore C. TI Broadly Neutralizing Activity of Zika Virus-Immune Sera Identifies a Single Viral Serotype SO CELL REPORTS LA English DT Article ID ANTIBODY-MEDIATED NEUTRALIZATION; DENGUE VIRUS; CLINICAL-TRIAL; DOUBLE-BLIND; PHASE-III; INFECTION; FLAVIVIRUSES; VACCINES; IMMUNOGENICITY; ENHANCEMENT AB Recent epidemics of Zika virus (ZIKV) have been associated with congenital malformation during pregnancy and Guillain-Barre syndrome. There are two ZIKV lineages (African and Asian) that share >95% amino acid identity. Little is known regarding the ability of neutralizing antibodies elicited against one lineage to protect against the other. We investigated the breadth of the neutralizing antibody response following ZIKV infection by measuring the sensitivity of six ZIKV strains to neutralization by ZIKV-confirmed convalescent human serum or plasma samples. Contemporary Asian and early African ZIKV strains were similarly sensitive to neutralization regardless of the cellular source of virus. Furthermore, mouse immune serum generated after infection with African or Asian ZIKV strains was capable of neutralizing homologous and heterologous ZIKV strains equivalently. Because our study only defines a single ZIKV serotype, vaccine candidates eliciting robust neutralizing antibody responses should inhibit infection of both ZIKV lineages, including strains circulating in the Americas. C1 [Dowd, Kimberly A.; DeMaso, Christina R.; Pelc, Rebecca S.; Speer, Scott D.; Smith, Alexander R. Y.; Goo, Leslie; Pierson, Theodore C.] NIAID, Viral Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. [Platt, Derek J.; Diamond, Michael S.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Platt, Derek J.; Diamond, Michael S.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Platt, Derek J.; Diamond, Michael S.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Platt, Derek J.; Diamond, Michael S.] Washington Univ, Sch Med, Ctr Human Immunol, St Louis, MO 63110 USA. [Platt, Derek J.; Diamond, Michael S.] Washington Univ, Sch Med, Immunotherapy Programs, St Louis, MO 63110 USA. [Mascola, John R.; Graham, Barney S.; Ledgerwood, Julie E.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Mulligan, Mark J.] Emory Univ, Sch Med, Dept Med, Hope Clin,Emory Vaccine Ctr,Div Infect Dis, Decatur, GA 30030 USA. RP Pierson, TC (reprint author), NIAID, Viral Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. EM piersontc@mail.nih.gov FU National Institute of Allergy and Infectious Disease; Emory University School of Medicine; Georgia Research Alliance; Moderna; Sanofi; Visterra; [R01AI073755] FX This work was funded by the intramural program of the National Institute of Allergy and Infectious Disease to the Division of Intramural Research and the Vaccine Research Center and extramural grant R01AI073755 to M.S.D. M.J.M. was supported by funds from the Emory University School of Medicine and the Georgia Research Alliance. We thank X. de Lamballerie (Emergence des Pathologies Virales, Aix-Marseille Universite) and the European Virus Archive Goes Global (EVAg) for providing the H/PF/2013 ZIKV strain and Stephen S. Whitehead (NIAID) for the Brazil Paraiba/2015 virus. We are grateful to the subjects for providing research samples and to Ingelise Gordon (VRC), Pamela Costner (VRC), Adam Dezure (VRC), Lilin Lai (Emory), Natalie Thornburg (Emory), Henry Wu (Emory), Srilatha Edupuganti (Emory), Allison Beck, (Emory), Sree Aramgam (Emory), and Pamela Lankford-Turner (Emory) for assistance with ZIKV patients and the collection of samples. We also thank Amanda Feldpausch (Georgia Department of Health), Jennifer Govero (Washington University), and Estefania Fernandez (Washington University) for their help with these studies. M.S.D. is a consultant for Inbios, Visterra, Sanofi, and Takeda Pharmaceuticals, is on the Scientific Advisory Boards of Moderna and OraGene, and is a recipient of research grants from Moderna, Sanofi, and Visterra. NR 39 TC 13 Z9 15 U1 14 U2 18 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 AUG 9 PY 2016 VL 16 IS 6 BP 1485 EP 1491 DI 10.1016/j.celrep.2016.07.049 PG 7 WC Cell Biology SC Cell Biology GA DT3ID UT WOS:000381373400001 PM 27481466 ER PT J AU Liu, JC Liu, J Holmstrom, KM Menazza, S Parks, RJ Fergusson, MM Yu, ZX Springer, DA Halsey, C Liu, C Murphy, E Finkel, T AF Liu, Julia C. Liu, Jie Holmstrom, Kira M. Menazza, Sara Parks, Randi J. Fergusson, Maria M. Yu, Zu-Xi Springer, Danielle A. Halsey, Charles Liu, Chengyu Murphy, Elizabeth Finkel, Toren TI MICU1 Serves as a Molecular Gatekeeper to Prevent In Vivo Mitochondrial Calcium Overload SO CELL REPORTS LA English DT Article ID RAT-KIDNEY MITOCHONDRIA; CA2+ UPTAKE; ENDOPLASMIC-RETICULUM; CELL-DEATH; UNIPORTER; STRESS; MCU; ACTIVATION; PROTEIN; HEART AB MICU1 is a component of the mitochondrial calcium uniporter, a multiprotein complex that also includes MICU2, MCU, and EMRE. Here, we describe a mouse model of MICU1 deficiency. MICU1(-/-) mitochondria demonstrate altered calcium uptake, and deletion of MICU1 results in significant, but not complete, perinatal mortality. Similar to afflicted patients, viable MICU1(-/-) mice manifest marked ataxia and muscle weakness. Early in life, these animals display a range of biochemical abnormalities, including increased resting mitochondrial calcium levels, altered mitochondrial morphology, and reduced ATP. Older MICU1(-/-) mice show marked, spontaneous improvement coincident with improved mitochondrial calcium handling and an age-dependent reduction in EMRE expression. Remarkably, deleting one allele of EMRE helps normalize calcium uptake while simultaneously rescuing the high perinatal mortality observed in young MICU1(-/-) mice. Together, these results demonstrate that MICU1 serves as a molecular gatekeeper preventing calcium overload and suggests that modulating the calcium uniporter could have widespread therapeutic benefits. C1 [Liu, Julia C.; Liu, Jie; Holmstrom, Kira M.; Fergusson, Maria M.; Finkel, Toren] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. [Menazza, Sara; Parks, Randi J.; Murphy, Elizabeth] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Yu, Zu-Xi] NHLBI, Pathol Core, NIH, Bethesda, MD 20892 USA. [Springer, Danielle A.] NHLBI, Murine Phenotyping Core, NIH, Bethesda, MD 20892 USA. [Halsey, Charles] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Liu, Chengyu] NHLBI, Transgen Core, NIH, Bethesda, MD 20892 USA. RP Finkel, T (reprint author), NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. EM finkelt@nih.gov OI Holmstrom, Kira/0000-0001-6434-7909 FU Intramural NIH funds; Leducq Transatlantic Network grant; PRAT postdoctoral fellowship from NIGMS FX We are grateful to Michele Allen for help with mouse phenotyping; Erin Stempinski, Camron Keshavarz, and Christopher Bleck for help with electron microscopic analysis; and Jeffrey Culver at the Sanford-Burnham Orlando Metabolomics Core for skeletal muscle lactate measurements. This work was supported by Intramural NIH funds, a Leducq Transatlantic Network grant (to T.F.), and a PRAT postdoctoral fellowship from NIGMS (to J.C.L.). NR 46 TC 5 Z9 5 U1 4 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD AUG 9 PY 2016 VL 16 IS 6 BP 1561 EP 1573 DI 10.1016/j.celrep.2016.07.011 PG 13 WC Cell Biology SC Cell Biology GA DT3ID UT WOS:000381373400009 PM 27477272 ER PT J AU Lee, SH Le Pichon, CE Adolfsson, O Gafner, V Pihlgren, M Lin, H Solanoy, H Brendza, R Ngu, H Foreman, O Chan, R Ernst, JA DiCara, D Hotzel, I Srinivasan, K Hansen, DV Atwal, J Lu, YM Bumbaca, D Pfeifer, A Watts, RJ Muhs, A Scearce-Levie, K Ayalon, G AF Lee, Seung-Hye Le Pichon, Claire E. Adolfsson, Oskar Gafner, Valerie Pihlgren, Maria Lin, Han Solanoy, Hilda Brendza, Robert Ngu, Hai Foreman, Oded Chan, Ruby Ernst, James A. DiCara, Danielle Hotzel, Isidro Srinivasan, Karpagam Hansen, David V. Atwal, Jasvinder Lu, Yanmei Bumbaca, Daniela Pfeifer, Andrea Watts, Ryan J. Muhs, Andreas Scearce-Levie, Kimberly Ayalon, Gai TI Antibody-Mediated Targeting of Tau In Vivo Does Not Require Effector Function and Microglial Engagement SO CELL REPORTS LA English DT Article ID ALZHEIMERS-DISEASE; TRANSGENIC MICE; PASSIVE-IMMUNIZATION; MOUSE MODEL; PROTEIN; PATHOLOGY; BRAIN; NEURONS; PHOSPHORYLATION; PROPAGATION AB The spread of tau pathology correlates with cognitive decline in Alzheimer's disease. In vitro, tau antibodies can block cell-to-cell tau spreading. Although mechanisms of anti-tau function in vivo are unknown, effector function might promote microglia-mediated clearance. In this study, we investigated whether antibody effector function is required for targeting tau. We compared efficacy in vivo and in vitro of two versions of the same tau antibody, with and without effector function, measuring tau pathology, neuron health, and microglial function. Both antibodies reduced accumulation of tau pathology in Tau-P301L transgenic mice and protected cultured neurons against extracellular tau-induced toxicity. Only the full-effector antibody enhanced tau uptake in cultured microglia, which promoted release of proinflammatory cytokines. In neuron-microglia cocultures, only effectorless anti-tau protected neurons, suggesting full-effector tau antibodies can induce indirect toxicity via microglia. We conclude that effector function is not required for efficacy, and effectorless tau antibodies may represent a safer approach to targeting tau. C1 [Lee, Seung-Hye; Le Pichon, Claire E.; Lin, Han; Solanoy, Hilda; Brendza, Robert; Ngu, Hai; Foreman, Oded; Chan, Ruby; Ernst, James A.; DiCara, Danielle; Hotzel, Isidro; Srinivasan, Karpagam; Hansen, David V.; Atwal, Jasvinder; Lu, Yanmei; Bumbaca, Daniela; Watts, Ryan J.; Scearce-Levie, Kimberly; Ayalon, Gai] Genentech Inc, San Francisco, CA 94080 USA. [Adolfsson, Oskar; Gafner, Valerie; Pihlgren, Maria; Pfeifer, Andrea; Muhs, Andreas] AC Immune SA, CH-1015 Lausanne, Switzerland. [Le Pichon, Claire E.] NINDS, NIH, Bethesda, MD 20892 USA. [Chan, Ruby] Gilead Sci, Foster City, CA 94404 USA. RP Scearce-Levie, K; Ayalon, G (reprint author), Genentech Inc, San Francisco, CA 94080 USA.; Muhs, A (reprint author), AC Immune SA, CH-1015 Lausanne, Switzerland. EM andreas.muhs@acimmune.com; kscearcelevie@gmail.com; ayalon.gai@gene.com NR 37 TC 1 Z9 1 U1 5 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD AUG 9 PY 2016 VL 16 IS 6 BP 1690 EP 1700 DI 10.1016/j.celrep.2016.06.099 PG 11 WC Cell Biology SC Cell Biology GA DT3ID UT WOS:000381373400019 PM 27475227 ER PT J AU Jourdain, G Ngo-Giang-Huong, N Cressey, TR Hua, L Harrison, L Tierney, C Salvadori, N Decker, L Traisathit, P Sirirungsi, W Khamduang, W Bowonwatanuwong, C Puthanakit, T Siberry, GK Watts, DH Murphy, TV Achalapong, J Hongsiriwon, S Klinbuayaem, V Thongsawat, S Chung, RT Pol, S Chotivanich, N AF Jourdain, Gonzague Ngo-Giang-Huong, Nicole Cressey, Tim R. Hua, Lei Harrison, Linda Tierney, Camlin Salvadori, Nicolas Decker, Luc Traisathit, Patrinee Sirirungsi, Wasna Khamduang, Woottichai Bowonwatanuwong, Chureeratana Puthanakit, Thanyawee Siberry, George K. Watts, Diane Heather Murphy, Trudy V. Achalapong, Jullapong Hongsiriwon, Suchat Klinbuayaem, Virat Thongsawat, Satawat Chung, Raymond T. Pol, Stanislas Chotivanich, Nantasak TI Prevention of mother-to-child transmission of hepatitis B virus: a phase III, placebo-controlled, double-blind, randomized clinical trial to assess the efficacy and safety of a short course of tenofovir disoproxil fumarate in women with hepatitis B virus e-antigen SO BMC INFECTIOUS DISEASES LA English DT Article ID PERINATAL TRANSMISSION; INFANT TRANSMISSION; SURFACE-ANTIGEN; INFECTION; PREGNANCY; METAANALYSIS AB Background: Chronic hepatitis B virus (HBV) infection is complicated by cirrhosis and liver cancer. In Thailand, 6-7 % of adults are chronically infected with HBV. The risk of mother-to-child transmission (MTCT) of HBV has been estimated to be about 12 % when mothers have a high hepatitis B viral load, even if infants receive passive-active prophylaxis with HBV immunoglobulin (HBIg) and initiate the hepatitis B vaccine series at birth. We designed a study to assess the efficacy and safety of a short course of maternal tenofovir disoproxil fumarate (TDF) among women with a marker of high viral load for the prevention of MTCT of HBV. Methods: The study is a phase III, multicenter (17 sites in Thailand), placebo-controlled, double-blind, randomized 1: 1, two-arm clinical trial of TDF 300 mg once daily versus placebo among pregnant women from 28 weeks' gestation through 2-month post-partum. All infants receive HBIg at birth, and a hepatitis B (HB) vaccination series according to Thai guidelines: birth, and age 1, 2, 4 and 6 months. Participant women at study entry must be age >= 18 years, hepatitis B surface antigen (HBsAg) and e-antigen (HBeAg) positive, have alanine aminotransferase (ALT) level < 30 IU/L at screening (confirmed < 60 IU/L pre-entry), negative hepatitis C serology, creatinine clearance > 50 mL/min, and no history of anti-HBV antiviral treatment. The target sample size of 328 mother/infant pairs assumed 156 evaluable cases per arm to detect a >= 9 % difference in MTCT transmission (3 % experimental arm versus 12 % placebo arm) with 90 % power. Mothers and infants are followed until 12 months after delivery. The primary infant endpoint is detection of HBsAg, confirmed by detection of HBV DNA at six months of age. Secondary endpoints are maternal and infant adverse events, acute exacerbations of maternal hepatitis B disease (ALT > 300 IU/ L, defined as a "flare") following discontinuation of study treatment, infant HBV infection status and growth up to 12 months of age. Discussion: The results of this randomized trial will clarify the efficacy and safety of a short course of antiviral treatment to prevent mother-to-child transmission of HBV and inform international guidelines. C1 [Jourdain, Gonzague; Ngo-Giang-Huong, Nicole; Cressey, Tim R.; Salvadori, Nicolas; Decker, Luc] Inst Rech Dev IRD France, PHPT, UMI 174, 187-10 Changklan Rd, Chiang Mai 50100, Thailand. [Jourdain, Gonzague; Ngo-Giang-Huong, Nicole; Cressey, Tim R.; Salvadori, Nicolas; Decker, Luc; Sirirungsi, Wasna; Khamduang, Woottichai] Chiang Mai Univ, Fac Associated Med Sci, 110 Intawaroroj Rd, Chiang Mai 50200, Thailand. [Jourdain, Gonzague; Ngo-Giang-Huong, Nicole; Cressey, Tim R.] Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, 677 Huntington Ave, Boston, MA 02115 USA. [Cressey, Tim R.] Univ Liverpool, Inst Translat Med, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England. [Hua, Lei; Harrison, Linda; Tierney, Camlin] Harvard TH Chan Sch Publ Hlth, Ctr Biostat AIDS Res CBAR, 677 Huntington Ave, Boston, MA 02115 USA. [Bowonwatanuwong, Chureeratana; Chotivanich, Nantasak] Chonburi Hosp, 69 M-2,Sukhumvit Rd, Muang 20000, Chonburi, Thailand. [Puthanakit, Thanyawee] Chulalongkorn Univ, Fac Med, 1873 Rama 4 Rd, Bangkok 10330, Thailand. [Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, 6100 Execut Blvd, Bethesda, MD 20892 USA. [Watts, Diane Heather] US Dept State, Off Global AIDS Coordinator, SA-22,2201 C St NW, Washington, DC 20522 USA. [Murphy, Trudy V.] Ctr Dis Control & Prevent, DHHS CDC NCHHSTP DVH Vaccine Unit, Bldg Corp SQ 12,Room 3111, Atlanta, GA 30329 USA. [Achalapong, Jullapong] Chiangrai Prachanukroh Hosp, Dept Obstet & Gynecol, 1039 Sathan Phayaban Rd, Muang 57000, Chiang Rai, Thailand. [Hongsiriwon, Suchat] Chonburi Hosp, Dept Pediat, 69 M-2,Sukhumvit Rd, Muang 20000, Chonburi, Thailand. [Klinbuayaem, Virat] Sanpatong Hosp, Dept Med, 149 M-15 Yuhwa, Chiang Mai 50120, Thailand. [Traisathit, Patrinee] Chiang Mai Univ, Dept Stat, Fac Sci, 239 Huaykaew Rd, Chiang Mai 50200, Thailand. [Thongsawat, Satawat] Chiang Mai Univ, Dept Internal Med, Fac Med, Chiang Mai 50200, Thailand. [Chung, Raymond T.] Massachusetts Gen Hosp, Gastrointestinal Unit, GI Unit, WRN 1007C,55 Fruit St, Boston, MA 02114 USA. [Pol, Stanislas] Cochin Univ Hosp, Dept Hepatogastroenterol, 27 Rue Faubourg St Jacques, F-75679 Paris 14, France. RP Jourdain, G (reprint author), Inst Rech Dev IRD France, PHPT, UMI 174, 187-10 Changklan Rd, Chiang Mai 50100, Thailand.; Jourdain, G (reprint author), Chiang Mai Univ, Fac Associated Med Sci, 110 Intawaroroj Rd, Chiang Mai 50200, Thailand. EM gonzague.jourdain@ird.fr FU Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) [U01HD071889] FX The study activities are supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) (U01HD071889) under a cooperative agreement between NICHD, the Centers for Disease Control and Prevention, United States of America, and Institut de recherche pour le developpement, France. NR 12 TC 1 Z9 1 U1 8 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD AUG 9 PY 2016 VL 16 AR 393 DI 10.1186/s12879-016-1734-5 PG 6 WC Infectious Diseases SC Infectious Diseases GA DT2YM UT WOS:000381347700010 PM 27506549 ER PT J AU Ordonez, AE Ranney, R Schwartz, M Mathews, CA Satre, DD AF Ordonez, Anna E. Ranney, Rachel Schwartz, Maxine Mathews, Carol A. Satre, Derek D. TI Hazardous drinking among young adults seeking outpatient mental health services SO Addiction Science & Clinical Practice LA English DT Article DE Alcohol; Hazardous drinking; Cannabis; Depression; Mental health; Young adults ID ALCOHOL-USE DISORDERS; RANDOMIZED CONTROLLED-TRIAL; SUBSTANCE USE DISORDER; NATIONAL EPIDEMIOLOGIC SURVEY; DRUG-USE; PSYCHIATRIC-SERVICES; BRIEF INTERVENTION; COMORBIDITY; CONSUMPTION; PREVALENCE AB Background: Alcohol use can have a significant negative impact on young adults in mental health treatment. This cross-sectional study examined prevalence and factors associated with hazardous drinking among young adults seeking outpatient mental health services, rate of alcohol use disorders (AUDs), and the relationship between hazardous drinking and other types of substance use. Methods: Participants were 487 young adults ages 18-25 who completed self-administered computerized screening questions for alcohol and drug use. Alcohol use patterns were assessed and predictors of hazardous drinking (>= 5 drinks on one or more occasions in the past year) were identified using logistic regression. Results: Of the 487 participants, 79.8 % endorsed prior-year alcohol use, 52.3 % reported one or more episodes of hazardous drinking in the prior year and 8.2 % were diagnosed with an AUD. Rates of recent and lifetime alcohol, tobacco and marijuana use were significantly greater in those with prior-year hazardous drinking. In logistic regression, prior-year hazardous drinking was associated with lifetime marijuana use (OR 3.30, p < 0.001; 95 % CI 2.05, 5.28), lifetime tobacco use (OR 1.88, p = 0.004; 95 % CI 1.22, 2.90) and older age (OR 1.18 per year, p < 0.001; 95 % CI 1.08, 1.29). Conclusions: In an outpatient mental health setting, high rates of hazardous drinking were identified, and drinking was associated with history of other substance use. Results highlight patient characteristics associated with hazardous drinking that mental health providers should be aware of in treating young adults, especially older age and greater use of tobacco and marijuana. C1 [Ordonez, Anna E.; Ranney, Rachel; Schwartz, Maxine; Mathews, Carol A.; Satre, Derek D.] Univ Calif San Francisco, Dept Psychiat, 401 Parnassus Ave, San Francisco, CA 94143 USA. [Ordonez, Anna E.; Ranney, Rachel; Schwartz, Maxine; Mathews, Carol A.; Satre, Derek D.] Univ Calif San Francisco, UCSF Weill Inst Neurosci, 401 Parnassus Ave, San Francisco, CA 94143 USA. [Satre, Derek D.] Kaiser Permanente Northern Calif Reg, Div Res, 2000 Broadway,3rd Floor, Oakland, CA 94612 USA. [Ordonez, Anna E.] NIMH, Off Clin Res, 6001 Execut Blvd MSC 9669, Bethesda, MD 20892 USA. [Mathews, Carol A.] Univ Florida, Dept Psychiat, 100 S Newell Dr, Gainesville, FL 32610 USA. RP Ordonez, AE (reprint author), Univ Calif San Francisco, Dept Psychiat, 401 Parnassus Ave, San Francisco, CA 94143 USA.; Ordonez, AE (reprint author), Univ Calif San Francisco, UCSF Weill Inst Neurosci, 401 Parnassus Ave, San Francisco, CA 94143 USA.; Ordonez, AE (reprint author), NIMH, Off Clin Res, 6001 Execut Blvd MSC 9669, Bethesda, MD 20892 USA. EM anna.ordonez@nih.gov FU NIAAA NIH HHS [R01 AA020463]; NIDA NIH HHS [T32 DA007250]; NIMH NIH HHS [R25 MH060482] NR 30 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 1940-0640 J9 ADDICT SCI CLIN PRAC JI Addict. Sci. Clin. Pract. PD AUG 9 PY 2016 VL 11 AR 12 DI 10.1186/s13722-016-0060-y PG 7 WC Substance Abuse SC Substance Abuse GA DS9RR UT WOS:000381121500001 PM 27506832 ER PT J AU Gach, JS Gorlani, A Dotsey, EY Becerra, JC Anderson, CTM Berzins, B Felgner, PL Forthal, DN Deeks, SG Wilkin, TJ Casazza, JP Koup, RA Katlama, C Autran, B Murphy, RL Achenbach, CJ AF Gach, Johannes S. Gorlani, Andrea Dotsey, Emmanuel Y. Becerra, Juan C. Anderson, Chase T. M. Berzins, Baiba Felgner, Philip L. Forthal, Donald N. Deeks, Steven G. Wilkin, Timothy J. Casazza, Joseph P. Koup, Richard A. Katlama, Christine Autran, Brigitte Murphy, Robert L. Achenbach, Chad J. TI HIV-1-Specific Antibody Response and Function after DNA Prime and Recombinant Adenovirus 5 Boost HIV Vaccine in HIV-Infected Subjects SO PLOS ONE LA English DT Article ID DEPENDENT CELLULAR CYTOTOXICITY; IMMUNODEFICIENCY-VIRUS TYPE-1; NEUTRALIZING ANTIBODIES; MONOCLONAL-ANTIBODY; EFFICACY TRIAL; ANTIRETROVIRAL THERAPY; MEDIATED CYTOTOXICITY; LONGITUDINAL ANALYSIS; ENVELOPE PROTEINS; EPITOPES AB Little is known about the humoral immune response against DNA prime-recombinant adenovirus 5 (rAd5) boost HIV vaccine among HIV-infected patients on long-term suppressive antiretroviral therapy (ART). Previous studies emphasized cellular immune responses; however, current research suggests both cellular and humoral responses are likely required for a successful therapeutic vaccine. Thus, we aimed to understand antibody response and function induced by vaccination of ART-treated HIV-1-infected patients with immune recovery. All subjects participated in EraMune 02, an open-label randomized clinical trial of ART intensification followed by a six plasmid DNA prime (envA, envB, envC, gagB, polB, nefB) and rAd5 boost HIV vaccine with matching inserts. Antibody binding levels were determined with a recently developed microarray approach. We also analyzed neutralization efficiency and antibody-dependent cellular cytotoxicity (ADCC). We found that the DNA prime-rAd5 boost vaccine induced a significant cross-clade HIV-specific antibody response, which correlated with antibody neutralization efficiency. However, despite the increase in antibody binding levels, the vaccine did not significantly stimulate neutralization or ADCC responses. This finding was also reflected by a lack of change in total CD4+ cell associated HIV DNA in those who received the vaccine. Our results have important implications for further therapeutic vaccine design and administration, especially in HIV-1 infected patients, as boosting of preexisting antibody responses are unlikely to lead to clearance of latent proviruses in the HIV reservoir. C1 [Gach, Johannes S.; Gorlani, Andrea; Dotsey, Emmanuel Y.; Becerra, Juan C.; Felgner, Philip L.; Forthal, Donald N.] Univ Calif Irvine, Dept Med, Div Infect Dis, Irvine, CA 92717 USA. [Anderson, Chase T. M.; Berzins, Baiba; Murphy, Robert L.; Achenbach, Chad J.] Northwestern Univ, Dept Med, Feinberg Sch Med, Div Infect Dis,Ctr Global Hlth, Chicago, IL 60611 USA. [Deeks, Steven G.] San Francisco Gen Hosp, Div HIV AIDS, San Francisco, CA 94110 USA. [Deeks, Steven G.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Wilkin, Timothy J.] Weill Cornell Med Coll, Div Infect Dis, New York, NY USA. [Casazza, Joseph P.; Koup, Richard A.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Katlama, Christine] Hop La Pitie Salpetriere, Dept Infect Dis, Paris, France. [Autran, Brigitte] Hop La Pitie Salpetriere, Dept Immunol, Paris, France. [Gorlani, Andrea] ModiQuest Res, Oss, Netherlands. RP Gach, JS (reprint author), Univ Calif Irvine, Dept Med, Div Infect Dis, Irvine, CA 92717 USA.; Achenbach, CJ (reprint author), Northwestern Univ, Dept Med, Feinberg Sch Med, Div Infect Dis,Ctr Global Hlth, Chicago, IL 60611 USA. EM jgach@uci.edu; c-achenbach@northwestern.edu OI Gach, Johannes/0000-0002-5043-5710 FU Objectif Recherche Vaccin SIDA (ORVACS) FX Objectif Recherche Vaccin SIDA (ORVACS) provided all funding for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 0 Z9 0 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 8 PY 2016 VL 11 IS 8 AR e0160341 DI 10.1371/journal.pone.0160341 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT3IE UT WOS:000381373500020 PM 27500639 ER PT J AU Hong, CS Singh, LN Mullikin, JC Biesecker, LG AF Hong, Celine S. Singh, Larry N. Mullikin, James C. Biesecker, Leslie G. TI Assessing the reproducibility of exome copy number variations predictions SO GENOME MEDICINE LA English DT Article DE Copy number variations (CNV); Exomes; CNV predictions; Reproducibility ID SEQUENCING DATA; DISCOVERY; VARIANTS; TOOLS; DEPTH AB Background: Reproducibility is receiving increased attention across many domains of science and genomics is no exception. Efforts to identify copy number variations (CNVs) from exome sequence (ES) data have been increasing. Many algorithms have been published to discover CNVs from exomes and a major challenge is the reproducibility in other datasets. Here we test exome CNV calling reproducibility under three conditions: data generated by different sequencing centers; varying sample sizes; and varying capture methodology. Methods: Four CNV tools were tested: eXome Hidden Markov Model (XHMM), Copy Number Inference From Exome Reads (CoNIFER), EXCAVATOR, and Copy Number Analysis for Targeted Resequencing (CONTRA). To examine the reproducibility, we ran the callers on four datasets, varying sample sizes of N = 10, 30, 75, 100, 300, and data with different capture methodology. We examined the false negative (FN) calls and false positive (FP) calls for potential limitations of the CNV callers. The positive predictive value (PPV) was measured by checking the CNV call concordance against single nucleotide polymorphism array. Results: Using independently generated datasets, we examined the PPV for each dataset and observed wide range of PPVs. The PPV values were highly data dependent (p < 0.001). For the sample sizes and capture method analyses, we tested the callers in triplicates. Both analyses resulted in wide ranges of PPVs, even for the same test. Interestingly, negative correlations between the PPV and the sample sizes were observed for CoNIFER (rho = - 0.80). Further examination of FN calls showed that 44 % of these were missed by all callers and were attributed to the CNV size (46 % spanned = 3 exons). Overlap of the FP calls showed that FPs were unique to each caller, indicative of algorithm dependency. Conclusions: Our results demonstrate that further improvements in CNV callers are necessary to improve reproducibility and to include wider spectrum of CNVs (including the small CNVs). These CNV callers should be evaluated on multiple independent, heterogeneously generated datasets of varying size to increase robustness and utility. These approaches to the evaluation of exome CNV are essential to support wide utility and applicability of CNV discovery in exome studies. C1 [Hong, Celine S.; Singh, Larry N.; Biesecker, Leslie G.] NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA. [Mullikin, James C.; Biesecker, Leslie G.] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20852 USA. [Mullikin, James C.] NHGRI, Comparat Genom Anal Unit, Canc Genet & Comparat Genom Branch, NIH, Bethesda, MD 20852 USA. RP Biesecker, LG (reprint author), NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA.; Biesecker, LG (reprint author), NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20852 USA. EM lesb@mail.nih.gov FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 28 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 1756-994X J9 GENOME MED JI Genome Med. PD AUG 8 PY 2016 VL 8 AR 82 DI 10.1186/s13073-016-0336-6 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA DT2XL UT WOS:000381345000001 PM 27503473 ER PT J AU Elwyn, G Frosch, DL Kobrin, S AF Elwyn, Glyn Frosch, Dominick L. Kobrin, Sarah TI Implementing shared decision-making: consider all the consequences SO IMPLEMENTATION SCIENCE LA English DT Article DE Collaborative deliberation; Shared decision making; Patient-centered care; Implementation; Practice improvement; Quality improvement; Multilevel; Conceptual model; Measurement ID SUPPORT INTERVENTIONS; HEALTH-CARE; MULTILEVEL FACTORS; CLINICAL-PRACTICE; PATIENT; AIDS; SATISFACTION; METAANALYSIS; ADHERENCE; OUTCOMES AB Background: The ethical argument that shared decision-making is "the right" thing to do, however laudable, is unlikely to change how healthcare is organized, just as evidence alone will be an insufficient factor: practice change is governed by factors such as cost, profit margin, quality, and efficiency. It is helpful, therefore, when evaluating new approaches such as shared decision-making to conceptualize potential consequences in a way that is broad, long-term, and as relevant as possible to multiple stakeholders. Yet, so far, evaluation metrics for shared decision-making have been mostly focused on short-term outcomes, such as cognitive or affective consequences in patients. The goal of this article is to hypothesize a wider set of consequences, that apply over an extended time horizon, and include outcomes at interactional, team, organizational and system levels, and to call for future research to study these possible consequences. Main argument: To date, many more studies have evaluated patient decision aids rather than other approaches to shared decision-making, and the outcomes measured have typically been focused on short-term cognitive and affective outcomes, for example knowledge and decisional conflict. From a clinicians perspective, the shared decision-making process could be viewed as either intrinsically rewarding and protective, or burdensome and impractical, yet studies have not focused on the impact on professionals, either positive or negative. At interactional levels, group, team, and microsystem, the potential long-term consequences could include the development of a culture where deliberation and collaboration are regarded as guiding principles, where patients are coached to assess the value of interventions, to trade-off benefits versus harms, and assess their burdens-in short, to new social norms in the clinical workplace. At organizational levels, consistent shared decision-making might boost patient experience evaluations and lead to fewer complaints and legal challenges. In the long-term, shared decision-making might lead to changes in resource utilization, perhaps to reductions in cost, and to modification of workforce composition. Despite the gradual shift to value-based payment, some organizations, motivated by continued income derived from achieving high volumes of procedures and contacts, will see this as a negative consequence. Conclusion: We suggest that a broader conceptualization and measurement of shared decision-making would provide a more substantive evidence base to guide implementation. We outline a framework which illustrates a hypothesized set of proximal, distal, and distant consequences that might occur if collaboration and deliberation could be achieved routinely, proposing that well-informed preference- based patient decisions might lead to safer, more cost-effective healthcare, which in turn might result in reduced utilization rates and improved health outcomes. C1 [Elwyn, Glyn] Dartmouth Inst Hlth Policy & Clin Practice, 37 Dewey Field Rd, Hanover, NH 03755 USA. [Frosch, Dominick L.] Palo Alto Med Fdn, Res Inst, 795 El Camino Real, Palo Alto, CA 94301 USA. [Frosch, Dominick L.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Kobrin, Sarah] NCI, 9609 Med Ctr Dr, Rockville, MD 20850 USA. RP Elwyn, G (reprint author), Dartmouth Inst Hlth Policy & Clin Practice, 37 Dewey Field Rd, Hanover, NH 03755 USA. EM glynelwyn@gmail.com NR 45 TC 3 Z9 3 U1 12 U2 18 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD AUG 8 PY 2016 VL 11 AR 114 DI 10.1186/s13012-016-0480-9 PG 10 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA DT7KJ UT WOS:000381665200002 PM 27502770 ER PT J AU Bissinger, R Lang, E Ghashghaeinia, M Singh, Y Zelenak, C Fehrenbacher, B Honisch, S Chen, H Fakhri, H Umbach, AT Liu, GL Rexhepaj, R Liu, GX Schaller, M Mack, AF Lupescu, A Birnbaumer, L Lang, F Qadri, SM AF Bissinger, Rosi Lang, Elisabeth Ghashghaeinia, Mehrdad Singh, Yogesh Zelenak, Christine Fehrenbacher, Birgit Honisch, Sabina Chen, Hong Fakhri, Hajar Umbach, Anja T. Liu, Guilai Rexhepaj, Rexhep Liu, Guoxing Schaller, Martin Mack, Andreas F. Lupescu, Adrian Birnbaumer, Lutz Lang, Florian Qadri, Syed M. TI Blunted apoptosis of erythrocytes in mice deficient in the heterotrimeric G-protein subunit G alpha i2 SO SCIENTIFIC REPORTS LA English DT Article ID IN-VITRO; SIGNAL-TRANSDUCTION; OXIDATIVE STRESS; SUICIDAL DEATH; CELL-DEATH; RED-CELLS; ACTIVATION; ERYPTOSIS; STIMULATION; SURVIVAL AB Putative functions of the heterotrimeric G-protein subunit G alpha i2-dependent signaling include ion channel regulation, cell differentiation, proliferation and apoptosis. Erythrocytes may, similar to apoptosis of nucleated cells, undergo eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine (PS) exposure. Eryptosis may be triggered by increased cytosolic Ca2+ activity and ceramide. In the present study, we show that G alpha i2 is expressed in both murine and human erythrocytes and further examined the survival of erythrocytes drawn from G alpha i2-deficient mice (G alpha i2(-/-)) and corresponding wild-type mice (G alpha i(2+/+)). Our data show that plasma erythropoietin levels, erythrocyte maturation markers, erythrocyte counts, hematocrit and hemoglobin concentration were similar in G alpha i2(-/-) and G alpha i(2+/+) mice but the mean corpuscular volume was significantly larger in G alpha i2(-/-) mice. Spontaneous PS exposure of circulating G alpha i2(-/-) erythrocytes was significantly lower than that of circulating G alpha i(2+/+) erythrocytes. PS exposure was significantly lower in G alpha i2(-/-) than in G alpha i(2+/+) erythrocytes following ex vivo exposure to hyperosmotic shock, bacterial sphingomyelinase or C6 ceramide. Erythrocyte G alpha i2 deficiency further attenuated hyperosmotic shock-induced increase of cytosolic Ca2+ activity and cell shrinkage. Moreover, G alpha i2(-/-) erythrocytes were more resistant to osmosensitive hemolysis as compared to G alpha i(2+/+) erythrocytes. In conclusion, G alpha i2 deficiency in erythrocytes confers partial protection against suicidal cell death. C1 [Bissinger, Rosi; Ghashghaeinia, Mehrdad; Singh, Yogesh; Honisch, Sabina; Chen, Hong; Fakhri, Hajar; Umbach, Anja T.; Liu, Guilai; Rexhepaj, Rexhep; Liu, Guoxing; Lupescu, Adrian; Lang, Florian; Qadri, Syed M.] Univ Tubingen, Inst Cardiol Vasc Med & Physiol, Tubingen, Germany. [Lang, Elisabeth] Univ Duesseldorf, Dept Gastroenterol Hepatol & Infect Dis, Dusseldorf, Germany. [Zelenak, Christine] Charite, Dept Internal Med, Berlin, Germany. [Fehrenbacher, Birgit; Schaller, Martin] Univ Tubingen, Dept Dermatol, Tubingen, Germany. [Rexhepaj, Rexhep] Univ Bonn, Inst Biochem & Mol Biol, Bonn, Germany. [Mack, Andreas F.] Univ Tubingen, Inst Anat, Tubingen, Germany. [Birnbaumer, Lutz] NIEHS, Neurobiol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Qadri, Syed M.] Catholic Univ Argentina, Sch Med Sci, Inst Biomed Res BIOMED, Buenos Aires, DF, Argentina. [Qadri, Syed M.] McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada. RP Lang, F (reprint author), Univ Tubingen, Inst Cardiol Vasc Med & Physiol, Tubingen, Germany. EM florian.lang@uni-tuebingen.de FU Deutsche Forschungsgemeinschaft [La 315/13-3]; NIH [Z01-ES-101643] FX The authors thank Prof. Bernd Nurnberg and members of his laboratory (Institute of Experimental and Clinical Pharmacology and Toxicology, University of Tubingen, Germany) for their valuable suggestions and for providing blood from G alpha i2-/- mice. The authors acknowledge the meticulous preparation of the manuscript by Tanja Loch and the technical assistance of Efi Faber and Annette Knoblich. This study was supported by Deutsche Forschungsgemeinschaft (Nr. La 315/13-3) and the Intramural Research Program of the NIH (project Z01-ES-101643 to LB). NR 60 TC 1 Z9 1 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 AUG 8 PY 2016 VL 6 AR 30925 DI 10.1038/srep30925 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT4NF UT WOS:000381457200001 PM 27499046 ER PT J AU Hirschman, L Fort, K Boue, S Kyrpides, N Dogan, RI Cohen, KB AF Hirschman, Lynette Fort, Karen Boue, Stephanie Kyrpides, Nikos Dogan, Rezarta Islamaj Cohen, Kevin Bretonnel TI Crowdsourcing and curation: perspectives from biology and natural language processing SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID ANNOTATION; RETRIEVAL; NETWORKS; IMPROVER; GENE; TEXT AB Crowdsourcing is increasingly utilized for performing tasks in both natural language processing and biocuration. Although there have been many applications of crowdsourcing in these fields, there have been fewer high-level discussions of the methodology and its applicability to biocuration. This paper explores crowdsourcing for biocura